I O O ! ** -ti. 2159 11 1 ¡,: í MIDLAND February 19, 196? ( 1 \ 0 01 • 00 CO CONFIDENTIAL - SUBJECT TO INJUNCTION' V ' E.D. Ml. 4-4-78; DOW/EPA AGREEMENT 9-79 WDIltni G. Dlaon iildpraducta Department L»F<. ce i V. U CorUn, DPC D, £. Pletcher, Bi*C J. H. Cowell, BPC V. 2, M cíovf BPC 1’/. C». holder, M.D., 607 z © ■Ni Vi tvs 00 9 ■ T H O iv iP B r .ii C ! . £ > . a C A i. C : - M P A N Y , ST . L j U IS , M I S S O U R I C t 1 tbruary ¿, 196?, V . J. McCoy inform ed me that a Mr. m , 8 , Buckley of T tom piso ( b em ltal bad called L'ow indicating that they had had an accident aeaoctatad «1th Ct« manufacture of trU h lorophonal* and that they had aom s men «U h «hat thay thought was chloracne. Thay ▼ \adared If wo could advise them lo regard to m edical practice. I contacted Dr. h old er, who then called Mr. CucfcJcy and dlecuaaed with him m odicnl a ep eett of the problem , ll ie toy understanding from i)r. holder that Mr, Buckley tteo started talking about the chem istry of Ikle m ats r ia l, end Lr. holder •ug£*atad that he contact me in regard to anything along Shia lin e. V f V •\ \ ■i ■A V V >? * } VJ ■i ■;o or about February f Mr. Buchley callad oía to cao « b l vo h » « •bcot chloracne causad by cotdoeí «itb otatertalo aeeociatod wUb £53 ^31 tha pianofáctore cf tflcblercpheool from tetrachlotobaaseoo, 1 GSD GL3 " toid bim that nadar certsia circomataorac, whUh I did oot describo, tha caoctic iAcdaUa olla could cú talo c acalda rabio amoanta oí a &s very idghly todc sohsíaace whlcb vo Cual Khctlflif fio 2» 9* V#8« €£$ r^aj tetrachlarodibeaccdloalc, KUdlcated to blm that thlo malaria! «as no3 oajy es&reissiy tóala oystfimlcaUy, bol Ü o a i tico fio «atrccoely C ‘il. 1£JL potas! cbloraccogofi, fía Indicaled that thay fcad becn diatUUcf «oaaa CJZ c aída e a olio or taro coafaiaiog antéalas «boa tha oparctloa gol c«3 oí costrol, and cha e a la r ü i «libar «pillad or apiaesod o¿&» a ta i encoclar©. Ha the%g3tt that Uto to ta s fiad vaporo cS tho «misóles k d csasad thslr fU I c d l;. I told U q t d!4 no) thlfik Ua a c u « a i cacsad by Uto anisólas, bel «atibar by ochar mataríais ymsaat la tha aaiaolae. ccd . 11- "'J. i c r ,,, . ' ■ |a a n ir.. r i■ . 742 - ths •■ ' - i MNt) 7 32 80 bcc : J ,;i#W:ilIbor5'-AC^-7 w.j.iicCcy-ACij-/.?.!! P.ri.lUtîry-.ACS-^B V.K.ncrrj-B.i . 1 rol ' ';1i-.'-■ ' v y y ; n : y v ,', : >:î k ï ';:v . ' ' 1:..■.iv..'" ’’ ' 7 ? . W M. H . T M U N , m i i i d < nt W M . M o n r o e C o u n ty 3 d E l e c t r ic ° - - 22ül m. M U1 '*. N l K I M U t O O C . C ooperative , Inc . DOW 075280 ^ Biochemical Research Dept. The Dow Chemical Company Midland, Michigan Dear Sir: Thank you for your letter dated September 1, 19511- giving us information with reference to the effect of Eeteron Brush Killer on skin and lung tissues. We note that this information covers cattle, whereas our request addressed to the Dow Chemical Company in St. Louis, Missouri, dated August 2lj., 195>Ut requested the same in­ formation with reference to the effect on human beings. We would appreciate receiving this information at your earliest convenience. Thanking you for thi3 courtesy, we are Yours very truly, n< MONROE? BOUNTY ELBCTR-Î& COOPERATIVE, IN' IN^ / / , Manager CMD:MP 16745 :} L:r . V. Ho-.a. , .... •v:;I'Mill . .THE'.-DOW "CHEMICAL':- COMPANY . ¿ 6 l5 : O live S treet.: '.' St .Louis , Miss turi-. •Louroo County..Electric Cooperat-ive , i-ic . >"afc<;rluo .'. ' '. ^ . Illinois .. •.v .:v t t e n t lo t i .D e a r o f . M r . ' C ; ; 11. ; I> o vi.g: I n c , : la e a g e r L r . ; D o u g la s Thla :wlil--->cknotfl©2ge:4^our; letter of August 24th in vihiuii; you requested information r»3 to whether the drift o f '.• -'LL Eateron Brush Killer .during application would be- injurious : .to skin or lung tissue. It- is your understanding that the ;spray does not inJure 1skin or lung tissues but you would like to have a'confirmation of this. :S v,;e .■* •■'1 quite sure-' that your a'>3u~;ption' Is'correct:in that this spray does not injure the ekiri or lung tissues, howover, we are asking our T!r. V. K . fiouo of our 'Biochemical Rose arch Lub at our Hc-no Office in Lidland, Michigan to •; .. advise you ulroct regard ing thin as bo •has been .'’working with 2,^-D type product.', irosi a toiviaolngisal. viewpoint and will be in a position to give you t;hi latest iru'oreati on on these materials. L L-''V-l -c ■ -i'er,y truly. yours .. R b A . Cra.idall . Agricultural_■.-Chemical Di vis ion .RAC ;ava 08Z E 20N W r- c , c C 0 M ° a m A ugust v .(, , SENT BY:CLARK, DRIMIIE, & CO. ïll-19-92 ; 3:18PM ; 506 459 6720;# 2/ 6 m /» e V: T H E DOW C H E M IC A L C O M PA N Y r/ F. H. Riley, Special Chemical« Sale«, ARB J. C. Tucker, Industrial Chemical« Sale«, ARB R. N. Sm iley, International Sales, ARB Xjìwfci k cc: J. W. H arris, Chemical« Sales, ARB L. B. Grant, Sales Administration, 47 Bldg. H. W. Feinaner, Chem icals Department, ARB C. O. Hutchenreuther, Organic Chem icals Prod." Dept. 2S8 Bldg. E. C. Staehling, Organic Chem icals Prod.' Dept. 172 Bldfr Cl. S . O tis, Bioproduct« D ept,, Bioproducts Center L. Silverstein, Biochem ical« Research Lab., 1701 Bldg. ♦ Subject: 2, 4, S Trichlorophenol The 2 ,4 , 5 trichlorophenol courent ly being manufactured has been found to contain 2 ,3 ,7 ,8 tetra chloro dibenzo-p-di-oxin and is suspected to contain 2, 3, 7, 8 tetra chloro dibenzo furan. It is known that both the 2 ,3 , 7,8 tetra chloro dibenso-p-dioxLn and the tetrachlorcdibenzo furan can produco chloracne. ! i •1* The concentration of these im purities has been found to be le ss than 0 .5 ppm of the 2 ,3 , T, 8 tetra chloro dibenzo-p-dioxin and approximately 20>2S ppm of the tetrachloro dibenzo furan if the present VPC analysis is correct. A nalysis of retainer sam ples shows that these concentrations are very clo se to the impurity lev el in the trichlorophenol we have shipped in the past. Up to our recent in-depth studies of our trichlorophenol and its im purities, we did not know that they were present in our product. Consequently, we do not have animal experience which indicates this impurity level is consistant with safe handling. We do know; however, that we have had no chloracne problems in our own operations in the handling and processing of these m aterials, and we have not heard form ally that any of our custom ers have. We are presently making animal studies to determ ine what the safe lev els for these im purities are. _ e While the current product is essen tially the sam e ae past m aterial, we feel it is im perative that our custom ers know this new Impurity and concentration information. They should, if they decide to accept our £ I 2 8 Ê(V vy o û Abbott Head Building Midland, Michigan February 16, 1969 SENT BY:CLARK, DRLMdlE, & CO. Jll-19-92 ; 3:19PM ; ■a- 506 459 6720;# 3/ 6 F e b r u a r y 16, 196$ r As I indicated before, we are carrying out animal tests to determine safe levels, and if needed, additional handling precautions. When this work is completed, we w ill make it available for you to pass on to your custom ers. Meanwhile, your custom ers should be informed of this information before any m aterial is shipped to them. 7 1 ¡fustic i f. D. Doedens Chemicals Department ARB \ \ 4 D O W 048516 m aterial with this new knowledge, be cautioned to ex ercise care in handling and processing this m aterial to avoid human exposure, THE DOW CHEwu- äl «.u m . - ami agricul tu ? i l pr ò d i ;«:; s o c P a ä : is o l a n o . michigah Ä*MCULTUiTAL P"0:)üC7S SPECIFICATION 8 7 52 3 SUPERSEDES DATE 2/13/70 NUMBER 87523 U E T H O O O F A N A L Y S IS DATE " ^irUüvJOJO NUMBER ¡a m 87523 2/27/69 2, 4, 5 - T R I C H L O R O P H E N O X Y A C E T I C ACID 2, 4, 5 - T r i c h l o r o p h e n o x y a c e t i c a c i d , m i n i m u m 98. 0 % F r e e z in g point, m in im u m 148.5° C 2, 3, 7, 8 - T e t r a c h l o r o d i b e n z o - p - d i o x i n < 1 ppm confidential - sueject to i njunction D .C ., E.D. 4 - 4 - 7 3 ; D O W / E P A A G R E E M E N T 9 -7 9 C T H E P O L I C Y O F T H L 0 0 * C H I'M 1 C A L C O M P A N Y iS O H E O F C O N T IN U L D I M P R O V E M E N T S a r R E S E A R C H A N O M A M lj r A C TU ft IN C W IlC K C v r -R P O S S IO L C TO A S S U R E A S T I L L F I N E R PROOUCT. H E M C t . S P t L H - I C A 1 I O N S A R C S U O i E C T T O C H A N G E W IT H O U T N O T IC E . FORM C-1W70 f M M It D IR U.S.A. H U C t 16749 ---------Q-Çyi?.} <> w4^-frich/oroph*noJ Cl 2,4,3-T I r TCDO FIGURE 1 Formation o f 2J , 7 ;3-«trachlarodibcnio-f>-dioxin (TCDD) as a by-product in the jynthesù o f 2,4 ^-T. 16751 3 methanol), of the heating system (steam instead of hot oil) and of the cooling system (flushing of cold water through the same heating coils and quenching the reaction DOW 2 7 5 0 9 8 choice of the solvents (ethylene glycol instead of mixture with a large volume of water in a matter of minutes). During the premanufacturing laboratory and pilot phase of production as well as during the later phase of routine manufacture no exothermic reaction which would elicit a runaway temperature rise,increased TCDD formation and explosive discharge, ever occurred. In order to abide by the regulations of the USA, where the trichlorophenol was delivered for the production of hexachlorophene, the quantity of the TCDD formation was carefully controlled and kept within the limit of 0.1 ppm recommended by the Advisory Committee to the Environmental Protection Agency Administrator on May 7, 1971 (16). The working and handling conditions in the Icmesa TCP plant were adequate with respect to hygienics and exposure of the plant operators. 16752 4 observed either in the workers of the Icnesa factory or in those manufacturing hexachlorophene in the USA and Switzerland. DOW 2 7 5 0 9 9 Chloracne, the indicator of TCDD exposure, was never On the day of the accident the production of sodium trichlorophenate in the reactor was completed and some IS % of the ethylene glycol had been removed. When the heating was switched off the final recorded temperature was 158° C. The workers night shift left the plant shortly after 6.00 a.m. and nothing happened until 12.30 p.m. when the accident occurred. 2. The causes of the accident The task of assessing the causes of the explosion has been given to several groups of scientists in- and outside our laboratories. It was assumed that the temperature increase which led to the accident was provoked by a slightly exothermical reaction proceeding very slowly already below 200° in alkaline surroundings and which had been unknown so far. Preliminary tests examining all conditions at which an exothermic reaction might have been provoked, i.e. long-term heating at 16753 D° W 2 7 5 1 0 0 critical temperatures, thermal behaviour of the reaction mix when exposed to air, accidental presence of metals, copper etc. and checking all materials used for the reaction and the operating procedures at the plant have led to the following reconstruction of the possible mechanism of the accident. At the beginning a slow exothermical reaction of as yet unknown nature may have taken place in alkaline environment raising the temperature of the reactor over several hours to approximately 250° with slow decomposition and with formation of gas. Possibly due to an obstruction of t:_i pipe that connects the reactor with the outside, this slow formation of gas may have caused a pressure increase inside the reactor greater than the one allowed by the rupture disc, thus .leading to the escape of gases together with glycol and other organic products. The chlorodioxins produced at the higher temperature in the reaction and particularly TCDD proved to be, under the conditions of the accident, much more volatile than one would have expected from known scientific data and foreseen on the basis of their physical properties. Further investigations and experiments are needed to prove that this explanation of the mechanism • 16754 28 the years 1976 and 1977 (19, 20, 59, 60) was substantially similar to that found in the previous years 1973-1974 and 1975 in the same region and which fluctuated between 9.0 and 10.3 % (Table 11). For the Lombardy DOW 2 7 5 1 2 4 of spontaneous abortions in the Seveso population for region, where Seveso is located, the rate of spontaneous abortions has been indicated to be in the-' range of 12-15 % (13) and world-wide an overall ratio of 15-20 spontaneous abortions per 100 pregnancies has been estimated (68) . This rate of pregnancy wastage seems to be common for all mammalian species which are said to rarely lose less than 30 % of their fertilized eggs (8). Tabla 11 « f s t i l l b i r t h * * spentaneeue and Indues* i k r t l m r u t s p e r n u a e e r • / c a lc u la te * p rtc n c n ftle * T im m MP r , ____ im * 1*7* * 1973 % 197« % 1977 « 9.41 15.5* 4 .1J a .lx 13.31 3-70 11.13 ».15 8.91 9.00 U .l b ».01 U -5* 4.70 u .c » 0«*U K*<* Im M 10.79 10.1* 13.*3 3 .« 7.1* M m d 10.3* »•31 10.2} »•33 u .o * I it ím s Im W rl* la lo u N 4.14 ».»* l .a a 11.»5 23-*« 13.1» 10O0 5. »3 11.03 1.13 13.7* 13.03 11.09 9.09 4.12 lb . 41 1.37 ».11 11.72 »■15 U .3 1 a .» r 12.42 1-3* U .1 7 13.31 a . 73 7.02 3-03 11-31 5-15 U .3 1 12.4* 12.07 10.3« iT m o ».*1 9.40 ».03 ».3» u .i* I s e e c t r**laa »•*J ».33 ».«> »•57 10.1* Vev* X. i« n * M (■ c e l* cl *## 13 • 20 % • t u s n i t y r eb o rn 12 • 13 %) 16755 M n n —y A closer analysis of the chronology of the fetal losses OtfTÇ/.Z for the months which immediately followed the accident and in correlation with their geographical distribution in the zones with and without contamination shows that (Table 12) Table 12 INCIDEK2 Of SfOITAREOUS ABORT!OfO |.i me U TCWSMPS Of JUTE PCR 4UK8ER Of CALCULATED PREGMnCIES k M O T IO M s iL iv n i» ¿ M U T IS M X U V U IIS ¿ m « t i «m H U V tllU ¿m u t is m S IL JV U IU !° 1° «° 2° l4 3 ° a u M T IR 2° 4° 1377 1377 auM T W Ï 5 « ! 3 ■* l i «• 1 1 a u M T tt 1977 137S a u /u rru 1977 a u u r u sw u m * 1377 IS 38 21 78 14 102 10 itv n o 12 49 9 35 7 52 U 21 0 (1 (0 S 38 13 93 24 104 17 105 N CSA 12 34 3 S3 9 68 10 75 TO T A L «s 313 S8 272 Î4 324 «8 <12 a (1 7 a (1 4 a 96 (1 4 a 237 M U S S IN A - 2S 3 11 - 8 - 3 M V tllQ s 38 5 28 9 35 7 38 UXTATI 7 35 - 35 9 41 10 «2 64 17 64 7 34 i 3 W U IO 1 : i NOVA 5 a o 5 s 3 w m a u M ru CZSAMQ m s auM T U 1377 L37S m SEYESO ZONE ?S0a JULY 1976 TO *UT£ 1977 e 17 14 37 21 73 15 71 13 73 M 12 129 7 U S 23 95 IS 117 VAJtCDQ 4 44 4 31 10 38 6 48 «23 62 353 33 351 S3 U M TO TA L so o o n U 4 a o s a (1 3 a 334 during the third quarter of 1976 the incidence of abortions for the 4 townships embodying the contaminated zones was 12 % and for the remaining townships of the territory under health surveillance was 10 %. The 16756 DOW 2 7 5 1 2 U incidence increased in the fourth quarter of 1976 to 17 % for the contaminated and to 14 % for the non contaminated part of the territory. At first sight the figures could be interpreted as showing a relation between incidence of abortions and degree of contamination. Yet if the analysis is extended to the following months, i.e. the first quarter of 1977, there is drop to 14 % for the contaminated townships and an increase to 19 % for the townships without contamination. In the second quarter of 1977 the values sure 14 % and 13 %. The fluctuations observed are therefore likely to be related to factors other than TCDD. Besides it should be noted again that the frequency of abortions in the contaminated area remained well within the normal incidence in Europe. b) Congenital malformations The same can be said for the frequency of congenital malformations. For the population of the western countries, the ratio of defective children reported when no special diagnostic procedures are used is of 2-3 % (21, 58). It increases to over 7 % of malformations if the cardio­ vascular system, respiratory tract, gastrointestinal tract and genitourinary system are considered (26, 66). 16757 O O In Seveso the number of malformations notified to the provincial health officers shows an enormous increase K, between 1976 and 1977 from 4 to 38. The number of on hto malformations reported during the first quarter of 1978 is 5. However if these numbers are related to the number of live-births that occurred in the corresponding periods of time (Table 13), the only possible explanation for the discrepancy is that the notification data on birth defects are incomplete. A previous survey (17) on the incidence of malformations in' the same territory based on data of better quality had revealed a ratio of 2.9 per 100 live-births. Table 13 Tmiwr •*uUmatlMa - ¿mm .(1141*crl«u) Jts u * t a a lf a m tiM U par loo T i*r im m iM l a i i t t r ftt ta« n t i af l.j« 3 A »17 » 1177 U aaaO a n m 1*7« (u n ir in 5 ( a . a *) 35 - U .M *) M - 10 (3.7* *1 lé - ZO 16768 (Table 14) Table ) 'y AAOO The polymorphism of the malformations observed 14 1 aair«natl«a la Sam t Tjrpa M fim n Pttlaonw i p i u i » iM fteepftalia i V M l t 9f IUAi1U7 I M t U CancwiLtal «ar«lapathgr T n i t a l M to p it < Jajtrlan i l u tr o p J tr X ftm v p M ly i l n w p M l i - XapiapaOla AM M lnal u U o i m U m ta a i u U m u l i a f a a a ila a a lf a r a a tta a Xenlncoeele iiaaplaala D tiN I M l l H O M l l Own S m ta a ty ly Cla n palasa O U p fe n p A tii l u n U Ira i 1774 iw i i X * l X X a a a 1774 n m q a a rta r a X X 10 X a i a ' a 3 - * * i X 3« 3 in the newborns of the Seveso region is another element in favour of the assumption that there is no causal relationship between the malformations registered and the chemical. Morphological heterogenicity of anomalies scarcely supports the presence of a single causal agent. Even in the groups of congenital cardiopathy (8) and pedalic malformations (10) it corresponds to the normal distribution of congenital spontaneous anomalies. The 16759 the geographical distribution of the mothers of the M '-NH this point of view convincing. A further aspect examined, ? morphological differences of these anomalies is from compared with those outside the contaminated communities H 7, malformed children in the zones contaminated by TCDD shows that the malformed children were equally distributed among the two groups (Table IS) Table 15 a m r »p»lm l d ia u ltn U a n a t ( u U M H t l m Olatrlata 197« 2&4 S«BMtcr Cana* IU4. Oh I s M l (•*«•« a l a 0 1977 197% la* quarter 2. 1 0 1 1 i 3 u fatal l n 3 taalaaalm k n it« le tU k *u«Sle Jfev* XU. Itrtp * a i a i 1 0 0 0 3 i 1 l 3 0 0 9 9 1 1 9 TatU 3 U 2 O rM t M l 4 3* 3 7 c) Neonatal growth Growth retardation, decreased survival and smaller size at birth have been observed in experimental animals under the effect of TCDD (12, 33, 40). The examination of about 16780 'IS A S M O a 2000 newly born infants of the Seveso region have revealed no abnormalities in respect of the somatic and psychic development of the child. d) Embryomorphological studies O Embryomorphological studies were performed in LQbeck on 34 cases of abortions. In 30 cases the pregnancy had been interrupted at the gestational age of 5/6 to 15/16 weeks. In 3 cases a spontaneous abortion followed an intrauterine death at the developmental stage of 8, 13 and 18 weeks respectively. In a 4th case of spontaneous abortion no embryo was found (49). Direct examination and radiophotography did not detect any gross or clear signs of abnormal development. Histological examination and morphological evaluation of the lymphatic and other visceral systems did not provide any sign of damage brought about by the action of an exogenous agent. The cases of spontaneous abortion showed different morphological alterations obviously due to a variety of causative factors. 16761 35 5. Cytogenetic studies most affected by the TCDD release in the second half of 1976. Chromosome analysis of maternal peripheral blood/ amniotic fluid cells and fetal tissues were performed for numerical and structural chromosome variations. No significant change in the chromosome number nor an increase in the frequency of aberrations was found in the blood samples.. There was a higher number of aberrations in the fetal tissues than in the blood samples or fibroblasts from adult tissues. However, the frequency of these aberrations was not greater than that expected in cultures of comparable cells (52, 57). Chromosome analysis have also been performed on the blood of people belonging to the group of acute (145) and chronic exposure (69), of the Icmesa plant workers (73), on children with (14) and without (15) chloracne and on a control group (87) . The average frequency of gaps, breaks and structural rearrangements found were within the accepted standard frequency (30, 66). 16782 D°W 275131 Induced abortion was sought by women of the communities DOW 2 7 5 1 3 2 6. Immunological studies Immunosuppression and decreased resistance to infections due to TCDD have been observed in several animal species (51, 61). Immunocapability was therefore examined from September 1976 to March 1978 at 4 months intervals in 45 children belonging to the zone at maximum level of exposure, of which 20 children had chloracne and concurrently on a comparable group of 44 children who had not been exposed to TCDD. The age range of the children was 3 to 7 years. The serum z immunoglobulins, the circulating level of complement, the ability of the lymphocytes'subpopulation T and 3 cells to react to non-specific mitogens were examined, ilo significant difference in the immunoresponse of the three groups has been so far detected. 7. Occurrence of infectious diseases The number of notifications for infections diseases submitted in 1977 to the provincial health officers of the 11 townships looked after by the medical commission shows a clear increase compared with that of the previous year, rising from 435 to as many as 1219 (30). 16783 37 DOW 2 7 5 1 3 3 This fact seems to contradict the results of the immunological investigations referred to above. In fact it has to be attributed to a better compliance to the mandating notification of the prescribed diseases during 1977. Indeed (Table 16) Table 16 U u i o f l a c l d a n c a o f L o f a c t i o u a d l a a a a a a p u r 10 0 00 p o p u l a t i o n u a l e a Z a fa c e io u a d ls a a e e a U «OVMAlpO (4 ) c o v u rtn * c o B g M iin e c o d V I* t o t m a h l p a (7) o u ta ld a c o a ta a ia a ta d are a n u tr& y e o M u a le y v i t d p o p u la tio n 220 000 fro ria a a of x ila n 1 720 OQO lo o n a r d y la q io a 1 900 000 1974 1977 117« 1977 197* 1977 117« 1177 1974 1977 0 a 47 1 .0 7 0 .4 * 1 .2 9 0 .2 2 0 .2 2 1 .7 9 1 .0 » 1 .1 « 0 .7 9 tel a c h w a a la M M llo u a 1 .0 « 1 .0 » 1 .1 2 1 .2 0 2 .5 » 2 .7 2 1 .9 2 l.U 1 .9 7 1 .7 7 vj _e U 2 .0 » 2 .2 * 2 .7 4 3 .2 4 4 .3 » 4 .0 9 4 .4 2 4 .1 7 4 .7 2 4 .4 2 0 0 0 0 0 0 0 0 0 0 0 .0 0 « O n faeal ttM U I lM lO a • J a la o n a lla L a i* 0 * 1 0 0 0 aj • ty p h o id itv a r h a p a u .u a - H lio e y o lie la 2) A i r a o r a o t r i n — la e io n - o ip n th a ria 0 0 0 0 0 0 0 .0 0 9 0 .0 0 2 0 .0 0 9 - I c a s l a « tmrms 2 .9 2 .7 0 .2 4 0 .9 S 9 .7 4 .4 9 9 .9 0 4 .1 9 4 .2 * 2 .7 7 • Mllia^OCOCTC t i s a n la fltla 0 .2 0 0 0 .1 7 0 .0 4 0 0 .0 7 0 .1 0 0 .0 9 0 .0 * - N rc a s iia 1 .4 0 .4 7 0 .7 7 1 .2 9 2 .2 1 1 .2 2 2 .0 « 0 .9 7 2 .4 9 1 .1 7 the increase affects 'mainly the infections for which the notification is normally made with greater frequency as for example viral hepatitis, salmonellosis, meningitis, scarlet fever, and pertussis. Furthermore, the increase 16764 - 38 - highly contaminated zone. Finally it does not involve poliomyelitis and diphtheria, diseases where vaccination is currently performed, thereby confirming a normal DOW 2 7 5 1 3 4 affects to a lesser extent the inhabitants of the more immunological reaction of the population to antigen stimulation. If compared with the incidence of a nearby community of equal population, of the Province of Milan and of the Lombardy region the infective pathology of the Seveso zones does not exceed the average of this part of Italy. 8. Birth rate and mortality The demographic trend recorded by the health statistic in the Seveso zone is caracterized by a constant decline in births. During the period 1975-1977 in the districts under consideration the birth rate fell from 17 % to 12.5 %. The fall was more pronounced in 1977 and affected particularly the four communities most involved by the accident (Table 17) J.S7B5 c c * Table 17 S lra lit CW U 4.24 I.H I.U 9 .U la a ra « « 9.14 7.i»7 7.47 4 .J 2 7.41 «— U a ^ a a 10.49 7.47 7a 71 4-30 3.44 «.*1 7.47 4.33 9.29 3.71 3.47 9.33 7.70 7.*3 4.24 10.43 4.90 t« n 4 a 3 .9 9 i.i* 9 .4 7 4 .9 4 4.34 i.n 4 .7 4 9.39 7.41 7.09 4.44 9-34 9.*4 4-7* 4.41 7 .» l iT m ntm 7.44 7.44 7 .!» - 4.14 7.90 7.9* 7.44 7.42 4.2» 7.75 1.29 9.39 9.43 9.30 9.44 J.9 4 Cm m S ta la «U-*. ta rla la la n tu •K H a s m ! .. lirm ta a a 9.*0 rrm m tam m m t U la n L eader*? r e c to * 7.44 4.44 7 . 4* 4.44 A breakdown by the place of residence of the death cases (Table 19) shows striking high values for the district of Seveso and at first sight the increase appears to be specific to the more highly contaminated zone. Table 19 ilatrlautlM mt iaataa an* 4rata rat* la nra il.trt.t* ./ o»a Ira«#* lana C itte « X*4. J ovom Z«M 1974 Asce 4« 1977 Asce 4« c lu ster 1974 Cluster l i t . 4a Cluster 1977 X«ta U (0.1 «) 8m U u ila a U :> u j •) 23 Ip w tim w tl'U l (100.4 %t y tv ( i ..i *) 3«ior» 30.0.137« 77*714 (»3.0 *1 4 # a tb a o r s * # r t* n a y tla u < A t« * 4. Analysis of tissue samples It is known that TCDD accumulates chiefly in the liver and fatty tissues. The veterinary service of the Lombardy region secured therefore a large number of livers from animals which had died or had been slaughtered. The chemical analysis (limit of detection: 2.5 ug/kg =» 2.5 ppb or 2500 ppt) demonstrated TCDD in the lives of some of the dead animals but not in all of them. TCDD has been detected in 71 out of 113 rabbits, 3 out of 3 goats, 2 out of 3 hares and 2 out of 27 chicken, but the organs of 6 ducks, 16776 3U ~ 2 hens, 1 cat, 2 guinea pigs and 1 peacock did not contain TCDD (1, 22). Tabla 24 Qlexln level« In the liver« « f r v O it« I« m / a i m * c ta u f ( 1J -MO* i n / o ¿ ) / * • /dim * < 1 -1 3 w / * 1 ) / d im » * / d im * TCSO la tk a L i» » r* in MC'fc* • f p t ( • * J / d im a to m / um C « m r* l / ilw itu n d - La 3* ; la (i*> la ? : n ( j) •3 1 “ J ! » ’ ( 13 ) 1) 1 ) ) 34 » U <î») *» ¿ 13 ( 3) < 4*3 ( }) r t y n a e u m * r m * ir e The levels found in the rabbits' liver are shown in Table 24. The amount of TCDD detected in the animals that died ranged between 50 and 200 ^g/kg in the livers, but levels of the same magnitude have also been found in clinically healthy rabbits. Of 14 rabbits, collected in the Zone A, which had rather large amount of TCDD in their liver (up to 300 ^ug/kg), all were apparently normal, .9 * T O / 7 aa I - JX had normal serological, hematological and enzymatic values and only 5 showed histologically hepatic lesions when sacrified three months after the accident (1 ). Consequently analytically measurable amounts of TCDD in the liver or in the fat do not necesserally correspond to anatomical or functional lesions. There is certainly an accumulation of TCDD in the liver and in the fatty tissues, but there is also an elimination from the body. The half-life of TCDD in the rat (43, 50) is approximately three weeks and'a steady state is reached after approximately 80 days. If doses of 0.01 j i q / k q TCDD are administered daily to the rat for a life time, the steady state level in the liver and fatty tissues is 20 respectively 50 yug/kg without prejudice for the animal. As soon as the rats are withdrawn from the contaminated food, the body TCDD level falls exponentially. The same applies to other animals (47) especially cattle, for whom the elimination rate (half-life) is in the region of 100 days (Figure 5) and 9 . c * * 9 « 3 to smaller animals (guinea pigs, rcoo oaspAnoN imm i * ICOUMCTIO OATAJ tooi*« 16778 5 ¿a ^ 52 sheep, monkeys) for whom the half-life is similar to that j- for rats, i.e. 3-4 weeks. Animals which have grazed on or c have been fed with TCDD contaminated food would therefore \ Vi no longer have any measurable tissue concentrations of TCDD after a corresponding feeding time with uncontaminated food. In fact, even affected animals have been known to recover after having been exposed to levels of TCDD much higher than those found in Seveso. At least six horses of the Arena B in Missouri (10), which had been ill, had recovered. The TCDD levels in.this arena as measured 3 years after the incident in the removed soil was 0.5 ppmr i.e. 1 0 0 times higher than in the zone at highest contamination in Seveso. The original contamination in the arena may well have been 10 times higher yet. Our own measurements with liver samples from animals slaughtered in Seveso (Table 2 5) in the last months of 1977 have revealed levels which are at most one thousandth of those measured in rabbits in 1976. Table 25 CM tialaiUM atf u l M l i La uia t tana La Savaaa (IM 1177 / !w«inaln4 1771) sum coo* mitra il on la ta . li»«r Animal* La »*/*€ la rrt ne < 0.31 < 10 e tn lt 0.0* 0.0« *0 lin n S u ti 3.13 90 130 18779 '- 'W exposure but also undoubtedly to the elimination of TCDD from the body. In due time, virtually all the liver samples would no doubt have been negative, despite the low detection limit of 1 0 - 2 0 opt reached in our laboratories. Table 25 shows also the difference between animal species in relation to the food. Swine, as non herbivorous, show no measurable traces of TCDD, whereas cattle, horses and goats appear to have been more exposed. Table 26 represents a cross section of TCDD concentrations found in healthy and unaffected wildlife and domestic animals in the OSA. The living organism examined by Young et al. (70) in Florida seem to tolerate soil concentrations of between 1000 and 1500 ppt without discernible damage. Commoner (11) shares the view that 5QQ ppt in the soils represents a tolerable level for the fauna. In Seveso the TCDD levels found in the soil after the vegetation had died out, i.e. in late autumn 1976 were of 150-20000 ppt for the Zone A which had been fenced in, ¿¡75149 This may to some extent be referred to a lower original 54 O . O of 50-150 opt for the Zone B and 0-50 ppt for Zone R. ** spring 1978, the TCDD surface concentration was below 10 75150 After the Zone R and B had been ploughed in the ro ppt throughout. Tabl 6 26 * 5 » l m l i l a h e a l t h y d o e e r t l e m i s a l e snd w i l d l i f e l a th e S i Ca m « at e e o t a a l a e t l o a State Old a l l t m t u o t a f s e l l te M a i d u es (su sfe e x a a ) X la e e u r l 7CSS e e a e e n t r m ti o a La w ittll S e r b le id e t f f l l e s t l e a i t a ; e e t u r e ( « » t i l e ( « M a i Lai C iltii C l e a t c a l in d u s t r y Pisa (suspected) I x p e r l a e n t a l h a r t LdL c a l ?rtcrs— » «f tha US nr fie rid a ea. 23- 90 ?yl la ths f it 5 7f t 13- ¡¿fleets ? a r ta . U rsa S tu r n a U a u t u Z e o a id u ra s e e * la -ijo o ra m U lla API 1941-1970 sell seAtsslAsUea lit. beep tissues mi .l e t r s f i a hypsela p ta n s O safluflis i f f l r u s l a p a u p u n e ta tu e X e p tl le s C haaL dorae • Is lla e s tu a le d easts fe re a y se u a p e l l one tu a la ta a r a t 1977 1971 20 9f t 1979 ** ?9* 197*/75 130-1339 7f t La th e U w 197*/75 1J7V 7J ppt la turn kmtt I j ppt la u * put 1973/ 7» 1973/ 7» 1973/ 7» :6 0 7 f t La th e b ed ? 197V 7* l a th e L iv e r 1973/ 7» th e l i t e r 5«PM La ta d r a t 12 12 ?pt la taa Stay 2 0 - 1 3 0 0 7f t 16781 - 33 - CONSEQUENCES ON THE CROPS AND THE LAND 1. The situation after the accident It should be remembered that the summer of 1976 was rather hot and dry in Lombardy. This was reflected in the condition of the crops at the time of the accident. The grasslands were ready for the second cutting and the cereals which had ripened slightly prematurely due to the drought, were nearly ready for harvest. The aerosol cloud which settled down southeast of the factory after the accident had practically no effect on the flora. Phytotoxic damage (Figure 6 ) throughout the affected area was confined to a few broad-leaved plants in the Immediate vicinity of the factory. Most of the damage was due to the high temperature and high alkalinity of the mass that escaped from the reactor and consisted in a drop like perforation and in a brownish change of the green colour of the leaves. There were no discernible changes anywhere in the remaining areas, either to crops or to shrubs in numerous little copses or to ornamental plants. 16782 00 Z v o L 'o Z It was the sampling of the vegetation and the chemical analysis of the samples which made possible the location of the areas which had been severely or slightly contaminated and those which had escaped. The map (Figure 7) Ny« a t J ---- - ---- j ‘ k—H- if ■ H i m ID O m to €/» O í.*&*i k■ . ' / •í¿ t *q ? -iO/»'*l-' ' ' ,, D lv-»^ • M n í t ^ - p ít □ „/'i »w--i‘ W L W S f f i & ‘ l & V T l f t ID O oso ^ r i •■•■/ *X ,‘t!k P j e 7 j / r t f/ - a s a ¿ v< o ! / (O O « U L k ® . * ^ 9 .o ■^ f e . í í <3 '^Ai _ V VI 7 > < O jp- i* * ]® i i iz> t í »-* m . i • U ü i O o % 1 -1 ¡* \^ -vs >r Ve5/^eO/?tQ3 t>4 - 57 £ (O i r J 6 represents the results of our sampling and of the chemical analysis of the Givaudan research laboratories and this map was the determinating factor for the decisions on all protective and preventive measures later taken by the Italian authorities. In respect of the crop and rangeland of the contaminated z o n e , an absolute ban on cultivation and grazing was issued for all three zones and the same regulation prohibited the use of plant products. At that time (August 1976), measurements showed 80 % or over of the total TCDD traced to adhere to the vegetation (foliage, grass, crops). This TCDD location would have been highly favourable for the decontamination work as will be related later.' It changed however rather rapidly toward the autumn. Heavy rains flattened the standing grass and overripe cereals and pressed them with the adherent TCDD to the ground. Young grass and weeds grew up and covered what remained standing. Consequently the TCDD adhering to the vegetation was transferred to the ground and by the activity of the rain as well as of the micro- and macroorganisms living in the soil, it was shifted to the upper layer of 1 to 2 cm. This made it more difficult to take rapid and effective measures of decontamination as by that time immediate removal of the : contaminated soil and its safe disposal were the only actions that promised a reasonable degree of success. The autumn storms, the heavy rainfalls which followed further complicated the situation created by the leaf fall rendering the TCDD penetration to deeper layers of the soil virtually inevitable. 2. The behaviour of TCDD in the environment At the time of the accident data on the TCDD behaviour in the environment - unlike those on animal toxicology were sparse as in previous accidents contamination had generally been restricted to the production buildings of the chemical industry. The only available findings from investigations of incidents comparable with that of Seveso were those obtained by the CJ.S. Air Force in connection with the use of "Agent Orange". On the basis of the references in the literature and of the data obtained by ourselves we can make the following comments on the effects of TCDD on ecology: TCDD is not mobile in the soil. Rain at most causes TCDD to be washed out and transported with simultaneous erosion of the soil. There is accordingly no risk for the ground-water (7, 27, 29, 32, 33, 34, 36, 70). pOW ^ 53 TCDD is transported within plants in only negligible amount or not at all. There is no accumulation of TCDD in the vegetation (14, 15, 16, 27, 29, 33, 34, 70). ZLZ m o q 59 d Ol TCDD is broken down in the soil under natural environmental conditions. Unless the breakdown is speeded up by additional measures, the half-life ranges from 200 days to one year (10, 27, 32, 33, 34, 69, 70). 3. Field and greenhouse trials The environmental behaviour of TCDD as outlined above were confirmed by a trial under controlled conditions in a greenhouse; by a field trial in Zone A and by sampling from various areas of the three zones. Leachability of TCDD was measured in soil columns with Mltscherlich containers using Seveso soil and showed that even at high TCDD levels and simulation of heavy rain precipitation (downpour of 200 mm in 20 minutes equivalent to am extremely heavy thunderstorm) no TCDD could be demonstrated in the percolated water. 16787 Systematic measurements of soil samples taken from different depths carried out in the course of a field 2 trial in Zone A (520 ;ug/m ) in spring 1977 showed that there was no leaching beyond a depth of 20 cm. The breakdown of TCDD corresponded to the findings reported in the literature. In our greenhouse trials (Table 27) the breakdown was measured on the” crops 2 obtained from the Zone A (520 /ug/m ) and transferred to greenhouse pots. The breakdown rate ranged here from 21 to 52 % for a nine months period. Table 27 M w t l « n t n M «aun in» W (Mil fnm Son* A) (320 it*/**) 4 la tn . •X30 trial» u im la pM tram 6 ptxa ter 1177 M m run at tut Ceeeafrer. 1977 i Aeduetlon X Satunlly U n i t o f le te a U o n • < 3 e * e e l PP* PPt < 1 3 -3 <0.7 < 1 .7 < 0 .* PP« PP* ppt ppt ppt < The crops collected from a highly contaminated part of Zone A (1000 ^g/m^) contained small amounts of TCDD. In this connection it was interesting to note that TCDD was contained on the surface areas of.the crops, i.e. in the skins of the fruits, the spathes of the corncobs etc. (Table 30). Table 30 9 t j m r lo M 7689 ^ 61*9 0 Mif IfA S M tnxn* iP P lM PM I riM . plant« fre e * 79« 7638 lA th e « « 1 1 10 *0 0 0 10 *0 0 0 la tfta •e^reXjr ee n te a tn a tw tone A ____i^iooa¿14/021 79« 7680 l a ta # p la n ts la % o f s o il e a n ta a ir .a tio n < 1 .3 < 0 .0 < 0. 0 1} < 0.CC4 < 13 7 2 .3 l.JT O < 0 .0 2 ) F u n p«i f lo o a 10*000 79 < 0 .3 0 .7 9 0 t 0 .0 0 ) 7e«o n ea •JCiA f lo o * 10*000 102 < 0 .4 1 .8 2 0 < 0 .0 0 4 «A «la f t v t t « 10*000 9 0 .0 9 P lu o * « « •1 « i n i to 10*000 7 0 .0 7 A pntota 1S790 -63- Thi 3 finding suggests that TCDD found in plants was chiefly derived from fine contaminated local dust deposited on the surface of the crops. The greenhouse trials seem to support this assumption because even where plants were grown in soil with high levels of TCDD, only 0.04 to 0.2 % - depending on the crop of the TCDD soil level could be found in the plant (Table 31) Table 31 C a n t M l n a t l a a « f p la n t* f r o w i i n tn # craafiftouaa an « o n tanlA A faft t a i l n u t (N aan ir o n 4 p a t a l ppa TCDO In ta a t a i l ppa 7CS0 I n iAa p U n t a 1 c u c u i« liilu i.i 9 .0 1 0 4 0 .1 3 t a r i f f (aara t U.i o .o c ftr 0 .0 ft V a«4a c r a m f r a . » M p r a a a a i Ui u i t u l lft.a b a l a v 4 * t* a t* * la lia it - la U iiiu ( J t i f f t i m a c fttlrm j U .i o .c a a o 0 .1 « 4. Decontamination methods A rapid collection and storage of the vegetation under safety precautions on the basis of the analytical tests carried out during the first days would have permitted the disposal of the major part of the TCDD. A second possibility would have been the spraying of an H doner and the utilization of the UV part of the August daylight. 1G 791 relatively rapid breakdown of TCDD. Corresponding experiments had been carried in our laboratories (63) shortly after the accident. Food quality olive oil was DOW 2 7 5 1 0 0 The photochemical reaction would have resulted in a used as H donor (Table 3 2) . Other agents proved equally active but had been shown in preliminary tests to be less tolerated by the plants than olive oil. A limited field trials carried out in Zone A confirmed the laboratory findings. Tatle 3 2 I r u U m o f ÌSS3 t t U r lU n o il o m a m SCSO I« *« l la 24 fi « ft« r 44 ii » it * r ru t XedM tiaiK la % 0U v* «U in I ile o hOQ U tr W h w tin 26.i 16.9 9.6 O lir« « li « re lo tu u n a l 400 1 i l i / * * 19-1 xa.s 10.7 . * j. i ih tm iH U.J» 1S.J X4.4 9 A decontamination program for the houses, gardens and land of the less contaminated part of the Zone A was worked out and operated by ourselves. The in- and outside of the houses were cleaned with special vacuum cleaners, 16 DOW washed and finally repainted. In the gardens 10 to 20 cm soil were removed, followed by a fresh layer of humus. The entire network of streets and paths was renewed and either paved with asphalt or stone slabs. Analytical tests c h C after the cleaning operations failed to detect any TCDD and the evacuated residents were allowed to return to their houses. The core of Zone A with TCDD levels of 150-5000 ;ug/m 2 is still sealed off and behind fences. Moreover, it has been used as dumping ground for waste from other zones. The natural course of the TCDD breakdown will take, in the light of our present knowledge, 6 to 8 years. The area could, be make accessible by removing the contaminated soil layers and burying them in a concrete pit. The process would have the advantage of eliminating TCDD from the environment completely and rapidly. 16*733 Conclusions Two years after the most publicized Seveso accident, when products containing the highly toxic TCDD descended M ^3 Ol on the surroundings of a chemical plant, an attempt can cn ro be made to summarize what happened. It is still not yet possible to explain the--, accident. The nature of the possible exothermic reaction which should have brought about a rise in the temperature in the reactor during the production of TCP with slow decomposition of the reaction mass, formation of gas and increase of the pressure, is #still unknown. Further experiments are needed to explain the mechanism of the accident. It was the chemical analyst who supplied the data for the assessment of the amount and location of the hazard. The detection of the TCDD and the measurement of its amount in our laboratories led to the definition of the contaminated territory and of the importance of the contamination. Neither the injuries on the humans nor the effects on the animals, on the vegetation and land would have been sufficiently relevant for the preventive and protective measures taken for the population and the territory. 16794 - 67 - DOW The harm induced by 7CDD on the health of the population Z 7 s ! ud either during the acute high level exposure of the first two weeks or during the lower level chronic exposure of the following 24 months shows the following main features: Chloracne, the-striking clinical feature which is suggestive of a TCDD exposure appeared in a very small percentage of the most sensitive group of the population involved. The manifestation was not limited to the first days after the accident but held on during the following months and is still lingering in the environment. The t skin lesions were rarely severe, mostly mild or extremely mild and always inclined to rapid and complete healing. Recidivism of the symptomatology was rare and occurred practically only in cases with mild or very mild lesions probably originated from low level and short duration of exposure. The incidence of chloracne and its degree of severity persistently decreased and has now reached a rate which is very close to the frequency of chloracne in the surrounding provinces. This fact suggests that the level of TCDD exposure has also decreased. The TCDD contamination of the environment has not affected neither the incidence nor the degree of severity of the puberty acne nor the current skin pathology of the region. One is inclined to 1S7SE assume that in these cases the skin lesion is the manifestation of the presence of TCDD in the environment Mon 63 more than a sign of the toxic effect of the substance on the human organism. The systemic effects of the TCDD exposure which have been reported in over 50 % of the chloracne cases occurred after occupational exposure in the past, have not been observed here. No laboratory evidence of significant hepatotoxicitv or deranged porphyrin metabolism, no abnormal neurologic findings have been observed in these cases. As for the other samples of the population (adults evacuated from the Zone A, inhabitants of the Zone B, plant workers of the Icmesa factory, decontamination parties) no prevalence in the current neurological and hepatic pathology of the region could be correlated so far with the exposure. The rata of abortions and malformations, the growth of newly born infants, the immunoresponse, the chromosome aberrations, the reaction to infectious diseases, the morbidity and mortality have not been affected by the amount of TCDD exposure. 16796 - 6 3 - In the wake of the accident a number of wild and domestic animals died in the contaminated zones. Affected were mainly small herbivores,- while only 1.7 % of the larger evacuated for study purposes i JiOi) animals died. A small number of the surviving animals were (8 6 ) while the rest (77 716) were slaughtered preventively in order to keep them out of the food chain. Chemical analysis of liver samples from dead animals confirmed TCDD in 78 of 158 samples collected immediately after the accident, at the original detection limit of ^ 2.5 jug/kg (highest values in the order of 300 ;ug/kg) . However, measurable amounts of TCDD in the liver do not necessarily imply anatomical or functional lesions. Apparently healthy rabbits with normal body functions were also found to have as much as 300 ^ug/kg TCDD in their liver. Many originally affected animals have recovered, consistent with other observed recoveries of horses in a Missouri mishap, where much higher TCDD concentrations occurred. This is due to the elimination of TCDD from the body. The elimination process has been studied in the laboratory. The half-life of TCDD in the body is 3-4 weeks for smaller animals (rats, guinea pigs, sheep, monkeys) and approximately .. .. J. - 70 - 100 days for cow 3 . If contaminated animals had been fed no longer have shown measurable TCDD concentrations in their tissues. Actual liver concentrations in the domestic animals slaughtered at the end of 1977 were at least three order’ s of magnitude less than in the rabbits in 1976. In many cases they were even below the new detection limit of 1 0 - 2 0 ng/kg (ppt). The study of the effect, persistence and mobility in the environment has shown that the cloud of chemicals which settled down southward of the plant had very little effect on the vegetation of the fallout area. About 80 % of the TCDD ejected with the reaction mixture adhered to the foliage, grass and crops for several weeks until it was transferred to the soil by the rain. Our field and greenhouse trials have shown that in Seveso TCDD does not leach vertically beyond a depth of 20 cm in the soil and that it disappears slowly by a natural degradation process and half of it is lost after 9 and 12 months. Plants do not take up significant amounts of TCDD. Only fractions of the quantity in the soil can be found in the vegetation and in DOW 27516(3 with uncontaminated feed sufficiently long, they would the fruits growing in the contaminated area. A useful area could have been applied immediately after the accident either by collecting and disposing of the vegetation or accelariting the natural process of degradation by spraying a suitable hydrogen donor. Today the remaining part of Zone A (115 acres) which is still fenced in could be made accessible by removing the contaminated soil layers and burying them in a concrete pit. The natural process of degradation would take 6 to 8 years. Reprints to be requested at the following address: Dr. G. Reggiani Research Department F. Hoffmann-La Roche 4 Co. Ltd. 4002 Basle Switzerland a »* method for removing large quantities of TCDD from the References 1. Abbruzzl, R. et al..: Identification and quantitative determination of 2 . 3 . 1 . 8 -tetrachlorcdibenzo-para-aioxin in animals from contaminated areas. 4th International Symposium on Mass Spectrometry in Biochemistry and Medicine, Riva del Garda, Italy, June 20-22 (1977) G ? 2. Adamoli, P. et al.: Analysis of 2,3,7,S-tetrachlorodibenzopara-dioxin in the Seveso area. Ecological Bulletins No. 27, Lund 1978 3. Allen, J.R., Barsottl, D .A : , Lambrecht, L.K., Van Miller, J.P.: Reproductive effects of halogenated aromatic hydrocarbons on nonhuman primates. Int. Conference on Health Effects of Halogenated Aromatic Hydrocarbons. New York Academy of Sciences, New York, June 24-27 (1978) 4. Baughman, R . , Meselson, M.: An improved analysis for tetrachlorodibenzo-p-dioxins. Adv. Chem. Series No. 120, 92-104 (1973) 5. Bleiberg, J . , Wallen, M . , Brodkln, R. , Applebaum, I.L.: Industrially acquired oorphyria. Arch. Dermatol. 89, 793-797 (1964) 6 . Buser, H.-R.: Analysis of polychlorinated dibenzo-p-dioxins and dibenzofurans in chlorinated phenols by mass fragmentography. J. Chromatography 107, 295-310 (1975) 7. Calvin, M . ; Oral communication. Summing up of TCDD Workshop, Milan, Oct. 23-24 (1976) 8 . Carr, D.H.: Detection and evaluation of pregnancy wastage. Handbook of teratology,vol. 3, 189-213. New York, London: Plenum Press 1977 1 6 8 0 0 10. Commoner, B., Scott, R.E . : Accidental contamination of soil with dioxin in Missouri: effects and countermeasures. Center for the Biology of Natural Systems, Washington University, St. Louis, Missouri, Sept. 29 (1976). Dioxin information project, Scientists' Institute for Public Information, New York N.Y. 11. Commoner, B., Scott, R.E.: US Air Force studies on the stability and ecological effects of TCDD (Dioxin): an evaluation relative to the accidental dissemination of TCDD as Seveso, Italy. Center for the Biology of Natural Systems, Washington University, St. Louis, Missouri, Nov. 13 (1976). Dioxin information project, Scientists' Institute for Public Information, New York N.Y. 12. Cunningham, H.M., Williams, D.T.: Effect of tetrachlorodibenzo-p-dioxin on growth rate and the synthesis of lipids and proteins in rats. Bull. Environm. Contamination a Toxicol. 7 (1), 45-51 (1972) 13. Dambroslo, F . ; Violenza, coscienza, aborto. Sapere No. 796, 85-90 (1976) 14. Dloguardl, N.: Critical considerations two years after the accidental pollution of Seveso "July '76 - July ’78". Paper presented at the Press Seminar, Milan, July 2 (1978) 15. Doss, M . : Diagnosis and therapy of porphyrias. Springer-Verlag, Berlin, 1978 DOW 27516Î) 9. Colombl, A.M.: Relationship between present volunteer research by scientific and technical popular ccmitee of_ Seveso and porphyrin and porphyrin pattern assessment on urines of TCDD exposed people in Seveso run by the Toxicological Department of the Agricultural University of Wageningen. Paper presented at the Thena Colloquium on "Chronic Hepatic Porphyria in humans" Agricultural University, Wageningen, The Netherlands, May 10 (1978) 16. Editorial; Pesticide programs. Rebuttable presumption against registration and continued registration of pesticide products containing 2,4,5-trichlorophenol and its salts. Environmental Protection Agency, Federal Register 43 (149), August 2 (1978) Part IX c C ¿*5 17. Fara, G.M., Marublnl, E . ; Monitoring birth defects: an Italian project. 3rd Conference of the European Teratology Soc., Helsinki, June 3-6 (1974) 18. Fara, G.M.: Introductory report on the epidemiological aspects. In Proceedings of the Expert Meeting on the Problems Raised by TCDD Pollution, pp. 39-46, Milan, Sept. 30 and Oct. 1 (1976) and Rapporto preliminare sullo stato di salute nella zona inquinata da TCDD. Quaderno di Documentazione 28.5.1977 19. Fara, G.M. : Seveso: Studies on teratogenic and otijer chronic effects of chemical pollutants following an accident in a chemical plant. Symp. Detection of t Teratogens, Montreal, August 21 (1977). A special Symposium held in conjunction with the 5th Int. Conf. on Birth Defects. 20. Fara, G.M.: Experiences of the accident in Seveso. European Teratology Society, 6 th Conference, Budapest, September 4-7 (1978) 21. Fraser, F.C.: Relation of animal studies to the problem in man. Handbook of teratology, voi. 1, 75-96. New York, London: Plenum Press 1977 22. Frlgerlo, A.: Identification and quantitative determination of 2,3,7,8-tetrachlorodibenzo-para-dioxin (TCDD) in animals from contaminated areas: the Seveso case. 26th Congress of the International Union of Pure and Applied Chemistry (IOPAC), Tokyo, Sept. 4-10 (1977) 23. Garattini, S .: TCDD DOisoning at Seveso. Biomed. 26, 28-29 (1977) 24. Gianotti, F.: Chloracne au tetrachloro 2,3,7 ,8 dibenzo-pdioxine chez les enfants. Ann Dermatol Venerol 104 (12), 825-829 (1977) 1S802 25. Glovanardl, A.: Introductory report on decontamination problems. In Proceedings of the Expert Meeting on the Problems Raised by TCDD Pollution, pp. 49-50, Milan, Sept. 30 and Oct. 1 (1976) 26. Helnonen, O.P., Slone, D., Shapiro, S.: Birth defects and drugs in pregnancy. Publishing Sciences Group, Inc. 1977 27. Helling, C.S., Isensee, A.R., Woolson, E.A., 'Ensor, P.D.J., Jones, G.E., Pllmmer, J.R., Kearney, P.C.: Chlorodioxins in pesticides, soils, and plants. J. Environ. Quality 2 (2), 171-178 (1973) o O ÎO <1 Cl <1 t— 28. International Agency for*Research on Cancer. Monographs on the evaluation of the carcinogenic risk of chemicals to man. Chlorinated Dibenzodioxins 15, 41-102 (1977) 29. Isensee, A.R., Jones, G.S.: Absorption and translocation of root and foliage applied 2 ,4-dichlorophenol, 2,7dichlorodibenzo-p-dioxin, and 2,3,7,8-tetrachlorodibenzo-p' dioxin. J. Agr. Food Chem. 19 (6 )§, 1210-1214 (1971) 30. Italian Parliamentary Commission. Report of inquiry on the release of toxic substances occurred on July 1976 in the Icmesa factory. Rome, July 1978 31. Jirasek, L . , Kalenskv, J., Kubec, K., Pazderova, J., Lukas, E .: Chlorakne, Porphyria cutanea tarda und andere Intoxikationen durch Herbizide. Hautarzt 27, 328-333 (1976) 32. Keamev, P.C., Woolson, E.A., Ellington, C.P.: Persistence and metabolism of chlorodioxins in soils. Environmental Science & Technology 6 (12), 1017-1019 (1972) 33. Kearney, P.C., Woolson, E.A., Isensee, A.R., Helling, C.S.: Tetrachlorodibenzo-dioxin in the environment: sources, fate, and decontamination. Environ. Health Perspect. No. 5, 273-277 (1973) 13803 34. Kearney, P.C., Isensee, A.R., Helling, C.S., Woolson, E.A., Pllmmer, J.R.; Environmental significance of cnlorodioxins. Adv. Chem. Ser. 120, 105-111 (1973) 35. Kocfba, R.J., Keves, D.G., Bever, J.E., Carreon, R.M., Gehrlng, P .J . : Long-term toxicologic studies of 2,3,7,8tetrachlorodibenzo-p-dioxin (TCDD) in laboratory animals. Int. Conference on Health Effects of Halogenatad Aromatic Hydrocarbons. New York Academy of Sciences, New York, June 24-27 (1978) 36. Matsumura, F. , Benezet, H.J. : Studies on ..the bioaccuraulation and microbial degradation of 2 ,3 ,7 ,8 -tetrachlorodibenzo-pdioxin. Environ. Health Perspect. No. 5, 253-258 (1973) 37. Matthlaschk, G . : Survey about toxicological data of 2 ,3 ,7,8 -tetrachlorodibenzo-p-dioxin (TCDD). Dioxin: Toxicological and Chemical Aspects. TCDD Workshop, Milan Oct. 23-24 (1976) 38. Moore, J.A., Gupta, B.N., Zlnkl, J.G., Vos, J.G.: Postnatal effects of maternal exposure to 2 ,3,7,8 -tetrachlorcdibenzop-dioxins (TCDD). Environ. Health Perspect. No. 5, 81-85 (1973) 39. Moore, J.A.: TCDD toxicity. Symposium on Chlorinated Phenoxv Acids and their Dioxins; Mode of Action, Health Risks and Environmental Effects. The Royal Swedish Academy of Sciences. Stockholm, February 7-9 (1977) 40. Murray, F.J., Smith, F.A., Nltschke, K.D., Humlston, C.G., Koclba, R.J., Schwetz., B.A.: Three-generation reproduction study of rats ingesting 2 ,3,7,8 -tetrachlorodibenzo-p-dioxin. Tox. appl. Pharmacol. 41 (1), 200-201 (1977) 41. Neubert, D., Dillmann, I.: Embryotoxic effects in mice treated with 2 ,4,5-trichlorophenoxyacetic acid and 2 ,3,7,8 -tetrachloro dibenzo-p-dioxin. Naunyn-Schmiedeberg's Arch. Pharmacol. 272, 243-264 (1972) 42. Neubert, D., Zens, P., Rothenwallner, A., Merker, H.J.: A survey of the embryotoxic effects of TCDD in mammalian species. Environ. Health Perspect. No. 5, 67-79 (1973) IS 804 43. Piper, W.N., Rose, J.Q./ Gehrlng, P.J.: Excretion and tissue distribution of 2 ,3,7,8 -tetrachlorodibenzo-pdioxin in the rat. Adv. Cherti. Ser. 120, 85-91 (1973) 44. Pocchlarl, F .: Accidental TCDD contamination in seveso (Italy): Epidemiological aspects. In long-term hazards of polychlorinated dibenzodioxins and polychlorinated dibenzofurans. International Agency for Research on Cancer. Internal Technical Report, Lyon, June 1978 45. Pocchiari, F.; Human health effects from accidental release of TCDD at Seveso (Italy). International Conference on Health Effects of Halogenated Aromatic' Hydrocarbons. New York Academy of Sciences, New York, June 24-27 (1978) 46. Poland, A.P., Smith, D., Metter, G., Posslck, P.: A health survey of workers in a 2,4-D and 2,4,5-T plant with special attention to chloracne, porphyria cutanea tarda, and psychologic parameters. Archives of Environmental Health 22, 316-327 (1971) 47. Private communication. Dow Chemical USA, Midland, Michigan 48. Reggiani, G.; Toxic effects of TCDD in man. NATO Workshop on Ecotoxicology, Guildford, England, July-August 1977 49. Rehder, H . , Sanchlonl, L., Cefls, F., Gropp, A.: Pathologisch embryologische Untersuchungen an Abortusfällen im Zusammen­ hang mit dem Seveso-Ungliick. Schweiz, med. Wschr. 10 8 (42) , 1617-1625 (1978) 50. Rose, J.Q., Ramsey, J.C., Wentzler, T.H., Hummel, R.A., Gehrlng, P.J.: The fate of 2,3,7,8 -tetrachlorodibenzo-pdioxln following single and repeated oral doses to the rat. (Toxicology and Applied Pharmacology 36, 209-226 (1976) 51. Sharma, R.P., Koclba, R.J., Gehrlng, P.J.: Immunotoxicologic effects of 2,3,7,8 -tetrachlorodibenzo-p-dioxin in laboratory animals. Tox appi Pharmac 45 (1), 333 (1978) -jj CH T'' 53. Smith, F.A., Schwetz, B.A., Nltschke, K.D.: Teratogenicity of 2,3,7, 8 -tetrachlorodlbenzo-p-dioxin in CF-1 mice. Toxicol. Appl. Pharmacol. 38 (3), 517-523 (1976) 54. Sgarschu, G.L., Dunn, F.L., Rowe, V.K.; Study of the teratogenicity of 2 ,3,7,8 -tetrachlorodibenzo-p-dioxin in the rat. Food & Cosmetics Toxicology 9 r 405-412 (1971) 55. Schwetz, B.A., Norris, J.M., Soarschu, G.L., Rove, V.K., Gehring, P.J., Emerson, J.L., Gerbig, C.G.: Toxicology of chlorinated dihenzo-p-dioxins. Environ. Health Perspect. No. 5, 87-99 (1973) s 56. Strik, J.J.T.W.A.; Porphyrins in urine as indication for exposure to chlorinated hydrocarbons. Int. Conference on Health Effects of Halogenated Aromatic Hydrocarbons. New York Academy of Sciences, New York, June 24-27 (1978) 5 7. Tenchlni, M.L., Glorqi, R . , Crlmaudo, C., Simoni, G., Nuzzo, F., De Carli, L.: Approaches .to examination of genetic damage after a major hazard in chemical industry: preliminary cytogenetic findings on TCDD-exposed subjects after Seveso accident. Paper presented at the Symposium of the European Society of Human Genetics, Oslo, May 11-13 (1977) 58. Tuchmann-Duplessls, H . : Drug effects on the fetus. Monographs on drugs, vol. 2, ADIS Press 1975 5 9 . Tuchmann-Ouplessls, H.: L'accident de Seveso; données actuelles sur le développement pré et post-natal. Bull. Acad. Nat. Méd. 162 (5), 389-394 (1978) 16806 W ¿V ( Ji. f i 52. Slmonl, G . , Larlzza, L ., Sacchl, N. , Della Valle, G., Dambroslo, F., De Carli, L . ; Chromosome lesions in amniotic fluid cell cultures. Paper presented at the Symposium of the European Society of Human Genetics, Oslo, May 14-15 (1977) 60. Tuchmann-Duolessls, H . : Pollution de 1'environnement et descendance. A propos de l'accident de Seveso. Médecine et Hygiène 36, 1753-1766 (1978) 61. Vos, J.G., Moore, J.A.: Suppression of cellular immunity in rats and mice by maternal treatment with 2,3,7,3tetrachloradibenzo-p-dioxin. Int. Arch. Allergy 47, 777-794 (1974) { f re -a cn 62. Vos, J.G.: TCDD effects, mechanisms. Symposium on Chlorinated Phenoxy Acids and their Dioxins; Mode of Action, Health Risks and Environmental Effects. The Royal Swedish Academy of Sciences. Stockholm, February 7-9 (1977) 63. Vos, J.G., Kreeftenberg, J.G., Engel, H.W.B., Mlnderhoud, A., Van Noorlejansen, L.M.: Studies on 2,3,7,8 -tetrachlorodibenzop-dioxin-induced immune suppression and decreased resistance to infection: endotoxin hypersensitivity, serum zinc z concentrations and effect of thymosin treatment. Toxicology 9, 75-86 (1978) 64. Waldenstrom, J.G.: The porphyrias as an inborn error of metabolism. American Journal of Medicine 22, 758 (1957) 65. Wassom, J.S., Huff, J.E., Loorleno, N.: A review of the genetic toxicology of chlorinated dibenzo-p-dioxins. Mutation Research 47, 141-160 (1977/1978) 6 6 . Wilson, J.G.: Embryotoxicity of drugs in man. Handbook of teratology, vol. 1, 309-355. New York, London: Plenum Press 1977 67. Wlpf, H.K. et al.: Field trials on photodegradation of TCDD on vegetation after spraying with vegetable oil. Dioxin: Toxicological and Chemical Aspects. TCDD WorkshOD, Milan, Oct. 23-24 (1976) 6 8 . World Health Organization Technical Report Series: Programmes of analy 3 i3 of mortality trends and levels, No. 440, 1970; Spontaneous and induced abortion, No. 461, 1970 69. Young, A.L., Arnold/ E.L., Wachinski, A.M.: 2,4,5-T, 2,5-D. Presentation to the Weed Science Society of America, Las Vegas, Feb. 13 (1974), Abstract No. 226 70. Young, A.L., Thalken, C.5., Arnold, E.L., Cuoello, J.M., Cockerham, L.G.: Fate of 2,3,7,8 -tetrachlorodibenzo-pdioxin (TCDD) in the environment: summary and decontamination recommendations. United States Air Force Academy, Colorado 80840, Department of Chemistry and Biological Sciences, USAFA-TR-76-13 16808 D O W C H E M IC A L U .S .A . A N O ^ C rf A I l N l j U N IT O P T H « O O W C l - lt M I C A l C O M P A N Y M ID LAN D . M IC H IG A N 4 8 6 4 0 SALES SPECIFICATION 'W u m ' b ' e r íi¡ O O ~ t — 20683 BÂTE- 7-9-'. SU PERSED ES NUMBER date 20683 1-17- M È T H O O r a F - 4 N A L Y 5 I 5 --------- 20683a o O 2,4-DICHLOROPHENOXYACETIC ACID 2,4-Dichlorophenoxyacetic acid, minimum 99.0% O QD C ♦ •■ D E N O T E S CH A N G E T h e p o l i c y o f T h e D o w C h e m ic o i C o m p a n y i s o n e of c o n fir m e d im p ro v e m e n t s b y r e s e a r c h o n d m a n u f a c t u r in g w h e r e v e r p o s s i b l e to a s s u r e a s t i l l lin e r p r o d u c t H e n c e , s p e c i f i c a t i o n s a re s u b ie c r to c h a n g e w it h o u t n a n c c__________ ________________________________________________ FQP m 20780 PRIN TED R.J.74 F o r a m o re c o m p le t e d e s c r i o r i o n of t h i s p ro d u c t , i n c l u d i n g o v e r a g e p h y s i c a l p r o p e r t ie s , p l e a s e re fe r to the a p p r o p r ia t e D o w b u l le t in t e c h n ic a l d o ia A l l s h ip m e n t s w i l l b e a c c o m p a n ie d b y m in im u m m a r k i n g s w h ic h i n c l u d e p r o d u c t id e n t if ic a t . c n . lo t o r p a t c h n u m b e r, n et c o n t e n t s , c o m p a n y nam e o n d a d d r e s s , o n d su c h p re ­ c a u t io n a r y l a b e l i n g a n d o t h e r in fo r m a t io n a s j e e m e d a p p r o p r ia t e for t h i s p r o d u c t 506 459 6720;# 4/ 6 3:20PM ; SENT BY:CLARK, BRUMMIE, S 00. ;11-19-92 2230 :\1 «•iV § # g r-; I c i I vflC J t'jj- --- * r j :o g | ■ £ rÇîss n-^.TvJ-v-w.. (¡j 2fi *• ,-ät < " g .* ■— V &>•» t* . ¿s-.-*?>,•*■ * y «y. i .à V 1V*- -•■••■¡.'J6'-.' -*.■:"?:*:•.■*.■-;- ■ to >V •'•.=:•:>i & C í-i-'* '?\:'V-. L < '■ * «■*£* ; sVji-^».«WUll tóÍR* _ _• I MT •j »*'í -vvT / *: ■•*•*■.;, * -n .» ^ V&k -v.'Lto.:J* Imw ~-If' :£*#*/ ps®»^v-rJ 16B1Ö* 2296 DOW CHEMICAL U.S.A. POST OFFICE BOX 1706 MIDLAND. MICHIGAN 48640 June 27, 1973 Mr. Richard F. Mountfort Fungicide-Herbicide Branch Registration Division Environmental Protection Agency South Agricultural Building 12th & Independence A v e ., S.W. Washington, D. C. 20460 b c c : D. M. R. L. L. E. D. McCollister/Action File L. Leng F. Flannery R. McCutchen Southwick ■ E. Kenaga o O Dear Mr. Mountfort: as o Ul 04 04 Subject: C3 HURON© Weed and Brush Killer EPA Reg. No. 464-162 Your letter of May 1, 1973 For convenience in review a copy of your May 1, 1973, letter is enclosed. We will discuss your comments by their numbers in that letter. Comment No. 1. At our May 31, 1973 meeting on Phenoxy Labels, Mr. Robert J. Taylor discussed our HURON label application of March 13, 1973 . In accord with that discussion and your letter we have deleted the recommendation for a tank mix of HURON and TORDON 101 Mixture for Forest Site Preparation until we have the phytotoxicity data requested concerning planting of conifer seedlings. To make your files more complete, we are enclosing copies of two brief research reports and a brief letter report indicating the general efficacy of such a tank mix for over­ all brush control. Notes on transmission line brush control test near LaPlace, Louisiana, 1972 by H. A. Nation March 1973. Report to The Dow Chemical Company. Notes on power transmission line brush control test near St. Francisville, Louisiana, 1972 by H. A. Nation March 1973. Report to The Dow Chemical Company. West Tree Service Inc. Letter report of October 6, 1972 to Mr. W. G. Wright, The Dow Chemical Company. A N O P E R A T I N G UNIT O F T H E D O W CHEMICAL C O M P A N Y oo CP- cc VO Mr. R. F. M o u n t f o r t -2- June 21f 1973 comment N o . 2. We had previously changed the statement (page 10) to read " . . . . along the shorelines of ponds and similar aquatic areas ...." We believe the use of the word "of" rather than "in" is a non-substantive change and that the sentence as written expresses the idea you had in mind. Under Comment No. 2 - a request for additional bird toxicity data, if available. We have no additional bird toxicity data to supply. This' matter was -discussed between our E. E . Kenaga and your A. J. Duvall in a phone call of-May 8 , 1973. It is my understanding that there were no further questions raise;;. I also understood from Mr. J. W. Akerman at the May 31, 1973 conference previously mentioned that if he wished further information he would contact Mr. Kenaga. O O 02 r t o Five copies of labeling for this product revised in accord­ ance with the above comments are enclosed . We believe this label therefore is acceptable to you and look forward to receiving such official notification. on Sincerely, Wendell R. Mullison Registration Specialist Ag-Organics Department Enc. cah 1S812 506 459 6720;# 5/ 6 SENT BY ¡CLARK, DRIMIIE, A CO. ;11-19-32 ; 3:22PM ; WUD LIST »tWiii Ctmmmi WMNMO WEED AG3D BRUSH KELLER =5=2=35=5 r a f t 6ÛNÎXQU1NO CERTAIN HERBACEOUS WIEDS, WOODY PLANTS ANO AQUATIC WEEDS f mmâm ■ÉfrtenA spisMMIftewftU M tfrhin rfMni ^MipéíZ|*^*"^2 M V n A M NUMMlwr I S TOWNOT M» CMIOM W— iU-gA*-Tii*fa^Aiiiiu ll MW"» « I N ( M 4 t»Ci M M M w h M . . ___ __ » M » A l­ ia M b *« N r «N» i # b •i ■*M _ ______ JLMh mu p a t i ni*' MMM —■ ■ * ' «*—« i l l ««MB ♦ * “* »Ml CAUTION o r our or mach Or cm uw in CAUTION ■mICMfilBiafamn»w«aW mwwl 1 0SUON io r u v n im m c tO M AwU C|>M with h * . IN« md Cìttiàrm b t f Om» **71* I n * ^ CMfa*» VÎïE ¿'fi1.'*! *€>i*92 m u ra tk p . s a . ora u w m 19*7 V m u a s sn c trx x u m jt-io s i m in e s is s o m a n . 1»*S. M B JULX. U t l . u ttiic s s ncuoE ; n i a s m e t e m i m os m m IM M K T SOI H i m "USED ABB B U S « n i n » ( 2 > MW PISCUÏHEE 5TATUŒIT. ( I ) B T IO D U Mw y r n . uaa rasose a turaicue is unsum. X-J''-'1 ?.U'!'1 « IM M ÉM r i »>4*1 M »'«»'H u 1 rfew,, Ik IM JN duhchms i* W f «I l * t f MW. w 1 I M * b t> - ktf I w * m ■■ « M l • * « * * * ■ • M * r •*■« - M r 4* M w M w M fr* » < t fi J — >himmh»»-«»«u7«mo >wmm mtmmi W T I M T M H I ,C i «MaCCMmMINV«M« tm* »M H ^ M >I« — N » I | » ^ I A » f W *I i gw— M • M , l « M > M < ft ♦« w < M « w f «M.M WMp*>— — - m u N t i t r w r n i w M w M 4 — l«| U > 5 ZC o c f t o a k tlH lM H p • •» Wlfcf *M>«k Uu * p- >■> r p |* «* « sa tira e in a m i ^ > i .«M n ■ w w tM U M M M p M m - ■ « » ! » M W < » « . l » r t « M * * J M w P » < H < l W I M w H l » WM » h w « ■ « NHf. i p » y H > iM tiifc »» *■ ■) WM ■<• aw M r w « ku w i i p á » H w 'n « » M il m USE JIECOMMfNDMIOM* IN SUGAI CAM KOtito t » »«W M W i k I •■ r*/r « « m w ■«■M» - » m M H M D r w ««• * WMHMA M l i m c i t a V I ta n a p p u M f H H . M W W p i (, > W P M W t , 4M*» * M ^ M i m i iKlw n * H W pw m >m > n r w n » « - w » w M « * - i më M l É M h fc » m» ■ ■ )■ ■ ■ r* M rt M i m i Nmm * « M M m * W» M m « k w - M m m i i - M r w i« n M l p m i l wm « M •* -m m W « n L m M » w i> M « m H y i l M i l W l W m w - m « r n « < w % tfM M — iM « . m -m . U ■ rM ifM p m fcm M M « M «M p m i »■ u l r CAUTION r or *ucm or o « m i - «» » ■■— «p p «r* «ni ■ M — 40 SÂiEiïïu:* i-d- /■••I li p *- 1* 16814 UUrtiîUÜZâ'tü T— ( O CO CQ A c t iv e In g r e d ie n t » S ilv c K I 2 ' 1 2 .4 .5 - T r ic h lo r o p h c n o a y •p r o p io n ic A c i d |. P r o p y l e n e G l y c o l B u t y l E t h e r E i t e r t . . . . . . 6 7 .9 % S i l v e s I 2 - * 2 , 4 , 5 - T r i c h l o r o p h e n o a y l p r o p io n ic A c i d I, E q u iv o lc n t 4 5 , 0 % In e r t In g r e d ie n t s . . .. ....................... ......... 3 2 . 1 % U . S .O .A . R c g iit r o t io n C o n t a in ! 6 .0 S IL V E X Pounds A C ID per G a llo n E Q U IV A L E N T No. 4 6 4 .1 6 2 of Low 4 .0 V o la t ilit y PO UNDS PER E ste rs of S t lv e x G ALLO N BRUS N ow R e c o m m e n d e d fo r A Q U A T IC W EED 4 tf* CON TROC^ Submerge*! Agaatit Submerge«! A«w*»i< Wferft (■ in Fondi Fendi é*4 0>k*r O iir t Still Wet«*: -To e>>n'»ol c o » " 0 < certom cer»o«n tub« w 'j f n l i«rri1\ wreclt n x h 4\ ond » o lr'w frd , u>f m rr'ft'jfni H>(h ot wgir> «gir> iThllloil, rmJHoil. Ignwgil lont*ownrf t>lor1 «tr»1 >«f kocre >n or* ond one foot OoiJ fool d ffp u o Thu\ on « oc»r 'r of »o'** wo'e» 5 left dcrp deep will rerKiirf terh/ttr 5«5 5«S Q«Ort% Qoort% of H«* C 25 goitont * Apt>l, .n ro>i> m » « x i » h f i wo'e* n ,np iio iw 'r it above SO F ood weedt o t r oDP'oochmg the w iif i w f o c r To oopfv piooerly. f'»tt d«lui* the Kwroo with rno^Qh w a in lor uniform dwtnbuton over the water twrfocr with the ipr0y etjuiflmenl Of hood ApoliCOtrOo roov fllVI bo mode Wrfh prOOfrly C0l*b'0«fd proportioning rqi/ipmeni which .oufcmoticoHy m>>ei Kwron ood pood water >o the pt/mp NOTE Do nqi freol How og wo*fr with Kuifln Ponjf with o %f»ght current con be t*eo'e>l if the woir*» lr»cf coo be lowered vo the»» will be no Overflow lor of Irot» 3 doyt ofter lreo,mrnt However, control will be lei\ around tport where uoireoted woter Hrw»t mto »he pond In Ireotmg thoreime of lo*>et or forge ptodt, ihrr« w»H be tome d^ufion coused hv 'he woter in the unirroted center o»eot of 'h e bond. ihv»*« fore. •> it betf to freot on o*eo at leo\> 200 tee* touore (M e ry iM Aewefic Weedir Tu confml r m r 'g f " ' weedt tucli ot wh.ie wafer lil*. •parrenmet pictpreiwecd orrowheod etc . ute On* gofl'm of Kw un m 10 0 rja'li'n-. i i wo'er Apply ot a writing tp»ov ro 'ro » rt and ilrm j when teo»e> ore fully ili'\clnped otv»»r the waterline Br.o eai at nncrttorv Special Freiawiiant ter U«e it* A *« » r« W eed C m ln l: Apply onl» m o t c n ig '- c r with troie and locol lewf and »fgutoiwm» governing chrm'col treatment ot buO*et of water tor control Of w ftdt To OvOid injury. da rvU ute Huron where pond water it being uved for trr>gat>On «in­ cluding r»ce production i. lor og’potu«e n I dptiioo'e »ig* eto'ion along the tftorelme Since tnev nxjy coute interference with the act«.n of Huron q q not opply olgoculet tuch at copper wllate lor J doyt before or alter ooo'vmg Cyron Here: T»*0f pond edget or (ok« thorcim* firtl to fith will not be trooped m tholiow pockety or mien. KEEP O U T OF REACH OF C H IL D R E N Read Complcfe Precautions on Rear Panel w uun¿tJ¿¿z 4/ HURON B R U S H K I L L E R Creane Aepli«art*n : U'.e t u ua " '-i " row «OMiroumptrl» >-ny ih n j ul in* to»Ol 0>rO- A M 'f-nd OW-MOImn I L> n**ijed On no» m as* o u o iko u u « o « n co»*e «' i *•» 3 1 r •«« t io*l M ove a w l x d " ' 5 rwinrni Itrliirp hn'vrvl A ir A a o l x a l a a * : U » I a iu O « Ol K u r o n p e ' o c 'e m n v w j h A p p l K o i v o c o n be «amie u p ift r w v a ih v lir li u ,* h o ' » r ' l ’t FOR C O N T R O L L IN G C E R T A IN HERBAC EO U S W EEDS A N D W O O D Y PLAN TS P a r t ic u la r ly P o l l O o k , B la c k ja c k O a k , a n d N o r t h e r n O a k x tu c h as P in O a k , Red O a k . W h it e O o k a n d Scru b O a k DIRECTIONS Kwf«n lol.oor heit»*tid* *s used >n controlling ceno*« wcodv ond herbottout plants growing ,n poviw'et. rqngrioodt, l i 'H f rows, iiglii*ol<*ovi< and on ai m controlling • — block,ock ook mopfet. such a» red, northern ipm, red. sugar, end big 1* 0 » «h u e K iu b 1 oofci mqplr C A U T IO N : To OvOid domou*v Mexico« t*lfd poke berry post Ook lend thinnyty ook wild biockbevry yucca ragweed tali cedar tun I lower Da not uve Kuron- for ih» control of Oth P R E P A R IN G T H I S M A Y : Add half the required omount el * o 'r r iu the spror lonk. then 0,4,1 Kw«in w.iK og.iptHn K u 'o « forms on emuluon *n wafer ond tendt to settle out on piMi.wvqeil \la«*!>ng Provide 0 gi* 0 " 0n lo prevent tuch sePO'Olton Ond «mure uniform maaiurr oeoil nynvlure is deficient Utuolfv o Srngle oppftcolton in ony one year ts suffi­ cient if new (»•••wih develops, repeat oPpiKanons may be necettory m succeeding years. A IR P L A N E A P P L IC A T IO N : for control of post and bfockiock ookt, ute 2 Ouorit of Kuron in I go'lon of J ir u l 0ol'CO*'»«n of Kuron. mia ' j cupful m ) gollons of wo'er. Wet oil lolioge thamaoghly W H O C O N TRO L IN ILAW NS A N O G O Lf COURSES-. for control ol b'ood-teoved plon* tom. buckhorn, common chm to 1 Quo« of Kuron in > golfo« diesel mi, ond water io moke 4 galluns loiol pe' ocre T * o to thrre opplicoiions qs necestary >n succrss-ve yeors moy be needril Apply ofirr fofioge « fulfy deveioped Consoli com prim i locai ouihomies for inlormoi>on on besi tele ond bevi lime for appl'CO'ion locai ceedilÙM may eflect iKt wte a» kribnidri, State africwllaral avlkeiiliei in many state« ino« ra:o'">n alirr Ihr Cone emrrget Ot toring growlh ond whrn wreits o»e growmg »laorously. bui befo'C ihev send up teed tloiWt A tecond applaCei'on con be mode fot loie cmr>gmg weadv NOTE: Do noi opply oller Ihe con« is 3 lo 3 ’ ; ferì ioli LO U ISIA N A for Ihe COnlruf ol <oirfy loHnwmg ibis npcioiion follow ihe cori* Ucormenl wh*n necettory wiih 2 poundt of Oowpon* grotv killer per ocre, epplied Over Ih* greti m ih * row (oooroatmoirly one-ihird ef ihe tuia! oreo> Tu c«»irnl w iM U'Mocr Curlnf iV»ck, on»J nihrr wi'vils ove "ne ol ihe Inllowmg procedure« whrn ihe werdv no* •i/y •• iu- |v w o«' 't*n or Irosi j- to to r i r v l v r w HAWAII fai |«r.rn y 0C*I' ,n ’’I •" 1 »)olk“*s i l v j l " O» O l i i ’O-HO'i sire» •rvwnv diaielv OHrr plqninH) « • IQr^aoning ««« twf>re Cone emvigence f-*» cv-si •*">•««« ••cv Contro! pi weeds o«cr cours h0»e emerged od.! ! ' .• *«' ■> pounds &>wp,v* pe* q<«e tu ih* toroy of Kuron in ruder ip cnnirol gaotves ond vproy Ih,- inifitanf soocr *laOn\ mus o«*Cl Iha* uM "* h fb 'C 'd l't Sio ln issue recummcndolaunv f0 fa* lOCOi conditions S ' 0 'e ognCwllU'Ol OpafVja.i^v .n mqny Dn noi oppi» Ku'Rn dirrc'l» *0 or •iihrrwive perm.i «| to corri* ,nlv conioc* w.lh o "» C " o pioni nr r.inonynlo' D'onf 'inclotlang t-ul ami limiteli la) peonott. SOvhv'onv t u o "* pnOV. l'tmoinev l'4aot( ai cralinn, nsfliy**, «vro m re i pntotnes, peppers. C rU 'v «nwerv .■•a*am, aatol*. Q'OI arv, alee >tu’. O'wl n*m,|, < >ilu -u. l'o 'l larfs 1 Onal »1 rv .1 per mi, Npir)« m.- r t -m. tO'nnag Kurnn In »(fili ,u-lii Ihrm i.mce m.n,,ip q uon'.lif, n o , (OHM t»-.rrp .temij-* durarvi |vlh griiwmg oivl .(.•rmflnf |,a •> I, ( o i y i (k o ,', o h ' Ir., M i 1, Appli««li«n| ky «irptane, ground rtgs «nd kand ¿iipcmcr« ihauld he ««m ef «al »«ly when «irr* il n« h **«i4 lr«m dnft. 0« nat apply by «arpione in Ihe vicinar* «f «ny e«t'(Oiiur* " e * Cfluse iniury in suvct'piiblc plonlv qa> wang ncov ion-y Or* nn* u v e K u 'la n On la e v h lv v e rd a 'd l o > " i p O 'lw 'e v u r 'o n d u n l i l Q »ovs h o v b r< >mc SVflI f s lo lll a s h r if Da* rsaal CIV’IO m in Q le ir r a ijn la i'n . |. t c l , i » n i «vO>r• u -I • I * •» 11 m n v l- f f,uitp-**V D o m » s tu r e n*O I I v r l a U jr a v v r r j lv m v * C lir » V v l u ''g * ( '•!»*> T >n-.u,v • I. •.»•O bif p i o n l s alo n o i v ln r e , h ija n llr *•' O M 't* • • 'k i 'i p'ì*i< .aliai'O l rh * m i r i t i , w iv . i n , v o - f < - - i o .......... Or rOu'pmenl OM'd fi» Kiliaci D * •«•! u -r K aa»- •« •*> 'l'io * ”*0 «,.|Uap'’ia ni ;■ i>aom.->Vj,r i| ».ih 2,4 .0 at thè 2.4 .0 «all **»H'ii'x ihr hacoM i • .l<-.a.oi>l>' «•(.)•«*^ fic iure (h o t m e o f t h ii p r o d u c i c o n fo r m i to o li o p p lie o b ie rcgu lo fro n s. M A Y C A U S E S K IN IR R IT A T IO N A v o id C o n fo c t w ith Eyes. S k in o n d C lo t h in g K ee p O u t o f the R e o ch o f C h ild r e n N OTICE: Seller motet nn «*orao>>iv ..I ■>*.. i Ol (has produci 0u*rr o « « "1«'* OH aavk ,.l uv direci'Ons nr not U K r •• •: h o n a l'a n g . w hr»r*.-a ’ JO 1* T ■»» o < t - •» P —•*** DOH2022542 directions . . .............. .. ,.,...1 1 .- 9 t«»«n *>*.•• >* •#•«■*«•'! . . , . • ,, I. . 1 » tl •»** W»*ki. len/e '©**» « " « •.9 W .Ql.-r 0 y» P 'o " H • " P O ,' >" ' • v i t i ».?d H oikbfrry. ............. .. « « .o n wood. curly ,ni,9,. lo r"b »• k...V l . . „ J - . . V . .« h a . . . « k l . b u . , , ........... ............ .. „ , , d . . . i . b c . n , . < o » ~ .« d . c o ll « d o . , t u n l l o w . r . NC’f 0'» '**» <•** < v'*« U» »be <•«•»•! « ih . : h ( IMAT A,H »nil is* »•n -**rd s » # v f l ' 9 I w ote* »0 »be »p ray to n k . »b eo o d d X v io " ~ ,,K .. r . . , . ••„.-» 0 « in «.aie» p n d ten d » to o u t on p r o l o n g e d t t o n d .n g , N o * » d * .................. f , . , . , . . Iv,ii t*fioMH.*n on d «n ivM v«ild rm m ì i i v f » in fb * »p to y ton k AOi I I U W t N t i s ..« / - w i t grn»rb v p to d or I fe * » to ll o ft « r »be f o i t o g e •» fu lly d e v e l o p e d . I . i. m , ] i i 4 *|vnr*t t l ItiigA p er 10 0 g o l l e m a ( W»tK »*«»»»•«* t p * » '* » . t o l l * . ». ,• • •<) » , , .I t*t>ogv •» o d t ( ) u o i t l f co -*» *d , O - p o * to s i»y a n d b ra m b le » tu cb 01 •• • ' .'» • • ) .» • ? ')•*»• •• a» ( v t i t p . i 1 00 flo ii« n t o f » 0 1 » . . S p t a y »K *w ld ( i t f n t h o il p la n t p a t i i tn» l‘.< lfO««\ »1«m» ». •>•'»*'» •* * «» .0 'v".ril m r o i, a o p I x a iio M n g d r u p to i k i r « e * ( U b e f o r e l o l l fro»t o* * . •>•*...,« • » c j l.t tc .j n .« i g i f ! • * - . • o n d lu ll T e .o t o n d O H a k e m q it n o t i t < c " * n » " ( i r d ) .*■*. '«•».*» r ...» :wtl j j i . f n (»tqr o n d »«go* m a y n ot q»«e tot» » le < » er y «on *rol l e u . 9,,/*« Sol, Hip u f v i li f « oK «o d r f p to il mo •« tur » it d e l *c i f *». O i u a l l y o t .n g l * • • •a « « »*••• •» u l r.(.fO i il f i . « g»o*>lh d e * * lo p t . r e p e a t a p y l i t d l i e n t n g y b e a e t* » » o * y , ^^ , ( , ■ ^ ,.t t * * ¥ ^ **' e* poi* o«H M q<1 | 0 ( 1 o o k i. y t e 7 q u a r t! o f Kurort 1*» I g a l l o « ot ^ * T ' l , *> 9 I wyter. «r J qwUiH t l Kwron in I V t *0 < „ p lut «n J g a l l o n i •< w a te r W e t aft - ^ COW C O U I W V ff>* (O nlrgl 0 I b r o o d l e o » e a p io n * a i" , h u r t t ’O*'*. * 1 • • n 1, . , . ,. , i( **, 'I M ,« l» r r r l, d a n d e lio n , a n d le g u m e » w d i o» wbi>e < la » e . a n d b lo t k * ‘ i , **. )(< 1 * HmO » «I I v 'o n tm 73 fa 4 0 g a l l a n t g l » g i t * p e» o c r e ftig tie » * o l - m e t , **' * - I »0 e " ' , n . i r d rift K a»o»d A p p .y l o l l or ea » ly »p**ng o t ^t»t — »<• g - e 4 |||f># ■ »' *° » • «♦» ^ l l t U n i f r r g v l g r a n e » twcK o t b e n t , * » ,!•»;», . # *# **»y rorie^y * . . ’ ^ ' * " i r •• *..l ^ . tp r a , . . m an n er wW,»n w. 11 t o w\* d o ta g e » tw |- | A v««p tp » a r< n g . S e n n o t i l e » ' “ >— y * nt k'1* ^ ** b a » k .» g „ P ' nmJ lk p8>w» #*• v p l» f vvri . N"ci i.. . , , . .. j * * ’ * '" * ■ • • • 11 I * ’* ' • — '? * - • * ef »**e »we W t n r l l . g d i H . • • . « i H i t . r i . ,.. * •* t .. ,• * * * »‘ g e d •!>•*» w%«e* o n d Ir a « # , a»» t 'o n b in g »•#<• U ie ». j t * W . » •• • *, it . ^ I* * ' ••*t*d *« « n Ji..«iV « .» *n f m nwmy |.iHa*.enp J pin»» .. * fe e t* » ,« « / a g o •« g»ow.K ( • « H .i ' « » , u p (r.- **" . . * '* * ’’• • d *n g n u vea lly to f# * pv«n M «od«n$ C o *» -M 0»IUC^AANo ■" ~ ,W , ^ .,.^ 1 * . *** '"**'** **eal••»•nnenbai.mi U« I 4 H 1 .1 .. I « .I I ., X I • » - e » a t » o q •« t « t < « d * n 16817- o r b . - r .d * r f A p p l , > h . , f o l . „ v , •„ l . i l r d , . , i . f . d in f o r m a t io n o n b e t i r a t « o .t d b «»t lim e K m a p p l ic a t io n fM |I S K ! USE RECOM M ENDATIONS IN SUGAK CANE » tc *»’r)i*« '<{ |i>|i'i F L O R ID A lr *•'»» et •«•rw-i ..,i,„ i„ jp | C :i: o n d o t h e r i v K e p f r b J e b r p o d l e o r e d » r e d « . a p p l y I to P / i g v ori» of f U f O * ** ? *« » « * 6 » - a r e 9 >o«>n9 v t g o r o w ily . bwt b e fo * « th e y t« « d v p te e d i 'o U i rt at , p „ - 9 rd »•*•»« .k A t«• J V j t«r< >«11 ft •* A L O U IS IA N A P t f * f M f I G l N C E : f o ' lb « (o n t r o i of ( r o b g i Q l l . b o r n y o 'd g r o ii ond Joh«»oi*9'O ii a p p ly •* s f t ' *e»i I q w n ii o f K v r a n in 1 5 gaf*O n» o f w o '« * p « r a c re «n »be r m ( o p P '« i" " L ii'i| #«e p ' r o ) »b o rt/y b e f o r e tb « t e e d t o r e « » p e tte d *• " f 1 • r *•* *»•Jd:» to g e rm in a te . «• .* m e d ia t e f y f o ff o w r n g tbi» o p « ro f< 0 n . f o ll o w t b * e a r ly freotm ent »>*«<» n e ce tio /f »»rt* ? peonOi r ‘ £/••*«• g r o t» k i ll e r p«» o r * « , a p p l i e d o * « r tKe g r o n in the » « • < o p p r o t'* o ‘» lr •**« *bnd «1 **>• ***»• fO S T E M E fG E N C E : To c o n t r o l w ild I r t t w t r , c o d e d d o ck , n w * n j g l* ' t , »<«***». i» p * r « '* * *“* b r o o d l e o v e d w e e d » trie o n « o f rb« f o llo w in g p r o c e d v 'c i « b e * '**t * r r d i o»e i ’ * " ' " ? G r o w n d A p p l i c a t i o n ; U t » I q v o r f o f K w ron in I j g a it » * * o f * * * * * pr* tft'e op et-+ 4 * * ,9 r m a » t ly o n e » b ird o l t h e t o t o l p r e o ) . A > « « *n d o p p lifo M o n {# » be "*odr «1 neeflre .!«<• f* » r'» t* A i f A p p l i c a t i o n : U »e 2 to 3 p in t» of Kw#on p e r a c re .n enough * * • * • fo •d ter feed w *»«■ N O T E : O o n o t a p p l y nrrtbin 3 m onth» o f k t t r r r i l to twgo* to n e to be p io te n e t r e a t m e n t c a n b e m a d e a t a n y tim e to * v g o r c » n * 1» b e v te d fo* plon*mg r » oo* — T" H A W A II _______________________..* 1 «1 L _ ____ u ______ _ . . l | n. imm In.I. r.rboirfr»- '» 1 to a n y o n e c r o p \ T ° !.." S r ^ T ~ V • ' "> - b - id » l HURON - • e d * f ^ C / N *' A 0 U A r * fo* S ' o 'r AQUATIC w e e d CONTtOl W T f D J JN ^ O M O i A fV D f ? W f | f « J W * f f i f# >#< ,r r . .#IS,«rrx"J•*—\ TM l bUdde^... . •o^.-eed ..e ! .. * « ' r f ii # * e n r M , ff o l * w, a *< bore JOV m *. •* **roo or i 7$ gatt»«, j ¿ p 9 lt ,e enrJf * - n-‘ J«erp'rp**»**1» „.d *ee * • ' e**»t*eiw d r f h .,|» * » ,,* e»# / rKv *,# » « , !«•<*#• * e *o*er •« •■ e P r o p e r ly fo / .b « o * * d y r e p e n . e e ^ y e « . . p - * - * ^— p ow g m o t» , ,» ■ •« •id ■ '* a no*fhvote,I ***,*m'* •p^'*<*— o 'o. ■ „.■ ■ >«-.d 9 * » W f + + J . f i o t o l a t « , it <« W »« H % o a t p a m m fio e iO A t 9, aoii i . t . y r ' M iaiii<«l a f * a g w o * d . d o g fo n n a l. g iw « r tJ • * J *uv« t d . i »« a i - r j - t i b . f >*»»«.*9 rk.i «p«*ai»0n f o i l « « lh * «o*f> lf * o l " » * « l «> r in | lo toni»o 1 «»Id W n v < 9 . tw i U d d o c k . *n * * « i« g g l e » , . ty P * P ti* * n # b » s ^ J )r a .r j » e r j* u«< on« «1 th* < a(lo««ng p f o t t d v * * » » a «*» Ik * w o o d s a t * g r o w i n g ««go«» C.O^Ad A , o * * * , ^ * . y |# j ^ wOM 0, X f f f 9 m f ** ,h* •••■I«.»*» ° m M g o llo n t «f v a to r p«r o t t t o p p iio d h# r » < ) « p p * o t . 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(it%t d t» « t* lh * < ««*n “ *4 S ,.,. I. . , . O , i . I . l l , » « . » .Ik l» i J d o . , b . i . . . . . o l i . > d o . U - t Xr ° N, , F0R AQUAT,C WEED CONT* OL ..I I I .,,1 ! 0 * | ___t I«* ag *» < « liw # al*p *o y » . dt ■<*<*< i« p p iy , a* lo* l»*oi»o» t • • " ' • n y " W * »»»f n »nr ■■»■•** »** (« « o n «* n « t o«d»nor»ly k u r n l « l to a g » o M o n .w o U , k«< t* * » <«»* U fl wo* w t v *y *» « i 4j - o « .» * » ( * a llr - ...........* " * C ** S l p t * o g * itw llw * a l •■ p*rM*>*n1 t to lio n » •» *iH * n » i*n •• "»any 4to t*» tt|w t r*« o o *n * *n d o t.o n i ta l it I C O N riO t W r — n *4 w w kw io » *> «1 — »* 0«0•»1 p*.*ie»-*k, |«nqlf *><«. puttloo« a n d ww ogtai »••«*•* . , « 0 ^ d a ih o ? P** 1 * * ,t'‘* 5 - M h i of h a r v t ir i s iv g o * c a n * i« b o p r o c o t t t d lo r fo o d a* fo o d . Mo odo a t any i IMPORTANT* r e Ao i n s t r u c t i o n s on r e v e r s e 2. name of economic poison 1. D A T E O F A P P L I C A T I D h (Must be same product name as on label—do not list active ingredients J KURON® 3. ¡ NAME » M A I L I N G A D D R C I I O F R E G I S T R A N T ' Dow Chemical U.S.A. P. 0. Box 1706 Midland, Michigan 48640 . R E G I S T R A T I O N HO. (Include Z i p Co de ) r 464-162 ^ C PROPOSED EF F EC TIV E DATE OF CHANGE O / As soon as possible. Q _ ! 6 , n a t u r e o f r e v i s i o n (Check applicable item and give details in item 7, when required J Attn: Fred lloerger ____________ G E N E R AL REVISION O F L A BE L I N G Q A DD I TI O NA L USES ADO ED TO L A B E L I N G - - C ] (List new recommendations in item 7) C H A N G E IN F O R M U L A T I O N Q ] (Give description of exact change in item 7) C H A N G E IN P R O D U C T N A M E I I (Give old name and new name in item 7) ' OTHER :-i 1 (Specify m item 7) BY r e v i s i o n c h e c k e o i n i t e m « (Attach additional sheets i f more space is needed) For a number of years, Louisiana has recommended the use of KURON [2-(2,4,5-trichlorophenoxy) propionic acid propylene glycol butyl ether esters1 herbicide in combination with dalapon, sodium TCA, and 2,4-D for control of a variety of weeds in sugarcane. Each of the herbicides is currently registered for use on sugarcaneein Louisiana, but the current labels do not bear specific directions for the combination treatments as recommended by Louisiana. . ..... ■ - 7, d e t a i l s r e o u i r e o This application therefore consists of a supplemental labeling brochure to cover the combination treatments. The brochure is intended to augment the individual product labels and pepresent too much printed material to include on each product package label*. Based on state recommendations, the combination treatments have been used commercially for a number of years. We believe that Federal registration would bring these practices ttithin the intent of the Federal Environmental Pesticide Control Act of 1972. The attached volume "Technical Information on Tank. Mixtures of Dow Herbicides for Louisiana Sugarcane" provides data supporting the practices. It also seems noteworthy that commercial field experience has been extensive with satisfactory weed control and no indication of adverse problems. I I CONTINUED ON A TTACHM ENT 8. T H E F O L L O W IN G M U S T B E S U B M I T T E D W IT H T H I S A P P L I C A T I O N • F iv e (5) c o p ie s of r e v is e d la b e lin g , in c lu d in g a n y p rin te d or g ra p h ic m o lt * ' .which m ay a cc o m p a n y the s a le p i t h is product. C o p ie s m ust be c le a r ly le g ib le and id e n tic a l. A t l l O C l l C u v If o c h a n ge in fo rm u la tio n is in v o lv e d , fiv e (5) c o p ie s o f o statem ent or r e v is e d form ula s h o w in g the p r e c is e nam e ond p re ce n to g e o f e a ch a c t iv e end each inert in gre d ie n t, IN ANY C O R R E S P O N D E N C E ON THIS PR O O U C T R E F E R TO R EG IST R A T IO N NO* IN ITEM 4 , ABOV E. (This information is treated confidentially) B WVi,n o pp ro prio te, th ro . (3) copia» of SuppoM Ing Dolo.Attachcd 9 . SIGNATURE OF A U T H O R IZ ED FIRM R E P R E S E N T A T IV E ^r 1 1 , D A TE SIGNED TITLE Sr. Registration S p e c ia lis t P R FORM 9-198 MAT 1969 ftetobac 17 . 1973 - EXISTING STOCK O F PR FORM 9 -1 9 8 (AUG. (9681 W ILL B E USED U N TIL EXH AU STED APPLICANT’SCOPY exhibit c (CONTINUED) Do W o a :;URON registration file including communications with 3 OO ß 1SDA and EPA 1963 - 1974. 30. Application of July 17, 1970 21. Application of November 10, 1964 22. Application of May 15, 1963 23. Application of October 17, 1973 '4. Label of September 19, 1966 and Application of July 12, 1966 25. Label of November 24, 1965 . -5. December 1964 revisions - Florida Sugarcane 2 7. Revisions of early 1964 38. Getzendane.r, RESIDUES OF SILVEX AND SILVEX ESTER IN SUGAR CANE RESULTING FROM AERIAL APPLICATIONS OF KURON' 29. DETERMINATION OF TRACE AMOUNTS OF 2,4,5-TP AND THE PROPYLENE CLYCOL ISOBUTYL ETHER ESTERS OF 2,4,5-TP IN SUGAR CANE PULP (April 9, 1963) 30. A RESIDUE STUDY OF KURON IN SUGAR CANE 31. DETERMINATION OF TRACE AMOUNTS OF 2-(2,4,5-T)-PROPIONIC ACID OF THE PROPYLENE CLYCOL BUTYL ETHER ESTERS OF 2(2,4,5-T)- PROPIONIC ACID IN SUGARCANE PULP (Sept. 24, 1959) 32. DETERMINATION OF TRACE AMOUNTS OF PROPYLENE CLYCOL BUTYL e t h e r e s t e r s o f 2-(2,4,5~ t ) p r o p i o n i c a c i d in s u g a r c a n e JUICE (August 13, 1959) I r ' 16821 USE RECOMMENDATIONS IN S U G A R C A N E 34. COMPARISON OF SILVEX AND DCMU WITH OTHER COMMONLYUSED HERBICIDES FOR PRE-EMERGENCE WEED CONTROL 35. COMPARISON OF SIMAZIN AND OTHER NEWER HERBICIDES FOR PRE-EMERGENCE WEED CONTROL 36 RECOMMENDATIONS FOR JOHNSON GRASS SEEDLING AND JOHNSON GRASS CONTROL IN SUGARCANE by Ernest R. Stamper and S. J. P. Chilton 37. REPORT OF THE DEPARTMENT OF PLANT PATHOLOGY TO THE AMERICAN SUGARCANE LEAGUE FOR 1958 c KURON 7? O W O a 99 3 0 0 33. 16822 HURON specimen labels dated: D i form reserved 96 DOW 1664268 KO.IOVKOLOflV \ND ENVIRONMENTAL SAFETY 4.96-102 (IVb'Ol 97 methodology and data used by the Environmental Protection. Agency in its recent action suspending the use of 2.4,5-T because of the possibility that spontaneous abortion rates increased in the Alsea basin area of Oregon. Dr. Coulston. in his opening comments, stated: The EPA is to be commended for its desire to insure the health of the public by removing any possible environmental hazard. The position of this meeting should not be forgotten. We are here not to judge whether 2.4.J-T is safe for use around man. Or. Barbara Blum. Deputy Administrator of the EPA. in the document of March 1, 1979 presented a number of interesting points: namely, that there was a problem, that according to information the EPA has received that there was an increased incidence of spontaneous abortions in a certain area of Oregon. Dr. Blum emphasized very carefully and I quote "We are not saying that the health efTects_in humans are positively proven, or that 2.4.3-T should never be used again. What we are saying is that there is sufficient evidence to stop further exposure to the chemical until the issues can be resolved." What was the evidence EPA used? Was this good evidence in the sense that it follows good scientific, epidemiologic procedures? Had the EPA acted too quickly? DOW 1 664269 PANEL REPORT The Panel considered the following points: (1) Whether the Control and Study areas were indeed comparable? (2) What was the true spontaneous abortion index? (3) What was the actual individual exposure and what other contaminants may have been present in the Study area? (4) Was the analysis of the data a correlative one and if so. does this relate to causation? (5) What kind of definitive study should be done to settle this controversial problem, namely, did 2,4,5-T indeed increase the spontaneous abortion rates? Available to the Panel were all pertinent reports from the United States as well as foreign countries on the subject of 2,4,5-T and spontaneous abortions. Most of the discussion related to Alsea I and II, but other documents were also considered in light of the experience of other epidemiologists and scientists from different geographic areas. The documents are listed in Appendix I. 2. SUMMARY OF FINDINGS 2.1. A lsea I R epo r t The Alsea I report was based on an extensive health questionnaire administered to nine women who had experienced 13 early spontaneous abortions in the Alsea. Oregon, area from May 1973 to March 1978. In general, the study design was adequate; however, several flaw s characterize the study: (I) A major flaw in the study w'as the failure to define the array of miscarriages that were distributed among the women reporting spontaneous abortions. Therefore, the possibility exists that at least a number of these miscarriages were experienced by miscarriage-prone women. (2) There was no attempt to identify specific causes for any of the miscarriages: for example, exposure to other pollutants and contaminants, advanced maternal age. prior history of abortion, heavy smoking, alcohol use, and chromosomal or morphologic abnormality in the embryo or fetus. (3) There w-as no documentation of exposure to 2.4.5-T. 2.2. A lsea II R eport The Alsea II report was a follow-up to the Alsea I study where it was noted that 12 of the 13 miscarriages reported by the original nine participants were for terms 16828 PANEL REPORT under 20 weeks. In the Alsea II report, the investigators compiled the rates of hospitalized early spontaneous abortions (less than 20 weeks term) in three areas of Oregon: (1) a Study area, which centered around the Alsea basin including additional contiguous areas: (2) a nearby Urban area (Corvallis): and (3) a Control area, a distant inland rural region located in eastern Oregon. Although the objectives of the Alsea II study were valid, the study was poorly conceived and designed. Indeed, even taking into account the aspects of confidentiality and public pressure, the study design was still inherently very weak. Numerous shortcomings, invalidities, and biases characterize the Alsea II study. A number of the most apparent deficiencies are described below. 2.2.1. Collection of Data and Data Input a. Only hospitalized spontaneous abortions were reviewed with no consideration of clinic data. This resulted in a significant bias when one compares the Urban area with the Study and Control areas. Spontaneous abortions were treated in hospitals in the Study and Control areas, whereas in the Urban area they were treated in hospitals and in clinics. The lack of data for abortions treated in the clinics in the Urban area seems to account for the notable difference in the overall spontaneous abortion rates among Study, Control, and Urban areas. b. The investigators of the Alsea II study examined the rates of spontaneous abortions in a Study area and compared those rates in a comparable Control area. In no manner are the Control and Study areas comparable: the Alsea II investigators had not determined whether real differences existed in demographic and geographic characteristics that could affect the rate and seasonal pattern of spontaneous abortions. The two areas are not compatible with regard to socioeconomic and population parameters such as: (1) life-styles: (2) emplpyment practices: (3) ethnic and racial makeup; (4) health care delivery systems: (5) medical practices: (6) environmental pollutants and infectious agents: and (7) additional background factors within the two populations. The demographic characteristics including occupation and ethnic composition may influence the use of medical services between the Study and Control areas, particularly, if related to season, may produce spurious results. More importantly, the Alsea II study had not analyzed the comparability of the Study and Control areas with respect to variables known to be associated with spontaneous abortion, namely, maternal age. cigarette smoking, and alcohol usage. c. The Alsea II investigators intended to compare only those abortions occurring within (he endogenous populations of the Control, Study, and Urban areas. The abortion and/or birth rates may have been significantly altered by the inclusion of abortions of seasonal residents in the Study area, which may experience an influx of population during the summer. The summer transients within the Study area coupled with the exodus of people from the Urban area would maximize me difference in the abortion rate that occurs during the summer months. d. The documented spray areas represented only a small proportion of the Study area, which in turn was defined by zip code. The question which immediately comes to mind is where in the area did the people live in relation to the 2.4,5-T-sprayed areas? Furthermore, the unjustifiability in using zip codes is also apparent when one considers the possibility that a summer transient hospitalized for an abortion in the oiz/?9dTnoG. 98 00W 99 Study area could have given her summer address at the time of hospitalization, and perhaps be classified as a resident of the area. Only those women who were living in the area at the time of spraying could have provided the necessary data base relatively free of variables. e. The Alsea II authors used two types of variables: the effect measure (hospitalized early spontaneous abortions/live births) and exposure data (acres or pounds of 2,4,5-T). As they stated in their report: 16642V! PANEL REPORT Thus, the data from the Alsea basin illustrate a pattern which may be considered as representative of the Study area. The above quote refers to the spray data and represents their justification for extrapolating the pattern of exposure from sampling 2,4,5-T usage in the Alsea basin to the entire Study area. The investigators of the Alsea II study have correlated exposure in a small area with outcomes in a larger area, and it is essential that they discuss how representative the Alsea basin spray data is of the use patterns in the entire Study area. One may question if the amount of 2,4.5-T acreage, and timing of the sprayings are similar; therefore one must know exactly to what extent they may differ. f. There was no attempt by the Alsea II investigators to estimate variability. 2.2.2. Ascertaining Reproductive Effects a. The overall incidence of spontaneous abortions as reported in the Alsea II study was as follows: (a) Study area (8.1%); (b) Control area (6.5%); and (c) Urban area (4.4%, unusually low). In a gener. ; discussion pertaining to the spontaneous abortion rate, it had been stated: We have estimates of the rate of spontaneous abortion (all recognized spontaneous abortions). Take the one good prospective study in Hawaii: maybe estimate that 1/4 of the pregnancies diagnosed after 4 weeks from the last period will abort. The highest we would estimate is that 1/4 of the pregnancies that you know exist at 2 weeks post-conception would abort. People estimate all the way up 10 90% but we think a sensible estimate would be that 1/4 of all recognized pregnancies will abort. It was the consensus of the panel that the hospitalized abortion rates reported in the Alsea II study were low. Estimates of hospitalized spontaneous abortion rates in the United States generally range from about 8 to 15%. It is not known whether this range reflects real differences between populations in the rate of spontaneous abortion or whether it reflects differences in patterns of service use. Estimates of the rate of spontaneous abortion from obstetric histories are usually somewhat higher, ranging from about 12 to 18%. The hospitalized abortion rates reported in the Alsea II study are on the low end of the spectrum when compared to other hospital-based studies. Since spontaneous abortion indicates a strong association with maternal age. evaluation of these rates should consider the maternal age distributions of the populations as well as the possibility of differences in service use as an explanation for the somewhat low rates. b. The study was not based on a cohort of women all concei ving at the same time. The importance in examining the outcomes in a cohort of women conceiving at the same time is that for reproductive health effects (as opposed to other types of 16830 100 PA NE L REPORT C~i effects) the timing of exposure is critical: for example, with radiation the conceptus is sensitive to particular outcomes at some stages of gestation and not at others. c. The gestational age was determined by the date of abortion and in some cases was not well defined. One must distinguish a preconception from a postconception effect, the miscarriage must be analyzed by date of conception or last menstrual period, and not just by date of abortion. The manner in which gestation was estimated varied tremendously from hospital to hospital: therefore, the possibility exists that women may not have conceived at the time of purported exposure to 2.4.5-T. d. The extracted hospitalized spontaneous abortions (HSA) were not identified with individual women: therefore, a small number of chronic aborters in the area could have significantly biased the results. e. The live birth database was collected in a differential fashion between Control, Study, and Urban areas. f. A serious bias was introduced in the computed hospitalized abortion indices (HSAI: HSAl = spontaneous abortion data/weighted live birth data). The weighted live births were derived from gestational ages aggregated over the entire 6 years, these weights were somewhat unrelated to the gestational ages of the monthly spontaneous abortions found in the numerator. The weighted aggregate method would potentially smooth out the denominator data which would make the index more dramatic in monthly peaks. A more serious error is noted in the weighted live birth data (denominator). The authors of the Alsea II report stated, and we quote “The computed monthly births for the six-year interval were divided equally between the two periods." This assumes that the births were relatively stable for all areas over the entire 6 years. The raw data provided by the EPA subsequent to the emergency ban clearly indicate that the above assumption was not valid. The births rise slightly in the Control area during the last 3 years, but more dramatically in the Study area. The equal division of births produces an artificial rise in the HSAI of the Study area for the second period. CO cU {C C TC 2.2.3. Documentation o f Exposure and Exposure Levels The EPA assumed a dose-response effect in the absence of validating exposure. The failure to examine the data with respect to exposure is unfortunate since it is absolutely critical in demonstrating that 2.4.5-T or any other compound was associated with or had caused an increase in the sDontaneous abortion rates. Normally, one. tries to establish the use pattern, occurrence, and the levels of whatever chemical agent is being examined in order to determine a correlation with a biological event. It is very disturbing that the authors of the Alsea II Study had not: a. provided data on human and animal exposure :o 2.4.5-T as well as providing an estimate ot the levels of 2,4,5-T in the aborted pioductx of conception (no attempt was made to determine the individual exposure or to ascertain whether any other contaminantts) was present in the Study area): b. attempted to identify an independent source of data existent, so one could cross-check exposures; c. concentrated on the time relations of the raw number o! abortions in the Study area (the lime exposure is absolutely critical, the data had not been examined in the above manner). 36231 101 3. CONCLUSIONS After reviewing all the documents and the data presented, including the Alsea I and II repons, the Panel expressed the following conclusions: a. The new evidence (Alsea II) did not demonstrate an effect or the absence of an effect. Neither cause nor even association of the use of 2,4,5-T to the incidence of spontaneous abortion had been demonstrated. b. There was no evidence to establish a causal relationship between 2,4,5-T exposure and spontaneous abortion. c. There were no data of individual exposure to 2,4,5-T or to. any other contaminant or pollutant in the Study area. d. With respect to 2,4,5-T exposure and spontaneous abortions, the majority concensus of other panels and expert reviewers of the Alsea II study was that no relationship exists. e. The overall spontaneous abortion rates reported in the Alsea I and II documents (8 to 14%) are well within the background spontaneous abortion rate of the general population. f. The Study and Control areas of Alsea II study were too diverse to be considered comparable. The abortion data for the Urban area cannot be properly compared to the abortion data for the Control and Study areas. In fact, the data base obtained from the Urban area should be dismissed completely. g. Only those women living in the area at tne time of the spraying of 2.4,5-T should have been used for the data base in the Study area (Alsea II study). h. The Panel could not draw valid conclusions from the cluster of 13 cases in the Alsea I study because the data base was derived from a very limited sample size. DOW 1664273 PANEL REPORT 4. RECOMMENDATIONS a. Both the Alsea I and II studies could be made more informative by reanalysis of the data and additional data. Pivotal to such a reanalysis would be the utilization of established cohorts, the uniform definition of gestation age. and the collection of complete spray data. However, even with such improvements a crucial problem would still exist; namely, that the population in the area is too sensitized in connection with collecting additional information. o. A comparison study in another area where 2,4.5-T is known to be used is essential. c. To settle the controversial problem as to whether 2,4.5-T is responsible for spontaneous abortions, and following definitive study is recommended by the Panel: One would design a prospective, long-term, dose-response epidemiological study with a clear understanding of the problem, appropriate modeling, and accessibility and control over the data. A study that goes beyond the level of an ecological study which permits hypotheses to be tested on an individual basis. The study would consist of a sufficiently large cohort of women of reproductive age. with a record of reproductive experience on every single woman in the defined cohort, utilizing reltively simple endpoints to determine reproductive effects. Also, the incorporation of reproductive history by interview of the population in the Study and Control areas that is solid, complete, and unbiased. The reproductive history is the truest estimate of pregnanes' history that can pros ide information os er and 16832 io: PANEL REPORT above that which comes to medicai attention. One would also establish gestational age based on a uniform definition of gestation, establish a baseline level of abortion rate, and acquire a control population that is virtually the same without exposure. Finally, definition of the exposure areas must be established using reliable measures of dosages and exposure. Validation of exposures to 2.4,5-T must be done through blood, urine, fat tissue analyses of the human and animal populations as well as tissue analyses of abortices. APPENDIX I: DOCUMENTS AVAILABLE FOR REVIEW OF 2,4.5-T DATA /. Emergency Action to Slop Spraying o f the Herbicides 2.4.5-T and Silvex, Press Conference Statement by EPA Deputy Administrator Barbara Blum. EPA, Washington D.C. 2. Forest Spra\ \liscarriage Investigations. Alsea, Oregon: Questionnaire Evaluation and Study Plan (Alsea I). EPA. Washington. D.C. 3. Report of Assessment of a Field Investigation of Si.v• Year Spontaneous Abortion Rates In Three Oregon Areas in Relation to Forest. 2.4.S-T Spray Pesticides! Alsea II). EPA. Washington. D.C. 4. Critique of "Report of Assessment o f a Field Investigation of Six- Year Spontaneous Abortion Rates in Three Oregon Areas in Relation to Forest 2.4.S-T Spray Practices." Epidemiological Studies Program. Human Health-Eilects Monitoring Brands. Benefits and Field Studies Division OPD. OTS. EPA. 5. Analysis of EPA Decision to Declare an Emergency Suspension of 2,4.5-T as Related to Studies in Animals, Dow Chemical Co., Midland. Mich. 6. Australian Communique. Press Statement by the Minister of Health. Canberra. Australia. 7. Foster Letter. Office of Disease Monitoring and Control. Department of Human Resources, Health Division. Portland. Ore. 8. Xiswander Review. EPA, Washington. D.C. 9. Slenchever Review, EPA. Wahsington, D.C. 10. Dumey Review. EPA. Washington, D.C. 11. Downs Review. F.PA, Washington. D.C. 12. Laharthe Review, EPA. Washington. D.C. 13. Mantel Review. EPA. Washington. D.C. 14. Bundle Review. EPA. Washington, D.C. 15. Hale Review. EPA, Washington. D.C. IS. Raw Data Provided by EPA on 14 March 1979, Live Births. EPA. Washington. D C. 17. Cook Reviews 15) with Printouts of Spontaneous Abortion Data as Provided by EPA on 14 March 1979. Dow Chemical Co., Midland, Mich. 18. Amended Live Birth Data Provided by EPA Witness (Duncan) on Last Day of Emergency Suspension Hearing—9 April 1979. EPA, Washington. D.C. 19. Cook Review of Amended Live Birth Data, Dow Chemical Co., Midland. Mich. 16833 2 ì ' s ’. j THE DOW-CHEMICAL COMPANY BIOCHEMICAL RESEARCH LABORATORY CHLORACNE STUDY CONDUCTED ON HEXACHLORODIBENZO-p-DIOXIN 2311 .-o í I , .n. ** P .y ■J Z JL fil¿BC T 36,25-84763-3 k5¡0 K84763 CHG. 0 1 2 1 2 - 0 0 0 - 0 2 9 ref . FDA-F9IT A E P o h la n d O A n ilin e 4 REP-T. b y J M N o r r i á ^ j ^ so u r c e su b , by C H E C K E D BY n m vo rti­ co I in (N DATE PJGehrjng 12/11/70 I N F O R M A T I V E SUMMARY WI TH C O N C L U S I O N J - B A S E O ON T H E S A M P L E R E C E I V E D . A O O I T I O N A L I N F O R M A T I O N I N C L U D I N G T h e E F F E C T S O F R E P E A T E D E X P O S U R E MAY B E R E Q U I R E D AS S P E C I F I C U S E S A NO F O R M U L A T I O N S A R E D E V E L O P E D O R I F pr o c ess cha nces o c c u r - A sample of hexachlorodibenzo-p-dioxin (95% pure) was received from A. E. Pohland of the FDA and submitted to the Biochemical Research Laboratory for evaluation as a chloracnegen. • VO m Two 0.005% solutions of the test material, one in dimethoxyethane and the other in chloroform, were" prepared. Each solution was ap­ plied to the inner surface of 3 rabbit ears, 5 days per week for 4 weeks at a dose of 0.1 ml/day. Both test solutions produced chloracne responses. All skin contact with the test material should be avoided. CJ m IA OC tu . 3* 8§ U« o w 31 CO CO ÎO ro CO JL- * DISTRIBUTION CORPORATE J. E. Johnson H. H. Melntyro C. E. Kirnnol L. K. Frovol O.D. Col listar (2) B. E. Burgort H. L. Gordon, MQ E.H . Blair A.J. Schwarz, MD S.M. MocCutchoon 0. Aniline, 1710 Me Z a L c.l ù l FORM 41740 PRINTED RI-70 W E S T E R N D IV IS IO N D.H. Clogg B. H. Lloyd, MD L. Pltchlorlh C. A. Goring Rx PH ARM ACEU TICALS M IDLAND DIVISION V. B. Robinson B. Holdor, MO Don Mors* T E X A S DIVISION D. Kilian, MD J. Barton ds r_rfE5TRICTEb FOR USE OF DOW EMPLOYEES ONLY CRUS) 16835 d (J_jj ( ' 3 4 O DOW CHEM ICAL U.S.A. — " .....fiR 0 u i.ir BENNETT March 21, 1979 B U IL D IN G : 2B3f>ÎC^W, M ID L A N D . M IC H IG A N 48640 ' ■-o i ON. D. STATE DEPARTMENT OF AGRICULTURE || ! (. SUPPLEMENTAL LABELING 2 ,4 , 5 - T AND SILVEX PRODUCTS The enclosed s t i c k e r s are being used on DOW products that are the sub­ j e c t o f the Emergency Suspension Orders by The Environmental P rotection Agency on 2 , 4 , 5 - T and Si 1vex. The Agency has chosen to handle t h i s as a compliance program independent of the in d iv id u a l r e g is t r a t i o n a ctio n s so our conmunication' with you i s to a llo w your f i l e s to r e f l e c t the O most c u rre n t la b e l in g f o r these products. I t i s our in t e n t that the O products l i s t e d below be moved in your S t a te with these s t i c k e r s a p p lie d . •*£ ESTEROrr Brush K i l l e r VEOMK 245 Weed and Brush K i l l e r KUROf!R Brush and Weed K i l l e r * CD Z C3 O K) Dl CZ ^ a\ ESTERON 245 Herbicide VERTONR 2T Herbicide Since only p a r t o f the r e g is t e r e d uses have been suspended, the use of these s t i c k e r s on c o n ta in e rs with non-suspended uses i s intended to • c l a r i f y the s t a t u s o f the remaining accepted uses f o r these products while the Emergency Suspension Order i s in e f f e c t . Th is procedure has been reviewed by the Agency, i s c o n s is t e n t with t h e i r programs, and is being implemented f o r compliance purposes by making s t i c k e r s a v a ila b le to d e a le rs who own sto ck s of these products and p lacing s t i c k e r s on DOW owned sto c k s p r io r to shipment. Vj>4 I -N - O ' «J1 You are undoubtedly aware th a t several a d d it io n a l leg al a ctio n s are underway regarding t h i s Order and the implementation of t h i s program fo r compliance purposes i s not to in d ic a t e t h a t The Dow Chemical Com­ pany has waived any r ig h t s o r recourse to challenge t h i s actio n on the part of the A d m in is t r a t o r . I t i s l i k e l y t h a t leg al a c tio n s w i l l again a l t e r t h i s s u b j e c t in the near fu tu r e . T h is program would a ls o apply to 2 ,4 ,5 - T products r e g is t e r e d to deplete stocks in your S t a t e . I f you have any questions in t h i s m atter, please do not h e s i t a t e to co n ta ct me. S in c e r e ly y o u r s , & A. T. T a l c o t t , Manager Product S a fe ty Compliance Q u ality Assurance jh E n c lo su re s: 2 , 4 , 5 - T and S i l v e x S t i c k e r s EPA Compliance P o lic y AN OPERATING UNIT OF THE OOW CHEMICAL COMPANY 16836 NOTICE The following uses for products containing 2.4.5-T have been suspended by the United States Environmental Protection Agency. All uses in forests, right-of-ways and pastures. Do not apply this product on any of the areas listed above. THE DOW CHEMICAL COMPANY. MIOIANO. Ml UMO o co CP ro / en CJT ro NOTICE The following uses for products containing Silvex have been suspended by the United States Environmental Protection Agency. 1. All uses around the home and recreation areas. 2. All uses in.forests, right-of-ways and pastures. 3. All aquatic uses. Do not apply this product on any of the areas listed above. THE DOW CHEMICAL COMPANY MIDLAND. Ml *36*0 18837 •» 2276 VfleaJus&bu (Snaa___uae-ftgt1& c C cr Stale Warning on 2,4-D Herbicide Exposure issued *T BOWALD B.TATLOB lb the first hazud alert of its kind, the state Department of Health Ser* ileai a •warning th« public today that sp an » to the herfatade 2.4-0 mar causa lasting nerve damage, as wail as cancer or birth defects. The unusual wanting, based on ex­ pert aarmnatlnn of seven persona who tagged nerve damage; is ex­ pected to set off another controversy over the connoted use of soch pbenn ry hartaicidea. Dt Mare Lapp«, chief of the Health Services Department's hazard alert system, said six of the people were exposed while working as pesticide applicators, the seventh waaa woman who knelt down in her garden an sod naked with herUdde. Two weeks after exposure, the sev­ en people reportedly developed tinring or numbness in their toes and fingtn. Mowed by weakness oftheir ansa and lege. Sane suffered “vir­ tually ccmpteia arm and leg paraly­ se.“ Lapp« said. Hernadae tike 2.4-0 and the no» banned 2.4J-T bam been widely used in faresa; on farms and along, pubhe rights of way to till weeds, crush and unwanted trees. In combination, these herbicides were called Agent Orange and were used to den­ ude the jungles of Southeast Asfe during the Vietnam war. Along California's north coast, in PlaaasTun to Page IS, Cal. i a ex Oc HERBICIDE A LER T However. EPA offldaie told The : i-DUfip the previous toxicology data i the timber country ofOregon andthe Times «w(p4an«tt of Homans, groups of was iucrmdusive. tfaat.it neither proved nor disproved anything aad concerned citizen« and doctors con­ the chemical companies'were being tend. 2.4-D Is causing birth defect* asked to do new studies; Such studies and miTjrnig»« amoog women who have been espoeed topesticids sprays. could take horn ana to three years to Lapps said the hazard alert report The timber hamating companies, is behif ses&out to workers and doeby the 05. Forest Service, ton in an effort to warn them that backed that the use of phenazy herbi­ 2.4-D has caused cancers and birth argue are critically needed if timber defects in laboratory animats- and cides harvests are to b e sustained. They nerve damagein humans. 2.4-D is a relatively mild According to Lapps; “Current work contend and that there is no proof it practices (in the forests and on pesticide is harmful to humans when used formal are inadequate to protect ■. P"P*tiy. ; . _ __ a^sim pvmHii neurocosicity.“ Lapp« sail that while affltiatty the hazard alert system was established to went workers of health problems, he was also concerned about home gardeners because one of the seven . victims had been exposed to the her* btide in her zarden. .. Lapp« explained the state wag is- ; ' suing the unusual warning because thesnvironmemai Protection Agen­ cy had foiled to act. He told The Times. “There is a pol­ icy vacuum in EPA. an absence at leadership. So we had tor move on . tha." n 16838 AN EVALUATION OF 2,4-D DATA •j >n O i < Foreward. The phenoxy h e r b ic id e s , in c lu d in g 2 ,4 -D , have re ce iv e d co n sid e ra b le a tte n tio n during th e l a s t decade in t h e ,p r e s s , in p u b lic h earin g s and by groups which have campaigned a g a in st the continued use o f these h e rb ic id e s fo r c o n t r o llin g unwanted ve g e ta tio n in f o r e s t s , on r ig h t s - o f way and on c e r t a in cro p la n d s. The groups a g a in s t the continued use o f « J h e rb ic id e s have sp ent co n sid e ra b le tim e and e f f o r t p rep arin g l i t e r a t u r e , p re ss r e le a s e s , m a ilin g s and in p a r t ic ip a t io n a t p u b lic h e a rin g s. The prim ary message o f th e se groups i s t h a t the use o f phenoxy h e rb ic id e s w ill in c re a s e b ir t h d e fe c ts and cause m is c a r r ia g e s , ca n ce r o r o th er p h y s ic a l ^ CD e f f e c t s . V a rio u s s c i e n t i f i c s t u d ie s as w e ll as a r t i c l e s from the p re ss a re ro CD used to support t h e i r a lle g a t io n s . Very fre q u e n tly o n ly th o se p o rtio n s o f the data in a g iven study which support the a lle g a t io n a re c it e d . The r e lia n c e upon data from s tu d ie s conducted in anim als to estim ate the e f f e c t s in humans has a ls o been debated. However, anim als are the o n ly s p e c ie s p h y lo g e n e t ic a lly c lo s e to humans which can be used f o r t e s t in g . T h e re fo re , i t i s n e c e ssa ry to c o r r e la t e data from animal s t u d ie s w ith the p o te n tia l f o r human exposure under w orst ca se co n d itio n s and d e fin e a sa fe ty fa c to r. In most s t u d ie s on l i v i n g organism s the data a re n e ith e r com pletely p o s it iv e nor co m p letely n e g a tiv e but re q u ire the e x p e rt is e o f knowledgeable s c i e n t i s t s f o r in t e r p r e t a t io n . H e re in , data and c o n c lu sio n s a re subm itted which are intended to p resen t an unbiased review o f the t o x ic o lo g ic a l i^ u u ie s on 2,4-D which have been conducted to d a te . 16839 1. What i s 2,4-D? 2,4-D (2 ,4 -d ic h lo ro p h e n o x y a c e tic a c id ) i s an h e rb icid e which s e l e c t i v e l y and ran g e la n d s, r ig h ts - o f- w a y , and on t u r f and law ns. 2,4-D was f i r s t introduced in the U .S . f o r use by farm ers in 1946 (P e te rso n , 1967). I t performs i t s co n tro l fu n ctio n by a lt e r in g the normal growth o f s u s c e p t ib le weeds and woody p la n t s . The m ajor use o f 2,4-D i s c o n t r o llin g b ro a d le a f weeds in c e r e a l g r a in s . I t does not k i l l most g ra s s e s . M W /249298 c o n tro ls many b ro a d le a f weeds, c e r t a in hardwood tre e s and brush on crop 2 ,4 -D i s u s u a lly a p p lie d a t the r a te o f k to h pound a c t iv e in g re d ie n t p er a c re f o r c e re a l g r a in s . way. 2. H igher r a t e s a re often used on r ig h t s - o f 2,4-D i s u s u a lly form ulated as amine s a l t s o r e s t e r s j How t o x ic i s 2,4 -D to a n im als? 2 .4 - D i s m oderately t o x ic to mammals. The th re e routes o f p o ssib le human exposure a r e : in g e s t io n , dermal c o n ta ct and in h a la t io n . The s in g le dose o ra l LD50 (dose determined to be le t h a l to 50% o f the tre a te d s p e c ie s ) f o r 2,4-D a c id i s g re a te r than 350 mg/kg o f body weight in r a t s , m ice, guinea p ig s and ch ick e n s (NRCC, 1978). In .th ese same sp e c ie s the acute o ra l LD50 f o r v a rio u s fo rm u latio n s o f 2,4-D s a l t s and e s t e r s ranges from 75 to 2000 mg/kg (Weed S cie n ce S o c ie ty o f A m erica, 1979) (IRAC, 1977). In a ca se o f a s u ic id e by a 23 y e a r old stu d e n t, the to ta l amount o f 2 .4 - D in the body was estim ated to correspond to a dose o f 80 mg/kg. (N ie lso n e t a l . , 1965) No adverse e f f e c t s were reported in a man who x. jk 500 mg 2,4-D o r a l l y d a ily fo»- 0 weeks (approxim ately 8 mg/kg/day) (IA RC, 1977). When 2,4-D was used as a treatm ent in a p a tie n t w ith 16840 term inal stag es o f d issem inated co ccid io m y co sis, no sid e e f f e c t s were observed fo llo w in g 18 in traven o u s doses o f 15-37 mg/kg o f body weight over 33 days (Seabury, 1963 in IARC, 1977). Dermal exposure i s perhaps the most freq uent route by which man becomes exposed to 2 ,4 -D . Kay e t a l . (1965) stu d ie d the e f f e c t s o f repeated butyl e s t e r o f 2,4-D on in t a c t and abraded ra b b it abdominal s k in . 249299 sk in a p p lic a tio n o f the dim ethylam ine s a l t , is o o c t y l e s t e r and the Skin a p p lic a t io n o f t e s t m a t e r ia ls , prepared as d ilu t io n s in w ater o r o i l o r both, was made 7 hours p er day, f iv e days p er week f o r th ree weeks w ith no s i g n if i c a n t sy ste m ic e f f e c t s , noted. S k in ab so rp tio n s tu d ie s were conducted on the shaved sk in o f a lb in o r a b b it s . The butyl e s t e r and the diethanolam ine s a l t o f 2,4-D were not absorbed in t o x ic amounts up to 3,980 mg/kg (th e h ig h e st r a te t e s t e d ) . For the butoxy ethanol e s t e r , ^the^ac ^ e sk in absjj£B£ign_LD50 in ra b b its was c a lc u la t e d to be 3980 mg/kg (Unpublished d a ta , The Dow Chemical C o .) --------------------- — • ■ ------ — There have been se v e ra l ca se s reported in the l i t e r a t u r e in which sp ray a p p lic a t o r s and production workers e x h ib ite d v a rio u s symptoms as a r e s u l t o f exposure was dermal c o n t a c t , in h a la tio n o r both. . However, a re ce n t re p o rt (O tt e t a l . 1978 and IARC, 1977) on workers exposed in a m a n u fa c tu -\ rin g p la n t t o 30-40 mg/day o f 2,4-D fo r p eriod s ranging from 0 .5 -2 2 y e a rs in d ic a te d no d if f e r e n c e s in h e alth param eters from a co n tro l group o f w o rkers. Men (248) and women (44) engaged in the manufacture of the amine s a l t or the butyl e s t e r o f 2,4-D w ith exposure p erio d s ranging from under 5 / DOW y e a rs to 6-10 y e a rs ( f o r 194 and 98 persons r e s p e c t f u l l y ) ; were screened /-- — ------ and 63% o f th ese w orkers rnmpl¡lin e d ■ 1249300 headache o r v e r t ig o . n f weakness, rap id f a t ig u e , About 20% had d istu rb a n c e s o f the c a r d io v a s c u la r system (m ain ly hypotension and bradyc a rd ia 1 and o f t he d ig e s t iv e organs - - (d y sp e p tic symptoms and g a str i t i s ) . The v a rio u s l i v e r d y sfu n ctio n s t h a t were found were more pronounced in wor k e r s w ith lo ng er exposures to the ^--- -- --- ---------------------- " h e r b ic id e s . (IA R C , 1977) x * ~ ‘ Feldmann & Maibach (1974) stu d ie d in man the ab so rp tio n through the s k in o f 4yg/cm2 llfC - la b e lle d 2,4-D d is s o lv e d in a sm all amount o f acetone. 1I*C a c t i v i t y was measured in u rin e o ver a 5-day p eriod and compared w ith th a t in u rin e a f t e r i . v . a d m in istra tio n o f the compound : ur in a r y e x c re tio n o f' 2^4-D a f t e r i . v . jadmini s t r a t i on was 100% o f the dose in 120 hour ^ w h ile 'J e x c re tio n a f t e r t o p ic a l a d m in istra tio n was 5.8% o f the dermal dose- Kohli et a l . (1974) ad m in istered 5 mg/kg body weight o f pure 2,4-D in a g e la t in ca p su le w ith w ater to 6 h e a lth y male v o lu n te e rs , aged 22-30 y e a r s ,/ None o f the s u b je c t s complained o f any i l l - e f f e c t s , no changes in blood p r e s s u re , p u lse r a t e , hemoglobin content o r t o t a l o r d i f f e r e n t i a l w hite c e l l counts were o b served . 2,4-D was absorbed f a i r l y r a p id ly . h ig h e st c o n ce n tra tio n in blood was reached in 7-24 ho urs. The In u r in e , 2.4-D was p resen t as e a r ly a s ?...hnnr<: a f f p r in g e s t io n , and more than 75% was ex creted in 96 hours w ithout undergoing tra n sfo rm atio n in the body. In 5 male vo lun teer« given a s in g le o ra l dose o f 5 mg/kg body w e ig h t, the h a l f - l i f e in the plasma was 11.7 h o u rs, and e lim in a tio n in the u rin e 16842 ' occurred w ith a h a l f - l i f e o f 17.7 hours. About 82% was ex creted as such and 12.8% as a conjugate (S a u e rh o ff e t a l . , 1976). DOWJ From the above s tu d ie s i t appears th a t 2 ,4 -0 i s r e a d ily absorbed from the g u t. Some ab so rp tio n through the sk in may o c c u r, but a p p ro p ria te precau­ / and a p p lic a t io n o f the h e rb ic id e . 249 3 01 tio n s w ill ad eq uately m inim ize exposure during the t r a n s f e r r in g , m ixing , Long term s t u d ie s conducted in la b o ra to ry anim als have been evaluated by se v e ra l eminent s c i e n t i f i c groups who have concluded th a t 2,4-D does not cause can cer . In 1969, a Report o f the S e c r e t a r y 's Commission on P e s t ic id e s and T h e ir R e la tio n sh ip to Environm ental Health was p u blished (Mrak, 1969). In th a t re p o rt the s tu d ie s conducted by Innes e t a l (1969) in two s t r a in s o f mice r e c e iv in g 4 6 .4 or 100 mg 2,4-D /kg/day by stomach tube from day 7 to 28 o f age follow ed by in g e stio n o f d ie t co n ta in in g 149 and 323 ppm o f 2,4-D f o r 18 months were review ed. Even under these r ig o r ­ ous c o n d itio n s th e co n clu sio n w as, "2 ,4 -D ich lo ro p h e n o x y a ce tic A cid (2 ,4 -D ) and f iv e compounds c lo s e ly re la t e d to i t s t r u c t u r a l l y were found to be nontum origenic :in the t e s t c ircu m sta n ce s" . The Food and A g r ic u lt u r a l O rg a n iza tio n o f the United Nations World H ealth O rg a n iz a tio n 's Working P a rty o f e x p e rts on p e s t ic id e re sid u e s a ls o reviewed the Innes study and concluded, "There i s no s ig n if ic a n t in c re a s e in tumors between the c o n t r o ls and the groups given the two le v e ls o f 2 ,4 -D " . (FAO/WHO, 1971). 18843 Hansen e t al (1971) adm inistered 2 ,4 -0 in the d ie t s o f r a t s fo r two y e a r s a t 0 , 5 , 25, 125, 625 or 1200 ppm. While the number o f r a t s employed in t h is study would not be adequate by todays sta n d a rd s, the authors concluded DOW J249302 t _?.4-D was not a c a rcin o g e n . A rk ip o r and K o z lo ria (1974) s t a t e th e re was no s ig n if ic a n t in c re a s e in tumors in r a t s o r mice from d ie t a r y o r sk in p a in tin g a d m in istra tio n o f 2 ,4 -D . B jo rk lan d and Erne (1966) adm inistered 2 ,4 -0 in the d rin k in g w ater o f r a t s f o r two y e a rs a t le v e ls up to 1000 ppm and observed no in c re a s e in tumors. 4. Does 2,4 -D cause b ir t h d e fe c ts in humans? T e ra to lo g ic a ! s tu d ie s (stu d y o f b ir t h d e fe c ts ) have been conducted w ith . 2 ,4 - 0 as the a c id and as c e r t a in e s t e r s in r a t s , m ice, ham sters and sheep. There are d if f e r e n c e s among s c i e n t i s t s in d e fin in g t e r a t o lo g ic a ! responses to tre a tm e n ts. In t h i s d is c u s s io n we w i l l c i t e the d e f in it io n s o f the N ational Academy o f S c ie n c e s' (1974) and t h e i r ex p lan a tio n o f each. "Prenat a l development i s d ivid ed in to the embryonic stage ( e a r ly ) when the organs are form ing, and the f e t a l stag e ( l a t e r ) when the org anism i s ma t u r in g d uring gest a t i o n . However, the d iv is io n i s not c le a r - c u t and the p ren atal organism w ill be re fe rre d to in t h is d is c u s s io n as an embryo even i f i t i s t e c h n ic a lly known as a f e t u s ." "An agent o r chem ical i s consid ered as te ra to g e n ic when i t causes develop­ mental d istu rb a n ce s in the embryo r e s u lt in g in co n g en ital m alfo rm ations. I f an agent k i l l s the embryo i t i s sa id to be e m b ry o cid al, and i f i t 16844 produces t is s u e damage (not n e c e s s a r ily r e s u lt in g in m alform ation) i t em bryopathie. The term em bryotoxic w i l l is r e f e r to any harmful e f f e c t on the embryo." of the compound, the route by which i t i s g iv e n , the g e sta tio n a l stag e 1249303 a t which the embryo i s exposed, and the g e n e tic c o n s titu tio n o f the , DOW "The harmful e f f e c t s o f b io ch e m ica lly a c t iv e compounds vary w ith the dose * exposed mother and embryo." "In g e n e r a l, the embryo i s more s e n s it iv e than the mother, and te ra to g e n ic doses a re l i k e l y to be low er than embryopathic doses w hich, in t u rn , are low er than em bryocidal d o ses. However, th e re i s a good deal o f o v e rla p , and much v a r ia t io n in t h is re sp e c t between d if f e r e n t compounds. For in s t a n c e , th alid o m id e i s te ra to g e n ic in pregnant women a t low doses but i s not t o x ic to the mother a t ve ry high d o ses. For many o th e r agents a te ra to g e n ic dose a ls o in c re a s e s the re so rp tio n (embryonic m o r t a lit y ) r a t e , but t h i s i s not always so . S t ill o th e r agents may not be te ra to g e n ic even a t doses th a t k i l l many o f the embryos, a t le a s t in some s p e c ie s . F i n a l l y , th e te ra to g e n ic e f f e c t may vary w ith the route o f a d m in is tr a tio n . Vitam in A, f o r in s t a n c e , may be te ra to g e n ic when given o r a l l y , but i s not when given in tra m u s c u la rly . In g e n e ra l, acute doses are more te ra to g e n ic than c h ro n ic ex p o su re s, p o s s ib ly because repeated exposure a llo w s the form ation (in d u c tio n ) o f enzymes which degrade the p o t e n t ia lly te ra to g e n ic compound. " " I t i s im portant to reco g n ize th a t sp e c ie s d i f f e r w id ely in t h e i r s u s c e p t i­ b ilit y to te ra to g e n s. An o utstanding example i s thalidom ide which i s h ig h ly te ra to g e n ic in man and the New Zealand grey r a b b it , but has only a very low le v e l of t e r a t o g e n ic it y in the mouse and r a t . C o rtiso n e 16845 causes c l e f t p a la te in the mouse and the ra b b it , but not in the r a t . We s t i l l do not know i f i t i s te ra to g e n ic in man. Thus, one cannot e x tra p o la te w ith any assu ran ce from o n e ,sp e c ie s to a n o th er, or even one in man from data on experim ental a n im a ls--o n ly from data on human b e in g s .” mental a n im a ls, p a r t i c u l a r l y ro d e n ts. IMany drugs have demonstrated t e r a to g e n ic it y : 249304 " I t must be emphasized th a t a g re a t many agents are te ra to g e n ic in e x p e ri­ DOW 1 s t r a in to a n o th er, and one cannot rig o ro u s ly prove an agent i s te ra to g e n ic v a rio u s a n t i b i o t i c s , amphetamines, a n tih is ta m in e s , a n tic o n v u ls a n t s , b a r b it u r a t e s , c a f f e i n e , clomiphene, c y c l i z i n e , LSD, th a lid o m id e , to lb u tam id e, and v a rio u s tran q u i l i z e r s . M etals (cadmium, c a lc iu m , le a d , m ercury)’, hormones (ACTH, a d re n a lin , androgenic hormones, a n tio v u la t o r y compounds, e s tro g e n s , g lu c o s t e r o id s , i n s u l in , s e r o t o n in ), * , and se v e ra l o th e r k in d s o f ch e m ical, p h y s io lo g ic a l, and environm ental agents (m aternal d eh y d ra tio n , maternal s t r e s s , carbon monoxide, n o is e , and hypoxia) have a ls o been shown to be te ra to g e n ic in la b o ra to ry a n im a ls. For s e v e ra l o f these there i s good evidence o f low o r no t e r a t o g e n ic it y in man ( e . g . , c y c l i z i n e ) , but f o r most o f them the p o s s i b i l i t y o f low l e v e ls o f t e r a t o g e n ic it y has not been ruleand i t would be very d i f f i c u l t to do so . )u t, Only f iv e have been c l e a r l y im p lica te d as humans terato g en s (d ip h en ylh yd an to in , androgenic p r o g e s t in s , o rg a n ic m ercury, r a d ia t io n , and th a lid o m id e )" (NAS, 1974). "Much le s s work has been done on the t e r a t o g e n ic it y o f 2 ,4 -D . One study ( B io n e t ic s S tu d y, see Mrak R ep o rt, 1969) suggested th at the b u t y l, i sopropyl and is n n c t v l e s t e r s o f 2,4-D may be teratogens o f low pote n cy . Schwetz e t a l . (1971). f i n i n g tho f r CO p|r -jH propylene g lyco l butyl e th e r e s t e r and the is o o c t y l e s t e r a t le v e ls up to 8 7 .5 mg/kg/day— 16846 the maximum tolerated level— on day 6-15 of pregnancy, found symptoms of em b ryo to xicity (edema, delayed o s s i f i c a t i o n , e t c . ) but no genuine t e r a t o 1 lo g ic a l e f f e c t s in r a t s even a t the h ig h e st dose. The h ig h e st le v e ls of --------■ ■ ■' /. ~ " ' -- » ■■■ - — ' — - ■ — ■ " ty and la c t a t io n in the mothers but had. no e f f e c t on the growth and development of the o f f s p r in g . —I Khera and M cKinley (1 9 7 2 ), working a ls o w ith r a t s and using fo u r samples o f 2,4-D and one . i each o f the b u t y l, i s o o c t y l, butoxyeth ano l, and dim ethylam ine d r i v a t i v e s , DOW 1 2 4 9 3 0 5 the e s t e r s decreased v ia b il — found s im ila r a b n o rm a litie s as in t h e i r experim ents w ith 2 ,4 ,5 - T and d e r iv a t iv e s , a t th e same dose le v e ls (100 mg/kg and ab o ve). C o llin s and W illiam s (1971) found in the progeny o f ham sters tre a te d w ith th ree samples o f 2,4-D some in c re a s e in m alform ations but th e re was no dosee f f e c t r e la t io n s h ip and the d iff e r e n c e s were not s t a t i s t i c a l l y s i g n i f i c a n t . 11 "An agent may be consid ered a potent teratog en i f i t has t e r a t o lo g ic a ! le v e ls f a r below the dose le v e ls th a t are le t h a ly t o x ic to the mother. By t h i s c r it e r io n 2,4-D would be consid ered to be a r a t h e r weak teratog en in experim ental a n im a ls. In view o f wide d iff e r e n c e s between sp e c ie s in te ra to g e n ic s u s e p t i b i l i t y , one cannot e x tra p o la te t e r a t o lo g ic a ! r e s u lt s from exp erim entáis anim als to man." (N .A .S . 1974) 16847 Is 2 ,4 -0 a Mutagen? F i r s t , a mutagen i s a m a te ria l th a t i s capable o f producing g en etic damage which can be in h e r it e d by fu tu re g e n e ra tio n s. evaluated in a number o f m u ta g e n icity s t u d ie s . 2,4-D has been I t has been demonstrated th a t 2 ,4 -0 i s not~a mutagen in a v a r ie t y o f m icro b ial s t u d ie s as w ell as in male f r u i t f l i e s (D ro sp h ila m elan o q aster) . 1974). (1972) found th a t a t o t a l o f 75 mg o f 2,4-D/kg o f E p ste in e t a l (Vogel - C h an d ler, body w eight given o ver a f iv e day period did not in c re a s e dominant le t h a l r m utations in m ice. Treatm ent o f in v it r o c u ltu re d human lym phocytes w ith 0.0 2 mg/ml. 2,4-D in cre a se d th e number o f chrom atid a b e rra tio n s and to a l e s s e r e x s te n t, chromosomal a b e r r a t io n s . In m ice, t o x ic co n ce n tra tio n s (100-300 mg/kg/body w eight) o f 2,4-D ad m in istered as a s in g le o ra l dose s i g n i f i c a n t l y in cre a se d the frequency o f a b e rra n t metaphases (2 -4 f o ld ) in lym phocytes; s in g le fragments were the prim ary a b e rra tio n ( P ilin s k a y a , 1974, c it e d in IARC, 1 9 7 7 ). 2,4-D had no e f f e c t on c u ltu re d c e l l s nor on bone marrow a f t e r i t s o ra l a d m in istra tio n to r a t s ( S t y l e s , 1973 c it e d in IARC, 1977). There was no in c re a s e in the m icro n u cle i in e ry th ro c y te s o f mouse bone marrow a f t e r in je c t io n o f 100 mg 2,4-D /kg/body w eig h t. Exam ination o f chromosones o f w orkers employed in the production o f 2,4-D in d ic a te d no changes (Johnson, 1971). The Royal Swedish Academy o f S c ie n c e s arranged a co n feren ce in Stockholm in F e b ru a ry , 1977 o rg an ized in to f iv e working groups com prising c h e m istry , p la n t p h y sio lo g y , t o x ic o lo g y , g e n e t ic s , and ecolo gy w ith econom ics. The co n clu sio n reached by the group o f in t e r n a t io n a l e x p e rts reg ard ing the m u ta g e n icity o f the phenoxy h e rb ic id e s was as f o llo w s . 16848 "The only s t a t i s t i c a l l y s i g n if i c a n t dem onstration that phenoxy a cid s induce m utations t r a n s m is s ib le to the o ffs p rin g was obtained in the r e c e s s iv e le t h a l t e s t in D roso phila m elan o g aster. Work on m icroorgan- / the t e s t c o n d itio n s used. DOW 1 2 4 9 3 0 7 isms s u s t a in s the co n clu sio n th a t the phenoxy a c id s are mutagenic under Two in v e s t ig a t io n s on 2 ,4 ,5 - T and one on 2 ,4 -D , both using pure a c id s , showed an in cre a se d number c f r e c e s s iv e le t h a ls in D ro so p h ila . From a t e n t a t iv e comparison o f the ra d ia tio n % J dose th a t would g iv e a s im ila r e f f e c t ,_ t h e mutagenic e f f e c t s o f 2 ,4 ,5 - T and 2,4-D were concluded to be weak. Som atic m utations have been observed in D ro so p h ila , and chromosomal a b e rra tio n s have been shown to be induced in p la n ts and mammals. The re le v a n ce o f th e se l a t t e r fin d in g s to a r i s k o f mutation from phenoxy a c id s (a s s o c ia te d o r not w ith h e r it a b le damage) re q u ire s f u rt h e r s t u d ie s . O bservation in one stud y o f a p o s s ib le r o le o f the e m u ls if ie r and/or s o lv e n t show the n e c e s s it y o f in c lu d in g th ese c o n s titu e n ts o f phenoxy a c id fo rm u la tio n s in fu tu re s t u d ie s ." 6. (Ramel, C . 1977). Are th e re " d io x in s" in 2 ,4 -D ? The g e n e ric term "d io x in " i s o ften used in c o r r e c t ly to d esig n ate one member o f the f a m ily , 2 ,3 ,7 ,8 te tra c h lo ro d ib e n z o -p -d io x in (TCDD). There a re 75 p o s s ib le p o ly c h lo rin a te d b en zo -p -d io xin s w ith a m illio n fo ld spread in the dosage le v e l re q u ire d to k i l l la b o ra to ry a n im a ls. Trace amounts o f p o ly c h lo rin a te d d ib e n zo -p -d io x in s can be formed during the m anufacture o f ch lo ro p h en o ls under a lk a lin e c o n d itio n s a t elev ated tem peratures and high p re s s u re . Trace amounts o f the h ig h ly t o x ic TCDD a re formed during the m anufacture o f 2 ,4 ,5 - t r ic h lo r o p h e n o l by a lk a lin e ■16849 h y d ro ly s is o f 1 ,2 ,4 ,5 te tra ch lo ro b e n ze n e . Any TCDD so formed can be c a r r ie d through in to products made from 2 ,4 ,5 - t r ic h lo r o p h e n o l, such as 2 ,4 ,5 No TCDD i s found ------ ----------- in 2,4-D (Ram el, C. 1977). v--------------------- 2 .4 - d ich lo ro p h en ate under th e a c id co n d itio n s used in i t s manufacture by c h lo rin a tio n o f phenol. 249308 The expected 2 ,7 -d ic h lo ro iso m e r i s not formed by condensation o f DOW 1 tric h lo ro p h e n o x y a c e tic a c id ( 2 ,4 ,5 - T ) and hexachlorophene. Of 28 samples o f 2,4-D te ste d f o r content o f c h lo ro d ib e n z o -p a ra -d io x in s, one was reported to contain le s s than 10 mg/kg (/of7f/H h exachlorod ibenzo-p- d io x in . 7. (Woolson e t a l 1972, c it e d in IARC, 1977) What E f f e c t Does 2,4-D Have on The Environment? The environment i s composed o f many compartments in c lu d in g s o i l , a i r , w a te r, man, b ir d s , a n im a ls, p la n ts and i n s e c t s , e t c . 2 ,4 -D , when used as d ire c te d on the l a b e l , e x e rts i t s e f f e c t on a s e le c t p o rtio n o f the p la n ts in the environm ent. A p p lic a tio n o f 2,4-D by means o f sp ra y in g , e it h e r by ground o r a i r , p ro vid es the p o te n tia l f o r contam ination o f the o th er compartments. Fa te in S o il In s o i l , in the presence o f m o istu re , even a t low l e v e l s , the e s t e r s o f 2 .4 - D a re hydrolyzed to the a c id form. The p e r s is te n c e o f the is o o c ty l e s t e r of 2,4-D was stu d ie d under f i e l d co n d itio n s by B u rca r et a l . (1966, c it e d in NRCC 1978) who noted the complete breakdown o f the e s t e r to the a c id in two weeks.. The fre e a c id s a ls o have a r e l a t i v e l y 16850 sh o rt l i f e in s o i l . Klingman (1961) s t a t e s th a t when used a t normal r a t e s , from 0 .5 to 3 Ib / a c r e , 2,4-D d isa p p e a rs from s o il in 2,4-D breakdown. DOW 1 2 4 9 3 0 9 M icro b ial degradation a ls o p la y s a s i g n if i c a n t r o ll in 4 . to 5 weeks. I t has been shown th a t repeated use o f an a g r ic u lt u r a l chem ical i s l i k e l y to in c re a s e the populatio n o f s o il m icrobes which can degrade i t . 2,4-D does not b u ild up in the s o i l , and treatm ents can be ap p lied to * . cropland y e a r a f t e r y e a r w ith out accu m u latio n . Fa te in Water D e te ctab le re s id u e s o f 2,4-D do not appear in su rfa ce w aters u n le ss i t i s added d i r e c t l y to the w a te r o r f a l l s th e re in c id e n ta l to spraying a d ja ce n t a re a s. In p r a c t ic e , re sid u e s in stream s o r la k e s r e s u lt in g from range and f o r e s t uses a re le s s than 0.1 ppm (Newton and Norgren, 1977). In the United S t a te s the maximum p e rm is s ib le co n ce n tra tio n o f 2,4-D in w ater which i s used f o r p u b lic su p p lie s i s only 0.1 ppm. Once intro duced in w a te r, 2,4-D undergoes r e l a t i v e l y rap id decom position. In 1971 over 7,000 a c re s in the Loxahatchee N ational W ild lif e Refuge, F lo r id a were sprayed w ith the a c id e q u iv a le n t o f 4 pounds 2,4-D per a cre to co n tro l w a ter h y a c in th . The h ig h e st 2,4-D re sid u e le v e l measured in w ater was 0.037 m g / lit e r found on the day a f t e r tre a tm e n t.. The h ig h e st le v e ls in h y d ro so l, 0.005 mg/kg, o ccurred 3 to 15 days a f t e r treatm en t. M u lliso n (1970) has review 150 s tu d ie s .o n the E f f e c t s o f H e rb icid e s on Water and I t s In h a b it a n t s . down in w ater q u ite r a p id ly . T h is review dem onstrates th a t 2,4-D breaks The r a te o f breakdown i s dependent upon 16351 tem perature, pH, presence o f org an ic m a tte r, s u n lig h t and m icro b ial f lo r a . At the la b e le d r a t e s o f a p p lic a t io n , 2,4-D would not be d etected in most a q u a tic environm ents 30 days a f t e r in t ro d u c t io n . HOW 1 2 4 9 3 1 0 T o x ic it y s t u d ie s w ith f is h have been review ed by M ullison (1 9 7 0 ). In g e n e ra l, under n a tu ra l co n d itio n s most f i s h sp e c ie s can t o le r a t e 2 ppm 2 ,4 - 0 . Sp rayin g 5 pounds 2,4-D per a c re in w ater about one fo o t deep would approxim ate 2 ppm. Under n a tu ra l c o n d itio n s f is h could u s u a lly swim away from a re a s o f high c o n c e n tra tio n s . Fate in A ir Form ulations o f 2,4-D are a p p lie d as aqueous em ulsions o r s o lu tio n s in o i l s by ground sp ra y e rs o r by a i r c r a f t . During a p p lic a t io n , some o f th e m a te ria l may d r i f t from the t a r g e t s i t e before being in te rc e p te d by the t a r g e t . The q u a n tity which may d r i f t i s dependent upon d ro p le t s i z e , wind v e lo c i t y , tem perature and h u m id ity , v is c o s it y o f the formu­ l a t i o n , d is ta n c e from a p p lic a t o r to t a r g e t , and perhaps the most im portant f a c t o r , the p re ca u tio n s e x e rc ise d by the in d iv id u a ls perform ing the a p p lic a t io n acco rd in g to the l a b e l . 2,4-D fo rm u la tio n s d i f f e r in t h e i r r a t e o f v o l a t i l i z a t i o n from the t a r g e t su rfa ce . The amine s a l t s a re l e s s v o l a t i l e than the e s t e r s . Proper s e le c t io n o f th e fo rm u latio n and o b se rv a tio n o f the c lim a t ic c o n d itio n s recommended on the la b e l can m inim ize v o l a t i l i z a t i o n from the ta rg e t s i t e to a d ja c e n t a re a s where damage may o c c u r. IS 8 5 2 req uired on the l a b e l . s tu d ie s in c lu d e : Subchronic o r le s s than one h a lf the lif e t im e 90 day d ie t a r y in r a t s , s i x month d ie t a r y in dogs, metabolism in two s p e c ie s . Chronic ( e s s e n t i a l l y lif e t im e ) d ie t a r y s tu d ie s a re conducted in r a t s and mice to determ ine a no e f f e c t le v e l DOW 1 t e r a t o g e n ic it y in two s p e c ie s , two generation rep ro d uctio n in r a t s and producing) e f f e c t s . - These comprehensive s t u d ie s re q u ir e a t l e a s t fo u r 249311 to a s s i s t in e s t a b lis h in g to le ra n c e le v e ls and p o s s ib le oncogenic (tumor y e a r s to com plete. During t h i s same tim e p eriod samples of the t a r g e t crop which has been tre a te d w ith the chem ical a t the maximum la b e l r a t e a re c o lle c t e d from v a rio u s geographical a rea s and analyzed f o r p o s s ib le r e s id u e s . R esidue s t u d ie s a re a ls o conducted in cows and ch ick e n s to determ ine i f re sid u e s which might be p re se n t in the food o f these anim als i s c a r r ie d in to m eat, m ilk o r eggs which humans might consume. The EPA then e v a lu a te s th ese data tog ether w ith the data which d e sc rib e the fa te , and e f f e c t s in the environment and o n ly a f t e r d e t a ile d a n a ly s is may grant * Residue to le r a n c e . The to le ra n c e g ra n tin g procedure i s very d e t a ile d and not taken l i g h t l y by the EPA nor the in d u s t r y . By the time a to le ra n c e i s granted an ex cess o f f iv e y e a rs have ela p sed s in c e the i n i t i a l data g a th e rin g . There may be t r a c e q u a n t it ie s o f 2,4-D in the food we e a t but an e x te n siv e review o f the data a ssu re s us i t i s a q u a n tity which w i l l not cause harm. The FDA market b aske t samples fo r 1974-1975 (PEMJJAA) which a re comprised o f c o lle c t io n s in 20 c i t i e s which range in pop: ' ' ions from le s s than 50,000 to more than one m illio n showed no re sid u e s o f ch lo ro p h en o x ya cid s. The study o f the ca rcin o g e n ic Vop. Pi t a n . , 5_, 8384. B jd rk lu n d , N .- E . a E rn e , K. (1966) T o x ic o lo g ic a l stu d ie s o f phenoxya c e t ic h e rb ic id e s in a n im a ls. A cta v e t, s c a n d ., 7 _ , 364390. C o l l i n s , T .F . X . & W illia m s , C .H . (1971) T era to g en ic stu d ie s w ith 2 ,4 ,5 T and 2,4-D in the ham ster. B u l l , environm : Contam. T o x ic o l., 6 , 559567. ~ 5 ~ FA0/WH0, 1971. 1970 E v a lu a tio n s o f Some P e s t ic id e Residues in Food, AGP: 1970/M /l2 /1 . Monograph. IARC, 1977 - In t e r n a tio n a l Agency f o r Research on Cancer Monographs on the E v a lu a tio n o f the C a rcin o g e n ic R isk o f Chem icals to Man, V o l. 15, A ugust, 1977. Johnson, J . E . (1971) The p u b lic h e a lth im p lic a tio n s o f w idespread use o f the phenoxy h e rb ic id e s and p iclo ra m . B io s c ie n c e , 2 1 , 899905. Kay, J . H . , e t a l (1965) H ealth - Vol I I , . Nov. Subacute Dermal T o x ic it y o f 2,4D . A rch . E n v iro n . K hera, K .S . & M cK in ley, W.P. (1972) P re - and p o stn a tal s tu d ie s on 2 ,4 ,5 - t r ic h lo r o p h e n o x y a c e t ic a c id , 2 ,4 -d ic h lo rp h e n o x y a c e tic a c id and t h e i r d e r iv a t iv e in r a t s . T o x ic o l, a p p l. Pharm acol. , 2 2 , 14-28. Klingm an, G .C . (1961) Weed Control as a S c ie n c e . W ile y , New York. Mrak, E .M ., chairm an , 1969. Report o f the S e c r e t a r y 's Commission on p e s t ic id e s and t h e i r r e la t io n s h ip to environm ental h e a lth . Dept, of H e a lth , Ed ucation and W e lfa re , Government P rin t in g O f f ic e , Washington, D .C. M u llis o n , W.R. 1970. The s ig n if ic a n c e o f h e rb ic id e s to nontarg et organ­ ism s. P ro c. 24th Annual M eeting, N o rtheast Weed Control C o n f ., pp. 111147. N ational Academy o f S c ie n c e s , U .S .A . (1 9 7 4 ). Committee on the E f f e c t s o f h e rb ic id e s in Vietnam . The E f f e c t s o f H e rb icid e s in South Vietnam . P a rt A. Summary and C o n clu sio n s. Newton, M ., and Norgren, J .A . (1977) S i l v i c u l t u r a l chem icals and pro­ te c tio n o f w ater q u a lit y . U .S . Environm ental P ro te ctio n Agency Rpt. 910/977036. N ielso n e t a I . (1965) F a ta l P oisoning in Man by 2,4-d ich lo ro p h en o xy a c e t ic a c id ( 2 ,4 - D ) : d eterm in atio n o f the Agent in F o re n sic m a t e r ia ls . Acta Pharm acol. T o x i c o l . , 2 2 , 224-234. f DOW 1 249312 A rkhipov, G.N. & K o slo v a , I.N . (1974) p ro p e rtie s o f the amine s a l t o f 2 ,4D . MRCC, 1978. Phenoxy Herbicides - Their E ffe c ts on Environmental Quality. 'N a tio n a l Research Council Canada No. 16075. PEMJJAA - 1977, P e s t ic id e and Other Chemical Residues in Total D iet Samples ( X I) P e s t ic id e Monitory J o u r n a l, V o l. I I , No. 3. The D isco very and Development of 2 ,4 -D . A g r ic . i S a u e rh o ff, M.W. e t a l . 1976. The Fa te o f 2,4-D ich lorp henoxy A cid (2 ,4 D) Follow ing Oral Admi ni s t r a t i on to Man. T o x ic o l. Appl. P h arm aco l., 37, 136-137. 249313 Ramel, C. 1977, C h lo rin a te d Phenoxy A cid s and T h e ir D io x in s, E c o lo g ic a l B u lle t in s No. 27. Report from a conference arranged by the Royal Swedish Academy o f S c ie n c e s , Stockholm , Sweden, 7-9 February 1977. DOW I P e te rso n , 6 .E . 1967. H is t . 41: 243-253. Schw etz, B .A ., S p a rsch u , G .L . & G eh ring , P . J . (1971) The e f f e c t o f 2 ,4 d ich lo ro p h e n o x y a ce tic a c id (2 ,4 -D ) and e s t e r s of 2,4D on r a t embryonal, fo e ta l and neonatal growth and development. Fe Cosmet. T o x i c o l ., 9 , 801-817. Weed S cie n ce S o c ie t y o f A m erica, 1979, H e rb icid e Handbook, 4th ed. 16855 O 3.^0 DOW J BIOCHEMICAL R ESEARCH DEP ARTMENT THE DOW CHEM ICAL O COMPANY DATA SHEET OF PROPERTIES, HEALTH HAZARDS, AND PRECAUTIONS CO O FOR SAFE HANDLING OF MATERIALS O M ID LA N D M O LECU LA R FORMULA M ICH IGAN CHEM ICAL NAME M-2121 M O LECU LAR WEIGHT INDUSTRIAL H YGIEN E STANDARD SYNONYMS S T R U C TU R A L FORMULA - OR COMPOSITION 25% 2 8 .5% 46.5% Silvex acid Silvex, Potassium salt 8/15 AA RVM Attaclay to contain 50% Silvex equ. BOILING POINT •C E X P L O S IV E LIM ITS f * B Y V O L. IN A IR ) mwH«. FLA SH POINT IGNITION TEM P. M ELTING POINT •c •f. CORROSIVENESS (T s C m « « Urtale) VAFOR P R E U U R C — Ha 2 J*C •c P H Y SIC A L S T A T E COLOR solid white ODOR (iMclud* C m c b w w I m la Air) CHEMICAL R E A C T IV IT Y ess., none S T A R IL IT T ( T . ,H O . » . . , H n , L l^ » | TYPE OF CONTACT EYE CLASSIFICATION OF TOXIC PROPERTIES May c a u e ao n i p e o i e or ao a m than m y slig h t to slig h t transitory pain so d /o r s lig h t tr a n s ie n t c a ra c a l in ju ry a a d /o r irrita tio n o f th e e y e lid s . □ May caoae id f i c ic o t injury to the eye to re soli ia lo s s of tia e (to o work. (T his iaclu d es damage to the cornea which h ea ls or oeaxljr heals ia s week s a d /o r coasiderah lc conjunctival in ita tio a w irb p H r in « ^ B SKIN _ Single proloaged exposure way caoae some reddening of the skin. po ssib ly s wild burn s a d /a r way ca u se ap preciable system ic iiijiiy due to absorption. DUST OR MIST I VAPOR □ □ □ □ No syeccw ic injury expected. No irricatioo co a o se aad throat ia dusty or w isry atm ospheres. T hroat aad a o se icritatioo ia a dusty or m isty atm osphere is painful btx aoc intolerable a a d /o r prolonged or rep eated e r posurcs may cao ae system ic injury. E xposures do ncc ca u se any effec ts oebet than some very slig h t tsitacio o or pain to the eyes or respirato ry p a s s a g e s at the most Single exposures exceeding 1/2 boar, or frequently repeated e r p o sares of shorter duration, may ca u se slig h t aaestfaesia an d/bt alight system ic injury, a a d /o r ca u se ap p reciab le, bte ooc iato lersb lc, isriratioa of respiratory p a s s a g e s . □ INGESTION m May c so se some perm anent lo se of v isio n (th is ia d a d e s damage to cocoes or ia ieraa l iajory which is incom pletely h ea led ia a e w eek.) Vapor exposure way cao ae sev ere pwta, lacrym acioa or seriows iajtv y to the ey es. -------------------------- Siagle proloaged expos ure (hours) c a u se s oo c i f c c t Several repeated prolonged cxposorca way or a i y nor cau se cbe develop’ we or of s o a r alight irritation. Ê ) R epeated prolonged co n tacts way ca u se appreciable irritation, S A. U X O P- □ □ □ □ □ □ □ □ Single abort expo«ore (minores) may c a u se co n sid erab le trrixwòoa a a d /o r sin g le proloaged er frequently rep eated abort expo«ores c a u se a b u n a a d /o r way ca u se sy stem ic injury, even d eath. Ao esp o sare rapidly c a n se s s e r e te h u u a a d /o r serio u s syseemic injury, even d ea th . D usty or m isty atm osphere painful ta uose aad throat (intolerable to moat peo p le) a a d /o r exposure smy c a u se serio u s system ic injury. S h an esp o sare (m iaates) may c a u se death or serio u s system ic injury. E sp eso res may cau se extreme ^ o w s ia e s a , a a d /o r seriomv sysrem ic iajury, aa d /o r may c a u se in to lera b le itricarioa te th r respirasary p o ssa g es. Shoct e sp o sares c-xy csao e uncoacioesw esa, s a d /o r serió o s syscew ic iajury, i w l 'd i a i A a t k Even eery short exponía« w ill cau se scriou» system ic injury or d eath. Amouots which may be swallow ed incidenta l to industrial hand Uag w ill nor cau se injury. □ Amounts which m«y be swallow ed incid en tal re in d u strial h ard i in g aad c t e may cau se i r r i s a iaju ry . XMMENTS (1) Applies when wet and confined under a bandage 16856 K PRECAUTIONS (SEE CODE BELOW) INHALATION* m if T nm VAPOR '"«1ST EYES 1 NO CONTACT C haracterised by remote operation with cquipmeoc iso la ted from th e work area. T h e p erro n s enter­ ing iso lated areas w ill require th e personal protection outlined for IV below. II MINOR CONTACT Q u a c t c u i t d by closed system s with equipment vented o u tsid e the work area; instrum ent control; mechanical handling of m aterials i s bulk. Exam ples are; continuous reacto r« , s tills and filters; enclosed conveyors; veotilaceu packaging. III OCCASIONAL C haracterised by manual handling of m aterials in p ac k ag es such a s b ag sydrums and fiberpnka. DAILY CONTACTS V cntiiauoo may be provided for sp ecific jo b s. Many b atch o p erations fall in to th is category. IV GROSS CONTACT LIKELY % ' r C haracterised by hand operation. Exam ples ares Em ergency rep airs, cleaning cquipmeoc, cleaning filte rs, taking care of s p ills , packaging v o la tile or dusty m aterials without ven tilatio n , wheeling and tray drying. A No eye protection M t d e i EY E CONTACT B U ae safety|1 umi «ichoat aide INGES7ÍÜN A A A A A A A A A B A U L * D U se chem ical workera goggles. abielda. E U se g s s dghc goggles or s full face g a s s a d . C Uae safety g laa s e a with side sh ield s. A SKIN** A bach and clean cloches ooce p er week a lo o f with the usual v u h i f l | ax mealtim es a bo old be adequate precautions. G rossly contam inated clothing aod sh o es m ost be removed nor later fi th a a th e cad a4 the work period so d m ost be thoroughly clean ed before re-aac. CONTACT _ Require s b o v o sx che cad of th e work period aod clcao clothing from ** che »H" m the s ta rt of each work day. DUST 0 tins toMod DEGREES OF EXPOSURE RELATED TO TY PES O r OPERATION O o th ia g should b e changed sad skin w ashed promptly upon any detectable con tact. Each u se w ill require sp ecial c o o tid e rs d o a to determine suit­ able p ro tectiv e devices sad standards of p erso n al c lean lin ess. Impervious clothing such s s rub b e r b oots, n ¿ b c r aprons, sad rubber E g lo v es w ill be required. S pecific item s will b e dies seed a s required by circum stance. No respiratory protection. Any exposure to obviously dusty atnioapbcres w ill require a dust reap»0 rater bearing the approval of th e U- 5 . B ureau o f Mice* for use with toxic o u sts. No protection required for expo sore of th irty mia. daracioo o r le s a co obviously dasry atm osphères. E xpoeorcs of longer d o rad o s w ill require che oac of a dust respirator bearing che approval of th e U- S. B uresu of N ines for th e use with to x ic d u sts. Any exposure *» duary atm ospheres will require th e e s c of an airline E resp irato r, blower mask, or Cbemox mask. OR MIST : < £ A No precautions n ecessary . B VAPOR No precautions A ccessary for sin g le exposures of le s s chan 1 /2 hour. Longer single c l o s u r e s , or frequently repeated exposures will require a g s s mask or respirator equipped with appropriate ca n ister. No precato io o a ac cessa ry for sin g le ex p o su res of no more chan tea minutes. Longer exposures citb et sin g le o* repeated, w ill require g as su n k or resp irato r equipped arich a^ivoprince ca n ister. 0 G as mask with appropriate c a n ister required a t a ll tim es. £ E v acuate area a t once and e s te r only with airlin e n a pit a u r , blower mask or Cbemox m ask. INGESTION COMMENTS . A No unusual procedures required. Food aod tobacco should not b e p resent in the work area. H ands aod face should be w ashed before smoking aod eating. »SUITACLE GAS MASK CANISTER GOOD PRACTICE REQUIRES THAT GROSS AMOUNTS OF ANY CHEMICAL BE REMOVED FROM THE SKIN AS SOON AS IS PRACTICAL dust respirator (l) Avoid confining to the surface particularly if moist or wet. 16857 SIGNED DATE P.0. K. J.O 12 27-61 - CHECKED DATE H.R.Hoyle *\ ~r 2 U i : w •4 4.^-1 js • & v; 1. C3 v fs■>'••••- i s 'Y T $ r k* • • * V ;. y HEH23. 1*1-11-2(3) *a :*k . ::■•! • . S-i • INDEX NO. i -ii oo CD'. - s i' ■ */ ; ; • v "• . ♦; 'V r.> •T . £ - T^. .•••# ... i .„ r S • 'l i -T ; i ... v ■ :r«r..*.»Vi--1, ... i7>;h v .r ..V..-.- :}r. f ‘ *. »r-* 1 ■4 . . i. •£» > i-? • 'v4 v - ■■■'■ 4' ■■ ■ . .; ’.W. ^ ^ r ¿\ /i » J .. *",s -;-•' ; •.* V;. • yi . h-. v. :I ¡•r a i •'•. ?■ . - i'. i . V.V- • ' \: i* ' ? r'.: . ^T-.r — 7-.V. r t•*” vv -i ■ ~ ' •• k '--"lit ^ '.-L- ti.fy ~ y ■. vi ; - - 'j ■ 'V . I;: -i. , ■ -i:.v5- ..■•■- .'.2 ^ •■ v . • . ■ , ■• *^ •» * ' '■¡i ;■» v.i . •'. -5. > • ••• ,-r- ^ j ' ' :l ■ x /. . > '*. .• in o v t .. : ■ ic’ . . ' ■ •> »• -- <7 4 9053 — ru r -'fi '' -V r ■ R. W. Bohl o r in J* * **;J - A u th o r: COMPREHENSIVE SURVEY OF EMPLOYEES* EXPOSURE TO AIRBORNE CONTAMINANTS IN THE MICHIGAN DIVISION 2,*»-D PLANT, 489 BUILDING, OCTOBER, 1977-MARCH, 1979 -i" ■r •j v # v - f n .» - : . i .r ^ . ri f-V- ■ - *• • • A f — *•*, . ».X** . (1*A... ." ' . ' *>’ Vi " .- 4 ! . ' V*SJ\ .. 1’ i-Sr' rv^.-8V-*■ ■* . ‘T i f t . . i A .. ' • , * <•: v< •S » ' . > *. . •5 i ’ i * 4; .. • »>«» t ’ r *>•’ < A «• ■ :* y ■■ c ■' * y rV i ; ' »• ;;L" * .. ’ ' . . ' A '■ i .. * 4-; . .. . .jf- ' b? ' <•" J•Vve:"»•• * •« ■ i .. ' ..\ ' - •, - ••; .S \ < ■r . .. , 1 1.“ ■; - j/ i '4 . jr • i’ i '* . S*> . r -j -« % OFFICE COPY ICAL U.S.A. 9053 HEH23.14-11-2(8) June 21, 1979 ACCO U N T N O .IV R O B L K M N U M B S « 9084000 L OYEES' EXPOSURES TO AIRBORNE CONTAMINANTS IN THE T , 489 BUILDING, OCTOBER, 1977-MARCH, 1979 or y .o o CO ■vl cnr. K. F . Davey h o m e contaminants were evalu ated during operatio n o f [:he packaging l i n e s . E ig h t-h o u r time-weighted average ¿ :B , Dowanol P IB , is o o c ta n o l, amnonia, dichlorophenol h s t e r , carbon monoxide and MCPA were measured fo r [ith the h ig h e st p o te n tia l fo r exposure to each. A ll he. The p o te n tia l fo r overexposures to Dowanol EB in the [ind Dowanol PIB in the " a c id “ e s t e r area was co rre cte d [ i s t high le v e ls of DCP were lowered to acceptable ’ clo su re through v e n t ila t io n Improvements made p r io r to igh ammonia e x cu rsio n s in the a c id e s t e r area w i l l be a n t , 489 B u ild in g 489 B u ild in g S e c t io n , 834 B u ild in g l i s t r a t io n , 834 B u ild in g 834 B u ild in g i l s R esea rch , 1710 B u ild in g il Department, 607 B u ild in g jie n e S e r v ic e s , 607 B u ild in g .a b o r a t o r ie s , 574 B u ild in g invironm ental S c ie n c e s , 1603 B u ild in g jp / S ilv e r s t e in / S c h n e id e r * 18859 2 An ev alu a tio n o f 2,4-D P la n t employee exposures was completed as part of t h e ir a c tiv e on-going in d u s t r ia l hygiene program. Survey work of the 2 ,4 -0 Acid operatio n reported by M. F . Stevenson in 1976, HEH23.141 1 -2 (6 ), found exposures to dichlorophenol in two job c l a s s i f i c a t i o n s to be in excess o f h e a lth g u id e lin e s . New v e n t ila t io n in the en clo su re area had been in s t a lle d and exposures were re e v a lu a te d . The l a s t employee exposure data to the a lco h o ls used in the two e s t e r production areas were reported by G. H. F lo re s in 1973, in rep o rt NBH2.1 -1 -5 3 (2 ). Process changes were made in the in te rv e n in g y e a rs and new employee exposure documentation was re q u ire d . E v a lu a tio n s during t h i s survey were a lso made in the packaging areas and when methyl chlorophenoxy a c e t ic acid was being handled. CONCLUSIONS AND RECOMMENDATIONS 1. New Chemical and P h y sic a l Agent In v en to ry sh e e ts were prepared fo r a l l job c l a s s i f i c a t i o n s . 2. Employees' exposures w h ile working in the 2,4-D a cid en clo su re area were reeva lu ated p r io r to e a r ly shutdown in 1978. 3. a. The C r y s t a l l i z e r O perators' and A s s is t a n t O perators' 8-hour TWA exposures to dichlorophenol (DCP) and 2 , 4-dichlorophenoxy a c e t ic a c id (2 ,4 -D a c id ) were w ith in accep tab le l i m i t s . b. The re a c tio n equipment was scheduled f o r removal. The packaging op eratio n of the p ro cess was s ta rte d again (on 2,4-D a c id ) in the f i r s t q u a rte r o f 1979. For the 2,4 -D "acid " e s t e r operation a re a : a. The E s t e r O p era to rs' and Form ulation O p erato rs' 8-hour TWA exposures to Dowanol EB, Dowanol P IB , iso o cta n o l and ammonia were w ith in a cce p ta b le li m i t s . b. T ra n sie n t co n ce n tra tio n s o f ammonia next to the r e a c t o r s , j u s t a f t e r the E s t e r Operator m anually added ‘V > in to an open manhole, o c c a s io n a lly exceeded the ex cu rsio n l i m i t . Although the o p erato r was able to avoid exposure by stepping away, t h is p o te n tia l fo r exposure w ill he e lim in a te d in 1979 w ith the i n s t a l l a t i o n o f a d ir e c t a d d itio n method. c. C o ncentratio ns o f alco ho l next to the open s lu r r y ta^k were the h ig h e st measured in the e s t e r p ro cess area and‘o cca sio n ­ a l l y were above recommended g u id e lin e s . T h is p a rt o f 't h e process was changed to a clo se d system to e lim in a te t h is source o f exp o su res. 94.68^9 l MOO PURPOSE 5 4. For the d ir e c t e s t e r a re a : The D ire c t E s t e r O perators' (two o p erato rs per s h i f t ) 8-hour TWA exposures to Dowanol EB, Dowanol PIS and Esteron 245 were w ith in a cce p ta b le li m i t s . b. C o n cen tratio n s o f Dowanol EB in the "high Bay" area were o c c a s io n a lly above the a ccep tab le ex cu rsio n l i m i t . The p o te n tia l f o r overexposure was reduced w ith the i n s t a l l a t i o n o f an improved tem perature c o n t r o lle r a t the decanter and by pip in g the s t r ip p e r column overflow to an o u tsid e sump. (EB and w ater phases in v e r t over a narrow temperature range and EB often was d ischarg ed with w ater in to an open tre n c h ). c. R éévalu atio n o f p o te n tia l exposures to Dowanol EB in the "high bay“ i s recommended fo r 1979 survey work. 5. C on cen tratio n s o f a irb o rn e 2 ,4 ,5 - T PIB e s t e r in the work area o f the M a te ria l H andlers a t the one g allo n can f i l l i n g machine area did not exceed 0 .0 0 4 mg/ra , which was judged a cce p ta b le . 6. The Lo ad e r/C h e ck e rs1 and M aterial Hanglers* 8-hour TWA and peak exposures to carbon monoxide (CO) in the drum f i l l i n g area and warehouse were w ith in accep tab le l i m i t s . A new continuous area CO monitor was i n s t a l l e d . P e rio d ic c a lib r a t io n i s to be c a r r ie d out by the Instrum ent Department. 7. The C lerk/Tank C ar U n lo a d e rs' estim ated 8-hour TWA and peak exposures to methyl chlorophenoxy a c e t ic a c id (MCPA) were w ell w ith in a cce p ta b le l i m i t s . The lo c a l exhaust v e n t ila t io n hood over the bag dumping hopper was a ccep tab le f o r the co n tro l o f dust from t h is l o t o f MCPA. An average hood fa ce v e lo c it y o f approxim ately 150 f e e t per minute i s reconmended i f a d u s t ie r product i s handled in the fu tu re . 8. V e n tila t io n to the drum f i l l i n g lin e s was in e f f e c t iv e and high t r a n s ie n t c o n c e n tra tio n s o f ammonia were n o ticed during the f i l l i n g o f drums w ith amine fo rm u la tio n s. A new exhaust v e n t ila ­ tio n system w i l l be in s t a lle d in 1979. 9. No data e x is t s f o r the Form ulation O p erato rs' exposure to dim ethylamine, and an e v a lu a tio n o f these exposures i s recommended fo r 1979. O Ml* I 548977 a. C 16861 PROCESS AND JOB DESCRIPTIONS i DOW. l '548978 , ,- N o 16862: S168PSI 5 2 ,4 -0 11A cid” E s t e r P ro cess * . ». »> 1 u m I 548980 CO C D SO ■sH! ■ •1. C 23* / 548981 Packaging and warehouse op eratio ns were contained on two f lo o r s with two can f i l l i n g machines on the second flo o r and two drum f i l l i n g lin e s on the f i r s t f lo o r . These lin e s were operated by M a terial H a n d le rs, Set Up Men and Loader/Checkers. Very l i t t l e v e n t ila t io n was in s t a lle d which allow ed a n o ticea b le odor when DMA form ulations were packaged. New v e n t ila t io n for the drum f i l l i n g lin e was planned fo r 1979. In 1978, two g a so lin e powered f o r k l i f t s were being operated and carbon monoxide fumes were generated. A continuous a n a ly z e r was in s t a lle d in the ce n te r of the drum f i l l i n g area to monitor carbon monoxide. The a n a ly z e r was found to be in accu ra te and was replaced in 1979. 8 o EVALUATION CRITERIA In d u s t r ia l Hygiene Guides do not rep re sen t fin e lin e s between sa fe and dangerous exposures. As the name in d ic a t e s , IHGs a re p ro p erly used as guides fo r p lan t design and fo r e v a lu a tin g o ccu p atio n al exposures-. IHGs fo r gases and vapors are u s u a lly expressed in p a rts p er m illio n (ppm, volume/volume); fo r d u s ts , fumes, a e r o s o ls , and m is t s , IHGs are u s u a lly expressed in m illig ra m s o f contaminant per cu b ic m eter o f a i r (m g/nr). Most IHGs are time-weighted average (TWA) co n ce n tra tio n s f o r an 8-12 hour workday and a 40 hour workweek. Lim ited e x cu rsio n exposures to co n cen tratio n s exceeding the IHG are p erm itted , provided th a t the TWA exposure fo r the e n t ir e work day i s accep tab le and the consequences o f exposure, w ith in the ex cu rsio n l i m i t , are minimal and r e v e r s ib le . For most c h e m ic a ls, excu rsio n l i m i t s a re c a lc u la te d from the IHGs and the excu rsio n fa c to rs recommended by the ACGIH. C e ilin g IHGs a re assigned to those m a te ria ls which cause s ig n if ic a n t or i r r e v e r s i b l e e f f e c t s at co n ce n tratio n s exceeding the IHG. Fo r these c h e m ic a ls , no excu rsio n exposures are allow ed. The fo llo w in g exposure c r i t e r i a c u r r e n t ly apply to the a irb o rn e contaminants measured during t h is su rv e y : IHG Excu rsio n 1 Dowanol EB 50 ppm 75 ppm Dowanol PIB mix 25* ppm Iso o c ty l alcohol 75 ppm 110 ppm Dimethyl amine 10 ppm , 2 0 .ppm Compound o r M aterial r~ V *Not e s ta b lis h e d by the Dow In d u s t r ia l H ealth Board, 25 ppm used as a temporary g u id e lin e . 15 4 8 9 8 2 Dow In d u s t r ia l Hygiene Guides (IHGs) a re co n ce n tra tio n s o f airborne substances to which n e a rly a l l employees may be re p e a te d ly exposed throughout a working lif e t im e w ithout adverse e f f e c t . IHGs are e sta b ­ lis h e d by the h ealth p r o fe s s io n a ls o f the Dow In d u s t r ia l Health 8oard fo r chem icals (raw m a t e r ia ls , in te rm e d ia te s, b y -p ro d u cts, w a stes, and products) handled w ith in The Dow Chemical Company. P u b lish ed exposure c r i t e r i a a re a v a ila b le f o r many in d u s t r ia l c h e m ic a ls; examples in clu d e the Threshold L im it Values (TLVs) of the ACGIH (Am erican Conference o f Governmental In d u s t r ia l H y g ie n is t s ) , the ANSI stan d ard s o f the American National Standards I n s t i t u t e , and the OSHA stand ard s o f the Occupational S a fe ty and Health A d m in istratio n o f the United S t a t e s Department of Labor. For most o f these ch e m ic a ls, the In d u s t r ia l H ealth Board has adopted the published exposure c r i t e r i a as the Dow IHGs. In a few in sta n ce s the IHG s e t by the In d u s t r ia l H ealth Board d i f f e r s from the published exposure c r i t e r i a . In e s t a b lis h in g IHGs f o r chem icals which lack published exposure c r i t e r i a , the In d u s t r ia l H ealth Board co n sid e rs to x ic o lo g ic a l in fo rm atio n , o ccu p atio n al exposure d a ta , and medical e x p erie n ce. IHG Ex cu rsio n L im it 2 ,4 -D ich lo ro p h en o l 1 ppm 3 ppm Methyl chlorophenoxy a c e t ic a c id 5 mg/m^ 10 mg/m^ 2 , 4-D ichlorophenoxy a c e t ic a c id 10 mg/m^ 20 mg/m'* 2 ,4 ,5 -T ric h lo ro p h e n o x y a c e t ic a c id 10 mg/m^ 20 mg/nf* Ammonia 25 ppm 35 ppm Carbon monoxide 50 ppm 400 ppm When the r e s u lt s o f an in d u s t r ia l hygiene su rvey in d ic a t e a need to reduce exposure, co n tro l measures should be implemented. T r a d it io n a l en g in eerin g co n tro l methods in c lu d e co n tain m en t, i s o l a t i o n , s u b s t i­ t u t io n , lo c a l exhaust v e n t i l a t io n , g en eral v e n t ila t io n and change of o p eratin g procedure. A d m in is t r a t iv e c o n tro l — lim it in g exposure time through remote c o n tro l o r jo b r o t a t io n — may a lso be e f f e c t iv e . P ersonal p r o t e c t iv e equipment may be used to p ro tect employees o n ly as a l a s t a lt e r n a t iv e when none o f the preceding co n tro l methods i s f e a s ib le o r u n t il c o n tro l measures can be e f f e c t e d . i PRRRfrcf Compound o r M aterial »Off 9 10 i AIR SAMPLING AND ANALYSIS ~'\ In an attempt to document exposures to airborne 2 ,4 ,5 - T Dowanol PIB e s t e r , a i r samples were drawn through midget impingers containing reagent iso o cta n e . A i r flow r a t e s and volumes in the beginning were 0.3 LPM with up to 10 l i t e r s o f a i r c o l l e c t e d . Breakthrough at the higher contaminant l e v e l s was common. A i r flow r a t e s were lowered to under 0 .2 LPM and volumes under s i x l i t e r s f o r l a t e r samples. Impinger s o l u ­ t io n s and knowns were analyzed with GC/EC techniques by R. G. Melcher CAL 78-50449) and L . Nauer CAL 78-50170 and AL 79-50029). Ammonia was estim ated on s i t e using Bendix Gastec No. 3L ammonia detection tubes with an expected accuracy w it h in 25%. Carbon monoxide was estimated on s i t e using Bendix Gastec catalog number ILa and IL L d e te c to r tubes and Draeger 50/a-L extended time d etecto r tu b es. A n a l y t ic a l accu ra cy has been determined to be within 25%. Airborne methyl chlorophenoxy a c e t i c a cid (MCPA) i s a s o lid at room temperature and was c o lle c t e d on 0 .8 micron membrane f i l t e r s using c a li b r a t e d a i r monitoring pumps operating a t over 3 LPM. The weights were determined g r a v i m e t r i c a l l y as t o t a l MCPA by R. W. Bohl. ..if. „ 154898-1 Airborne dichlorophenol and 2,4-dichlorophenoxy a c e t i c acid were c o lle c t e d with both a c t iv a t e d alumina adsorber tubes and midget impingers containing 0.1 N sodium hyd ro xid e. A i r sampling was completed using c a lib r a t e d personal monitoring pumps operating a t about 0.1 LPM fo r the tubes and up to 0.5 LPM f o r the impingers. Both the tubes and the impinger s o lu ­ t io n s were e x tra cte d with a 50/50 hexane/diethyl eth e r solution and methylated with diazomethane. A nalyses were performed by L . Nauer by GC/EC (gas chromatography/electron capture d e te c tio n ) (AL 78-50015). MW Airborne Dowanoi EB (2-butoxy ethanol) Dowanol PIB-T [mixed (mono, d i , t r i ) propylene g ly c o l isobutyl e t h e r ] and iso o ctan o l were c o lle c t e d on commerical adsorber tubes packed with 800 mg o f s i l i c a g el. Each tube was connected to p o rtab le b a tte ry operated personal monitoring vacuum pumps, c a lib r a t e d before and a f t e r sampling and operated a t about 0.1 l i t e r s per minute (LPM). The pumps and tubes were worn by operators to c o l l e c t personal breathing zone samples or placed in s p e c if ie d work a re a s to c o l l e c t area samples. The sample tubes along with tubes prepared with known co n ce n tra tio n s were l a t e r desorbed with car6on d i s u l f i d e with 1% methanol or with methanol and then analyzed by gas chromatography and flame io n iz a t io n d e te ctio n (GC/FID ). A n a ly t ic a l work was performed by R. G. Melcher (AL 77-51116 and AL 78-50450), L . Nauer (AL 78-50170), J . Warren and P. K a stl (AL 79-50107). 11 DISCUSSION OF RESULTS Table 1 i s a summary o f employees' exposures to chemical and physical agents by va rio u s job c l a s s i f i c a t i o n s . The degree o f exposure, hazard r a t in g and e v a lu a tio n r e s u l t s are shown fo r those p o te n tia l contaminants with a hazard r a t in g of 1 to 3 f o r any job c l a s s i f i c a t i o n . The four r a t in g s f o r the degrees o f exposure are the same as the one defined on the back o f the I n d u s t r ia l Hygiene Data Sheets. I NO CONTACT Il MINOR rnwTûf t C h a ra cte riz e d by remote operation with equipment is o ^a t e d from the work a re a . The persons entering is o la te d areas w i l l r e q u ire the personal p rotection o u tlined in iy helow. CT C h a ra cte riz e d by clo se d systems with equipment vented o u tsid e the work a r e a , instrument c o n t r o l, mechanical handling of m a t e r ia ls in bulk. Examples a r e : continu­ ous r e a c t o r s , s t i l l s and f i l t e r s , enclosed conveyors v e n t ila t e d packaging. OCCASIONAL I I I DAILY CONTACT C h a ra c te riz e d by manual handling o f m a te ria ls in packages such as bags, drums and fib e rp a k s. V e n t ila t io n may be provided f o r s p e c i f i c j o b s . Many batch opera­ t io n s f a l l in to t h i s category. GROSS CONTACT LIKELY C h a ra cte riz e d by hand o p era tio n . Examples a r e : emergency r e p a i r s , cle a n in g equipment, clea n in g f i l t e r s , taking c a r o f s p i l l s , packaging v o l a t i l e o r dusty m a t e r ia ls without v e n t i l a t i o n , wheeling and t r a y drying. IV 154898 DEGREES OF EXPOSURE RELATED TO TYPES OF OPERATION The degrees o f exposure, as rated by p la n t su p e rv isio n and reviewed by the in d u s t r i a l h y g i e n i s t , were based on normal operating c o n d itio n s. Each was based on r e g u la r o b servations o f the operating procedures and work p r a c t ic e s employed by operators in the s p e c i f i c job c l a s s i f i c a t i o n . The hazard r a t in g found in Table 1 i s defined as fo llo w s : 16089 A numerical r a t in g ranging from 1 (high) through 5 (low) which estimated the p r o b a b il i t y that an i n j u r y or overexposure w i l l occur in a given s i t u a t i o n or environment. I t i s based on the degree of exposure and the p h y sical and t o x ic p ro p e rtie s o f the chemical. The degree o f exposure i s influenced by the type o f process (open v s . closed system) and the type of operation req u ired (manual v s. autom atic). The i n d u s t r i a l h y g ie n is t has the r e s p o n s i b i l i t y f o r s e t t i n g the hazard r a t in g s based on h i s observations o f the p la n t , the degree of exposure and the a b i l i t y o f the m a te ria l (o r p h y sic a l s t r e s s ) to cause i n j u r y . The hazard r a t in g s were unique f o r each jo b c l a s s i f i c a t i o n . Within any given p l a n t , the hazard r a t in g fo r a chemical may be d i f f e r e n t fo r the vario us jo b c l a s s i f i c a t i o n s because o f a varying degree o f exposure. The ev alu a tio n r e s u l t s may include measured TWA exposures f o r each job c l a s s i f i c a t i o n o r a p ro fe ssio n a l judgment that given exposures would be acceptable based on past exposure data or other data th a t would In d ica te a low p r o b a b il i t y o f overexposure. Tables 2 and 3 show an in c re a se in the l e v e l of exposures by the D ire c t E s t e r Operators to Dowanol EB over a one y e a r period . Concentration in the d i r e c t e s t e r high bay area were, at tim es, i r r i t a t i n g and o c c a s io n a lly exceeded the e x cu rsio n l i m i t . Water from the decanter and s t r i p p e r column o c c a s i o n a ll y contained e x ce ssiv e Dowanol EB due to a water/alcohol phase in v e rsio n which occurred w ith in a narrow temperature range. In 1979, a new temperature c o n t r o l l e r f o r the decanter and piping of the s t r i p p e r overflow d i r e c t l y to an outside waste water sump has decreased odor l e v e l s . A r é é v a lu a tio n of exposures was reconmended and scheduled for 1979. No o th e r a l c o h o l s , e i t h e r r e s id u a l from previous runs or recycled from c u r re n t operations of the "acid" e s t e r p r o c e s s , were detected in the d i r e c t e s t e r area . Table 4 shows the r e s u l t s o f monitor­ ing at the d i r e c t a c id process f o r Dowanol PIB and the r e la t e d 2 ,4 ,5 - T e s t e r . While IHG's had not been e s t a b lis h e d fo r these two m a t e r i a l s , PWA co n cen tratio n s o f 25 ppm f o r PIB and 5 mg/nr f o r the 2 ,4 , 5 - T e s t e r were co n se r v a tiv e vaues used as interium g u id e lin e s . [The lowest IHG fo r any-Dowanol (Dowanol EM) i s 25 ppm and the IHG f o r 2,4-D a c id is 10 mg/m . ] Exposures were well below these values and no health ahzard would be a n t i c i p a t e d . Tables 5 , 6 and 7 show the r e s u l t s o f monitoring f o r p o t e n t ia l Dowanol EB, Dowanol P IB , is o o c t y l alcohol and . J exposures in the 2,4-D "acid" e s t e r process a r e a . Eig h t-h our TWA exposures to a l l four were well w ith in a ccep tab le l i m i t s . The E s t e r Operators were p o t e n t i a l l y exposed to e x c e s s iv e ammonia when adding through an open manhole in to the r e a c t o r s . Operators were observed to step back away from the fumes to minimize actual exposures. A d i r e c t a d d jtiorç method i s scheduled f o r i n s t a l l a t i o n in 1979. The open s l u r r y - t a n k ' a l ^ . - c o n ­ trib u te d a p o t e n t ia l ex cursion exposure as seen in Table 6. T h is tank was clo sed to e lim in a t e the source. 13 While no hazard was expected, data on airborne 2 ,4 ,5 - T e s t e r s was req uested , and the r e s u l t s o f monitoring at the one gallon can packaging area are shown in Table 8. Work area concentrations were very low, and the M aterial Handlers' exposures were judged to 6e well w ith in acceptable 1i r a i t s . ) cr 1548987 G a so lin e powered f o r k l i f t s were in use in the warehouse and drumming a re a s through 1978. Carbon monoxide exposures were evaluated and found to be w ith in acceptable l i m i t s , as shown in Table 9. The f o r k l i f t t r a f f i c pattern and the a i r sample lo c a t io n s are shown in Fig ure 5. The fu tu re conversion to e l e c t r i c o r l i q u i f i e d petroleum gas powered equipment should minimize both carbon monoxide and odor l e v e l s . U n til t h i s re p la c e ­ ment o c c u r s , new continuous carbon monoxide analyzer located between the drumming l in e s should be maintained and c a lib r a te d r e g u l a r l y . The new a n a ly z e r manufactured by Dynamation has operated in an acceptable manner s i n c e i t was i n s t a l l e d the f i r s t q u a rte r of 1979 to rep lace an old er Dynamation model which c o n t i n u a ll y l o s t c a li b r a t i o n . The h ig hest exposure to methyl chlorophenoxy a c e t ic a cid (MCPA) encoun­ tered by the Clerk/Tank Car Unloaders occurred while opening and pumping purchased bags at the hopper fo r the mix tank. Exposures were well under acceptable l i m i t s as shown in Table 10. Also no skin i r r i t a t i o n was reported. The MCPA f la k e used was reported to be l e s s dusty than m a te ria l purchased one y e a r ago when sk in i r r i t a t i o n was experienced. The lo c a l exhaust v e n t i l a t i o n hood over the hopper was evaluated and the a i r flow measurements are shown in Fig ure 6. For the dust l e v e l s observed, the hood was a cce p ta b le . For hig h e r dust l e v e l s , dependent on the co n d itio n of the purchased MCPA, the a i r flow into the hood should be in cre a se d to an average hood face capture v e lo c i t y o f a t l e a s t 150 fe e t per minute. The 2,4-D acid process was operating in 1977 and was to Be phased out as the new 2,4-D acid p la n t a t 948 B u ild in g was brought up to c a p a c it y . It was expected th a t t h i s operation might continue well in to 1978. Th erefo re, exposures to dichlorophenol (DCP) and 2 ,4 - 0 ac'H were evaluated to a ssu re th a t the m a rg in a lly e x c e s s iv e concentra,. jns o f DCP measured in 1976 had been reduced through the i n s t a l l a t i o n of a new v e n t i l a t io n system in 1977. As shown in Table 11, exposures were w ith in acceptable lim its . The production process was shut down at the s t a r t o f 1978 and the r e a ctio n equipment scheduled f o r removal. The packaging end of the p rocess was kept on stand-by co n d itio n and was sta rte d again in 1979 to package 2,4-D a cid produced at the new p la n t. In developing a new Chemical and P h y s ic a l Agent Inventory (Appendix 2) w ith exposure and hazard r a t in g s f o r a l l job c l a s s i f i c a t i o n s , the Formu­ l a t i o n s Operators' p o t e n t ia l hazard to amines was not well e s t a b lis h e d with d a ta , and i t was reconrnended th a t exposures to dimethyl amine and p o s s ib ly diethylamine be evaluted in 1979. ' ... . - ‘tr •*«. i* A n o is e survey completed by the ACPD s a f e t y re p re se n ta tiv e ( 0 : Bugg) found employees’ TWA exposures were acceptable A report o f t h i s survey i s kept at the 2 , 4 - l» r i a n t su p erin te n d e n t's o f f i c e and in the In d u s t r ia l Hygiene Laboratory's f i l e s . 1687 14 Four sealed sources used in process instrum entation and in a n a lt y ic a l equipment were surveyed and wipe tested tw ice in 1978 by J . M. Bronson and R. W. Bohl of the I n d u s t r ia l Hygiene L a b o ra to ry . A ll sources were found to be in acceptable co n d itio n . Documentation i s kept at the Health P hysics se c tio n of the In d u s t r ia l Hygiene Laboratory with copies mailed to each plant superintendent. 1548988 . . % > . : 1 16872 ^ Table ., ) { ) SUMMARY OF DEGREE OF EXPOSURE RATINGS, HAZARD RATINGS AND EXPOSURE EVALUATION RESULTS BY JOB CLASSIFICATION IN THE MICHIGAN DIVISION 2,4-D PLANT, 489 BUILDING, OCTOBER, 1977-FEBRUARY, 1979 D ir e c t E s t e r Operator DE HR ÊE 2,4-D E s t e r Operator DE HR EE 50 ppm 3 3 2.5 3 4 1.5 2 4 0.4 1 5 JA 1 5 JA NE* 3 4 1.0 3 4 1.9 2 4 0.5 1 5 JA 1 5 JA Isooctyl alcohol 75 ppm 3 4 JA 3 4 0.5 2 4 0.1 1 5 JA 1 5 JA Diinetiiylamine (DMA) 10 ppm 1 5 JA 1 5 JA 2 3 JA** 3 3 JA** 1 5 JA 1 ppm 2 4 JA 1 y JA 1 5 JA 3 3 JA** 1 5 JA Methyl chlorophenoxy a c e t ic acid (MCPA) 5 mg/m3 1 5 JA 1 5 JA 1 5 JA 4 3 0.07 2 4 JA 2,4-Dichlorophenoxy a c e t ic acid (2,4-D acid) 10 mg/m3 1 5 JA 2 4 JA 4 3 JA*** 3 3, JA*** 1 5 JA 10 mg/m3 3 4 0.2 1 5 JA 1 5 JA 1 5 JA 3 4 0.001 Ammonia 25 ppm 1 5 JA 3 3 0.5 (e s t.) 1 5 JA 1 5 JA 1 5 JA Carbon monoxide,. 50 ppm 1 5 JA 1 5 JA 2 4 JA 3 4 15 3 3 15 Sodium hydroxide 2 mg/m3 2 4 JA' 1 5 JA 1 5 JA 3 3 JA*** 1 5 JA Material IHG Dowanol EB (2-butoxy ethanol) Dowanol PIB Mix (72% mono, 22% d i , 4% trip ro p y le n e glycol isobutyl eth e r) 2,4-Dichloropheno.l (DCP) 2 , 4 ,5-Trichlorophenoxy a c e t ic e s t e r (Esteron 245) Clerk-Tank Car Unloader bE HR EÉ Loader-Checker DE HR “ I T / ■ « ¿ if. *NE - Not esta b lish ed **To be measured in 1979 * * * P r im a r ily a potential skin contact hazard 16873 DE - Degree of exposure HR - Hazard rating EE - Exposure evaluation JA - Judged acceptable Formulations Operator DE HR JtT Table 1. CONTINUED Material Dowanol EB (2-butoxy ethanol) IHG Material Handler DE HE EE Set-Up Man DE HR EE 2,4-D Enclosure P rio r to Shutdown A s s is t a n t C r y s t a l l l 2 er Operator (2,4-D) Operator (Not a ctiv e in 1978) (Not a c tiv e in 1978) DE HR EE DE HR EE 50 ppm 1 5 JA 1 5 JA 1 5 JA 1 5 JA NE* 1 5 JA 1 5 JA 1 5 JA 1 5 JA Iso o ctyl alcohol 75 ppm 1 5 JA 1 5 JA 1 5 JA 1 5 JA Dimethyl amine (DMA) 10 ppm 1 5 JA 1 5 JA 1 5 JA 1 5 JA 2 ,4-Dichlorophenol (DCP) 1 ppm 1 5 JA 1 5 JA 3 3 0.05 2 4 0.05 Methyl chlorophenoxy a c e t i c acid (MCPA) 5 mg/m^ 3 3 0.07 3 3 0.07 1 5 JA 1 5 JA 2 ,4-Dichlorophenoxy a c e t ic acid ( 2 ,4-D a cid ) 10 mg/m^ 3 3 JA** 3 3 JA** 2 3 0.09 3 3 0.07 2 , 4 ,5-Trichlorophenoxy a c e t ic e s t e r (Esteron 245) 10 mg/m^ 3 4 0.001 2 4 JA 1 5 JA 1 5 JA Ammonia 25 ppm 1 5 JA 1 5 JA 1 5 JA 1 5 JA Carbon monoxide - 50 ppm 3 3 15 3 3 15 2 4 JA 2 4 JA Sodium hydroxide,, 2 mg/m^ 1 5 JA 1 5 JA 2 4 JA 2 4 JA Dowanol Pill Mix ( 7 2 % mono, 22% d i , 4!í trip ro p y len e glycol isobutyl eth e r) ? *NE - Not esta b lish ed **To be measured in 1979 Note: Exposures by a l l other job c l a s s i f i c a t i o n s l i s t e d on Appendix 1 to a l l chemicals above and l i s t e d in Appendix 2 were judged acceptable. 05 S 0S68TS/ . MOO O Table 2. AIR MONITORING FOR DOWANOL EB AND DOWANOL PIB-T IN THE DIRECT ESTER OPERATION DURING PRODUCTION OF DOWANOL EB ESTER OF 2,4-D (DOWANOL PIB ESTER BEING PRODUCEDI IN 2,4-D ACID ESTER PROCESS), IN THE MICHIGAN DIVISION 2,4-D PLANT, 489 BUILDING, NOVEMBER, 1977 Description Date Concentration (ppm) Dowanol EB Dowanol PIB* Personal Samples (Approximate Û Hour TWA Exposure) Personal breathing zone of the D ire ct E s t e r Operator for the high bay process area 10/24/77 0.6 . ND** Personal breathing zone of the D ire c t E s t e r Operator for the high bay process area 10/26/77 0.8 ND Personal breathing zone of the D irect E s t e r Operator fo r the high bay process area 10/28/77 2.7 ND Personal breathing zone of the D ire ct E s t e r Operator fo r the low bay area 10/24/77 0.5 ND Personal breathing zone of the D ire ct E s t e r Operator fo r the low bay area 10/26/77 0.4 ND Personal breathing zone of the D ire ct E s t e r Operator fo r the low bay area 10/28/77 4.5 ND 10/26/77 10/28/77 0.8 0.7 ND ND 10/24/77 10/26/77 10/28/77 23 28 17 ND ND ND Area Sampling 1 Control room., D ire ct E s t e r Process ■•■¿A D ir e c t Eisfer, high bay, f i r s t level 'r 16875 ♦From acid room **ND - Not detected at a n a ly t ic a l s e n s i t i v i t y of <0.3 T668FS| J Table 2. CONTINUED D escription Area Sampling D ire c t E s t e r , high bay, 2nd level ' (Odor i r r i t a t i n g ) D ire c t E s t e r , high bay, t h ir d le v e l D ir e c t E s t e r , low bay, f i r s t level D ire c t E s t e r , low bay, second level In sid e the 2,4-D a cid enclosure Open a re a , north end of 409 Building between D irect E s t e r and Acid E s t e r rooms In sid e 2,4-D a cid e s t e r room In d u stria l, Hygiene Guide Excursion Lim it *From a cid room **ND - Not detected at a n a ly t ic a l s e n s i t i v i t y of <0.3 ***ND - Not detected at a n a ly t ic a l s e n s i t i v i t y of <0.2 o CO Date Concentration (ppm) Dowanol EB Dowanol PIB* 10/24/77 10/26/77 10/28/77 10/28/77 6.8 10 16 • 38 ND** ND ND ND 10/28/77 6.3 0.4 10/24/77 10/28/77 0.4 0.9 ND ND 10/24/77 10/26/77 10/28/77 0.6 0.4 1.1 ND ND ND 10/28/77 0.3 0.2 10/28/77 0.5 ND ND*** 50 - 75 0m r* / J Table 3. AIR SAMPLING FOR DOWANOL EB AT THE DIRECT ESTER PROCESS DURING PRODUCT OF DOWANOL EB ESTER OF 2 ,4 -D , 2,4-D PLANT, 489 BUILDING, JANUARY, 1979 D escription Date Dowanol EB (ppm, voi; Personal Samples (Approximate 8 Hour TWA Exposuire) Personal breathing zone (BZ) of D ir e c t E s t e r Operator (operating high bay) 1/18/79 1/20/79 5.0 3.4 Personal BZ of D ir e c t E s t e r Operator (operating low bay) 1/18/79 1/20/79 3.5 2.8 Control room, D ire c t E s t e r Process 1/15/79 1/17/79 1/18/79 1.8 2.9 1.5 High bay, f i r s t f lo o r 1/18/79 1/20/79 25 27 High bay, second f lo o r 1/15/79 1/17/79 1/18/79 1/19/79 1/20/79 59 5.4 64 26 61 1/15/79 1/17/79 1/18/79 1/19/79 47 55 77 44 1/15/79 1/17/79 1/19/79 44 49 44 Area Samples (Odor very strong) (Odor very strong) High bay, .-3rd f lo o r • (Odor very strong) ■ High Bay, fourth f lo o r 18877 C668PS| MOO Table 3. CONTINUED D escription Area Samples Low bay, f i r s t f lo o r Low bay, 2nd f lo o r In d u s t r ia l Hygiene Guide Excursion L im it ï ■ \+*. V-> J (Minimal odor) Date Dowanol EB (ppm, vcil/vol) 1/17/79 1/18/79 3.0 5.5 1/17/79 1/18/79 1/20/79 3.3 5.4 5.2 50 75 O O fable 4. RESULTS OF AIR MONITORING FOR DOWANOL P1B-T AND ESTERON 245 AT THE DIRECT ESTER PROCESS DURJN? PRODUCTION OF DOWANOL PIB ESTER OF 2 .4 ,5 - T IN THE MICHIGAN DIVISION 2 .4 - 0 PLANT, 489 BUILDING, FEBRUARY-MAV, 1978 Date Dowanol PIB-T (PPm) Breathing zone of D ir e c t E s t e r Operator for High Bay 2/24/78 1.0 Breathing zone of D ire c t E s t e r Operator fo r Low Bay 2/24/78 1.0 2/20/78 2/24/78 5/01/78 10.0 0.3 0.6 - 0.1 2/20/78 2/24/78 2/24/78 5/01/78 5/01/78 3.9 4.5 7.5 0.3 0.3 - 0.2 0.2 2/20/78 2/20/78 2/24/78 5/01/78 _ D e scrip tio n 2 ,4 ,5 - T ÇJster (mq/m ) Personal Samples (Approximate 8 Hour TWA Exposure) Area Samples - D ir e c t E s t e r Area High bay, f i r s t f lo o r High bay, second flo o r Low bay, second f lo o r Control room il i1 ^ »» In d u s t r ia l Hygiene Guide 2/24/78 2/24/78 5/01/78 - - 0.3 0.4 0.5 0.6 1.9 3.7 0.3 1.1 - 0.2 NE* NE C alcu la ted 8 Hour TWA Exposures: D ire ct E s t e r Operator ( f o r high bay) D ire c t E s t e r Operator ( f o r low bay) (Assume both spent 702 of time 1n control room, 0.2 0.2 I 1n process a re a , 152 out of area) *NE - Not e sta b lish e d CO Z C £ 6 6 8 H I &ÜÎÏ 3 Table 5. RESULTS OF AIR MONITORING FOR DOWANOL EB, 2,4-D "ACID" ESTER PROCESS IN THE MICHIGAN DIVISION 2,4-D PLANT, 489 BUILDING/MAY, 1978 D escription of Samples Dowanol EB (ppm) 5/01/78 Personal breathing zone (BZ) of 2,4-D E s t e r Operator on re g u la r work (loaded two r e a c t o r s ) , sample time 6.3 hours, approximate 8 hour TWA exposure 1.5 5/04/78 Personal breathing zone (BZ) of 2,4-D E s t e r Operator on re g u la r work (loaded two r e a c t o r s ) , sample time 6.1 hours, approximate 8 hour TWA exposure 1.4 5/01/78 Breathing zone of 2,4-D E s t e r Operator while making up two r e a c to r batch es, 52 minutes 0.9 5/01/78 Breathing zone of 2,4-D E s t e r Operator while changing S p a rk le r f i l t e r at f i r s t f l o o r , 20 minutes 21.0 5/01/78 Personal BZ of Formulations Operator on r e g u la r work o f which one hour of h is 8 hour s h i f t was spent in the 2,4-D e s t e r room, sample time 6.3 hours and t h is approximates n is 8 hour TWA exposure 0.3 5/04/78' Personal BZ of Formulations Operator on re g u la r work of which one hour of h1s 8 hour s h i f t was spent in the 2,4-D e s t e r room, sample time 6.1 hours or approximate TWA exposure 0.4 Date Personal SampHnq Area Sampling 1 5/01/78 ' , - 2nd f lo o r , center next to north a i s l e near r e a c t o r s , stro ng est odor le v e l room at the time, sample time 6.3 hours 5/Al/7 8 2nd f lo o r , south a i s l e , south of r e a c t o r s , sample time 6 .3 hours, odor j u s t noticeable * 0.8 2nd flo o r west, sample time 52 minutes 0.9 ' r> 5/01/78 R R R P tC l In 7.3 O ' Table 5. 0 O CONTINUED Date Dowanol EB (ppm) D escription of Samples Area Sampling 5/01/78 1st f lo o r under r e a c t o r s , sample time 53 minutes 1.0 5/01/78 2nd f l o o r , center next to north a i s l e near r e a c t o r s , sample time 29 minutes 2.2 5/04/78 2nd f l o o r , center of north a i s l e 2.8 5/04/78 2nd f l o o r , center of south a i s l e on control panel ' 0.7 In d u s t r ia l Hygiene Guide 50 Excursion Lim it 75 I Vj O O Ç 05 h * ¿GBSfSI 1 MOU 1 jb l e 6. J o RESULTS OF AIR MONITORING FOR DOWANOL PIB-T AT THE 2,4-D ACID ESTER PROCESS DURING PRODUCTION' OF DOWANOL PIB ESTER OF 2,4-D IN THE MICHIGAN DIVISION 2,4-D PLANT, 489 BUILDING, OCTOBER, 1977 AND FEBRUARY, 1978 D escription Date Concentration 1n ppm (v o l/ v o l) Dowanol PIB Ammonia Personal Sampling (Approximate 8 Hour TWA) Personal breathing zone of 2,4-D E s t e r Operator 10/24/77 10/26/77 10/28/77 02/24/78 1.2 2.0 3.0 1.4 10/28/77 4.9 Work areas on second f l o o r , near r e a c t o r s , during production of 2,4-D PIB e s t e r 10/24/77 10/26/77 10/28/77 0.9 0.9 1.7 MO MO M Work areas on second f l o o r , near re a cto rs during reacto r changes 10/28/77 02/24/78 3.2 7.6 MO ND*(<0.5) Next to s l u r r y ta n k , 2nd f lo o r (hig hest odor le v e l 1n room) 10/28/77 83 Wor 10/24/77 10/26/77 10/28/77 02/24/77 0.7 0.5 1.0 5.4 North end'bf 489 Bu ild in g between d i r e c t e s t e r room and lunch room ■ 10/28/77 ND(<0.20) Between thé d i r e c t e s t e r and a cid e s t e r rooms 02/24/78 ND(<0.30) Between the acid e s t e r room and lunch room 10/26/77 ND(<0.20) In sid e 2,4-D enclosure 10/28/77 0.2 Personal Sampling (Short Term High Exposure Job) Personal breathing zone of 2,4-D E s t e r Operator while charging a l l four re a cto rs (h1s highest p o te n tia l exposure p e r io d ) , 56 minutes Area SampHnq - 2,4-D E s t e r Room areas on f i r s t f lo o r ND(<0.5) NE** In d u s t r ia l Hygiene Guide 25 *ND - Not detected at a n a ly t ic a l s e n s i t i v i t y indicated In parentheses **NE - Not e sta b lish e d c p ce ©3 n p o n t n i MOO \ O u Table 7. AIR SAMPLING FOR ISOOCTYL ALCOHOL IN THE 2.4-D ACID ESTER PROCESS OF THE MICHIGAN DIVISION 2,4-D PLANT, 489 BUILDING, OCTOBER, 1978 Iso o ctyl Alcohol _________(ppm) Description Personal Monitoring Personal breathing zone o f 2,4-D E s t e r Operator during production o f iso o cty l e s t e r of 2,4-D , approximate 8 hour TWA exposure 0.5 Personal breathing zone of Formulations Operator, approximate 8 hour TWA exposure 0.4 Area Monitoring* At desk on 2nd l e v e l , west of south a i s l e of acid e s t e r room 0.3 Nexf to No. 4 r e a c t o r , 2nd f lo o r e a st 0.3 Nex'w to s l u r r y tank, 2nd f lo o r about s i x fe e t from open manhole in work area 0.5 Near f i l t e r s , northeast on f i r s t f lo o r 0.5 Walkway four feet o f f f lo o r and running east-west under reacto r area 0.5 % In d u s t r ia l, Hygiene Guide »* 75 • ♦Noticeable odor permeated the room which was considered by operating personnel to be ty p ic a l and normal. M W GO m s K I m o Table 8. AIR MONITORING FOR AIRBORNE ESTERON 245 IN THE WORK AREA OF THE ONE GALLON CANNING LINE DURING PACKAGING OF ESTERON 245 (DOUANOL PIB ESTER OF TRICHLOROPHENOXY ACETIC ACID) IN THE MICHIGAN DIVISION 2,4-D PLANT, 489 BUILDING, FEBRUARY, 1978 2 ,4,5-T/PIB (mg/nr) Description Next to M aterial Handler at can f i l l i n g machine ND* Next to M aterial Handler at can f i l l i n g machine ND Next to Material Handler at capping machine 0.001 Next to Material Handler at capping machine 0.002 Near two Material Handlers loading empty cans onto the conveyor ND Near two Material Handlers loading empty cans onto the conveyor ND Near M aterial Handler loading p a ll e t s with f i l l e d cans and working near canner 0.004 I n d u s t r ia l Hygiene Guide NE** ( t 1 3 *ND - Less than the lower detectable l i m i t of 0.001 mg/m with a 10 l i t e r a i r sample **NE - Noticestabl 1shed GO oooGf’Si MOO O J Table 9. O RESULTS 0F AIR SAMPLING FOR CARDON MONOXIDE (GASOLINE ENGINE FORKLIFT EXHAUST) IN THE WAREHOUSE AREA OF THE MICHIGAN DIVISION 2,4-D PLANT, 489 BUILDING, NOVEMBER, 1978 Date D e scrip tio n * Carbon Monoxide (ppm) 11/02/78 Between drumming l i n e s , 1st f lo o r warehouse area (one f o r k l i f t operation) 35** 11/02/78 Next to ea st drumming (one f o r k l i f t operating) 20 11/02/78 Next to west drumming l in e (one f o r k l i f t operating as c lo se 11/02/78 Between drumming l i n e s ( l a t e r in day) 10** 11/02/78 Between drumming U n e s about 10 minutes a f t e r a l l f o r k l i f t operations had ceased 5 11/12/78 West of drumming l i n e s 1n warehouse during f o r k l i f t operation 1n building 5 11/08/78 .A is le w a y south of 5 gallon f i l l i n g l i n e 15 11/21/78 Between drum f i l l i n g l i n e s (one f o r k l i f t operating in area) 25 11/21/78 Between f i l l i n g l i n e s ( l a t e r ) next to continuous monitor which indicated 45-75 ppm (maintenance work was ordered) 25 11/21/78 Next to f o r k l i f t during drum removal from 55 gallon l i n e (near operator of f o r k l i f t ) 30 11/21/78 Between drum f i l l i n g U n e s 15 11/22/78 Between drum f i l l i n g l i n e s by a nalyzer with 2 f o r k l i f t s operating reading approximately 250 ppm) 11/22/78 Storage area (west) random times as 20 f t away) 50 (one f o r k l i f t operating) (analyzer 45 5 11/08/78 Personal breathing zone sample o f Loader/Checker while working at drum ' ' f i 1ïin g l ’i nes (S nour sample) 14 ll/0 8 / 7 8 : 16 , Personal breathing zone sample o f Loader/Checker while d riv in g f o r k l i f t (5 hour sample) "•ft In d u s t r ia l Hygiene Guide 50 Excursion Lim it 400 15085 *Area samples unless otherwise noted **These values were over 253! lower than the continuous analyzer value. The continuous analyzer was positioned between the two f i l l i n g l i n e s and about 25 feet from the warehouse o f f i c e (Instrument Department evaluation was scheduled). T006TS] MfifI Table 11. RESULTS OF AIR MONITORING IN THE 2,4-D ENCLOSURE DURING DICHLOROPHENOL AND 2,4-D ACID PRODUCTION IN THE MICHIGAN DIVISION 2,4-D PLANT, NOVEMBER 11, 1977 Dlchlorophenol _______ (PPm). Dichlorophenoxy A c e tic Acid (PPm) Trlchlorophenols (ppm) Personal breathing zone sample of the C r y s t a l l i z e r Operator (approximate 8 hour TWA exposure) 0.049 0.087 0.093 Personal breathing zone sample of the A s s is t a n t Operator (approximate 8 hour TWA exposure) 0.049 0.069 0.073 2,4-D a cid f i l t e r wheel a re a , 4th f lo o r 0.083 0.11 0.084 0.12 0.32 0.37 South of f i l t e r wheel a re a , 4th f lo o r 0.065 0.059 0.038 0.094 0.19 0.14 Packaging a r e a , 1st f lo o r 0.008 0.005 0.015 0.007 0.011 0.047 0.007 0.019 0.034 Next to bulk tank manhole, 3rd f lo o r 0.014 0.013 0.036 1.0 1.1 , (.10 mg/nr) 1.0 D escription Personal Samples Area Samples . »» In d u s t r ia l .Hygiene Guide C006ÊS | FIGURE I. DIRECT ESTER PROCESS IN THE MICHIGAN DIVISION 2,4-D PLANT, 489 BUILDING ' (549004 ‘«\ FIGURE I I . ACID ESTER PROCESS IN THE MICHIGAN DIVISION 2,4-D PUNT, 489 BUILDING O s J 549005 O FIGURE 3. 489~BUILDINGR0CESS ^ THE MICHIGAN 0 IV IS 0 n 2,4-0 PLANT, j]0 iy : ' 1549006 16819 FIGURE 4(a). PLANT AREAS IN THE MICHIGAN DIVISION 2,4-D PLANT 489 BUILDING FLOOR A 1 DE low bay B 1 OE high bay C 1 S h i f t foremen's o f f i c e D 1 Coffee room E 1 Shop F 1 Lab G 1 2 .4 - D H 1 2 . 4 - 0 enclosure I 1 2 .4 - J 1 Acid e s t e r K 1 DMA L 1 55 and 30 gallon packaging lin e M 1 5 gallon packaging N 1 Warehouse o f f i c e 0 1 Warehouse P 1 Tank ca r house Q 2 De low bay R 2 DE high bay S 2 Lunchroom T 2 2 .4 - D U 2 2 . 4 - D enclosure V 2 2 . 4 - D reacto rs w 2 Acid e s t e r X 2 DMA Y 2 Warehouse Z 2 O f f ic e s AA 3 DE high bay BB 3 2 .4 -D CC 3 2 . 4 - 0 enclosure PROCESS AREA D re a cto r •• - ~ .. *. D fljafj 5 4 9 0 0 7 LOCATION N j URE 4( b ). FIRST FLOOR OF THE 2,4-D PLANT IN ' __MICHIGAN DIVISION, 489 BUILDING s-> CO t o ÖOOGi'Si 'M W FIGURE 4 ( c ) . SECOND FLOOR OF THE 2 , 4 - 0 F-.fON ™ E MICHIGAN DIVISION, 489 BUILDING IV lOC 6006Ï-2 I ^0(1 FIGURE 4(d). THIRD FLOOR OF THE 2, ^ ( Q a NT IN THE MICHIGAN DIVISION, 489 BUILDING 0T06ÊS I WAREHOUSE TRAFFIC FLOW AND SAMPLING POINTS FOR CARBON MONOXIDE IN THE MICHIGAN DIVISION 2 ,4 -0 PLANT, 489 BUILDING CONVEYORS T T 0 F^r* » Mflw FIGURE V. A V \ ( V ) = SAMPLE POINTS = TRAFFIC PATTERN FOR GAS JEEP DURING SAMPLE PERIOO ib i« o 238 9 o ? i\D % CO CD CO K a ro n fo liage herbicide it used . in co n tro llin g c c d o in w o o dy o n d he rb ace ous p io n tt g r o w in g on p o sture o nd ronge londt. ditch bonk*, fence row s o n d r ig h t -o f-w a y s . D IR EC T IO N S P R E P A R I N G T H £ S P R A Y ; A d d h o lf the reguire d o m o u n i o f w ate r to the ip r a y took, then o d d K u ro n w ith o gita fio n . K u r o n form s o n em u lsio n in w o le r o n d tends to settle out on p ro lo n ged stand« ing. P rovide og<>otion to prevent such se oo ro tion o n d ensure u n ifo rm m ixture in the sp ray tan k . F O L IA G E T R E A T M E N T : S p ray w o o d y g ro w th up to 6 or 8 feet toll a lte r the fo liage is fully d e v e l­ oped, u sin g a sproy co n ta in in g 3 to 4 q u a rts o f K u r o n per 100 g a llo n s o f woter. W i t h sensitive species, toller b rush or trees m o y be co ntro lled if fo lioge it ad e q u a te ly covered. O n po ison ivy o n d brom b le s such o s.w ild blockberry, use 2 q u o rts o f K u ro n per 1 00 g a llo n s o f w ater. Spro y sho uld drench all p io n t port« in c lu d in g leave« o nd item «. D e lo y spro ying new sprouts from recently cut stum ps until they ho ve m ode a p preciable gro w th . U n d e r go od g r o w in g conditions, in h u m id areos, o p p lic otion s m o de u p to three w e eks before foil frost ore usuoN y effective. ( A p o lic o lio n in lote Sum m er ond foil in T e x o s an d O k la h o m a is not recom m ended.) S p ra y in g offer leoves ho ve lost their norm oi green color an d v igo r m o y not giv e satisfacto ry control. Less effective control m a y result during hot. dry w e ath e r w h en deep soil m o isture is deficient. U su a lly a sin gle ap p lica tio n in o n y one yeor is sufficient. If n e w gro w th develops, repcot a p p lic a tio n s m o y be necessary in Succeeding yeors. A I R P L A N E A P P L I C A T I O N : For control o f past o n d b lo ck io ck ooks, use 2 c u o rts o f K u ron in I go H o n o f diesel Oil o n d 2 V x to 3 Vx g o llo n s o f w oler, or 2 qu a rts o f K u r o n in 3 V x to 4 V x g a llo n s of diesel oil per acre. A p p ly o ffe r folioge is fully developed (u su a lly in M a y an d J u n e ). A n a d d i­ tio nal sproy u sin g I to 2 q u a rts o f K u ron m a y be necessary the second or third year. These a p p licotions w ill effe ctive ly control b r o o d -le av e d w eeds in sproyed o'Cos. S P O T T R E A T M E N T : For k n o p so ck a p p lic a tio n o f Kuron, m ix V x Cu o fu l in 3 ga llo n s o f w ater. W e t oil folioge thoroughly. W EED CONTROL IN LAW NS AND GOLF C O U R S E S : For control o f bro o d -le o v e d p lonto in, buckhorn. co m m on ch ick w ecd , m o use -e a re d c h ic k weed, dondehon, a n d le gum e s such o s w h ite clover o n d block m edic in estab lished turf, op p ly 1 Vx qu a rts of K u ron in 25 to 4 0 g o llo n s o f w a te r per ocre. H ig h e r volum es, up to 10 0 g o llo n s per acre, m o y be used to m in im iz e drift hozord. A p p ly in fall or early sp rin g os h o t-w e o th e r use m a y cau se excessive d o m a g e to turf. D o not opply to t ta lo nifoiou« g r o iic s lu c h a« bent, B erm uda an d St. A u g u ilin e or to now turf of ony vorioty. C A U T I O N : T o o vo id d a m o g e to turf, do not sproy in o n y m o nner w h ich w ill couse excessive d o soges. A v o id overtopping o n d double coveroge w h e n b o c k in g up, o n d ot turns. A v o id sp ro yin g w h en n o zzles ond b o om ore not m o ving, such as w h e n C leo n in g or testing n o zzles. U se a positive q u ic k sh u t-o ff v alve o n b o o m sp ro yin g equipm ent. W E E D L IST W E E D C O N T R O L I N R JC C : T re o t 4 to 8 w e e k s ofte r em ergence of the nee. W h e r e flooded, treot betw een 7 o n d 9 w e e k s after seeding, w h e n p la n ts ho ve em erged obove w o te r o n d le o ve s are s t a n d ­ in g erect. U se I Vx to 3 pints o f K u ro n in the o m ou n t o f w oter needed for even d istribu tion . For m o n y situations, 2 pint« per ocre Is odeq uate. W h e r e w eeds tend to be re sisfo nt b e cause o f specie, o ge or gro w th condition, u p to 3 p in ts w ill g iv e better control. T rea tm e nt o ffe r flo o d in g is u su o lly sofer th an be fore Hooding. C o n su lt yo u r S to le Experim ental S ta tio n o r E xtensio n Service for spe cific loco! recom m endations. K u ro n (• effective In co n tro llin g — post o ak , b lo c k jo c k o ak , gro und ivy, northern (p in , rod, w hito, le r u b ) a o k t, m osquito, m opl«« (su c h os red, su g a r, a n d b ig le af m a p le ), po ison ivy, sa n d sh in n e ry oak, y u c ca, w ild blackbe rry, a lso ce rtain b r o a d -le a v e d w o o ds su ch os bcoom w aed, cocklebur, croton weed, cu rly In d ig o , lo m b 't querters, M e x ic a n w ood, pokeberry, ra gw e e d , salt cedar, sunflow er. NOTE: FO R C O N T R O L OF Y U C C A A N D S A N D S H IN N E R Y O A K : U se I p in t to l q ua rt o f K u ro n in I g a llo n o f diesel oil, o n d w a te r to m o k e 4 g o llo n s total per ocre. T w o to three o p p lic o tio n s as ne cessary in successive years m a y be needed. A p p ly a fte r fo lia g e is fully developed. C o n su lt com petent lo ca l au th o ritie s for in fo rm a tio n on best rote a n d best tim e for ap p lica tio n . H A W A I I ■ — C o n tin u e d q u o rts K u ro n per o cre In 2 0 to 4 0 g a llo n s o f w o te r os o broo dco sf spro y Im m e d ia te ly o fte r p la n tin g Of ro to o n in g o n d before Cone em ergence. For p o st-e m e rge n ce co ntro l o f w e eds o fte r co nes have em erged, o d d 2 Vx lo 5 p o u n d s o f D o w p o n per ocre to the spray o f K u r o n In order to control grosses, o n d sproy the interline sp a ce w ith o u t sp ro yin g the cone directly. T h is o p p lic o tio n c o n be m o de u p to the tim e of " c lo s in g i n " b u t not less th o n ^ n w i i i l x before harvest. D o not m o k e m ore Ih o n tw o o pp lic o tio n s o f 5 q u o rts e a ch o f K u ro n to o n y one crop. USE R E C O M M E N D A T IO N S IN SU G AR C A N E F L O R ID A For post em e rgence co ntro l o f rogw eed, d o g fennel, g ro u n d cherry, purslane, w ild lettuce, n ig h tsh a d e a n d other susceptible broo dleo ve d w eeds, o p p ly I to 1 Vx qu a rts o f K U R O N in 2 0 to 4 0 g o llo n j o f w a te r per acre os b ro a d ca st sproy. M a k e the 1st a p p lic a tio n afte r the ca n e em erges a s sp rin g gro w th o n d w h en w e eds ore g r o w in g v igoro usly, but b e ­ fore they send up seed slo ik s. A second a p p lic a ­ tio n c o n be m o de for lote em e rgin g w eeds. N O T E : Loco! co n d itio n s m o y a ffe ct the use o f herbicides. Stote o gric u ltu ro l a u th o ritie s in m a n y sla te s Issue re co m m e n d a tio n s to fit locol co n ditio n s. W A R N IN G L O U IS IA N A For the control o f crob grass, b o rn y o rd g ro ss o n d Jo h n so n g ra ss se e d lin g s in su g o r cone, o p p ly 1 quo rt o f K u ro n in 15 g a llo n s o f w a te r per acre On the ro w (a p p ro x im a te ly o n e -th ird o f the total are o ) shortly before the seeds ore expected to ge rm in ate . I f Cone is sh a ve d o n d o ff-b a rre d , treot im m e d iate ly fo llo w in g th is operation. F o llo w the early treatm ent w h e n necessary w ith 2 p o u n d s o f D o w p o n A per acre, a p p lie d Over the g r a ss in the ro w (o p p ro x im o te ly o n e -th ird o f the to tal a r e o ). T o control w ild lettuce, curled d o c k .^ o n d otherr " w e e d s use one o f the fo llo w in g pro cedure s w h e n N — . O the w e eds are g r o w in g vigorously. G ro u n d A p p lic a tio n : U se 1 q ua rt o f K u ro n in 15 g a llo n s o f w o te r per ocre ap p lie d over the ro w (a p p ro x im a te ly o n e -lh ir d o f the total o r e o l. A se con d a p p lic a tio n c o n be m o de if needed. D o not m o k e ap p lica tio n o ffe r f a n p . n A i r A p p lic a tio n : U se ia s u u E t x o f K u ro n per o cre In e n o u gh w a te r for u n ifo rm coverage. A p p lic a tio n c o n be m ad e u p before harvest. H A W A II For p re-e m ergen ce co ntro l o f h a iry c rob gross, ye l­ lo w foxtoil, rich o rdso n ia, fireweed, slender a m a ­ ranth, F lo ra 's p o intb rush , jungle rice, pu rslon e a n d w ire g ro ss In H o w o ilo n su go r cone, o p p ly 4 to 5 "86 —l-03L2^Prlnced la U.S.A. In November 1 (C o n tin u e d on Side P a n e l) 9 6 5 D o net use K u ro n for tho co ntro l o f e ih . 4 5 6 D o not a p p ly K u ron d irectly lo, o r oth erw ise pe r­ m it it lo com e Into co nta ct w ith , a n y crop p la n t or o rn a m e n to! p lo n l (in c lu d in g but no t lim ite d to peonuts, soybeans, beans, peos, tom otoes, tobacco, cotton, m elons, okro, sweet potatoes, peppers, celery, flowers, o rn o m cn fo ls, gropes, d e cidu ou s o n d no n d e cid u o u s fruit trees! a n d do not p e rm it sp tay m ists c o n ta in in g K u ro n lo drift o n to them , sin e* even m inute qu a n titie s m o y co use severe d a m o g e d u rin g bo th g r o w in g o nd d o rm a n t periods. C o arse sproys are less likely to drift. A p p lic a tio n s by a ir ­ plane, g ro u n d rigs a n d Hand dispenser» should ba c a n ta d out only w h en there is no h a t a r d from drift. Do net ap p ly by airp lan e In the v icin ity o f a n y de sirab le crops or o rn a m e n ta ls in c lu d in g these tilted above. A t elevate d tem pe ratu re s v a p o r­ iz atio n m o y couse injury to susce ptible p la n ts g r o w in g neorby. D o not use K u ro n o n fresh ly seeded (ow ns, p o s ­ ture or ro n g e la n d s until gro ss h o s becom e w e ll estab lished- D o not co n ta m in a te ir rig a tio n ditches or w a te r use d for do m estic purposes. D o not store n e ar fertilizers, seeds, insecticides or fu n gicid e s. T o o vo id injury to desirab le p lants, do not store, h a n d le or o p p ly other o gric u ltu ro l ch e rm cols w ith the som e co n ta in ers o r equipm ent used fo r K u ron . D o not use K u ro n in sp ra y in g e q u ipm en t c o n ta m i­ nated w ith 2 , 4 - 0 if the 2 , 4 - 0 w ill increose the h a z a rd to desiro ble plants. Ba sura th a t usa af this pradwet co n fo rm s to all a p p lic a b la re gu latio n s. C A U T IO N — M A Y C A U S E S K IN IR R IT A T IO N A v o id C o n ta c t w ith Eyes. Sk in a n d C lo th in g K a a p O u t a f T h a R e ach af C h ild re n — ' REPLACES SPEC Ei~ao_-J.09.2-P RTîFÎTÎDIN APRIL 1065 THE REVISION IS IN JlTUi-SECTlÔîî~uUSE^RECOMMENDATIONS IN SUCAR^ANS-r"— AMONG T1IE CHANGES WÀS~Th OS-THE"RECOMMENDATION FOR USE IN FLORIDA. Proposed Revisions - July 11, 1966 Substi tu te : - "within 60 days of harvest” 1. cypressvine" Add: - "morningglory, tievine 2. 3 . Add: - "broadleaved" 4 , Substitute: - "within 60 days o f harvest" Substitute: - "2 to 3 pints" 5. Substitute : - "60 days tt 6. Substitute: - "60 days ft 7. 16885 . THE GLOBE AND MAIL Thursday October 30, 1980 23di a By ROBERT STEPHENS Workers exposed to toxic and carci­ Dr. Epstein said one of the favorite nogenic substances are little more strategies of industry was to “blame 1 than guinea pigs, and their employers . the cancer victim himself" by linking are purposely withholding Informa­ his disease to smoking, diet, and even ' tion about the very real risks of indus­ his genetic makeup. “ Industry tries to ' trial cancer, a expert on occupational deny the evidence for occupational 1 health has warned. cancer.” Dr. Samuel Epstein, professor of . He said industry also frequently occupational and ' environmental resorts to the argument that the costs medicine at the University of Illinois, ' of complying with exposure regula­ told a conference In Toronto yester- • tions will result in plant shutdowns ' day that workers who are exposed to and higher unemployment. hazardous substances “are the throw­ He said chemical companies in the away segment of society.” United States had fought regulations He'condemned the governments of on vinyl chloride (or years, and that the United States, Canada and Britain their spokesmen had claimed the for failing to regulate toxic substances costs of compliance would be JSO-bilIn the workplace. While regulations llon and 2.2 million lost jobs. controlling the use of seven designat­ "But when BF Goodrich came ed substances were proposed in Ontar­ under the regulations in the spring of io more than two years ago, these : 1975 — its cost was $35-million — it regulations are yet to be passed. actually began to make money on the Dr. Epstein said the incidence of recovery of vinyl chloride, and then, cancer is increasing among the gener­ complaining of unreasonable govern-, al population at an alarming rate that mcni interference, it had the nerve to reflects the huge growth in the pro­ raise its prices," Dr. Epstein said.. i duction of synthetic organic chemi­ cals beginning 30 years ago. One of the delegates at the confer­ He said the worker is being sacri­ ence asked what workers could do to ficed by government and Industry ' protect themselves.from exposure to because “they believe that economic dangerous substances in the absence growth is paramount.” And he of government regulation, and Dr. charged that industry was engaged in Epstein replied: “ if you have an op­ a massive coverup to keep its employ- • tion. I'd say get the hell out of hazard­ ees ignorant of the risks of cancer in . ous workplaces.” the workplace. DOW ; 0 5 0 4 7 9 Employers withhold truth about toxics, MD warns workers ■ > ,< 2 ^ 0 : 2409 COMMUNICATIONS TO: CHARLTON RE: STEVENS STUDY I KNOW. PIECE. I THOUGHT I TOLD YOU ABOUT THE KINGSLEY STEVENS THING IS, I CAN'T FIND AN EASY WAY TO MOVE BETWEEN PARTS PER AND mg/KG. HAVE TO TALK WITH DAVTDSCN ABOUT THAT. IT'S A SKILL I'LL BE NEEDING FOR THE NEXT TWO YEARS. ONCE I'VE LEARNED HOW TO DO THAT, I CAN REALLY MAKE USE OF THE STEVENS PIECE. FROM: GARRY HAMLIN 2020 Dow Center 636-1325 i O < ) i oo; PUBLIC A F F A IR S 'U / U m DOu/ 2 fi G04 0 7 <5.6. M u r W S€ S r P$. 3 0 ^ s S M ^ --- j \ 7 3 ~ [ t p y w b - f i — 3 W G i e ir c ( 4 - 0f ° - p e A Fccefc.“ z r M m e t t r W # F c — t f e b P G c n & J f t . M 7 ibi& O U U H t T t o p / y f r o m -. m S v m M ft& rn w - £[Ut> V BOB CHARLTON 7 z> IM 7 ^ ® 'R p r v fr l w z S ^ T F f *-E F . F e e E - 636-9303 1 6 8 S8 1. UV- Human Toxico/.(19Sl),l,31-39 f^ O Q A gent Orange Toxicity: a Q uantitative Perspective Kincslev M. Stevens 0 G H 9 J Z Department of Medicine, State University of New York at Stonv Brook, Stonv Brook, New York 11794, USA 1 The minimum toxic dose of tetrachloro-dibenzo-p-dioxin (TCDD) for man has been calculated from monkey and human data to be 0.1 Mg kg"1. 2 The amount of TCDD which man takes in from his environment is about 1/2050 of that present in one square metre of his immediate environment. 3 The average concentration of TCDD present in Vietnam immediately after spraying Agent Orange was S Mg m~:. 4 A soldier directly sprayed would attain an internal body concentration of 7 x l0 _iMgkg"1 or 1/1750 of the minimum toxic dose; soldiers moving through previously sprayed areas would ingest much less. 5 Tnese quantitative aspects indicate that the dioxin sprayed with Agent Orange in Vietnam cannot have caused systemic illnesses in Vietnam veterans or birth defects in their children. Introduction To evaluate the probable toxic effects of the dioxin in Agent Orange upon Vietnam veterans requires three steps. First, the minimum toxic dose (MTD) of 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD) must be established for man. Sec­ ond, the fraction of the TCDD which is actually transferred into humans, within a unit area, must be estimated. Using these figures, the known amounts of TCDD which contaminated the Agent Orange sprayed in Vietnam can be converted into fractions of the minimum toxic dose. Minimum toxic dose of TC D D in man The herbicides 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5trichlorophenoxyacetic acid (2,4,5-T) composing Agent Orange have very low mammalian toxicity but the 2,4,5-T was contaminated with TCDD producing an average concentration of TCDD in Agent Orange of 2 p.p.m. (Young era/., 197S). Whereas the herbicides contain a single benzene ring, the dioxins are one of a large group of polychlorinated aromatic hydrocarbons with two rings. There is a very wide range in the toxicity of these compounds but the pathology produced in a given animal species is the same once the toxic level is reached (McConnell &. Moore, 1979). Hence quantitative data on poisoning by one compound can be 014-1-5952/81/010031-09 S01.00 , © Macmillan Publishers Ltd 19S1 8 i 32 i KINGSLEY M. STEVENS convened to TCDD equivalents if the comparative toxicity of that compound to TCDD is known. One way to estimate the MTD of TCDD in man is by extrapolation from primate experiments. When rhesus monkeys were fed small amounts of TCDD in the daily food ration, they showed puffy eyelids, loss of facial hair and scaly skin after a cumulative ingestion of 1 figkg- ' (Allen et al., 1977). Minimal signs must have appeared earlier, thus 0.5 fig kg-1 should approximate the MTD. The number of monkeys was small and this value as the MTD for man must remain suspect because of basic differences unless supported by more direct data. Human data to determine the MTD are available from the Japanese studies of Yusho or oil disease (Kuratsune et al., 1972). In 1968 an oil made from rice bran was contaminated with a commercial polychlorinated biphenyl (PCB) which contained trace amounts of the highly toxic 2,3,7,S-tetrachloro-dibenzo-p-furan (TCDF), the furan analogue of TCDD. D ie structures of TCDD and TCDF appear below. TCDD D Haj i I CO CO CO t I TCDF The contaminated rice oil contained between 5 p.p.m. (Nagayama, Masuda &. Kuratsune, 1975) and 2p.p.m. (Bowes etai, 1978) of polychlorinated dibenzofurans of which about 30% was TCDF (Nagayama et al., 1975). Taking 30% of the mean of 3.5 p.p.m. yields TCDF of 1 p.p.m. or 1 fig ml-1 of rice oil. This oil was incorporated into a commercial chicken mash which caused illness in 2 million chickens wiih death in 400,000 of them. The oil was also marketed as a home cooking oil and consumed by about 2500 people over a period of several months. About two-thirds of those people who ingested the oil became ill. Frequent signs and symptoms in males were eye discharge (89%), chloracne (88%), oedema of upper eyelids (72%), asthenia (5S%), and transient visual disturbance (56%). Gastrointestinal symptoms were less common with vomiting in 24%, diarrhoea in 19% and jaundice in 11%. Serum chemistries showed very few changes, the most frequent being increases in cholesterol and triglycerides. Severe cases developed anaemia and elevated alkaline phosphatase (Kuratsune, 1972). In the following decade there were 51 deaths among the 1665 patients, the first being about a year after the onset of symptoms (Urabe, Koda &. Asahi, 1979). Several early deaths were associated with pericardial disease (Kikuchi &. Masuda, 1976). There have been two deaths from malignant lymphomas which will be discussed later. Thirteen babies were delivered of mothers who ingested TCDF. Most babies showed some of the signs of Yusho found in adults. Some babies were small at birth and grew more slowly but later resumed normal growth rates (Yoshimura &. Ikeda. 1978). There were no birth defects. Of two stillbirths, one was autopsied; it showed minor signs of Yusho but death was due to asphyxia from a rwisted umbilical cord (Kikuchi etal., 1969). 16900 • ( ( ] £ V a n . tl rr u se fl: w di. ha he ha he (R wh ex; AGENT ORANGE TOXICITY 33 Of 141 patients with Yusho whose dietary intake of oil was carefully studied, only two adults had ingested less than 200 ml of oil when they first developed signs or symptoms (Hayabuchi, Yoshimura &. Karatsune, 1979). Their oil intake was 2.1 and 3.0 ml k g '1respectively or 2.1 and 3.0 fig k g '1of TCDF. SinceTCDD is 20 times as toxic as TCDF (McConnell & Moore, 197S), the minimum-toxic dose of TCDF of 2 fig kg"1 is equivalent to 0.1 fig k g '1 of TCDD. Humans can describe symptoms while monkeys cannot, hence one would expect the true MTD for man to be lower than that obtained by extrapolation from monkey studies. The agreement between 0.5 fig kg"1 from monkey studies and 0.1 fig kg"1 from the Yusho studies in man is good. The value from the human studies of TCDD of 0.1 pg k g '1will be used as the cumulative minimum toxic dose in man. Intake transfer factor Chloracne can be caused by TCDD acting externally at local sites (Crow, 1971) or by systemic TCDD. The major concern of Vietnam veterans is not with chloracne but with other possible long-term systemic effects. Hence one must determine what fraction of TCDD present in a unit environmental area is introduced into a human in that environment; the intake transfer factor is the ratio of the intake of TCDD to the environmental TCDD. This factor w'iil be estimated from two accidents which dispersed TCDD. In May and June of 1971, TCDD contaminated waste oil sludge was sprayed for dust control on one outdoor and two indoor horse arenas in Missouri.'The sludge contained waste from the purification of 2,4,5-T; its TCDD content was 330 fig g-1 (330p.p.m.) and a soil sample from one covered arena contained 3 2 fig g '1 (Kimbrough e: aL, 1977). TCDD does not leach into soil even from oil (Wipf etal., 1978), thus most of the TCDD would remain in the top centimetre of soil. If the soil surface is equated with the top millimetre, then a square centimetre of soil would contain 3.2 fig of TCDD or 32,000 figm '2. Of 85 horses exercised in the arena, 5S became ill and 43 died. There were 26 known abortions in horses and many foals died young. In the second covered arena 12 out of 25 horses died; in the open arena 7 out of 40 horses died. There were hundreds of deaths of birds, many cats and a few dogs. Despite this extreme animal toxicity no human illness was associated with the open arena. Two three-year-old boys who played in the second arena developed chloracne only. A six-year-old girl played daily on the floor of the arena with 32,000 fig m '2 of TCDD from May 26 until mid-August when she developed mild chloracne (Reggiani, 197S), nosebleeds, headaches, diarrhoea and bloody urine. Examination revealed an acute nephritis and haemorrhagic cystitis. Within a week after removal from contact with the arena her symptoms had disappeared. Cystoscopy 3 months later revealed punctate haemorrhagic areas of the bladder but no haematuria. Her ten-year-old sister and her mother also entered the arena frequently. They developed very mild chloracne (Reggiani, 1978), abdominal pain, diarrhoea and intermittent headaches, all of which promptly subsided when arena contact stopped. Five years later, extensive examinations of all three revealed only normal findings (Beal e: a!., 1977). 34 KINGSLEY M. STEVEN’S m ut r o a This six-year-old girl had an unparalleled opportunity to take in TCDD from her daily environment. It was during summer so her clothing was light. Systemic toxicity can occur from TCDD applied to large skin areas (Schwetz et al, 1973). She played on the floor where TCDD was easily available to hands and thence to mouth and vet she became less ill than the average case of Yusho. That average case ingested 6S8 ml of oil (Hayabuchi, Yoshimura &. Kuratsune, 1979), equival­ ent to 34 pg of TCDD or 0.7 Mg kg"1. Hence the symptoms shown by this girl would be consistent with a cumulative intake of not more than 0.7 MSkg-1 of TCDD; for her 20 kg weight this would be 14 Mg. The ratio of 14 Mg to 32,000 Mg eq' : is 1 :2300, the intake transfer factor based on this incident. About noon on July 10, 1976, a factory north of Milan which produced trichlorophenol had an explosion which released boiling reagents into the atmos­ phere. Most of the cloud settled on a 110 hectare (1 ha = 2.47 acres) area in the town of Sevaso where it deposited about 2 kg of TCDD. This area was designated Zone A and a larger,'more distant area of 269 ha which received only 20 g of TCDD was designated Zone B. The 733 residents of Zone A were evacuated 2 weeks after the explosion. The 4800 residents in Zone B were not evacuated but were prohibited from raising or using produce from either Zone B or the surrounding 1430 ha Zone R. These amounts of TCDD would produce average concentrations of 1800 and 7 Mg of TCDD per square metre in Zones A and B respectively. Analyses carried out days to weeks after the explosion showed a very' spotty distribution with a range in Zone A from 5447 Mg per square meter to not detectable (Pocchiari, Silano &. Zampieri, 1979). Actual concentrations on vege­ tation and soil shortly after the explosion were undoubtedly higher than these recorded values. Birds began dying in Zone A a few days after the explosion. Birds preen their feathers regularly. The surface area of the feathers is many times that of the skin surface so even a small bird must have at least 0.1 m3of feather surface. If the feathers held the average concentration of 1800 Mgm':, then 180 Mg would be present on a bird weighing only 30 to 100 g. Thus the bird could ingest 1000 Mg k g '1, about ten times the acute LDJ0 for birds (Young el al, 1978). Rabbits which ate fresh vegetation from local fields died next. A 1 kg rabbit consuming vegetation from an area of one square meter would take in at least 1800 Mg, over ten times the LD50 for rabbits. More cats than dogs died since cats both groom frequently and eat birds. Later a number of sheep and cattle died; most livestock in Zone A was destroyed. In Zone B, however, birds and rabbits would consume TCDD in the order of 7 Mg k g '1(below the acute toxic dose) and here few of these animals were found dead. The early toxic effects in man were not due to TCDD but to other chemicals, for example sodium hydroxide. Chloracne has been the only prominent effect found to be caused by TCDD; 193 cases have been diagnosed with 50 cases in residents of Zone A. The diagnosis in the 143 cases outside Zone A is confused because these were found by screening 49,000 people for an incidence of 0.39c and this percentage is reported to be the incidence of chloracne in more northern industrial Italian cities not involved in the accident. How-ever, in Zone A the incidence of chloracne was 79c : 23 times this base rate. In addition, about 10% of the Zone A population showed either minor clinical signs of polyneuropathy or laboratory co CO . ; i 37 of the MTD. Even if a soldier were exposed to 8 pg m '5 each day of his one year tour in Vietnam and each day was treated as a new exposure, his cumulative intake would be only 1.4 pg or 0.02 pg kg"1of TCDD. Since it would take about 5 years of daily close contact with Agent Orange to reach toxic levels of TCDD, claims that illnesses in Vietnamese (Tung eial., 1971, 1973) and Americans (Bogen, 1979) were due to Agent Orange are without merit. However, certain workers in forest industries have been exposed to 2,4,5-T over many years. Although the present concentration of TCDD in 2,4,5-T is < 0.1 p.p.m., it w’as considerably higher than 2 p.p.m. before the 1960s. Commerdal spraying rates were usually less than 3 gallons per acre but higher TCDD concentrations could lead to toxic cumulative intakes after several years. Two patients with Yusho have died from lymphomas and recently six cases of lympho­ ma of histiocytic type were reported in patients w'ho had an average of 8 years exposure to 2,4,5-T in years past (Hardell, 1979). Hence the possibility that cumulative intakes of TCDD above the MTD may have increased the inridence of lymphoma must be further investigated. R eferences ALLEN, J. R.. BARSOTTI, D. A., VAN MILLER. J. ?.. ABRAHAMSON, L. J. &. LAUCH, J.J. (1977). Morphological changes in monkeys consuming a diet comaining low levels of 2,3,7,Stetra-chlorodibenzo-p-dioxin. F o o d C o sm e t. T a x .. 15, 401-410 ALLEN, J. R., BARSOTTI, D. A., LAMBRECHT, L. K. &. VAN MILLER. J. P. (1979). Reproductive effects of halogenated aromatic hydrocarbons on nonhuman primates. A n n . AY. A c a d . Sci., 320, 419-425 BEAL, M. G„ SHEARER, W. T„ KARL, M. M. <£ ROBSON, A. M. (1977). Long-term effects of dioxin exposure. L a n c e t, 1, 748 BOGEN, G. (1979). Symptoms in Vietnam veterans exposed to agent orange. J. A m . m e d . A c s., 242,2391 BOWES, G. W„ MULVTHILL, M. J., SIMONEIT. B. R .T ., BURLINGAME. A. L. & RISEBROUGH, R. W. (1978). Isolation and identification of chlorinated aibenzofurans from polychlorinated biphenyls and from Yusho rice oil containing PCB. In D io x in : T o xic o lo g ic a l a n d C h e m ic a l A sp e c ts, pp. 79-98. New York: Spectrum CROSBY, D. G. & WONG. A. S. (1977). Environmental degradation of. 2.3.7.8tetrachlorodibenzo-p-dioxin (TCDD). S cien c e, 195,1337-1338 CROW, K. D. (1971). Chloracne. T ra n s. St. J o h n 's H a sp . derm . S o c.. Lond., 56, 79-99 HARDELL, L. (3979). Malignant lymphoma of histiocytic type and exposure to phenoxyacetic acids and chlorophenols. L a n c e t. 1,55-56 HAYABUCHI, H.. YOSH1MURA, T. & KURATSUNE, M. (1979). Consumption of toxic rice oil by ‘Yusho- patients and its relation to the ciinical response and latent period. F o o d C o sm e t. T ox., 17.455-461 KIKUCHI. M- HASH1MOTO, M., HOZUMI. M., KOGA. K , OYOSH1. S. ¿e NAGAKAWA.M. (1969). An autopsy case of stillborn of chlorooiphenyls poisoning. F u k u o k a A c t a m e d ., 60, 489-495 KIKUCHI, M. & MASUDA. Y. (1976). The pathology of Yusho. In P C B P o iso n in g a n d P o llu tio n , pp. 69-86. New York: Academic Press KIMBROUGH, R. D.. CARTER, C. D., LIDDLE ,J. A.. CLINE. R.E. 4: PHTLLIPS. P. E. (1977). Epidemiology and pathology of a tetrachlorodibenzo-dioxin poisoning episode. A r c h enuir. H ltk . 32, 77- 85 KURATSUNE. M. (1972). An abstract of results of laboratory examinations of patients with Yusho and of animal experiments. E n v ir. H h h P erspcct., 1, 129-136 t*Ü Ü AGENT ORANGE TOXICITY 00 c'ri _ KINGSLEY M. STEVENS KURATSUNE, M., YOSHIMURA, T.. MATSUZAK, J. & YAMAGUCHI, A. (1972). Epidemiologic study on Yusho, a poisoning caused by ingestion of rice oil contaminated with a commercial brand of polychlorinated biphenyls. E n v i r H ith PerspecL, 1, 119-128 LAMB, J.C.IV, MOORE, J. A. ¿¿MARKS, T.A."(19S0). Evaluation of 2.4-dichlorophenoxyacetic acid (2.4-D), 2,4,5-trichlorophenoxyacctic acid (2,4,5-T), and 2.3,7,8-tetrachlorodibenzo-pdioxin (TCDD) toxicity in C57BL/6 mice: reproduction and fertility in treated male mice and evaluation of congenital malformations in their offspring. N a tio n a l T o xic o lo g y R e p o r t N 1 f - 8 0 ~ 4 4 , Research Trianale Park, N.C. 22709 LIBERTI, A., BROCCO. D.. AJLLEGRINI, I.. CECINATO. A. St POSSANZINI, M. (1978). Solar and ultraviolet photodecomposition of 2,3,7,8-tetrachlorodibenzo-p-dioxin in the envi­ ronment. Set. T o ta l E n v ir ., 10, 97-104. McCCNNELL, E. E. Foreward. yv The phenoxy h e r b i c i d e s , in c lu d in g 2 ,4 -D , have re ce iv e d c o n sid e ra b le a tt e n t io n during the l a s t decade in the p r e s s , in p u b lic h earing s and by groups which have campaigned a g a in s t the continued use o f th ese h e r b ic id e s f o r co n tro l-lin g unwanted ve g etation in f o r e s t s , on r i g h t s - o f way and on c e r t a i n cro p la n d s. The groups a g a in s t the continued use of ^ h e r b ic id e s have spent c o n s id e r a b le time and e f f o r t preparing l i t e r a t u r e , 0 p re ss r e l e a s e s , m a ilin g s and in p a r t i c i p a t i o n a t p u b lic h e a rin g s. \ 551081 The primary message o f these groups i s th a t the use o f phenoxy h e r b ic id e s w ill in c r e a s e b i r t h d e f e c t s and cause m i s c a r r i a g e s , ca n ce r or o th er p h y sic a l e f f e c t s . V ario us s c i e n t i f i c s t u d ie s as w ell as a r t i c l e s from the p re ss are used to support t h e i r a l l e g a t i o n s . Very f r e q u e n t ly only those p o rtio n s of the data, in a given study which support the a l l e g a t i o n are c i t e d . The r e l i a n c e upon data from s t u d ie s conducted in anim als to estim a te the e f f e c t s in humans has a ls o been debated. However, anim als are the only s p e c ie s p h y lo g e n e t ic a lly c l o s e to humans which can be used f o r t e s t i n g . T h e re fo re , i t i s n e c e s s a r y to c o r r e l a t e data from animal s t u d ie s with the p o t e n t ia l f o r human exposure under worst ca se c o n d it io n s and d e f in e a safety fa c to r. In most s t u d ie s on l i v i n g organisms the data are n e i t h e r com pletely p o s i t i v e nor com pletely neg a tiv e but r e q u ir e the e x p e r t i s e o f knowledgeable s c ie n t is t s for in te rp re ta tio n . H e re in , data and c o n c lu s io n s are submitted which are intended to present an unbiased review o f the t o x ic o lo g ic a l conducted to d ate. s t u d ie s on 2,4-D which have been What i s 2,4-D ? 2 . 4 - D (2 ,4 - d ic h lo ro p h e n o x y a c e tic a c id ) i s an h e rb ic id e which s e l e c t i v e l y c o n t r o ls many b ro a d le a f weeds, c e r t a i n hardwood t r e e s and brush on crop and rang eland s, r ig h t s - o f - w a y , and on t u r f and lawns. 2,4-D was f i r s t introduced in the U .S . f o r use by farmers in 1946 (P e te rso n , 1967). U U W 1 551082 1. I t performs i t s co n tro l fu n ctio n by a l t e r i n g the normal growth o f s u s c e p t i b l e weeds and woody p l a n t s . The major use o f 2,4-D i s c o n t r o l l in g b r o a d le a f weeds in c e r e a l g r a i n s . I t does not k i l l most g r a s s e s . 2 . 4 - D i s u s u a l l y a p p lie d a t the r a t e o f h to per a c re f o r c e r e a l g r a i n s . way. 2. h pound a c t i v e in g re d ie n t Higher r a t e s a re often used on r i g h t s - o f 2,4-D i s u s u a l l y formulated as amine s a l t s o r e s t e r s . How t o x ic i s 2,4-D to anim als? 2 . 4 - D i s moderately t o x ic to mammals. The th ree routes of p o s s ib le human exposure a r e : i n g e s t io n , dermal co n ta ct and i n h a l a t i o n . The s i n g le dose oral LD50 (dose determined to be l e t h a l to 50% o f the t re a t e d s p e c i e s ) f o r 2,4-D a c id i s g r e a t e r than 350 mg/kg o f body weight in r a t s , m ice, guinea pigs and ch ick en s (NRCC, 1978). In these same s p e c ie s the acute oral LD50 f o r v a r io u s form ulations o f 2,4-D s a l t s and e s t e r s ranges from 75 to 2000 mg/kg (Weed Scien ce S o c ie t y of America, 1979) (IRAC, 1977). In a case o f a s u i c i d e by a 23 y e a r old stu d e n t, the t o t a l amount of 2 . 4 - D in the body was estimated to correspond to a dose o f 80 mg/kg. (N ielson e t a l . , 1965) No adverse e f f e c t s were reported in a man who took 500 mg 2,4-D o r a l l y d a i l y f o r 3 weeks (approxim ately 8 mg/kg/day) (IARC, 1977). When 2,4-D was used as a treatment in a p a tie n t with 16809 /Men (248) and women (44) engaged in the manufacture of the amine s a l t or the butyl e s t e r of 2,4-D with exposure periods ranging from under 5 y e a r s to 6-10 y e a r s ( f o r 194 and 98 persons r e s p e c t f u l l y ) ; were screened and 63% o f these workers complained f re q u e n t ly o f weakness, r a p id f a t i g u e , headache o r v e r t ig o . About 20% had d istu rb a n ce s o f the c a r d i o v a s c u l a r system (mainly hypotension and b rad y card ia) and of the d i g e s t i v e organs ^ - j I ^\ (d y sp e p tic symptoms and g a s t r i t i s ) . The v a rio u s l i v e r d y s fu n c t io n s th a t • were found were more pronounced in workers w ith longer exposures to the h e rb icid e s. Feldmann & (IARC, 1977) Maibach (1974) stud ied in man the absorp tion through the sk in o f 4yg/cm2 ^ C - l a b e l l e d 2,4'-D d is s o lv e d in a small amount o f acetone. 1!*C a c t i v i t y was measured in u rin e over a 5-day period and compared with t h a t in u rin e a f t e r i . v . a d m in is t r a t io n o f the compound: u r in a r y e x c re t io n o f 2,4-D a f t e r i . v . a d m in is t r a t io n was 100% o f the dose in 120 ho u rs, w h ile e x c r e t io n a f t e r t o p ic a l a d m in is t r a t io n was 5.8% o f the dermal dose. i Kohli e t a l . (1974) adm inistered 5 mg/kg body weight o f pure 2 ,4-D in. a g e l a t i n capsule with water to 6 h e alth y male v o lu n t e e r s , aged 22-30 y e a r s . None o f the s u b je c t s complained o f any i l l - e f f e c t s , no changes in blood p r e s s u r e , pulse r a t e , hemoglobin content or t o t a l or d i f f e r e n t i a l white c e l l counts were observed. 2,4-D was absorbed f a i r l y r a p i d l y . h ig h e st co n centration in blood was reached in 7-24 hours. The In u r in e , 2,4 -D was present as e a r l y as 2 hours a f t e r i n g e s t i o n , and more than 75% was ex creted in 96 hours without undergoing tra n sfo rm atio n in the body. In 5 male vo lun te ers given a s in g le oral dose o f 5 mg/kg body w e ig h t, the h a l f - l i f e in the plasma was 11.7 hours, and e lim in a t io n in the u rin e Hansen et al (1971) adm inistered 2 ,4 - 0 in the d i e t s of r a t s f o r two y e a rs at 0 , 5, 25, 125, 625 or 1200 ppm. While the number o f r a t s employed in t h i s study would not be adequate by todays sta n d a rd s, the authors concluded 2 ,4 - 0 was not a ca rcin o g e n . A rkipor and K o z lo r ia (-1974) s t a t e there was no s i g n i f i c a n t in c r e a s e in ■ < tumors in r a t s o r mice from d i e t a r y o r sk in p a in tin g a d m in is t r a t io n o f 2 ,4 -D . Bjorkland and Erne (1966) adm inistered 2,4-D in the d rin k in g w ater o f r a t s f o r two y e a r s a t l e v e l s up to 1000 ppm and observed no in c r e a s e in tumors. 4. Does 2,4-D cause b i r t h d e f e c t s in humans? T e r a t o lo g ic a l s t u d ie s (stu d y of b i r t h d e f e c t s ) have been conducted with 2,4-D as the a c id and as c e r t a i n e s t e r s in r a t s , m ice, hamsters and sheep. There are d i f f e r e n c e s among s c i e n t i s t s to treatm ents. in d e f in in g t e r a t o l o g i c a l In t h i s d is c u s s io n we w i l l National Academy o f S c ie n c e s ' responses c i t e the d e f i n i t i o n s o f the (1974) and t h e i r ex p lan a tio n of each. "Prenatal development i s d iv id e d into the embryonic stage ( e a r l y ) when the organs are forming, and the f e t a l stage ( l a t e r ) when the organism i s maturing during g e s t a t io n . However, the d i v i s i o n i s not c l e a r - c u t and the prenatal organism w i l l be r e f e r r e d to in t h i s d is c u s s io n as an embryo even i f i t i s t e c h n i c a l l y known as a f e t u s . " "An agent or chemical i s considered as t e r a to g e n ic when i t causes develop­ mental d istu rb a n c e s in the embryo r e s u l t i n g in cong enital m alform ations. I f an agent k i l l s the embryo i t i s s a id to be em b ry o cid a l, and i f i t -1-16911 causes c l e f t p a la t e in the mouse and the r a b b i t , but not in the r a t . We s t i l l do not know i f i t i s te r a t o g e n ic in man. Thus, one cannot e x tr a p o la t e with any assurance from one s p e c ie s to another, or even one s t r a i n to a n o th er, and one cannot r ig o r o u s l y prove an agent i s t e r a t o g e n ic in man from data on experimental a n im a ls - - o n ly from data on human b e in g s ." " I t must be emphasized t h a t a g reat many agents are te r a t o g e n ic in e x p e r i ­ mental a n im a ls, p a r t i c u l a r l y rod ents. te ra to g e n icity : Many drugs have demonstrated v a r io u s a n t i b i o t i c s , amphetamines, a n t ih is t a m in e s , a n t ic o n v u ls a n t s , b a r b i t u r a t e s , c a f f e i n e , clomiphene, c y c l i z i n e , LSD, th a lid o m id e , tolbutam id e, and v a rio u s t r a n q u i l i z e r s . Metals (cadmium, c a lciu m , l e a d , m ercu ry), hormones (ACTH, a d r e n a l i n , androgenic hormones, a n t io v u la t o r y compounds^ e stro g e n s, g l u c o s t e r o i d s , i n s u l i n , s e r o t o n i n ) , vitam in A, and se v e ra l o th er kinds o f c h e m ic a l, p h y s i o l o g i c a l , and environmental agents (maternal d eh y d ra tio n , maternal s t r e s s , carbon ^'monoxide, n o is e , and hypoxia) have a ls o been shown to be t e r a to g e n ic •b in la b o ra to ry a n im a ls. For se v e ra l o f th ese th ere i s good evidence o f low or no t e r a t o g e n i c i t y in man ( e . g . , c y c l i z i n e ) , but f o r most o f them the p o s s i b i l i t y o f low l e v e l s o f t e r a t o g e n i c i t y has not been ru le d o u t , and i t would be v e ry d i f f i c u l t to do so. Only f i v e have been c l e a r l y im p lica te d as humans teratogens (d ip h en y lh y d a n to in , androgenic p r o g e s t in s , org anic mercury, r a d i a t i o n , and th a lid o m iJ - ' " "Much l e s s work has been done on the t e r a t o g e n i c i t y of 2,4 -D . One study ( B io n e t ic s Stud y, see Mr'jajk Report, 1969) suggested th a t the b u t y l, isopropyl and i s o o c t y l e s t e r s o f 2,4-D may be teratogens of low potency. Schwetz e t al_. (1 9 7 1 ), feeding the f r e e a c i d , the propylene g lycol F i r s t , a mutagen i s a m a teria l th a t i s capable o f producing g en etic damage which can be i n h e r it e d by fu tu re g e n e ra tio n s. evaluated in a number o f m u tagenicity s t u d ie s . 2 ,4-D has been I t has been demonstrated DOW 1 551090 Is 2,4-D a Mutagen? th a t 2,4-D i s not a mutagen in a v a r i e t y o f m icro b ial s t u d ie s as well as in male f r u i t f l i e s (D ro sp h ila m elanogaster) . 1974). (1972) found th a t a t o t a l o f 75 mg of. 2,4-D/kg o f E p ste in et a l (Vogel - Chandler, body weight given over a f i v e day period did not in c r e a s e dominant le t h a l mutations in mice. Treatment o f in v i t r o c u ltu re d human lymphocytes with 0.02 mg/ml^ 2,4-D in cre ased the number o f chromatid a b e rr a tio n s and to a l e s s e r e x | t e n t , chromosomal a b e r r a t io n s . In m ice, t o x ic co n ce n tra tio n s (100-300 mg/kg/body weight) o f 2,4-D adm inistered as a s i n g le o ral dose s i g n i f i c a n t l y in cre ased the frequency o f a b erra n t metaphases (2-4 f o ld ) in lymphocytes; s in g le fragments were the primary a b e rra tio n ( P i l i n s k a y a , 1974, c i t e d in IARC, 1977). 2,4-D had no e f f e c t on c u ltu re d c e l l s nor on bone marrow a f t e r i t s oral a d m in istra tio n to r a t s ( S t y l e s , 1973 c it e d in IARC, 1977). There was no in c re a s e in the m icro n u clei in e ry t h ro c y t e s o f mouse bone marrow a f t e r i n j e c t i o n of 100 mg 2 ,4-D/kg/body weight. Examination o f chromosomes of workers employed in the production o f 2,4-D in d ic a t e d no changes (Johnson, 1971). The Royal Swedish Academy of S cie n ce s arranged a conference in Stockholm in February, 1977 organized into f iv e working groups comprising ch e m istry , i p la n t ph y sio lo g y , t o x ic o lo g y , g e n e t i c s , and e ' " ' — w i4-^ « r r - — 13 h y d r o ly s is o f 1 , 2 , 4 , 5 tetra ch lo ro b e n ze n e . Any TCDD so formed can be c a r r ie d through into products made from 2 , 4 , 5 - t r i c h lo r o p h e n o l , such as 2 , 4 , 5 No TCDD i s found ? fiO T c ;S f t ric h lo ro p h e n o x y a c e t ic a c id ( 2 , 4 , 5 - T ) and hexachlorophene. in 2,4-D (Ramel, C. 1977). 1 'L 'i f a - iJ The expected 2 ,7 - d ic h lo ro iso m e n / i s not fonpecT'by co n d en sa tio n "o r 1 / 2 ,4 -d ich lo ro p h e n a te under the acid> oflnditions used in i t s manufacture by c h l o r i n a t i o n o f phenol. -dJf 28 samples o f 2,4-D te s t e d f o r content o f c h lo ro d ib e n z o - p a ra - d io x in s , one was reported to co n ta in l e s s than 10 mg/kg~ hexachlorodibenzo-p- d io x in . 7. (Woolson e t al 1972, c i t e d in IARC, 1977) What E f f e c t Does 2,4-D Have on The Environment? The environment i s composed o f many compartments in c lu d in g s o i l , a i r , w a te r, man, b i r d s , a n im a ls, p la n ts and i n s e c t s , e t c . 2 ,4 - D , when used as d ir e c t e d on the l a b e l , e x e rt s i t s e f f e c t on a s e l e c t p ortion o f the p la n ts in the environment. A p p lic a t io n o f 2,4-D by means o f s p r a y in g , e i t h e r by ground or a i r , provides the p o t e n t ia l f o r contam ination o f the o th er compartments. Fate in S o il In s o i l , in the presence o f m o istu re , even a t low l e v e l s , the e s t e r s o f 2,4-D a re hydrolyzed to the acid form. The p e r s i s t e n c e o f the is o o c t y l e s t e r of 2 ,4 - 0 was studied under f i e l d c o n d it io n s by B u rcar et a l . (1966, c i t e d in NRCC 1978) who noted the complete breakdown of the e s t e r to the a c id in two weeks. The f r e e a c id s a ls o have a r e l a t i v e l y ..o pH, presence o f org anic m a tte r, su n lig h t and m icro b ia l f l o r a . >;ed ra te s o f a p p l i c a t i o n , 2,4-D would not be detected in most , : rcnments 30 days a f t e r in t r o d u c t io n . : . : i e s with f i s h have been reviewed by M ullison (1 9 7 0 ). - In natural" c o n d itio n s most f i s h s p e c ie s can t o l e r a t e 2 ppm :ng 5 pounds 2,4-D per a cre in water about one foot deep •—ate 2 ppm. Under n a tu ra l c o n d itio n s f i s h could u s u a ll y - areas o f 'h ig h c o n c e n t r a t io n s . "f 2,4-D are a p p lie d as aqueous emulsions or s o l u t i o n s in s p r a y e r s 'o r by a i r c r a f t . During a p p l i c a t i o n , some o f the '•’ f t from the t a r g e t s i t e before being in te rc e p te d by - q u an tity which may d r i f t i s dependent upon d ro p le t "••ty, temperature and hum id ity, v i s c o s i t y o f the formufrom a p p l ic a t o r to t a r g e t , and perhaps the most important ••itions e x e r c is e d by the i n d i v i d u a l s performing the ''in g to the l a b e l . d i f f e r in t h e i r r a t e o f v o l a t i l i z a t i o n from the t a rg e t r s a lt s a re l e s s v o l a t i l e than the e s t e r s . Proper '"■'-nation and o b serva tio n o f the c l i m a t i c c o n d it io n s :'918 typical GC-MS data for a urine sample from a 2,4,5-T plant‘worker, i ig n a t u * « ~ - . . a y / Marsha L. Landrhorst Data Book AL 1207 p. 118 Í O R M M •60 940 PHONE 6-6207 auiLO iN s 574 OATE FINISHED HOURS 7/13/78 RESULTS PHONED 37 h J u l y 28, 1978 -2- AL 78-50668 Figure 3 shows typical GC-MS data for a blood sample from a 2,4,5-T plant worker. The presence of Silvex was asked to be confirmed. It pound by GC-MS six-ion monitoring or whether Silvex or an interference could be created from 2,4,5-T during the sample preparation or analysis. To check the creation of an interference during sample preparation, a urine and blood sample were spiked with high levels (1.85 jig/gm sample) of 2,4,5-T. The sample was pro­ cessed through the usual procedure and analyzed. were found other than 2,4,5-T. DOW 1512709 was questioned whether Silvex could have an interfering com­ No peaks See Figure 4. To check if the ethyl ester of 2,4,5-T might interfere with the methyl ester of Silvex, MS at m/e =* 282) by GC-MS, with ethanolic HC1. (both have parent ions by A sample of 2,4,5-T was ethylated The sample was analyzed by GC with electron capture detection and found to elute at a different retention time than Silvex. Therefore, it could not inter- fere by GC-MS and produce a response interpreted as Silvex. In addition, to check if any ethyl ester of 2,4,5-T is formed during methylation, a relatively high concentration of 2,4,5-T was methylated. No peaks were detectable except the methyl ester of 2,4,5-T, This evidence is shown in Figures 5 and 6 . The identify of Silvex in urine and blood samples is confirmed by retention time, ions in the mass spectra, and ion abundance ratios (.282/198) , 16919 July 28, -3 1978 AL- 7 8 - 5 0 6 6 8 REFERENCES 1. Marsha L. Langhorst, "Determination of Phenoxy Herbicides in Human Urine and Blood Samples - (Validation 2. Marsha L. Langhorst, "Determination of Phenoxy Herbicides in Human Urine and Blood Samples (RESTRICTED REPORT)" ML-AL 78-50405, 3. Marsha L. Langhorst, "Determination of Phenoxy Herbicides in Human Urine and Blood Samples from 2,4,5-T Plant Personnel, (.RESTRICTED REPORT)" ML-AL 78-50489. DOW 1 512710 Data)", ML-AL 78-50252. td 1&920 J u l y 28, AL 78-50668 1978 TABLE X RESULTS PHENOXY HERBICIDES IN 2, 4y5WT PLANT PERSONNEL. Sample Type Concentration found Cng/gm Sample1 Silvex 2,4,5-T 2,4-D U-l Amble U-2 Crivac a - 3 Falkowski U-4 Swogger Urine Urine Urine Urine 380 520 510 270 B—1 Amble B-2 Crivac B-3 Falkowski B-4 Swogger Blood Blood Blood Blood 2.0 8.6 9.3 3.8 21 540 4.1 23 220 11 310 170 N . D . (1) N.D. (1) N . D . (1) N.D. (1) 8.7 5.6 7.9 2.4 DOW 1 512711 Person NO, SPIKED SAMPLES FOR RECOVERIES No. Sample Type U-l B-l Urine Blood NOTES: 1850 ng/gm urine N.D. (1) N . D . (0.5) 1850 ng/gm blood N . D . (2) N.D. (1) 1540 1400 83 76 N.D. = Not detected with minimum detection limits shown in parentheses. Compound in ng/ml in nq D 1 Minimum detection limits 200 10 Silvex 100 2,4,5-T 100 to % Cone found (ng/gm) 2,4-D Silvex 2,4,5-T Recovery Spiked with 2,4,5-T (MDL 1's) are: in ng/gm urine in ng/gm blood 1 2 5 0.5 1 5 0,5 1 assuming 50 yl final volume assuming 1 0 gm urine sample asstaming 5 gram blood sample 1 Methods are validated down to 3 ng/gm urine and 5 ng/gm blood. • i . 11 ^ ; : T ..-j C j.ï.-V - ►- : i L hbLil STA N PARO ' ' G C - hê>~ DATA , ' ‘ f l Gu ieè ; ¡ . ~ ' lT '” ■*: i i » . *' ■0 ri í ; I Lì F b. - :.¡F :f: : ¡ i R R u c . INSTRUMENT.1 HcultH -fa cía rzi S W Z hVrí : '_ F 2 _ 2 FOR R I J M tf G-c-M S Cc u im n : H ' X Z m * ¡■ cL^hss/ 3 7 • SP'240l »n , - I ££*■ "v'ÔL i tfUt-. --1000 ribUMli’-iî-io-c *■ 1 ï';3 a 3 2 3 2 S S 3 9 « “ *«»»a ———---J = 4 *7 ' J » j x> SILVER ll3 a a B « a a a .. * ¡ii/-. i Cas 2,4,'S’*T t ‘ 2 8 2 .0 0 1 7 5 .8 5 2 3 3 . tí 03 c•J cO-J c . -J •- -? I 2 b 3 . O0 2 0 2 * 2r Ü T t-* ■ 0- '■ '- - . 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OF PWENOXY AND H e »«-Bi c,»r s STANPARP - 1,4,S-T AS E W Y L ESPER STANDARD* PH6MOXV HERflICIpeS AS METHYL ESreR S EFHYL ESTER. OF Z ^ S-T Cm ppm) FlG U p " JT y j\ 5 -il (2 .1 3 p p m ) Opefolor.Mjr?Y)k a T’» ri n ' i Si f 4 : N «1 S' y o U __________I 4 8 mmuieS - ) v z tv) Cf5 i 12 I o I I 4 I I t minuTti —^ 9 T iS T 9 l MOQ 1 Fieru/u OF 2 ^ 5 -f A FHffc I6THYLA770M " Sm>kU,KIGr 'mAT ^ ESTER IS FORMEP DU£|kj • SrT)Nfíflep '/ ) í ^ í - T a P -U i,ß? ppM ít r y « 'w t T ít y J a f a n o aHertuaiftui ’ fr4*i£) O - lS / r m ) 1 C’iïR.OMfWDGrflAMS < r> ?* v> C /Ï ¿ - % t s - T - ¡ lo i t* < V »7 . f*A í. £ . Ü) 4* 04' «/I '-V L r\S p í: r . i ec J --- I ' o 1 4 i I % rv>iruJLÍi25 —9 I T2 ¿T¿ZTá I O I IMOO i i 4 « rmViuT <*S —? 2418 A LONGEVITY SURVEY OF EMPLOYEES EXPOSED TO or 2,4,5-TRICHL0R0PH5N0XYACETIC ACID CD CJJ ro M. G. Ott, H.s. B. B . Holder, M.D. R. D. Olson, B.S. Medical Department The Dow Chemical Conpany Midland, Michigan RECEIV ED MAR 2 1 1973 REGISTRATION //A a - 1 6 8 .2 8 A B S T R A C T cn O cn A LONGEVITY SURVEY OF EMPLOYEES EXPOSED TO CO 2,4,5-TRICHLOROPKENOXYACETIC ACID Ott, M.G., Holder, B.B., Olson, R.D. There have been few published reports regarding epidemiologic surveillance of individuals occupationally'exposed to 2,4,5trichlorophenoxyacetic acid (2,4,5-T). The present study examined the mortality experience of 204 persons exposed to 2,4,5-T during its manufacture. Exposure durations ranged from less than one year to a maximum of approximately 10 years over a period from 1950 to 1971. Within the scope of this mortality survey, no adverse effects were observed with respect to occupational exposure to 2,4,5-T. 1 Q B 2 B p -si9S i> I MOO A LONGEVITY SURVEY OF EMPLOYEES EXPOSED TO 2,4,5-TEICHLOROPHENOXYACETIC ACID Introduction In 1976 Muranyi-Kovacs et al published results of a bioassav of 2,4,5-trichlorophenoxvacetic acid genicity^. (2,4,5-T) for c a r c i n o ­ The 2,4,5-T, w h i c h c ontained less than .05 ppm of 2,3,7,8-tetrachlorodibenzo-p-d ioxin (TCDD), was found to produce a significant increase in non-incidental tumors (diagnosed during life or causing the death of the animal) in C3HF mice, but not in XVII/G mice. Both groups of mice had be e n fed 80 ppm 2,4,5-T on a daily basis until death. Previously, considerable variation had been demonstrated in the kinetics of excretion on 2,4,5-T between species 2 . An earlier screening bioassay study by Innes et al was not positive for tumorigenicity in two hybrid strains of mice fed 60 ppm 2,4,5-T m bioassay article, Innes, their diet 3 . The authors or the 1975 aware of the kinetic studies and paper by suggested that additional testing of 2,4,5-T was needed. A two year feeding study in rats is c urrently underway at The Dow Chemical Company Toxicological Laboratories in Midland, Michigan. Only limited epidemiological investigations of w o r k m e n exposed to 2,4,5-T have been c o n d u c t e d ^ '^ . In 1971, Poland et al 2,4,5-T Survey, Ott et al reported results of a health survey of 73 male employees in a 2,4,5-T and 2, 4-dichloropher.oxyacetic acid facturing plant'*. (2,4-D) manu- CD This survey was a followup of studies same p l a n t ^ . An important finding in the follovnip was evidence of varying degrees of acne in 48 of the 73 employees 456155 published by Bleibarg et al in 1964 on 29 employees in the The term "chloracne" was employed to describe the moderate to severe lesions observed for 13 (18%) of the individuals. Evidence of abnormal excretion of uroporphyrins was not found in the followup study in contrast to the original work. Also the authors in their summary stated that markedly less evidence of toxicity was found in other organ systems, than was reported in previous studies. such as the liver, It was noted, though not judged to be explanatory of differences in toxicity seen from the earlier work, survey, that six months prior to the second contamination of the process starting material, 2,4,5- trichlorophenol (TCP) , with TCDD had been reduced from 10 to 25 p p m to 1 ppm. No detailed industrial hygiene measurements of 2,4,5-T or TCDD levels in the work environment were provided. The present study examines the mortality experience of a cohort of 204 employees engaged in the manufacture of 2,4,5-T. A review of health exam findings of phenoxv herbicide workers 7 in this plant was discussed in a paper by Johnson . The current survey compares mortality due to specific causes, with the corresponding U.S. white male population and with reference to other mortality studies conducted at this company location. 2,4,5-T Survey, Ott et al Historv o£ Process and Industrial liverione Measurements 1950,- with the original process being operated con­ tinuously until May, In 1967, 1971, ]456156 March, DOW The commercial production of 2,4,5-T in the company began in when it was permanently shut down. a second operation v/as developed that utilized different personnel and which has continued in production. Personnel from the second process were not included in the p r e s e n t study, because of the shorter latency period and because this more recent process produces esters of 2,4,5-T with o u t isolation of the acid. The departmental unit under whi c h the original process v/as first organized also was responsible for manufa c t u r i n g a variety of other products ranging from styrene butadiene latex to herbicides such as 2,4 , 5-trichlorophenoxy propionic acid and 2-methyl-4-chlorophenoxyacetic acid. Thus, many of the individuals included in the present study were potentially exposed to numerous other substances during their employment with this unit. The 2,4,5-T was manufactured by reacting sodium monochloracetate with the sodium salt of TCP, by adding caustic to TCP. to the acid. process, the salt being prepared This v/as followed by conversion A n additional step not considered part of the but taking place in the same building, was esterifi­ cation of 2,4,5-T with propylene glycol butyl ether or isooctyl alcohol. Continuing efforts were made to minimize TCD D con­ tamination in the 2,4,5-T plant by proper control of a separate 2,4,5-T Survey, Ott et al 3 plant which produced OOW 1 process. the TCP later used in the 2,4,5-T Wipe testing in 1970 failed to detect TCDD in the 2,4,5-T work area using a combined gas chromatography, mass spectrometry method sensitive to approximately 1 pg/sample 456157 depending upon interferences. The 2, 4 , 5-T process was specifically run by a craw of four operators: operator, a salt wheel operator, a reactor an acid wheel operator, and a dryer operator. The reaction port i o n of the process in w h i c h the sodium salt of 2,4,5-T was produced was nearly a closed system. During the subsequent wheeling operations, v/as converted to the acid. the sodium salt The 2,4,5-T dust levels found in the plant were believed to have resulted primarily from finishing operations where the end product v/as dried and fed through a hammer mill. A n industrial hygiene survey of the process was conducted in 1969 at which time 50 area and breathing zona samples wer e collected using a midget inpingsr containing isooctane at a flow rate of 2.2 liters per minute. The samples were subsequently analyzed by gas chromatography for TCP, and 2,4-D. Concentrations of 2,4,5-T or its sodium salt ranged from <.l mgs/m average 2,4,5-T, 3 to 6.21 m g s/rn 3 . Estimated time-weighted- (TWA) concentrations for the three compounds by job classification are shown in Table 1. Concentrations of these substances were relatively similar for three of the job 2,4,5-T Survey, Ott et al .4 classified tiers reactor operator, salt wheel operator. dryer operator, and The acid wheel operator was exposed to lower 2,4,5-T levels and higher TCP co n c e n t r e t i o n s . The 2,4-D measurements are maxi m u m levels. This product was dried occasionally in the building where 2,4,5-T was cn Ob h-* made. cn oo Often dust levels in the finishing area were high enough to be noticeably irritating. irritation, sneezing, Sensory responses such as nasal and a bitter taste were reported by unacclimatsd industrial hygienists to result from exposure levels of approximately 4 mg/m^ of TCP. .1 m g / m 2, 4 , 5-T and/or less than A review of medical visits from 1954 to 1970 revealed 19 episodes associated with acute exposure to 2, 4 , 5-T or its esters among the 204 men in this study. reported exposures involved eye o r skin contact, All v/ith the mild to moderate responses apparently resulting from the irritating effects of the materials. Six of the exposure episodes occurred while the men were working as ester operators rather than directly on the 2 , 4 , 5-T process. The esters of 2,4,5-T are believed to exert similar toxicological effects as the acid after adjustments for the molecular weight of the ester itself. Method of Analvsis The employees included in the study wore determined by a two-stage procedure. In the first step all persons working n 2 , ,1 c ,5 - mi Survey, Ott et al in the department under which the process was organized were identified from annual census lists covering the 1951, through January, 1971. DOW 1 4 5 6 1 5 9 period January, The second step was a review of the complete work history for eachindividual to determine those who had experience on any of the four jobs of interest. population of concern. These employees constituted the This met h o d of selecting the exposed population insured that all employees who worked continuously for at least one y e a r with the 2,4,5-T wo r k area were included, b u t could have missed some personnel who worked in the exposure area for shorter periods of time. A crew of 8 to 12 men operated the 2,4,5-T process on a daily basis. The flow of employees in and out of the department over the 21 year period resulted in 204 me n having worked for I t months on at least one of the four jobs involved. The m ortality experience was compared with the U.S. white male experience 1962, (5 year age intervals) for the years 1952, 1957, 1967 and 1971 by the indirect method. The vital status of former employees was initially traced through the Social Security Administration. Subsequently, verification of vital status has been obtained through contact of the individual or r elatives who could account for the former e m p l o y e e s ’s vital, status. In this analysis exposure is expressed only in terms of length of e mplovment on the four jobs of primary concern. Exposure 2,4,5-T Survey, Ott et al 6 ie e a ? ) durations co not take into account the unmeasured exposures within the production department. DOW 1 4 5 6 1 6 0 to 2,4,5-T or esters of 2,4,5-T encountered on other jobs One job did involve exposure to esters of 2,4,5-T and several other jobs may have required filling in on a day-to-day basis for the operators in the four classifications of interest, as other duties with minimal exposure. as well Since many of the employees in the 2,4,5-T study work e d on a number of jobs wit h i n the d e p a r t m e n t , .the durations of exposure are c o n s e r ­ vatively estimated. Sixty of these employees are also known to have worked in a styrene/butadiene latex pla n t organized within the production department. Thus, the persons included in the present study have bee n exposed during their emp l o y ­ men t to a variety of chemical compounds. Results The vital and employment status of the 204 workers exposed to 2,4,5-T and its sodium salts are shown in Table 2. Fifty-three of the 56 former employees have been traced through personal cont a c t of the man himself or someone who currently knows him. For three persons vital status was verified at least through 1973, but not through 1976, security c h e c k s . by personal contact or social Two of the former employees had died as of followed through employment and retiree records. 2,4,5-T Survey, Ott et al . 7 The distribution of employees by duration of exposure and date first exposed is shown in Table 3. More than 752 of th men had worked for less than 12 months in jobs involving defined exposure. None of the men were exposed to 2,4,5-T Medical records of employees were reviewed for evidence of 456161 over a working lifetime. chloracne or porphyria cutanea tarda, which might indicate exposure to TCDD. No case of chloracne or porphyria cutanea tarda was found. Tables 4 and 5 summarize mortality by duration of exposure and interval since first exposure. In Table 4 observed deaths were increased over expected only for the cause of death category deaths). "External Causes" (6 observed vs. 3.7 expected Three deaths in this category were due to separate automobile accidents, none of which took place while the individuals we r e employed on jobs involving 2,4,5-T exposure. One death was the result of a nonindustrial fire, and the .remaining two deaths were suicides among former employees that occurred more than 10 years after exposure had ceased. The single observed malignancy death in the cohort to date v/as a respiratory malignancy which was discovered in a 63 year old retiree who had been exposed to 2,4,5-T for 8 years and had a past history of cigarette smoking of up to two packs per day. 2,4,5-T Survey, Ott et al ‘3 ■*S 1 exposure follows a pattern which we have observed in other The most favorable exposure followed by a relative increase compared to general population mortality. We have interpreted these findings to indicate a preselection effect due to initial employment or DOW 1 4 5 6 1 6 2 g studies at this company location . transfer of individuals in a state of good health which becomes less important b o t h as the interval since employment increases and as the employees become older. Comment At the exposure levels experienced by the workmen in this study, no adverse mortality effects have been observed in association with the work environment. this limited survey, Within the scope of mortality has been favorable compared with the U.S. white male population and also compares well with the background mortality experience at this manufacturing g location . Because of questions raised by recent animal toxicological studies, mortality surveillance of this limited employee population will be continued. We recommend the initiation of mortality surveillance of other populations w h i c h have had past exposure to 2,*i,5-T. Ott et al 9 REF DREI:CjL.O 1. 2. Muranyi-Kovacs I, Rudali G, and Imbert J: Bioassay of 2,4,5-Trichlorophenoxyacetic Acid For Carcinogenicity in Mice. Er J Cancer 33:626-633, 1976. cn cn K* and Rowe VIC: CD Gehring PJ, Kramer CG, Schwets BA, Rose JO, The Fate of 2,4,5-Trichlorophenoxyacetic Acid (2,4,5-T) Following Oral Admini s t r a t i o n to Man. Toxicol. Appl Pharmacol 26:352-361, 1973. 3. Innes JRM, Ulland BM, Valerio MG, Petrucelli L, Fishbein L, Hart ER, Pallotta AJ, Bates RR, Falk HL, Gart JJ, Kle i n M, Mitchell I, and Peters J, Bioassav of Pesticides and Industrial Chemicals for Tumorigenicitv in Mice; A Preliminarv Note. J Nat Cancer Inst., 42:1101-1114, 1969. 4. Aocelson 0, Sundell L: Herbicide Exposure, Mortality and Tumor Incidence. A n epidemiological investigation on Swedish railroad workers. Work-Environ-Hlt 11:21-28, 1974 . 5. Poland AP, Smith D, Metier G, and Possick P: A Health Survey of Workers in a 2,4-D and 2,4,5-T Plant. Arch Environ Health, 22:316-327, 1971. 6. Bleibarg J, Wallen M, Brodkin R et al: Industrially Acquired Porphyria. Arch Derm, 89:739-797, 1964. 7. Johnson JE: The Public Health Implications of Widespread Use of the Phenoxy Herbicides and Picloram. Bio-Science 21:899-905, 1971. 8. Ott MG, Holder BB, Gordon HL: Determinants of Mortality in an Industrial Population. J O M 13:171-177, 1976. ¡ 0 CO 1. D O w iv s k /t y Table Time-Weighted-Average Exposure Estimates for 2,4,5-T Process Based on 50 Samples of Up To Five Minutes Duration and Time Studies for Each Job, 136". TCP (mg/in3) Job 2,4-D (mg/m3)* J* • 2.1 Salt Wheel Operator 2.1 0.5— <0.4 . Acid Wheel Operator 9.7 0.2 <0.4 Dryer Operator ' 1.6 0.5 <0.4 o ’ CO Reactor Operator 2,4,5-T1 (mg/m3) _ r-.VJ. <0.4 ^Highest possible values using levels of detection as real values. **Present in work environment as sodium salt. ^Product specifications for 2,4,5-T in 1966 called for a maximum of lppm T~DD, the sensitivity of the method of detection. In 1972, the maximum was lowered to .lppm TCDD. 1 Ii f > •r ; •' « • ' ; ----------- ------------- <--------------------- ? — .i w. »« -■ «v ... • ■;* ^ i - '* * - r ‘~ ■Tr'.rTi~ :* »..vr.:c?vi'*vr';^r ''r,~y.v7-s-_Tv:u ....... ■■ J vV y , ■• ■M . . ■ ■ _. s r r .. ..................j p . , m 5r y jH h t * . '¿¡C * ty jV W W 1*^5 .. Table 2. Vital and Employment Status of 204 Workers Exposed to 2,4,5-T as of 12/31/76. Vital and Employment Status Number of Workers Total Group 204 Still Employed 121 13 Retired (Company Records) 9 Left Emplo y m e n t Other Than Through Retirement 56 Deceased Deceased Known Alive Followup Through 1976 Incomplete 2 51 3 Table 3. Duration of Exposure by Date First Exposed A m o n g 204 2,4,5-T Exposed Employees. Duration of Exposure* Date Exposure Began Total <1 Year 1-2 Years 3-4 Years 5+ Years 204 157 30 9 8 50 30 17 5 6 1955-1959 45 36 6 2 1" 1960-1964 51 44 4 2 1 1965-1969 35 32 3 0 0 19 70 + 15 15 0 0 0 TOTAL 1950-1954 ‘ 16942 *Fifty-nine of the 204 employees worked as ester operators for from <1 up to 77 months (11 of these employees had worked for at least one year as ester o p e r a t o r s ) . The exposure durations as ester operators, or while employed in other capaciti.es within the production department, were not included in the table since exposure intensities had not been estimated. 99T92^ wj ( m Tabic 4. Observed and Expected* Deaths Among 204 Employees Exposed to 2,4;5-Trichlorophenoxy 7vcctic Acid, by Cause and Duration of Exposure, 1950-1076. Duration of Exposure Cause of Death Category Total Exposed Group <1 Year Total Exposure 1+ Years Total Exposure Observed Expected Observed Expected Observed Expec ted All Causes 11 20.3 6 13.3 5 7.0 Total Malignant Neoplasms 1 3.6 0 2.3 1 1.3 Diseases of Cardiovascular Sys torn 4 9.1 1 5.6 3 3.5 External Causes and Suicides) 6 3.7 5 2.8 1 0.9 0 3.9 0 2.6 0 1.3 All Other Causes (Accidents *Expccted numbers of deaths based on U. S. white male mortality rates. ¿9I9S* C T> to (J Ù l MOO Tabic 5. Observed and Expected* Deaths Among 204 Employees Exposed to 2,4,5-Trichlorophenoxy Acetic; Acid by Cause and Interval Since First Exposure, 1950-1976. *Expccted numbers of deaths based on U.S. white male mortality rates 89T9£f> I CTj CD MOO 2419 AGRICULTURAL PRODUCTS DEPARTMENT o o COPIES: 12/19/78 ■NJ sO B. A. R. L. J. R. B. Schwetz, 1803 \ Morgan, 9008 \ Kodba. 1803 N E. Warren, Davis Davidson,9008 Johnson, 2040 Holder, 2030 DOW 1 3 6 2 5 6 8 from: JOHN H. DAVIDSON 636-4826 ASSESSMENT OF HAZARDS ASSOCIATED WITH USE OF 2,4,S-T, 2,4-D, AND SILVEX IN REFORESTATION PRACTICES In such a report as this it would be highly desirable to prepare a hazard analysis for each compartment or trophic level in the potentially affected ecosystem. This is at least very difficult and perhaps impossible to develop in a single document with the complexities of inter-level de­ pendence and ultimate dependence on many target plant species. There is an made to concentrate on potential human impact. In that process, essential information on lower species appears to the extent necessary. There is an extensive literature on persistence, physical trans­ port, and degradation mechanisms of the phenoxy herbicides in the environ­ ment and their behavior is well established. These areas are discussed only in sufficient detail to establish essential facts. The section on TCDD is an exception and includes as complete a treatment as possible because of the unique character of the chemical. Furthermore, the author is not competent to critically analyze the entire literature on physical and chemical behavior. Problems Associated With Assessment of Human Health Hazard Associated With Use of Phenoxy Herbicides There are fundamental differences of opinion in philosophy of her­ bicide usage. A significant segment of the population consider insertion of any synthetic chemical into the environment as fundamentally wrong, regardless of benefits, however well documented. There are as well groups and individuals who are unable to accept any suggestion that some chemicals, as used successfully and with apparent impunity for decades, might constitute a hazard which is only now becoming evident. 116 6 9 5 Z 9 C IW 0 Q extensive literature on such effects, but in this report a decision has been This issue is no more clouded by those viewpoints than is any other debate over chemical usage, and we are best served by dealing with the problem without those extremes. Without question, the issue of phenoxy herbicides use has evolved to concerns about the contaminant TCDD in 2,4,5-T and silvex. Though 2,4-D has no such impurity, it has become tarred with the same brush, and it is not unrealistic to devote more space to the contaminant than any of the primary chemicals. trinsic toxicity of TCDD, the most critical technical question about that chemical centers on analytical methodology. There are few labora­ tories with the sensitivity to deal with concentrations on the order of 10 ppt or less, and there is real disagreement about reliability of detec­ tion or measurement at such low levels. When the data are considered, some samples in which TCDD was undetectable had high detection limits, some areas with no spray history were found to have measurable TCDD. Also, many samples of similar origin differed widely. Nonetheless, the data appear to be telling us clearly that some TCDD is present in some segments of the environment, that the amounts are uncertain, and that existing residue information must be augmented if we are to understand the behavior of TCDD. With any effort presently imaginable, however, it will probably not be possible to directly monitor the amount of TCDD in the physical environment. ' A proper analysis of hazard requires consideration of chemical be­ havior and ambient levels of the potential intoxicant, but in the case of TCDD we must rely on indirect assessment. 117 The extent of uptake in DOW 1 3 6 2 5 7 0 Because of the extremely low environmental levels and enormous in­ organisms that might concentrate TCDD, as compared with residues follow­ ing known laboratory exposures is of some value, but is still inadequate. There is a pervading argument over the problem of a specially sensi­ tive or idiosyncratic individual who responds to ouch lower doses than the surrounding population, or who responds in a highly exaggerated manner. Such cases are so rare that usually no field association with the causa­ tive event can be made. The effect is virtually impossible to find ex­ perimentally because it may have never been identified, and if it had, The argument about idiosyncracy follows every chemical in commerce, and society has not learned how to cope with it, or even whether it wants to try. In the context of excessive sensitivity there seems to be no reason to treat the present group of chemicals differently from any others. That is to say, every reasonable attempt must be made to locate or predict adverse effect, but it does not seem possible to anticipate the extremely rare response in areas not supported by research findings. A hazard analysis dealing with TCDD may or may not be strengthened by a position that EPA will apparently take; i.e., that 80-200 ppt TCDD in beef fat is an "effect level." The EPA document in question is as yet in draft form and will not be specifically attributed or referenced in this report. If the figures indicated are correct, any levels in beef thus far detected are within levels which will not do harm. The conclu­ sions were reached with the assumption that beef fat will constitute no more than 2.5% of the human diet. The concern in present forestry usage is primarily with deer which browse on treated foliage, and there is no clear indication of TCDD levels which might be expected in these ani­ mals. 118 D0W13 6 2 5 7 1 the genetic and species factors probably prevent any useful modeling. The most difficult problem of the several that axe a part of the task of hazard assessment is, again, part of the decision pattern for any chemical, the risk-benefit analysis. Risk benefit analysis is an excellent basis for conversation but nearly useless in decision making. In the present case there seems to be a general conviction that herbicide appli­ cation is a highly useful tool in forest production. At the same time, estimates of differences in actual relative costs of tree production or Technically, economic benefit should be an accessible factor, but it seems elusive. Risk, on the other hand, is not quantifiable unless major and obvious effects occur; such situations make the decisions for us. If we are able to show any human illness resulting from environmental practices of chemi­ cals, almost certainly they will be disqualified. An exception may be in effects which axe certainly reversible. As a society we have yet to learn a usable method of determining whether, or how much, human injury can be considered acceptable. The assessments of hazard in this report axe therefore opiniors by one person about the potential for human harm resulting from distribution of the chemicals at tive. levels that will achieve the forestry objec­ This document should be taken as a working base enabling incor­ poration of other opinions, and it should be subject to periodic updating, based on new findings, existing papers inadvertently missed in review, and existing papers which may become more pertinent in the light of other new findings. 119 -4 DOW 1 3 6 2 5 7 2 retail materials, either near-term or long-term, axe difficult to find. Assessment of Human Hazard Resulting from TCDD as a Contaminant of Fhenoxy Herbicides Two arguments emerge frequently in discussion of TCDD. One is that the manifest injuries to workers and citizens in or near sites where trichlorophenol plants have had run-away reactions or explosions dictates a cessation of use. The several such accidents, some near catastrophic are certainly unique because of the enormous toxicity of TCDD. The argument has merit but the issue here is whether specified uses are hazar­ There is little doubt that industrial safety often lags far behind existing capacity for safety, but specific industrial hygiene and health problems should be dealt with on the basis of their own weaknesses. In other words, solving the factory and community exposure problem by plant shut down may make sense, but solving it by stopping use of the agent does DOW 1 3 6 2 5 7 3 dous. not. Another argument is that laboratory data is unrealistic and not useful if it doesn't duplicate potential human exposure. Nothing fills that criterion except accidental human exposure, which we do not need. Experience has given us considerable (albeit not perfect) confidence in our ability to estimate field consequences from laboratory findings. The concept of dose dependent response has been proven valid, although there are admittedly possible discrepancies at the very low dose range. In any case, without the expenditure of enormous amounts of time and money, we cannot have studies that precisely duplicate field exposure. It is possible to estimate a TCDD exposure rate that will not cause effect in the most sensitive parameters now known to be affected by TCDD. In rats, 0.001 yg/kg/day S days a week for 13 weeks, totalling 0.065 yg caused no detectable effect. Guinea pigs given «.008 yg/kg/weekly for eight weeks also were not affected. 120 Existing data from monkey 16 95( experiments has not produced -a "no observed effect" dose because the de­ tailed analyses available only through interim sacrifice have not been made in primates. The group of monkeys studied in Allen's laboratories first showed clinical symptoms after three months of exposure to about 0.01 yg TCDD/kg/day, or a total dose of somewhat less than 1 ug/kg, but there is no way of knowing whether pathologic examination would have detected changes at the more than 10-fold lower dose found ineffective in the rat and guinea pig. The existing literature also does not provide There is no useful data that relates specifically to human effects. It therefore seems reasonable to accept 0.06 yg/kg as a subchronic total dose over a short term, say, one year below which no effect can be detected. From this point it follows that some attempt must be made to judge potential human exposure levels. It is clearly impossible to directly evaluate acquisition by surface contact with treated foliage. Direct analytical methods for TCDD are probably more sensitive than for any other organic compound, but measurement of foliar distribution can­ not be made at field application levels. In my opinion significant TCDD exposure by inhalation is highly im­ probable. An intake of 0.02 yg of TCDD would require inhalation of one g 2,4,5-T containing 0.02 ppm TCDD, along with 10 g of diluent at usual dilution rates. very large. The volume of air in which the spray is distributed is Such an intake for a 50 kg person would constitute 1/150 of the assumed no observable effect dose. The potential for inhalation of TCDD formed during combustion of 2,4,5-T is infinitely less, because of the enormous dilution in air. 121 DOW 1 3 6 2 5 7 4 access to a useful single dose no observable effect level. Oral exposure in drinking water is also extremely unlikely because TCDD partitions from water to sediment very efficiently. With dilution in flowing water, TCDD at levels deposited during spraying disappears quickly. Furthexmore, TCDD deposited on soil and surfaces binds tightly, and while some material can wash off of leaves, once on soil it remains, neither leaching downward or migrating toward water courses. An acute spill of large amounts of undiluted spray formulation into a water course could present an isolated hazard but 2,4,S-T and its car­ provides its own alarm. However, a theoretical but remote possibility in such an accident is the selective extraction of TCDD onto sediment, fol­ lowed by very slow loss of TCDD from sediment to water over a sustained period. D0W13 6 2 5 7 5 riers are objectionable enough in taste and smell that such an accident Probably the only way such an accident can occur is through a vehi­ cular accident resulting in loss of herbicide drums into a water course. Oral intake through consumption of meat or milk presents at least theoretical possibility that an individual might consume enough deer meat containing, say, 10 ppt TCDD to acquire a significant burden of the dioxin. The question then becomes one of the probability that such a circumstance can come to pass. TCDD in concentrations of this order have been found in cattle grazing on 2,4,S-T treated range land; we may assume that an occasional deer can accumulate similar amounts if forage is poor and the animals must eat forage that they have been observed to discriminate against. If uniformly distributed in all edible tissues the amount of TCDD in a pound of meat would be about 4.S ng. The no observed effect level in a SO kg human is assumed at 3.0 yg. To reach that amount would require nearly 666 meals of one pound of meat, or the meat from 5-10 deer, 122 16952 and assumption of perfect retention of TCDD or its effect. In point of ' fact, the high TCDD concentrations are in liver and fat and such a hypo­ thetical whole animal concentration would not be approached. A slightly different approach by Dr. George Streisinger makes as­ sumptions about fat concentration and the percentage of fat in, as an example, ground meat. He has concluded that either 78 or 408 (depending on different no-effect assumptions) half-pound meals would exceed the danger barrier. Dr. Streisinger included a 100/1 safety factor, however, of a possibly harmful intake. 2,4,5-T is applied on a given forest area only 1-3 times in a timber growth cycle. While it is possible for a deer to acquire significant residues in a single year, the likelihood of a long-term continuous ex­ DOW 1 3 6 2 5 7 6 and the specified number of meals would bring a person to within l/100th posure of deer would require migration among sprayed plots, or repeated treatment of a single area, and is therefore remote. Even range land is not usually treated annually. The significance of TCDD in mothers milk is considerably greater than consumption in meat. The analyses by Dr. Meselson's group indicate the possibility that TCDD on the order of 1-2 ppt may be present in human milk. Dr. Meselson has been careful to state that while he has great confidence in the individual analyses, they are close to detection limits, and the data really asks rather than answers the question. For the sake of discussion, a sustained output of 1 ppt in human milk could provide an infant dose approaching the no observed effect level. Assuming a liter of milk consumed daily at 100 days, total intake would be 0.1 pg. If the average weight of the infant were 6 kg, the 100 day 123 I? q er <3 Ou U m dose would be 0.016 Ug/kg, or about 1/4 of the no observed effect level. Exposure for 200 days would produce a somewhat lower dose per unit weight because infant weight increases but milk output may not. It is appropriate to inquire how a human mother can acquire enough TCDD to excrete 1 ppt or 1 ng/L in milk. If a constant input by consump­ tion of one pound of meat daily is assumed, the individual will take in 4.5 ng daily. Almost all ingested TCDD is excreted in feces, with a minor component Most chlorinated hydrocarbons emerge in milk to a limited extent, and it is not unexpected that TCDD should be found at low levels in milk. A pound of meat containing 10 ppt TCDD ingested daily would bring into the body 4.5 ng daily. As with any chemical, an equilib­ rium will eventually be reached where excretion and metabolism of the chemical will equal intake. forms is minimal. DOW 1 3 6 2 5 7 7 excreted in urine. In the case of TCDD, metabolism to other There are not data on the fraction of TCDD excretion in milk, but it may be expected to be quite small. If we assume a high figure of 20%, however, an output of about 1 ppt is at least possible. The possibility of such sustained intake of TCDD is remote, however, re­ quiring consumption of 2-3 deer over a 6 month period. An alternative is a more massive exposure over a short period. We have no knowledge of the distribution into milk of, for example, 1 yg TCDD/kg as a single dose. We do know, however, that TCDD has a half-time of residence in the body of no more than 30 days, and probably closer to 20 days. Milk concentrations will decrease at the same rate as tissue residues, if not faster, and a 200 day nursing period covers more than 6 half-times. A one ppt concentration in milk arising from a single expo­ sure will dwindle to 0.5 ppt in 20-30 days, to 0.25 ppt in 40-60 days, and 124 10354 0.12 ppt at 60-90 days. Exposure of a nursing infant will therefore be minimal. It appears to me therefore that the potential for harmful exposure of infants through human milk should be negligible. This route is none­ theless the most probable of the several potential means of contact, and demands a thorough analysis of human milk in exposed populations. The data on TCDD carcinogenic potential suggest that it is not a carcinogen. It has been suggested that TCDD is a promoter of carcinogenic long exposure period by the Wisconsin group. The recently completed Dow Qiemical Co. study indicates that tumor incidence changed only at doses that were lethal to many animals over the two-year test period. The data base exists for one and probably several human epidemiological studies D0W13 6 2 5 7 8 activity on the basis of a wide variety of tumor types developed over a irfiich could answer the question of influence on human cancer incidence. A recommendation is made later for such studies. Of the toxicological data evaluated, perhaps the most disturbing is that of Allen et al. (1977} suggesting that the lethal dose in monkeys is similar whether the agent is administered over a short period or over several months. Time independence of dosage has never been demonstrated for a chemical. If it truly exists for TCDD, there is implication that the compound leaves permanent damage, even though it has departed from the body. In this situation, continual low level impact would cause gradually accumulating injury until clinical illness would prevail. In that sense, the idea of a no-effect level would not be applicable, and no exposure would be permissible. As with radiation, however, a small intake is possible without endangering health over a lifetime. case of TCDD this amount is not known, but it is finite. 12S In the In view of a QK long history of use without apparent injury and an apparently rapidly improving data base, it seems justifiable to allow use of 2,4,5-T and silvex under conditions that will permit virtually no inadvertent or unknowing exposure. It appears to be practical to diminish ambient contact to levels which will have no significance, accepting minor one­ time defects in the system which should also have no consequences, and to allow individuals the informed opinion of exposure. Such a stringent condition is not necessarily incompatible with use of a necessary herbicide. It seems possible to design application methods exposures of humans to TCDD. The present knowledge of dioxin effects and behavior is not suffi­ cient to make an unqualified statement of reasonable safety. Several areas of needed research, suggested in a later segment of this report, should improve our level of confidence. Nonetheless, it is my opinion that 2,4,5-T containing less than 0.02 ppm TCDD can be used safely in reforestation if certain protective practices listed later are instituted. In brief, these, involve absolute avoidance of spray intrusion across property lines, identification and protection of dwellings and water supplies reentry discipline and adequate public information programs. i 126 4 DOW 1 3 6 2 5 7 9 and associated policies that would prevent involuntary and inadvertent Hazard Assessment— 2,4,5-T The acute toxicity of 2,4,5-T is quite low and in itself is not a factor in the environmental hazard potential of the herbicide. This seg­ ment is concerned only with 2,4,5-T; the implications of the dioxin con­ taminant have been considered earlier. A wide variety of specific toxic changes have been found in experiments with acute or short-term repeated administration of high doses of 2,4,5-T. 2,4,5-T is teratogenic, but again, only at high doses. The dose is required to produce birth defects. There are substantial differences in effective teratogenic doses among strains of mice. The lowest effective dose is still substantial, however, and the kind of teratogenic response remains the same. The dif- DOW 1 3 6 2 5 response to 2,4,5-T is such a large fraction of the maternal lethal dose Co o ferences among the genetically very specific mouse strains do raise the possibility of high individual sensitivity in the heterogeneous human population. This question applies to any potential effect in humans by any chemical and really constitutes a common social question that we have not learned to handle. The excretion of 2,4,5-T by mammals is rapid, with relatively little conversion to other compounds. Initial residues after application are high enough to possibly cause some temporary slight tissue deposition of 2,4,5-T in tissues of grazing animals, if sustained for a period of more than two weeks, but environmental degradation of 2,4,5-T is rapid and the chemical does not migrate extensively, once deposited. For these reasons and because general toxic responses to the herbicide only occur at high doses, I do not consider that 2,4,5-T as used properly in forestry proce­ dures represents a general toxic or teratogenic hazard to the human popu­ lation. 127 iC S '5 7 The bulk of evidence available at this time indicate that 2,4,5-T is not carcinogenic or mutagenic. It oust be emphasized that this evi­ dence really assures us only that the herbicide is not highly carcinogenic. An epidemiological study of humans occupationally exposed has also been negative, although other herbicides were found in the same study to be possibly associated with an increased incidence of tumors. Mutagenic assessment in a number of experimental systems has shown no evidence of such change, and epidemiological study of 2,4,5-T produc­ I do not believe the issue of carcinogenesis by 2,4,5-T can be arbi­ trarily closed yet, although at this time it appears that there is not a carcinogenic or mtagenic hazard at exposure levels «countered following typical application. I have made recommendations relating to needed in­ DOW 1 3 6 2 5 8 1 tion employees has shown no evidence of cytogenetic change. vestigations which should establish a more specific level of confidence in that opinion, or possibly cause it to change. An industrial study of carcinogenic effect of a two-year treatment of rats with 2,4,5-T is almost complete and should also shed more light on the issue. I do not believe that 2,4,5-T per se as used in forestry constitutes a human health hazard. Hazard Assessment— 2 f4-D The acute toxic dose of 2,4-D is quite high, but a number of indivi­ duals occupationally exposed to 2,4-D have suffered severe neuromuscular and gastrointestinal effects. These incidents have been the result of gross mishandling of the chemical and are not a part of the environmental health issue. 128 16958 The reproductive effects of 2,4-D do not\appear until doses approach* ing the lethal level axe reached, and there seems to be no reason for concern in this province. As a potential carcinogen, 2,4-D has had very little study. The only evaluation of which I am aware was negative, in one species, which indicates that the compound is not highly carcinogenic. This finding of course can give no confidence about low level carcinogenicity. Sev­ eral studies of mutagenic potential have been negative, adding some Perhaps the key information lies in the rapid excretion of intact 2,4-D in the urine. This process is rapid and relatively complete. In some species a portion of the compound is converted to other forms for excretion, but the process is rapid. Rapid excretion probably is the factor that prevents 2,4-D or its products from reaching the detectable margin in milk after field exposure. It is possible experimentally to overload an animal to the extent that the material will appear in milk. Because of its short persistence in the environment and the absence of toxic responses at any doses that might be found in the field, I be­ lieve the uses of 2,4-D in practices presently considered standard is not hazardous. There are, as with any chemical, some open questions, which are addressed in the section on recommendations. These relate primarily to epidemiological needs and clinical surveillance. Hazard Assessment— Silvex The general considerations applicable to 2,4,5-T may also be applied to silvex. There are some minor differences between the compounds, but the ranges of toxicity, the manner of biological disposition, and the 129 DOW 1 3 6 2 5 8 2 confidence. environmental behavior are similar enough that similar standards should apply. In the absence of data on silvsx, findings from studies of 2,4,5-T should be considered applicable. As with 2,4,5-T, the issue of TCDD contamination overshadows the characteristics of silvex itself. The one mitigating circumstances is the more limited distribution of silvex and therefore less extensive distribution of TCDD. It is my opinion that present uses of silvex do not constitute a hazard, from silvex itself. There is, however, further information needed to in­ crease confidence in that opinion, and recommenations have been made in the appropriate section. 130 DOW 1 3 6 2 5 8 3 rately addressed. The issue of the TCDD contaminant is sepa­ K Û Û f t RECOMMENDATIONS OF STEPS WHICH SHOULD BE CONSIDERED TO ASSURE THAT EXPOSURE TO TCDD IS MINIMIZED OR PREVENTED I have stated my opinion that 2,4,5-T can be used safely, with cer­ tain additional safeguards. as new data emerges. I believe that opinion should be reviewed A number of clinical questions now being asked have accessible answers, and these must be obtained. In addition, the toxic nature of TCDD and our inability to measure it satisfactorily in the environment dictates a very conservative attitude about its distribu­ I see no inconsistency in accepting its presence in small quanti­ ties and recommending unique steps to prevent those quantities from reaching people. To assure public protection and a more compatible relation with the public, I suggest the following considerations in designing a spray pro­ gram. 1. With the consideration of health hazard, there is a political reality that needs more attention. Every treatment operation oust be designed to prevent intrusion of spray onto premises not under control of the agency or firm using the chemical, as a matter of principle. I would not be surprised if Forest Service policy includes that concept, but I would also be surprised if its application is somewhat leas than perfect. Personal rights are becoming more and more clearly defined, and it seems to be time to decide where such rights begin and end, and take a visible public position on the issue. 2. As a means of preventing any involuntary exposure, there should be assurances that every residence is identified, with any water sources that may be in the Forest. Non-legal residents should also be identified. 131 1?9939ClM0a tion. Questions of liability and informed consent and other relationships with the Forest Service ought to be clearly laid out. 3. Present buffer procedures should be examined in detail and pub­ licly shown to be adequate. If a 100-foot zone cannot be proven certainly safe, it should be expanded. 4. An intensive posting and advertising program should be used to notify the public where herbicide treatments are located. The informa­ tion should be directed toward special users of the area, such as hunters, 5. There is definite need for documented assurance that applied .herbicides arrive only at the intended target area. If this requires a spat monitoring program during and after application it should be insti­ tuted. Here again is an issue of public confidence; precision of appli­ cation may be very, high, but no one outside the industry knows about it, if it is so. RESEARCH NEEDS TO MORE CERTAINLY ESTABLISH THE SAFETY OF PRESENT USES OF PHENOXY HERBICIDES 1. During discussions of herbicide use issues we are confronted \ by innumerable allusions to people made ill by application of the agents. These incidents range from word of mouth descriptions of a neighbor's experience to an extensive series of carefully constructed interviews with Vietnamese who were subjected to herbicides as chemical warfare. As they appear in the context of our forestry practices, these anecdotal descriptions of illness cannot be documented and are of little value in assessing toxic hazard. They are of concern, nonetheless. A clinical surveillance team should be commissioned to evalua*immediately any alleged herbicide contact incidents. 132 There is no doubt DOW!362585 as well as the adjacent population. in my mind that people complaining of physical injury are in fact affected. I am skeptical that the application of herbicide causes these effects in more than a few incidents, but it is possible. Of more importance, there may be some other public health hazard operant in the area which causes the symptoms. It is even possible that other illness is brought to the attention of the victims by their immediate concern about improper her­ bicide intrusion on their private property. 2. The opinion of Van Miller et al. (1977) that TCDD is a promoter of carcinogenic effect by other compounds seems reasonable according to If the forest application of 2,4,5-T containing TCDD is inserting effective levels of TCDD into the human environment, epidemio­ logical evaluation should disclose higher than normal incidence of various forms of cancer in 2,4,5-T use areas. Lane County, Oregon, has a very effective tumor registry program, with virtually all pathology of human cancer examined by a single consortium of specialists. These data should provide evidence of any existing difference in cancer patterns from other areas. A more definitive study should be possible in rangeland or rice­ growing areas where the herbicide is used annually. Epidemiological studies such as these may settle the persistent question of cancer latency, because on an area basis, the pattern of past use of herbicides should be reasonably accessible. 3. A thorough health surveillance should be made of all herbicide applicators and others with industrial or agricultural exposure to 2,4,5-T or silvex. Cytogenetic evaluation through several seasons of the year should be an integral part of the study. Design of the medical components of the survey should be by a nationally constituted panel. 133 DOW1362586 their evidence. 4. Environmental degradation of TCDD is still inadequately under­ stood. Photodegradation by light reflected from or transmitted through foliage must be measured» as must reaction in shade and under cloud cover. 5. With, present sensitivities of analysis, translocation of TCDD in plants should be restudied. 6. Affinity of TCDD to plant surfaces should be examined directly, to determine how efficiently the chemical can be removed by surface contact and by animal digestion of forage. Augmentation of industrial efforts to eliminate TCDD from tri- chlorophenol derivatives seems to be a legitimate governmental concern, and should be encouraged. Elimination of the contaminant would obviously eliminate the issue. 8. A search should be made for chemical additives that would react with TCDD or accelerate its breakdown. 9. The human milk and fat biopsy program being developed by EPA should be encouraged. DOW1362537 7. ASSESSMENT OF HAZARDS ASSOCIATED WITH USE OF 2,4,5-T, 2,4-D, AND SILVEX IN REFORESTATION PRACTICES In such a report as this it would be highly desirable to prepare a hazard analysis for each compartment or trophic level in the potentially affected ecosystem. This is at least very difficult and perhaps impossible to develop in a single document with the complexities of inter-level de­ pendence and ultimate dependence on many target plant species. There is an extensive literature on such effects, but in this report a decision has been made to concentrate on potential human impact. In that process, essential information on lower species appears to the extent necessary. port, and degradation mechanisms of the phenoxy herbicides in Che environ­ ment and their behavior is well established. These areas are discussed only in sufficient detail to establish essential facts. The section on TCDD is an exception and includes as complete a treatment as possible because of the unique character of the chemical. Furthermore, the author is not competent to critically analyze the entire literature on physical and chemical behavior. Problems Associated With Assessment of Human Health Hazard Associated With Use of Phenoxy Herbicides There are fundamental differences of opinion in philosophy of her­ bicide usage. A significant segment of the population consider insertion of any synthetic chemical into the environment as fundamentally wrong, regardless of benefits, however well documented. There are as well groups and individuals who are unable to accept any suggestion that some chemicals, as used successfully a ’*ith apparent impunity for decades, might constitute a hazard which is only now becoming evident. 116 DOW1362538 There is an extensive literature on persistence, physical trans­ AGÏ S JLTURAL PRODUCTS DEPARTMENT - 9001 Midland, Ml 48640 COPIES TO: INDEX 13 o B . SCHWETZ 1 8 0 3 -K. WATSON R. MOFFAT B- MOSS HONG KONG R« COOK 1 8 0 3 w- CRCJMMETT 5 7 4 ':»V^/y ■•‘ ¿-J-• Xi O 'O ro D. MORGAN B- MCCREDIE :- ÎO -vl h -* JS. o # r ■;s en ro - -^-^%r^T-i'v-_ — 1V.;,■■// ■■’-r ., r- ■' t - « -J ■ " rr. - _T ■ ■ r'.'F V u " a r * ^ . ■ —i .......... ■ ■ ¿-a V- / - ; - ~ •• ■ •T *f ~t from: JOHN DAVIDSON 517 636-4826 16ÜS8 - i'.-L//*:“.;.* — ‘ —-•'*'■' - •— ■ - X- -r ■ . * -.ru — • v *La -?s ^ > «■ ‘* « - * = » •1 H Environmental Health Perspective» Voi. 36, pp. ¿21-240, 1930 Long-Term Hazards of Polychlorinated Dibenzodioxins and Polychlorinated Difaenzofurans* by J. E. HufV J. A. Moore,1 R. Saracci,* and L. Tornatisi / 271527 During January 10-11, 1978 in Lyon, France, a joint National Institute of Environmental Health Sciences/International Agency for Research on Cancer ad hoc Working Group consid­ ered and discussed the feasibility of coordinating epidemiological studies on the long-term haz­ ards associated with the chlorinated dihenzo-p-dioxins and chlorinated dibenzofurans (PCDDs and PCDFs). Nineteen invited scientists from eight countries presented introductory working papers summarizing the most up-to-date and relevant information available from their individ­ ual programs. This report represents the collective views and scientific opinions of the Working Group. The greater part of this document comprises epidemiological studies related to episodes of human exposure. The review begins with a brief section concerning possible routes of human exposure, an overview of the pertinent chemical characteristics, and the salient toxicological properties of the structurally siimilar PCDDs/PCDFs. The Working Group report ends with recommendations for future activities. Introduction Human exposure in the workplace can occur when chlorinated dibenzo-p-dioxins (PCDDs) are formed during the production of certain com­ pounds such as the herbicide 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), the fungicide pentachlorophenol, and the germicide hexachlorophene (1). The dioxins, impurities/contaminants * This report was prepared by the NIEHS/1ARC Working Group and the full proceedings were printed in June 1978 as IARC Internal Technical Report 78/001. References cited in this report rellect in general those published prior to June 1978. Participants of the NIEHS/IARC Working Group: A. (J. Ar­ atila, University of JyvaskylS. Finland: 0. Axelson, Regional Hospital, Linloping, Sweden (Vice Chairman); H. Bartseh, IARC, Lyon, France; P. J. Baxter, Employment Medical Advi­ sory Service, London, England; F. Bercino, Instituto Nazionale per lo Studio e la Cura dei Tumori, Milano. Italy; L. Bisanti, Uffici Regione. Milano. Italy; R. Frentzel-Beyme, Deutsches Krehsforschungszentrum, Heidelberg, Federal Republic of Germany; A. Hay, University of Leeds, United Kingdom; J. £. Huff, IARC, Lyon. France: L. Jiràsek. Università Karlova FVL, Prague, Czechoslovakia; T. Kuroki. IARC, Lyun, France; G. May, Derbyshire, United Kingdom; R. Montesano. IARC, Lyon, France: J. A. Moore, National Institute of Environmen­ tal Health Sciences, Research Triangle Park, N.C., U.S.A., (Chairman): J. Parizek, WHO, Geneva, Switzerland; G. F. November 1980 associated with these end-products, result most often from treatment of chlorinated benzenes at elevated temperature and pressure under alkaline conditions. Via the widespread use of these com­ mercial products (J, 2) the general population may also become exposed. In recent years, out-of-control chemical reac­ tions during the production of 2,4,5-trichlorophenol have proceeded to the explosive Peruzzo, Uffici Regione. Seveso. Milano, Italy; F. Pocchiari. Is­ tituto Superiore di Sanità, Rome. Italy; A. Poland. University of Wisconsin Medical School. Madison, Wise.. U.S.A.; C. Rappe, University of Umeà. Umeà, Sweden; V. Riihimàki. institute of Occupational Health, Helsinki, Finland; R. Saracci, IARC, Lyon, France; I. J. Selikolf, Mount Sinai School of Medicine, New York, N. Y., U.S.A.; R. R. Suskind. Kettering Laboratory, University of Cincinnati Medicai Center. Cincinnati. Ohio U.S.A.; L. Tomatis, (ARC, Lyon, France; J. G. Vos. Rijks Instituut voor de Volksgesondheid, Bilthoven, The Netherlands: N. Wald. University of Oxford. Oxford. United Kingdom; J. Wilhourn, IARC. Lyon, France. Address reprint requests to J. E. Huff. National Toxicology Program, P.O. Box 122:t3, Research Triangle Park. NC 27709. f National Toxicology Program, P.O. Box 12223, Research Triangle Park. N.C.. 27709. * International Agency for Research on Cancer, 150 Cours Alhert-Thomas, 69372 Lyon, Cedex 2, France. 221 stage thereby exposing persons to toxic levels of PCDDs. From certain of these accidents, more­ over, not only did those occupationally involved receive dangerous exposure but also those in­ habiting the surrounding areas received uncom­ mon risk. The structurally-related chlorinated dibenzofurans (PCDFs) are contaminants found in some polychlorinated biphenyl compounds: Aroclor, Clophen, Phenoclor (3). These impurities are more toxic and represent a greater environmental hazard than the com­ pounds they contaminate (1, 3-9). For instance, 2,3,7,8-tetra-CDD has been recently found in beef fat from cattle grazed on 2,4,5-T-treated rangeland and in breast milk from women living in areas where 2,4,5-T is used on rangeland or in for­ est areas (10). Various investigators (11-14) have also discovered PCDDs and PCDFs in fly ash and flue gas from municipal incinerators, and in dust from fungicide-treated wood (15). Chemical Aspects The PCDDs and PCDFs are two series of tri­ cyclic aromatic compounds which exhibit similar chemical and physical properties (1, 3, 4). The basic two-dimensional structures (I, II) have eight possible points of chemical addition. From the monochloro to the octachloro derivatives, a va­ riety of positional isomers are possible: 75 PCDDs and 135 PCDFs (Table 1 ). The extreme toxic potency of some of these compounds, as well as the large number of poten­ tial isomers, warrant analytical methods exhib­ iting high sensitivity and specificity to monitor the environment. A desirable detection limit of one p art per trillion (ppt, 1 picogram /gram sample) is being reached with current methodol­ ogy. Essential requirements included efficient clean-up, good separation and selectivity, ultra­ sensitive quantification, and validation (IS, 17). Toxicological Aspects Animals The prototype and most extensively studied iso­ mer of the PCDDs and PCDFs is the 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-tetra-CDD), perhaps the most potent man-made toxin pres­ ently known. The comparative oral lethal dose val­ ues for various PCDDs in mice and guinea pigs (Table 2) show dearly that the 2,3,7,8-tetra-CDD and the 1,2,3,7,8-penta-CDD isomers are the most toxic (IS). Toxic effects induced by PCDDs and PCDFs vary quantitatively and qualitatively among dif­ ferent species; however, within a single species the untoward consequences are markedly similar for all PCDDs and PCDFs that have been studied. For example, the toxic effects induced by 2,3,7,8tetra-CDD which are most often observed in mice, guinea-pigs, and monkeys, are illustrated in Table 3 (20). In a brief report, daily oral intake (12-61 days) of < 1 pg/kg body weight 2,3,7,8-tetra-CDD was stated as being lethal to young male rhesus monkeys (21), whereas McConnell et al. (22) re- ^ 5 ; ported an LD*, in female rhesus monkeys as <70 pg/kg body weight. A preliminary report on 2,3,7,8-tetra-CDF con- cerning the toxicity of PCDFs (23), and a report on PCDFs (24) have been published. ^ The toxic syndrome produced by PCDDs and PCDFs may be divided into seven categories: Chloracne. 2,3,7,8-Tetra-CDD and the tri- ^ PCDF and tetra-PCDF were found to be active^-* skin irritants and to induce acneform lesions in^O the skin of rabbit ears (25). Classical chloracne is a hallmark of PCDD ex­ posure in humans and an analogous hyper­ keratosis and the modulation of sebaceous struc­ tures to keratin cysts have been observed in monkeys, rabbits, and hairless mice. Chloracne or acneform dermatitis is a common occupational dermatitis characterized by com­ edones, keratin cysts, pustules, papules, and ab­ scesses. In 1957, Kimmig and Schulz (26) found that 2.3,7,8-tetru-CDD was the agent responsible for causing occupational chloracne in employees of chlorophenol-producing factories. Further, in 1971 PCDDs were implicated as causing chloracne in male workers in a plant producing 2,4-D and 2,4,5-T (27, 28). Chloracne may appear weeks or months after the initial exDosure to PCDDs and PCDFs. H eputoxicity. The degree of hepatic in­ volvement appears to be dose-dependent, and the severity of the changes produced varies between qpocies (29). Hepatic necrosis produced by 2,3,7,8tetra-CDD is prohably a contributing cause of death in rats and rabbits, while hepatic necrosis and liver insufficiency are less extensive in mice and are minimal in comparison in guinea pigs and monkeys (22, 30-37). Hepatic porphyrin accumu­ lation has been observed in mice, rats, and chick­ ens. H y p o p la sia o f the L y m p h o id T is ­ sues. Particularly involved are the cortical cells of the thymus and this hypoplasia has been ob­ served in mice, rats, guinea-pigs, and monkeys. The most significant findings in both mice and Environmental Health Perspectives % o Cly I II Table 1. Possible number of isomers for polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans. Chlorine atoms PCDD isomers'* PCDF isomers* l 2 3 4 5 6 7 8 Total 2 10 14 22 14 10 2 1 75 4 Id 28 38 23 16 4 I 135 ‘ Chlorinated dibenzo-dioxins: empirical formula C,2H7.U Cli.,0-; molecular weight ranges, 213—WO. h Chlorinated dibenzofurans: empirical formula. Cl2HT.0 CIi . hO; molecular weight ranges, 202-444. November 1980 (44) • The marked thrombocytopenia was associ­ ated with widespread hemorrhage. Death oc­ curred in five of the eight monkeys between months 7 and 12 of the experiment at total ex­ posure levels of 2,3,7,8-tetra-CDD of 2-3 /tg/kg body weight. At autopsy, in addition to extensive hemorrhage, there was a distinct hypocellularity of the bone marrow and lymph nodes. Hyper­ trophy, hyperplasia, and metaplasia of the epithe­ lium in the bronchial tree, bile ducts, pancreatic ducts, salivary-gland ducts, and palpebral conjunctivae were observed. Squamous metaplasia and keratinization of the sebaceous glands and hair follicles were present in the skin. Death was attributed to complications from the severe pan­ cytopenia (44). General Debilitation and Wasting. Animals that receive a toxic or lethal dose of PCDDs or PCDFs exhibit a chronic and progressive weight loss with parallel mobilization of peripheral fat, increased serum triglyceride levels, and develop­ ment of a fatty liver. Death due to PCDDs or PCDFs intoxication is delayed, as exemplified by an elapsed time period of 6 to 8 weeks following administration of a lethal dose and eventual death DOW J2 7 1 5 2 9 guinea-pigs treated with sublethal doses of 2.3.7.8- tetra-CDD were in the lymphoid system, resulting in suppression of cell-mediated immu­ nity, particularly in young animals (36, 38). Low levels of 2,3,7,8-tetra-CDD that did not produce overt clinical or pathological changes still reduced host defences: 1 /tg/kg bw given orally once weekly for 4 weeks to mice before infection with Salmonella increased mortality and decreased the time from infection to death (39). The increased mortality may be caused by the endotoxin content of these gram negative bacteria, since 2,3,7,8tetra-CDD markedly increases the susceptibility of mice to endotoxin (lipopolysaccharide of Esche­ richia coii) (4 0 ). Treatment of female mice and rats with 2,3,7,8-tetra-CDD during the latter half of gestation and in the postnatal period resulted in a severe depletion of lymphocytes in the thymic cortex of the offspring (At). Cellular immunity was impaired. Hematological changes in mice, rats, and guinea pigs treated with 2,3,7,8-tetra-CDD in­ clude lymphopenia and thrombocytopenia (12, 43); manifest also is an increased susceptibility to infection concomitant with the suppression of cell-mediated immunity. For 9 months, female rhesus monkeys received a diet containing 500 ppt 2.3.7.8- tetra-CDD; within 6 months, the monkeys became anemic and after 9 months pancytopenic (18, 22, 44). Embryotoxicity and Teratogenicity of 2,3,7,8tetra-C D D . In repeated or single doses of 2,3,7,8-tetra-CDD to mice, as little as 1-10 /tg/kg cause increased frequencies of cleft palate and kidney abnormalities (43-43) (see Table 4). In rats, embryo-lethal effects occur under experi­ mental conditions (49, 50), and kidney anomalies (4-5), intestinal hemorrhages, and general edema can be produced in the fetuses (51). Few follow­ up studies of the effects of prenatal exposure on postnatal functions have been published. In mice, fetal kidney abnormalities caused by 2,3,7,8-tetraCDD may progress into a hydronephrosis during the postnatal period (52). Chick Edema Disease. Hydropericardium, as­ cites, subcutaneous edema, liver necrosis, and death were described in 1957 following the acci­ dental administration of toxic fats in the feed of broiler chickens (ascites have been observed also in mice) (l). The toxic material was later identi•WJ Table 2. Estimated single oral LD50-30 values of certain polychlorinated dibenzo-p-dioxin isomers.* Guinea pigs •iÿ; è &■ s^. Mice Chlorine isomer Mg/kg /imole/kg 2,8 2,3.7 2,3,7,3 1,2,3.7,3 1Z4.7.8 1,2,3.4,7,8 U.3.6,7,3 1,2,3,7,3,9 1,2,3,4.6,7,8 l-NO-3,7,3 1-NHL3.7.8 l-NOo-2,3,7,8 l-NHj-2.3,7.8 >300,000 29,444 2 3.1 1,125 72.5 70-1006 60-100b >500 >30,000 >30,000 47.5 194.2 >1,180 120.41 0.006 0.009 3.15 0.185 0.178-0.255 0.153-0.255 >1.400 >90 >99 0.129 0.576 >1 5r =*: Table ;{. Summary of the toxin effects of 2,3,7,3tetr.ichlorodihenzn-p-dioxin.* % 3 -i 5» 'V Mice -4» ■ «. 7 i ? -M Ì pmoie/kg __ >3,000 283.7 337.5 >5,000 825 1,250 >1,440 >10 0.88 0.94 >14 2.11 3.19 >3.67 >2,000 >4,300 >5.4 >14.2 __ __ __ __ __ __ * Data from McConnell et al. (IS). The LDw.jl0 was calculated by the Spearman-Karber method (19). b Estimated range due to variability in replicates. fied in commercial oleic and stearic acids produced from inedible tallow recovered from animal hides; trichlorophenols and pentachlorophenols had been used in the curing of the hides. The edema causa­ tive was termed toxic fat and more specifically chick edema factor and was characterized by xray crystallography as 1,2,3,7,8,9-hexa-CDD (53). 2,3,7,8-Tetra-CDD, hexa-CDD, and octa-CDD have been also identified in several commercial fatty acids (5U). Daily doses of 10 or 100 /zg hexaCDD/kg bw, or of 1 or 10 /tg 2,3,7,8-tetra-CDD/kg bw, produced a positive response in the chick edema bioassay; 0.5% octa-CDD in the diet had no effect (35). Similar edematous effects were ob­ served in rats, pigs, dogs, and monkeys, but not in 3U- n/kg Thymus involution Spleen reduction (white pulp) Bone marrow hypoplasia Liver megalocytosis/generation Bile duct hyperplasia Testicular degeneration Renal pelvis hyperplasia Urinarv bladder hyperplasia Adrenal cortical atrophy (zona t j L o m u r u l o a a ) Hemorrhage Intestinal Adrenal Ascites Cutaneous lesions * Data from Moore (¿0). 221 ++ + + Guinea Monkeys (female) P'K* +++ ++ + + + - • ++ ± ++ + ++ ++ ++ + + ± +++ ± ++ - — ++ - 4* +++ NA + — — — - - + ++ to guinea pigs (55). Decreased serum albumin m ay^o be associated with the edema; edema has b e e n ^ j also shown to occur in chicks dosed orally with 2.3.7.8- tetra-CDF (56). Other Effects. In one or more species of labo­ ratory animals, bone marrow hypoplasia, testicu­ lar degeneration, renal pelvis and urinary bladder hyperplasia, and hemorrhage in the intestines and adrenals have been observed. Enzym e Induction. 2,3,7,8-Tetra-CDD and other halogenated dibenzo-p-dioxins and dibenzofurans stimulate a number of enzyme activities, most notably in the liver (1). 2,3,7,8-Tetra-CDD is a potent inducer of hepatic and renal microsomal drug metabolizing enzymes (57-6*5). Intoxication with 2,3,7,8-tetra-CDD results in a marked in­ crease in the ceilular smooth endoplasmic reticu­ lum content of hepatic and renal cells (60,69). 2.3.7.8- Tetra-CDD can simultaneously activate and suppress certain microsome-associated for­ eign-compound and steroid-horm one-m etabo­ lizing enzyme systems (63) as well as increase the activity of both renal and hepatic glutathione-S transferase (70). 2,3,7,8 -Tetra-CDD is the most active of the PCDDs in inducing hepatic S-aminolevulinic acid (ALA) synthetase and aryl hydrocarbon hydroxy­ lase (AHH) in chick embryo liver preparations (71, 72). The PCDDs that induce ALA synthetase in chick embryo have two common properties: ( 1 ) halogen atoms occupy at least three of the four ring positions (2,3,7.8), and (2) at least one free, nonhalogenated carbon atom is unoccupied (72). The available toxicological data (35) indicate that those PCDDs that are lethal at low doses, terato­ genic, or produce acne also induce ALA syntheEnvironmental Health Perspectives 16b70 Table 4. Evaluation of reported embryotoxic and teratogenic effects induced by 2,3,7,8-tetrachlorodibenzo-p-dioxins in rats and mice* Dose, pg/kg Species Strain Rat Mouse CD CD-I C57BL/6J NMRI Intestinal hemorrhage Kidney abnormality Cleft palate 0.125 0.5 1? 3 1 3 3 3 3 3 9 15 5 Kidney abnormality Cleft palate Kidney abnormality Cleft palate Kidney abnormality Cleft palate ED*,5 Period of dosing, days Route Reference 0.5? >1 6-15 Oral S.C. (50) (45) >3 1-3 >3 >3 >3 <3 6.5 <9 40 15 6-15 6-15 6-15 6-15 6-15 6-15 6-15 9-13 13 11 S.C. S.C. S.C. S.C. S.C. S.C. Oral Oral Oral Oral (45) (45) (45) (45) (45) (45) (45) (45) (47) (47) * Data from Neubert et al. (47). b The lowest dose with which an embryotoxic or teratogenic effect detectable at birth has been produced is indicated. Since sometimes only one dose level was tested, this does not necessarily represent the lowest dose from which an effect could result. * EDjo-dose required to produce an embryotoxic effect in 50% of animals. 271531 Lowest Tested0 BOW] DBA/2J Embryotoxic/ teratogenic effect tase; those PCDDs that are not toxic generally do of its relative potency (or rank order) to produce not induce ALA synthetase. The structure-activ­ other toxic manifestations. Hepatic Cytosol Binding Protein. A macroity relation of PCDDs to induce AHH in chick em­ molecular binding species has been characterized bryos was identical to that in inducing ALA syn­ in the hepatic cytosol fraction of mouse and rat thetase (71). liver which has the in vitro binding properties Mixed-function oxidase enzyme systems of predicted for the receptor for the induction of mouse strains “non-responsive” to other aromatic AHH activity based on the in vivo biology (78): hydrocarbons were induced by single doses of 2.3.7.8- tetra-CDD, as evidenced by increases in namely, (1) JH-2,3,7,S-tetra-CDD binds to this cytosol protein reversibly with a high affinity (K d hepatic monooxygenase activities and in concen­ = 0.27 nM ) comparable to the ED^ for hepatic trations of cytochrome P-448 ( 73-76). Genetic resistance to induction of AHH by 3-methylAHH induction (EDWin mice = 1 nmole/kg); (2) cholanthrene in DBA/2J mice was overcome by the binding affinity of halogenated dibenzo-p-ditreatm ent with 2,3,7,8-tetra-CDD. This result con­ oxins and dibenzofurans for this protein in vitro flicts with the hypothesis that induction of AHH corresponds to their potency to induce hepatic activity is a consequence of the formation of cyto­ AHH activity in the chicken embryo; and (3) other compounds, such as the polycyclic aromatic chrome P-448 (77). A component that has a high hydrocarbons, which induce AHH activity and binding affinity for 2,3,7,8-tetra-CDD was found cytochrome Pt-450 also compete for this cytosolic in mouse liver cytosol (73). 2.3.7.8Tetra-CDD induces AHH even in ‘poorly binding protein, but compounds which induce other types of microsomal monooxygenase activi­ responsive’ strains of mice (79), not only in liver ties (e.g., phenobarbital) and steroids fail to bind. but also in lung, kidney, and colon. The DBA/2N strain, which responds only weakly to the sarcoThus, this cytosolic binding protein may be the re­ ceptor for the induction of AHH activity. matogenic action of 3-methylcholanthrene, be­ ¡Structure-Activity Relations. The pathologic comes highly susceptible after treatm ent with 2.3.7.8- tetra-CDD (74, SO). effects produced by the toxic PCDD and PCDF 2.3.7.8Tetra-CDD is approxim ately 30,000 isomers are similar to those of 2,3,7,8-tetra-CDD times more potent than 3-methylcholanthrene in fo ra given species, differing only in the intensity inducing AHH activity in rat liver (SI). of the toxic etFect produced by a given isomer. The toxic PCDDs have chlorine atoms in at least McConnell et al. (IS) reported that the com­ three of the four lateral ring positions (2,3,7, and parative toxicity of 13 PCDDs in mice and 8) with at least one unsuhstituted ring position guinea-pigs (see Table 2) supports the idea that (the octa-CDD is comparatively inactive). To the the relative potency (or rank order) of a congener extent that the toxicity has been determined, a to produce one toxic response is a good indicator November l!).SO 6971 226 .,1— T ppt, four 4/10; 1 ppb, five observed in 4/10; 5 ppb, ten observed in 7/10. Neoplasms were not observed in the controls (52). Environm ental Health Perspectives O V' & »VC. DOW / 2 7 1 5 3 2 S similar structure-toxicity relation has been ob­ served for the PCDFs. The structure-activity relation established for PCDDs and PCDFs for the induction of hepatic aryl hydrocarbon hydroxylase (AHH) activity and for binding to the hepatic cytosol binding species has been extended to other classes of chlorinated aromatic compounds. 3,4,3'4'-Tetrachloroazoxybenzene (TCAOB) and 3,4,3',4'-tetrachloroazobenzene (TCAB) are potent acnegens formed as trace contaminants in the synthesis of 3,4-dichloroaniline or herbicides based on this compound (82). At high doses in animals, TCAB is reported to produce thymic involution and liver damage similar to 2,3,7,8-tetra-CDD (83). Both TCAOB and TCAB are potent inducers of hepatic AHH activity and bind to the hepatic cytosol binding protein with a high affinity. Congeners such as 3,5,3'5'-tetrachloroazoxybenzene and 3,5,3',5'-tetrachloroazobenzene fail to induce AHH activity, fail to bind to the hepatic cytosol species, and fail to produce chloracne. Of 16 halogenated biphenyl compounds tested, only 3,4,3'4'-tetrachIoro-, 3,4,5,3'4'5'-hexachloroand 3,4,5,3'4'5'-hexabrom obiphenyls induced hepatic AHH activity and bound to the hepatic cytosol binding species (84). The 3,4,3'4'-tetrachlorobiphenyl has been reported to produce chlor­ acne. McKinney et al. (58) found that of five h e x a c h lo ro b ip h en y ls te s te d in ch ick en s, 3,4,5,3'4'5'-hexachIorobiphenyl was by far the most toxic, and the only one that induced signifi­ cant chick edema and involution of the thymus. Pharmacokinetics. In the rat, following acute or chronic administration, 2,3,7,8-tetra-CDD is ac­ cumulated primarily in the liver and to a lesser extent in the fat, and is largely eliminated unme­ tabolized in the feces with a whole body half-life of about 3 weeks. Some pharmacokinetic experi­ ments suggest the formation of a polar metabo­ lite appearing in the urine, but direct attempts to demonstrate metabolism with hepatic microsomes in vitro have been negative (1). Mutagenicity. Only four dioxin isomers have been evaluated for mutagenicity: the 2,7-di-, 2,3,7,8-tetra, and octa-CDDs as well as the un­ substituted dibenzo-p-dioxin (55). 2,3,7,8-Tetra-CDD increased the reversion fre­ quency to streptomycin independence in Esche­ richia coli Sd-4. In Salmonella typhimurium. fram eshift mutations in strain TA1532, but not base substitutions in strain TA1530, were induced by toxic concentrations of 2,3,7,8-tetra-CDD (86). In plate assays, the response was positive with typhimurium TA1532. doubtful with TA1531 and TA1534, and negative with G46 and TA1530 (57). *Xt — ■**'* f T » - _ . i V . - . — ■*~~t - r » r > l ■j g ^ g s a S i g Groups of 100 Sprague-Dawley rats (50 males and 50 females) received for two years diets con­ taining 0, 22, 210, and 22.000 D D t . equivalent to 0.0, 0.001, 0.01, and 0.1 pg 2,3,7,3-tetra-CDD/kg/ day. Continuous ingestion of 0.001 /ig/kg/d ay did not cause any chemically related changes in tumor incidence or toxicity; feeding with 0.01 p g/kg/day induced an increased incidence (p < 0.05) of he­ patocellular hyperplastic nodules (female: 18/50 versus 8/86 controls), of focal alveolar hyper­ plasia in the lungs, and of urinary excretion of porphyrins (fem ale). Dietary intake of 0.1 /ig /k g / day caused an increased incidence (p < 0.05) of hepatocellular carcinomas (female: 11/49 versus 1/86) and squamous-cell carcinomas of the lung (female: 7/49 versus 0/86), of the hard palate/ nasal turbinates (male: 4/50 versus 0/85; female: 4/49 versus 0/86), and of the tongue (male: 3/50 versus 0/85). Further increased were adenoma of the adrenal cortex (male) and hepatocellular hy­ perplastic nodules (fem ale). At this dose, certain age-related lesions were reduced (males: acinar adenoma of the pancreas; females: granulosal cell neoplasm of the ovary, benign and malignant tu­ mors of the mammary gland, pituitary adenoma, and benign tumors of the uterus). Also, chronic administration of 2,3,7,8-tetra-CDD caused mul­ tiple toxicologic effects, including increased mor­ tality, decreased body weight gain, slight depres­ sion of certain hematologic parameters, increased urinary excretion of porphyrins and ¿-amino­ levulinic acid, increased serum levels of alkaline phosphatase, glutamyl transferase and serum glu­ tamic pyruvic transam inase, and morphologic changes primarily of the hepatic, lymphoid, res­ piratory, and vascular tissues of the body (55). These two reports show that^ehronic adminis­ tration of 2,3,7,3-tetra ODD clu ses an increased incidence of neoplasms, but not whether 2,3,7,8tetra-CDD acts as an initiator or promoter. This consideration is particularly important because unequivocal evidence is lacking that 2,3,7,8-tetraCDD is a mutagen or is metabolized, and no evi­ dence ¡^available that 2,3,7,8-tetra-CDD and/or metabolite (s) bind covalently to macromoleculcs. As summarized in Table 5, at least 24 long-term carcinogenicity studies on mice and rats are in progress (94). Humans Toxic Effects in liumsms. Toxicity due to 2,3,7,8-tetra-CDD has been reported after occupa­ tional exposure during tfi|! industrial synthesis of 2,4,5-trichlorophenol (TCt?) and 2,4,5-T, after ex­ posure in factories and in the surrounding envi­ ronment due to accidents occurring during the November 1980 .-r.v- T synthesis of TCP, and after exposure to herbi­ cides and other materials containing 2,3,7,8-tetraCDD. Exposed subjects have been found to de­ velop a wide variety of lesions and symptoms (Table 6). For instance, a typical exposure victim experiences a number and a variety of clinical signs and symptoms: early exposure symptoms may include a burning sensation of the eyes, nose, and throat followed by headache, dizziness, nau­ sea, and vomiting. Some days later, severe itch­ ing, redness, swelling of the face, more marked ^ over the eyelids, nose and lips, may develop. ^ Within the initial weeks after exposure, inflamed w g . nodules as well as pustules appear on the face, forearms, shoulders, neck, and trunk, leading then«»»* to comedones and cysts. A fter a month or two, a c -j^ neform eruptions emerge and the skin becom es«^ hyperpigmented. At about the same time, aching , muscles, mainly in the thighs and chest area, be-^-j • come m anifest and aggravated on exertion. In-r n somnia, extreme irritability, and loss of libido alsq^j occur during this stage. Other than the consistently found clinical feature of acne, other findings in humans mayinclude: neuromuscular symptoms (weakness and pain with nerve conduction abnormalities), porphyria cutanea tarda, hepatic dysfunctions, hyperiipidemia, cutaneous hyperpigmentation and hirsutism, chronic eye irritation, emotional dis­ orders, and neuropsychiatric syndromes. Chloracne, one of the most constant and promi­ nent features of 2,3,7,S-tetra-CDD exposure, has been described as a refractory acne characterized by inclusion cysts, comedones and pustules, with eventual scarring of the skin, more frequently originating on the face and sometim es spreading to other parts of the body. Many patients also have blepharoconjunctivitis and irritation of other mucous membranes. Sometimes the chlor­ acne is preceded by erythematous and edematous skin lesions. The latent period between exposure and the appearance of clear signs of chloracne ranges from a few weeks to several months (106). An im portant and unique episode revolves around three scientists who were self-exposed to 2,3,7,8-tetra-CDD: one heated trichlorophenol in an alkaline solution, a second heated potassium trichlorophenate, and a third svorked in the same laboratory as the second and used a diluted solu­ tion of the synthesized dioxin (107). The first two scientists developed chloracne eight weeks after exposure, whereas the third showed no evidence of the characteristic acneform lesions; Delayed symptoms, probably due to 2,3,7,8-tetra-CDD, developed approximately two years later, and the second two scientists showed personality changes ' 1i [ '* i ? j ; ] ! ;; \ i j ! :: i ; j j i ! ; I I | j j .j ; Table 5. Ongoing long-term carcinogenicity testing of chlorinated dibenzo-p-dioxins.*-* Number of studies Compound Route 4 Oral (diet) Skin 2,7-Di-CDD 4 Oral (diet) Skin 2,3,7-Tri-CDD 3 2,3,7,8-Tetra-CDDd 5 Oral (gavage) Skin Oral (diet) Oral (gavage) Oral (gavage) Skin Oral (gavage) Skin Oral (gavage) Skin Oral (diet) Skin , l,2,3,6,7,S-Hexa-CDDd 3 l,2,3,7,8,9-Hexa-CDDd 2 1,2,3,4,6,7,8,9-Octa-CDD 3 Species l Mouse, rat Mouse Mouse (with DMBA)' Mouse, rat Mouse Mouse (with DMBA)' Mouse, rat Mouse Rat Mouse Mouse, rat Mouse Mouse, rat Mouse Mouse Mouse (with 1,2,3,6,7,8-hexa-CDD) Mouse, rat Mouse DOW F 1 Dibenzo-p-dioxin * Data taken from Information Bulletin on the Survey of Chemicals Being- Tested for Carcinogenicity, No, 7 (H). Details of these studies as well as the authors/institutes are available in this source reference document. b As of October 1979, carcinogenesis bioassay testing within the National Toxicology Program included unsubstituted dibenzop-dioxin (UDD: CAS 262-12-4; NCI Tech. Rept. No. 122), considered not carcinogenic to Osborne-Mendel rats and B6C3F1 mice when administered in feed at dose levels of 5 and 10 ppb, and 2,7-dichlorodibenzo-p-dioxin (DCDD; CAS 22857-26-0; NCI Tech. Rept. No. 122), considered not carcinogenic to Osborne-Mendel rats and female B6C3F1 mice but suggestive of a carcinogenic ef­ fect in male B6C3P1 male mice when fed concentrations of 5 and 10 ppb. Studies are in progress on 1,2,3,6,7,8-hexachlorodihenzop-dioxin (HCDD, CAS 57653-85-7) and 2,3,7,8-tetrachIorodibenzo-p-aioxin (TCDD: CAS 1746-01-6) by gavage to Osborne-Mendel rats and B6C3F1 mice ami by skin painting on Swiss mice. Testing on 2,3,7,8-tetrachlorodibenzofuran (TCDF; CAS 51207-31-9) is to begin in fiscal year 1980. For chemical disposition studies octachlorodibenzo-p-dioxin, 2,3,7,8-tetrachlorodlbenzofuran, and the stereochemically related 2,4,3',4'-tetrachIoroazobenzene are also proposed. ' DMBA = dlmethylbenzanthracene. d The National Toxicology Program has completed and reported the results for the long-term carcinogenesis hioassay studies on 2,3.7,3-tetrachlorodibenzo-p-dioxin and l,2,3.6,7,8-/l,2,3,7,8,9-hexachlorodibcnzo-p-dioxins, with the following results. 2,3,7,8-tetrachlorodihenzo-p-dioxin—gavage, carcinogenic for Osborne-Mendel rats (increased incidences of follicular-cell thy­ roid tumors in males and of liver tumors in females) and carcinogenic for B6C3F1 mice (liver tumors in both sexes and thyroid tumors in females); dermal, carcinogenic for female Swiss-Webster mice (fibrosarcoma in the integumentary system) and al­ though not shown carcinogenic for male Swiss-Webster mice, an increase in the same tumor type was observed. Mixture of hexachlorodibenzo-p-dioxins—gavage, carcinogenic for female Osborne-Mendel rats (hepatocellular carcinomas or neoplastic nod­ ules), carcinogenic for male and female B6C3F1 mice (hepatocellular carcinomas and adenomas), and not demonstrated as carcinogenic for male Osborne-Mendel rats; dermal—not considered carcinogenic for male and female Swiss-Webster mice. (mainly loss of energy and drive); impairment of vision, taste, and muscular coordination; sleep dis­ turbances; gastrointestinal symptoms; and hir­ sutism. The first of the three experienced none of these adverse effects. All three exhibited hyper­ cholesterolemia (>300 mg/100 ml).• • Human Exposure to PCDDs and PCDFs Major sources of human exposure to PCDDs and PCDFs include: exposure in the workplace; exposure in factories and in the surrounding envi­ ronment from industrial accidents; exposure to contaminated materials, wastes, or food in the general environment; and exposure in Vietnam and other intensive herbicide spraying opera­ tions. (Prior and subsequent to use as a defoliant, 2,4,5-T was used in weed-killing and forest-thin223 ning operations in the United States of America and elsewhere). Occupational exposure may occur in manufac­ turing plants producing chlorinated phenols (tri-, tetra-, and pentachiorophenols), or phenoxy acid herbicides (2,4-D, 2,4,5-T), or PCBs; in factories utilizing these chemicals for the production of other substances (hexachlorophene from 2,4,5-trichlorophenol) ; in factories manufacturing or re­ pairing transformers and capacitors or having heat exchange or heat hydraulic system s contain­ ing PCBs; and in the use processes of these chem­ icals under various occupational conditions such as spraying of herbicides, using chlorinated phe­ nols for a variety of applications (especially wood preservative), sawing, or otherwise processing treated wood, and using hexachlorophene in sani­ tary occupations. Environm ental H ealth PersDe£ti>UiS 07 GD Table 6. Toxic effects of 2.3.7,8-tetrachlorodibenzo-pdioxins in humans. Effects Dermatological Chloracne Porphyria cutanea tarda Hyperpigmentation and hirsutism Internal Liver damage* Elevated serum hepatic enzyme levels Disorders of fat metabolism Disorders of carbohydrate metabolism Cardiovascular disorders Urinary tract disorders Respiratory disorders Pancreatic disorders Neurological Polyneuropathies (peripheral neuritis) Lower extremity weakness Sensory impairments (sight, hearing, smell, taste) Psychiatric Neurasthenic or depressive syndromes References (25, 28. 95-108) (27, iOi, 105,109) (27, 28,107) ' (27, 95, 98, 101,102, 104106, 110) (27, 28. 96,104-106, 110) (28, 104, 107) (23, 101, 102, 104. 105) (101, 102, 104, 105) (97, 101, 102) (95, 101. 102) (101, 102) (101, 102, 104,105) (23, 95, 99, 101, 102, 104, 105,108) (28, lût, 102, 107, 110) (28, 95, 99, 101, 102, 104, 105, 107) * Mild fibrosis, fatty changes, hemofuscin deposition and pa­ renchymal-cell degeneration were observed in a few cases. The burning of materials impregnated with commercial 2,3,4,6-tetrachlorophenates yielded 150-1000/tg of mixed PC DDs/g chloropnenate. Al­ though only found as a minor constituent, 2,3,7,8tetra-CDD has been quantified at levels exceeding 1 0 /xg/g chlorophenate (111). Pyrolysis of a technical grade PCB mixture yielded many PCDF isomers; the total yield could be as high as 3-25%. One of the main constituents is 2,3,7,8-tetra-CDF, the most toxic PCDF-isomer. Consequently, uncontrolled burning of PCBs can be an important environmental source of the haz­ ardous PCDFs, and operations such as welding or soldering electrical equipment containing PCBs, or using casting waxes in foundries, may possibly entail a significant exposure (112). A PCB used in a heat exchange system for two years contained approximately 1.25 ppm of 2,3,7,8-tetra-CDF and a total of 15 ppm of PCDFs (113). Apart from accidents such as the one which oc­ curred in Seveso in 1976, general environmental exposure may originate from herbicide spraying and waste disposal. An outbreak of PCDDs poisoning in humans. November 1980 horses, and other animals occurred in Missouri in 1971 (97, 11U) following the spraying of contami­ nated oil for dust control in horse arenas. Another possible source of exposure to PCDDs and PCDFs pollution are waste oils, and possibly other waste, when burned both in industrial and municipal incinerators. Under simulated environ­ mental conditions, the combustion of a standard 2,4,5-T formulation led to form ation of small amounts of PCDDs and PCDFs (115). Buser and Bosshardt (11) quantified the total amount of PCDDs and PCDFs in fly ash from an industrial incinerator heating facility as 0.2 and 0.1 ppm, and in the fly ash from an industrial heating facil­ ity in Switzerland as 0.6 and 0.3 ppm. More than 30 individual PCDDs can be identified in the fly ash, but the known highly toxic PCDD isomers are only minor constituents (12). The number of PCDF isomers was larger; but, in this case, the CH known highly toxic isomers are major constitu­ CO ents (13). cn An additional potential source of human ex­ posure has been revealed: beef fat taken from cattle grazed on 2,4,5-T-treated rangeland con­ tained 2,3,7,8-tetra-CDD; of the 11/14 positive samples, the four with the highest levels had 12, 20, 24, and 70 ppt (10). In another study, 3 of 24 sam ples of beef fa t contained 3-4 ppt 2,3,7,8tetra-CDD (116). Moreover, in a preliminary re­ port of an ongoing enlarged study of women liv­ ing in areas where 2,4,5-T is used on rangeland, 4 / 18 breast milk samples each contained approxi­ mately 1 ppt (10). Workers in wood processing industries are ex­ posed to wood dust containing preservatives as well as accompanying impurities and degradation products. Wood dust from a saw-mill in which a 2,3,4,6-tetrachlorophenol formulation was used as a fu n gicid e was found to contain 1-10 ppm PCDFs and <0.5 ppm PCDDs (15). In 1968, more than 1200 persons in South-west Japan were intoxicated by consum ing a com­ mercial rice oil contam inated with 1000 ppm PCBs. Nagayama et al. (117) analyzed the rice oil (Yusho oil) and found 5 ppm PCDFs, the major constituents of which were tetra- and pentaCDFs. Buser et al. (113) recently showed that 2,3,7,8-tetra-CDF was the main PCDF in the Yusho oil (0.45 ppm). The high level of PCDFs was caused by leakage from heat exchangers con­ taining PCBs contaminated with PCDFs. Workers manufacturing 2,4,5-trichlorophenol (TCP) or 2.4,5-T during normal production opera­ tions, and/or following explosions taking place in these plants, may have been exposed to a variety of polychlorinated chem icals whose type and 16975 229 A l- - - c quantity depends on the particular chemical proc­ esses in use and on the phase of the reaction in which the accident took place. Apparently, for in­ stance, PCDFs are produced in the earlier stages when mainly tetrachlorobenzene is present and PCDDs are produced nearer the end of the reac­ tion when primarily trichlorophenol is extant. The concentration of chlorophenols and chloroben­ zenes, for example, was probably higher in the 1963 episode in The Netherlands, where the acci­ dent took place at the beginning of the reaction, then in the 1968 episode in the United Kingdom, or the 1976 accident in Italy, where the explosion took place at the end. A thorough description of the reported indus­ trial accidents and other cases of intoxications ob­ served in exposed workers is given in the IARC Monograph (1). In this present report, only those episodes specifically discussed at length by the NIEHS/IARC ad hoc Working Group will be con­ sidered. (A sequential perspective of known acci­ dents is given in Table 7). In 1949, the first reported cases of industrial poisoning due to the formation of 2,3,7,8-tetraCDD in uncontrolled exotherm ic reactions oc­ curred during the m anufacture o f 2,4,5-trichlorophenol at a 2,4,5-T-producing factory in Nitro, West Virginia; 288 persons were affected (99, 118). In November 1953, an accident occurred in Ludwigshafen, Federal Republic of Germany, during the manufacture of TCP (101,102,119,120); 53 workers were affected by chloracne. Five cases of chioracne were reported following an industrial accident in an Italian TCP-producing factory (121). In 1963, an accident occurred at the 2,4,5-T-producing factory in The Netherlands; approximately 50 persons were affected by chlor­ acne (122, 123). In 1966, Dugois et al. (98) ob­ served 21 cases of chloracne after an accident in a French factory producing TCP in the Grenoble re­ gion. In 1968, an accident occurred at the TCPproducing factory at Bolsover, D erb ysh ire, United Kingdom (103, 106). Within the next 7 months, 79 workers developed chloracne. In 1971, 2,3,7,8-tetra-CDD contaminated waste oil caused an outbreak of poisoning in humans, horses, and other animals (97, 124). In July 1976, an accident at the TCP-producing factory in Meda, Italy (96) resulted in the contamination of a large, densely populated area, including the towns of Seveso, Meda, Cesano Maderno, and Desio. Key information concerning the effects of hu­ man exposure to herbicides in Vietnam, especially to the so-called ‘‘Agent Orange” (a 50:50 mixture of the n-butyl esters of 2,4-D and 2.1,5-T, contain­ Ü ing up to 30 m g/kg or more 2,3,7,8-tetra-CDD), may be found in the literature (1,110,125-127).* Exposure Episodes Considered in Detail by the NIEHS/IARC ad hoc Working Group The text below is a condensed version of the discussions which took place during the two-day NIEHS/IARC ad hoc Working Group Meeting. Phenoxy Acids Exposure ^ Cohort studies on herbicide sprayers have been conducted or are being planned in Scandinavian^countries. The more advanced of these concerns* _ Swedish railroad workers with exposure to a vari-T*“? ety of herbicides. These people exhibited a sign if-- r. icantly increased tumor incidence (apparently^'' dose-dependent) and tumor mortality (129). The^excess of tumors was found particularly among w orkers w ith exposure to am itrole (am inotriazole) , whereas those exposed to phenoxy acids (2,4-D and 2,4,5-T) showed only a slightly in­ creased excess of cancers. The study was small­ sized, comprising 2978 person-years at observa­ tion in the total cohort and with 18 deaths versus 20.54 expected. The original conclusion from this study was that am itrole exposure may have caused an excess of tumors, whereas there was probably no pertinent increase in tumor incidence associated with exposure to phenoxy, acids. The study has been recently reanalysed using a casecontrol approach, and through stratification on amitrole when considering the effect from phe­ noxy acids, and vice versa. The results show a p o s-' sible and previously masked tumor-inducing e f­ fect also from phenoxy acids. Another retrospective cohort mortality study, conducted in Finland on workers of five com­ panies involved in spraying 2,4-D and 2,4,5-T on brushwood, did not show any increase in mortal­ ity. During 1955-1971, in the younger group of workers (under 45 years of age), however, four cancer deaths were observed versus less than two expected (no statistically significant difference). A prospective follow-up study for the period 19721976 revealed fewer cancer-related deaths than expected in all age groups. Clinical and anamnes" More than 2.000.000 gallons of Agent Orange remaining from military defoliant operations were destroyed by in­ cineration on Imard ship in the Pacific Ocean, 120 miles from Johnston Island. Temperatures not lower than I250°C were used. The steel containers were melted ( /ti.V). Environm ental Health Perspectives > 16978 tic investigations were also performed showing a , picture of acute complaints during and following the spraying operations: headache, transient diz­ ziness, fatigue, abdominal complaints, skin and mucous irritations, and a few cases of persistent papulae. Interestingly, some samples of 2,4,5-T used in Finland for spraying operations contained from 0.04 to 0.07 ppm 2,3,7,8-tetra-CDD. This may im­ ply that the 2,4,5-T produced before 1965 con­ tained lower levels of 2,3,7,8-tetra-CDD impur­ ities than has been observed subsequently from 2,4,5-T used elsewhere. However, the analytical methods used in the determ ination of 2,3,7,8tetra-CDD in the Finnish samples were anti­ quated in view of the rapid advancements made in an a ly tica l m ethodology and thus a con­ firmatory analysis of the samples using modern techniques was made by Rappe et al. (130). Five samples of 2,4,5-T ester dating from 1962 to 1967 were analysed for PCDDs and PCDFs; levels of 0.1-0.95 ppm 2,3,7,8-tetra-CDD and 0.1-0.15 ppm tetra-CDF were found. A second feasibility study was designed and conducted in Finland to determine whether one could obtain anamnestic, clinical, hematological, and im m unological in form ation on F in n ish railway and forestry workers who had been ex­ posed for several years to herbicides containing 2,3,7,8-tetra-CDD. The exposed group consisted of 30 men who were control-matched to persons of the same age coming from the same district with similar job backgrounds and living conditions. Of the tests made, including liver and immunofunction studies, no differences were observed be­ tween the exposed and control groups. Although the population study is too small to permit any general conclusions as to the potential adverse health effects from long-term exposure to phenoxy acids, the investigation shows that follow-up is possible on the health status of persons exposed for several years to 2,3,7,8-tetra-CDD-containing phenoxy acids, and then to compare the exposed group results to carefully matched controls. The study is in progress. Hexachlorophene Exposure An excess of malformations, some severe, has been reported among children whose mothers were em ployed as nurses in a hospital. The mothers were exposed to hexachlorophene soap during early pregnancy, and the hypothesis of a causal relation between such an exposure and the occurrence of the malformations has been ad- vanced (131); five severe and six slight malforma­ tions were observed in 65 children in the exposed group, whereas only one slight malform ation was observed in the 68 children of the unexposed group. This report has been followed by another study (to be published) of a similar group of chil­ dren of exposed mothers in comparison to chil­ dren of unexposed mothers. Again a high fre­ quency of malformations among the offspring of exposed mothers was reported (132). From these studies, however, it is not clear if exposure to other hazardous chemicals could be excluded. A retrospective-prospective study is being initiated among long-term workers of an United States’ factory which used Seveso-produced 2,4.5-trichlorophenol in the manufacture of hexachlorophene. However, in the case of hexachlorophene, polychlorinated xanthenes have been also identi­ fied as contaminants at a higher level than 2,3,7,8tetra-CDD (133). i «&? Phenoxyacids and Chlorophenols Exposure in Forestry and in Wood Industry Workers At the Regional Hospital in Umea (Northern Sw eden), Hardell (134) observed that several pa­ tients suffering from mesenchymal tumors re­ ported occupational or other exposures to phen­ oxyacids. More specifically, 87 mesenchymal tumors were diagnosed during the years 1970 through 1976. Of these cases, 55 were men (more than expected) and 43 of these 55 men were known by profession: 19 were either forestry workers, farmers and forestry workers, or work­ ers in sawmills and papermills where exposure to chlorophenols is common. Based on the official sta­ tistics of Sweden, one can calculate approximatively the expected fraction of tumors within these trades, resulting in an expectancy of approxi­ mately 11 cases versus the 19 observed. The Mount Sinai School of Medicine in New York is currently planning a field survey on long­ term health effects on wood-preservative workers in Arkansas and Oklahoma in the United States of America. ft«, Z-&: tes & iaK' Exposure to 2,3,7,8-Tetra-CDD during Production of 2,4,5-T or Polychlorinated Phenols and Following Industrial Accidents The following cases, as well as others not con­ sidered at the meeting, have been described in 1ARC Monographs Volume 15 (1), and only some November 1980 • 169?^ _ _ -- ¿3 • , ~ “ j j j j i Environm ental Health Perspectives 16978 271538 r All the 75 workers could be traced in a cohort study 25 years later; mortality was compared both with the regional and national mortality and with a control group of workers from the same factory. In the exposed group, 17 deaths were observed (11 to 25 expected depending on the control popu­ lation); six from cancer (four or less expected), five from cardiovascular diseases (as expected), two from suicides (0.2-0.6 expected), one from liver cirrhosis, one from a urogenital tract dis­ ease, and two from traffic accidents. Of the six cancer deaths, three were from stom ­ ach cancer and occurred in the age group of 60-69, which is significantly more than expected. This effect was more pronounced when a minimum ob­ servation period of 10 years was considered, and more so for stomach cancer after a 20-year obser­ vation period. (Use of a long observation period permits a better estimation of the relation be­ tween exposure and disease when long “latency" periods are involved, as for cancers). A similar accident occurred at the 2,4,5-T-producing factory in The Netherlands in 1963; 106 men are likely to have been exposed to 2,3,7,8tetra-CDD (and possibly PCDFs) as they were in the building where the accident occurred during the subsequent period, March-July 1963. These workers may be divided into three groups: (A) factory employees (exposed during all phases of the cleaning and reconstruction activities), 44 men; (B) clean-up crew (nonfactory personnel, exposed during the months May-July), 18 men; and (C) plumbing, painting, and insulating per­ sonnel (nonfactory workers, exposed during the months May-July), 44 men. During the explosion in Amsterdam, two oper­ ators were present in the building. With the ex­ ception of these men, who were probably exposed primarily by the inhalation route, all other work­ ers used safety masks and were probably exposed by dermal contact. Chloracne was the most com­ mon and prominent lesion observed follow ing 2,3,7,8-tetra-CDD exposure (26/44 examined in group A, 10/16 in group B, and 8/16 in the group C). Liver function tests (thymol turbidity and serum glutamic pyruvic transaminase and serum glutamic oxaloacetic transaminase) did not in­ dicate liver damage. A few men complained of fa­ tigue. The latent period between exposure and the appearance of chloracne, characterized by comedones, pustules, and cysts on the face and sometimes on other parts of the body, was ap­ proximately 4-6 weeks. Som etimes, erythematous and edematous skin lesions, possibly due to phe­ nolic compounds, were noted one day after ex­ posure. No skin iesions (chloracne) were reported j ^ SJS "t* ■'' of the previously available information will be given here. The ongoing epidemiological studies on these cohorts are summarized in Table 7. As each individual cohort has a relatively small number of person-years, a study has been pro­ posed in which all the cohorts would be pooled and the mortality compared to that expected from the national statistics. The first reported cases of industrial poisoning due to the formation of 2,3,7,8-tetra-CDD in un­ controlled exothermic reactions occurring during the manufacture of TCP were seen in 1949 at a 2,4,5-T-producing factory in Nitro, West Virginia, USA; 228 persons were affected. These individuals were studied by Suskind and Ashe (135) and foilowed up for a period of four years. Symptoms ineluded chloracne, nausea, vomiting, headaches, severe muscular aches and pain, fatigue, emotional instability, and intolerance to cold. Laboratory findings showed raised total lipids and raised pro­ thrombin time. Among those affected were not only workmen, but also laboratory personnel, medical personnel, and even the Safety Director who visited the areas of exposure. Several wives who had never visited the plant also developed acne, usually at the same time as their employee hushands. It is important to note that information on the toxicity as -well as on the stability (long per­ sistence and slow degradability) of 2,3,7,8-tetraCDD was not available at the time the first re­ ports of acute toxicity were observed, and no measures were taken to decontaminate the facto­ ries and control the residue levels of 2,3,7,8-tetraCDD. In fact, the presence of 2,3,7,8-tetra-CDD or other PCDDs and PCDFs was not even suspected. Workers, therefore, were probably exposed for a considerable time to 2,3,7,8-tetra-CDD following the first observations of acute toxic efFects. In November 1953, an accident occurred at a TCP factory in Ludwigshafen, Federal Republic of Germany; 75 workers were exposed to the reac­ tion products during the accident and the sub­ sequent cleaning work; most were affected by chloracne, 42 severely: 21 of the 42 suffered con­ sequent damage to internal organs or disturbances of the nervous system. The most relevant features were polyneuritis, sensorial impair. ments, and liver damage. The son of one of the workers developed chloracne following contact with his father’s work clothes. An additional case of poisoning occurred 5 years later in a worker who was involved in repair work (welding one of the auto-claves) at the contaminated site; subsequently this worker died with necrotic pancreatitis. f ^riy~ -'liüy in family members of the employees. Of group A, 3/44 workers died, one of pancreas carcinoma in 1964, one of myocardial infarction at the age of 69, and one of a traffic accident. Of the 17/18 traced individuals in the B group, four have died (three from sudden death, probably of myocardial infarction, at ages, 41, 53, and 65, and one of illdefined pulmonary or cardiac cause at age 44). Only 32/44 of the C group were traced, and one of them died of sudden death, probably myocardial infarction, at age 50. Jirâsek et al. (104, 105, 109) studied 55 subjects from a cohort of 78 workers from a factory in C zechoslovakia producing 2,4,5-T and pentachlorophenol, who were affected by chloracne. The workers were probably exposed during the years 1965-1968 to unknown levels of 2,3,7,8-tetraCDD. A significant symptom was the disturbance in porphyrins metabolism with signs of porphyria cutanea tarda. Many workers also suffered severe hepatic and neurological damage and had raised blood levels of cholesterol and total lipids. In the first years of follow-up, five deaths were observed, two from bronchogenic carcinoma at age 47 and 59 (only 0.12 lung cancer deaths were expected from national mortality sta tistics), one from atypical atherosclerosis at age 57, and one from the acute occupational intoxication. One further death, probably from iiver cirrhosis, has recently been observed and 50 workers are still being fol­ lowed. Many workers continue to show lipemia and hypercholesterolemia and have developed prediabetic changes and hypertension. The work­ ers lost to follow-up are mostly foreigners who re­ turned to their country of origin. In July 1976, an accident in a TCP-producing factory in M eda, Italy resulted in the con­ tamination of the towns of Seveso, Meda, Cesano Maderno, Desio, Nova Milanese, and possibly oth­ ers of a large, densely populated area called the Brianza di Seveso with a total population of about 220,000 inhabitants. A retrospective health survey conducted on the workers of the ÎCMESA factory revealed that two workers among those directly involved in the production of 2 ,1,5-trichlorophenol suffered from skin lesions previous to July 1976. These facts may be indicative of a previous 2,3,7,8-tetra-CDD exposure. A large and intensive follow-up program is in progress in the Seveso area; data were presented about the first dermatological, neurological, clini­ cal, and laboratory findings, as well as about fetal damage. Dermatological examinations, including’ the. screening of 32,000 children, resulted in the finding of hundreds of children with skin lesions, 135 of which were eventually identified as chlor- acne; 59 cases were from the more contaminated area (Zone A). However, precise description of diagnostic criteria and accurate anamnestic infor­ mation, including, among others, data on places of residence, were not included. This information is needed before evaluating the m eaning of the chloracne incidence data by territorial areas and efforts should be made obtain it. Chloracne cases were not systematically searched for in adults. Neurolog'cal examinations showed both signs of subclinical neurological damage and cases of clini­ cally detectable polyneuropathy in adults (34/338 persons from zone A and 8/185 from the sur­ rounding areas). In about 30% of 1654 adults from both A zone and nearby zones, hepatomegaly was reported to be present on clinical investigation. No informa­ tion, however, is given on the criteria by which the hepatomegaly was evaluated. The same per­ centage of abnormalities was observed in one or more liver tests (mainly glutamyl transferase and serum glutamic pyruvic transaminase and serum glutamic oxaloacetic transam inase). Ex­ tensive monitoring of various hematological pa­ rameters from 25,000 persons is now in progress and the data are expected to become available during 1978. Results of this investigation should allow a better understanding as to whether or not these a lteration s are caused by exposure to 2,3,7,8-tetra-CDD and PCDDs. So far, immunological investigations, cyto­ genetic research, and embryomorphology analy­ ses on cases of therapeutical abortions have not given abnormal results. However, the study of the frequency of congenital malformations and spon­ taneous abortions seems to be very difficult to ac­ complish. The importance of a system atic study on this subject has been stressed by the Working Group, because the questions on the teratogeni­ city of 2,3,7,8-tetra-CDD in humans cannot be solved by any other study. A preliminary mortality study has been pos­ sible in 2 of the 11 towns of the Seveso area. The 1975-1977 mortality rates from liver cirrhosis and leukemia in these two limited zones of the Seveso area were compared to that of a nearby area (province of Varese). Within an overall mortality which did not appear different, an increase of deaths from liver cirrhosis and from leukemia was noted. The validity and significance of these observations should be carefully evaluated. Recommendations A chemical analytical program should he en­ couraged to identify and standardize analytical 233 November 1980 16979 u ■g i: i ' I • * • •!-iV-.•* M/ì.vCÀ Iv W Table 7. Epidemiological studies on 2,3,7,8-tetrachiorodibenzo- p-dioxin; human exposure episodes caused by accidental or occupational exposure occurring in factories producing2,1,5-trichloroplienol and/or 2,-1,5-lrichfornphcnoxyucetic acid. Town and country Accidental exposures Nitro, West Virginia, Number Year of of exposed exposure persons 19-19 228 Only 36 individuals were followed, for a period of ■I years I.udwigshafen/Rhein, Federal Republic of Germany 1953 75 A mortality cohort study has conducted 24 yr after the accident; all exposed workers were traced for a total of 1525 person-years of ob­ servation Amsterdam, The Netherlands 1963 106 Preliminary observations on mortality are available; 93 exposed workers have been traced up to 1977 Uolsover, Derby­ shire, United Kingdom 1963 90 Of the workers belonging to the original cohort, 50% are still employed and routinely undergo clinical and laboratory investiga­ tions (U.S.A.) n 3 < 3 3 it 3 * 3 Clinical follow-up and cohort studies Observations to date No significant long-term observations arc yet avail­ able (some fulfowed-up individuals had symptoms of severe intercostal neuritis 6 Cancer deaths were ob­ served: 3 of stomach cancer in the age group 60-69 (significantly higher than expected), 2 of oat-cell carcinoma of the lung, and 1 of colonic adenocarcinoma Of 8 deaths, 5 or 6 were from cardiovascular diseases, 5 probably from myocardial infarctions; the myocardial infarction death rate seems higher in the most heavily exposed workers all'ected by cbloracrie. One worker, who did not develop chloracne, died from puncreatic car­ cinoma 14 months after the accident; however, he com­ plained of abdominal pain prior to the accident One worker is known to have ilied from coronary thrombosis Proposed actions Mortality cohort study being planned Follow-up to be continued Comments and recommendations of theNIEHS/IARC Working Group Efforts should be made to trace the individuals who were exposed, possibly through the employment compensation files. The results of the continuing follow-up study should periodically be made avail­ able. Full report planned for 1978 Efforts should be made to trace all the wurkers who were exposed. Epidemiological cohort study to be planned when the results of the present clinical follow-up investiga­ tion become available Efforts should be made to trace all the workers who were exposed. H4 ~ 05 =r co? 00 2 Oa n> ts. Q iS U Z I f la g V. November 19f<0 Mcda, Urianza ili Sovcso,Italy Occupational exposure Czechoslovakia 1376 19651969 80 3J d 9 8 X A clinical follow-up of the inhabitants from the more contaminated areas is being carried out. At the time of the accident, living in Zone A was a population of 760 people, with 200 of those being between 0 -1-1 years of age. Of these 730 persons, 623 (125 between 0-14 years of age) were followed-up. Zone II con­ tained a population of 4732 inhabitants with 1203 between the ages 0-14 years. An accurate count of those followed in Zone B is nut available, but 943 young­ sters between 0-14 years of age are included in the follow-up Initial clinical observations showed a high incidence of 2,3,7,8-tetra-CI)IJdependenl skin lesions among children living in the more contaminated area. Also, a number of persons residing in the zone sur­ rounding the more con­ taminated areas hud skin lesions, hut with poorly de­ fined, clinical features; these lesions may be the result of 2,3,7,8-telra-CDD ex­ posure. Moreover, both clinical and laboratory find­ ing's suggest an increased incidence of hepatic suifercnce among adults living in the highly contaminated areas. A preliminary mortal­ ity study suggests that al­ though the overall rates from 2 Seveso‘lowns are not different from a nearby area, an increase of deaths from liver cirrhosis and leukemia was noted Among other ongoing investigations, a long-term morbidity study has been Initiated Possible teratugenic and other adverse reproductive and developmental effects from 2,3,7,8-tetra-CDI) exposure shuuld be investigated. A mortality register and pop­ ulation tiles, suitable fur adequate descriptions of morliidity data, should be established. Further, the cancer registry that already covers a nearby province, should be extended to in­ clude the Seveso urea. A follow-up has been made regularly on 55 workers of the original cohort. Thu workers lost to follow-up are mainly foreigners who left the country Five patients died during the first 5 year-follow-up period: 2 died from bron­ chogenic carcinoma and 1 from a rapidly developing atypical atherosclerosis. One further death, probably from liver cirrhosis, has recently occurred. Many of the workers are now suffer­ ing from hypertension and show signs of hyperlipi­ demia and hypercholeste­ rolemia us well as predialictic symptoms and signs Follow-up to he continucd.A 10-year report will be prepared during 1978 The results of the continuing follow-up study should periodically be made available. ‘ No reliable information was availatde to the Working Group about the actual number of exposed persons; the entire area has a population of approximately 200,000 people. 235 ifsiLz I MOlf This report represents the views ami opinions of the U.S. NIEHS/fARC (National Institute of Environmental Health Scienres/internationnl Agency for Research on Cancer mi hitr Working Group which met January 10-11, 1973 in I.von France to review the history of human exposure to these chemicals, to collate current information, anti to plan anil fore­ cast neetleil new ilirections. The meeting was funded jointly by NIEH.S and IARC. REFERENCES l. International Agency for Reserach on Cancer. 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Dugois; P., Amblard, P„ Aimard, M., and Deshors, G. Acné chlorique collective et accidentelle d’un type nouveau. Bull. Soc. Franc. Derm. Syph. 75: 260 (1968) 99. Firestone, D. The 2,3,7,8-tetrachlorodibenzo-para-dioxin problem: a review. In: Chlorinated Phenoxy Acids and their Dioxins: Mode of Action, Health Risks and Environ­ mental Effects. Ecol. Bull. pp. 39-52. Vol. 27, C. Ramel, Ed., Stockholm, 1978. 100. Gianotti, F. Chloracne au tétrachloro-2,3.7,8-dibenzo-pdioxine chez les enfants. Ann. Dermatol. Venereol. 104: 325(1977). 101. Goldmann, P. J. Schwerste akute Chlorakne durch Trichlorphenol-Zersetzungsprodukte. Arbeitsm ed. Sozialmed. Arbeitshyg. 7: 12 (1972) . 102. Goldmann, P. J. Schwerste akute Chloracne, eine Masse­ nintoxikation durch 2,3,6,7-TetrachIoridbenzodioxin. Hautarzt 24: 149 (1973). 103. Jensen, N. E., and Walker, A. E. Chloracne: three cases. Proc. Roy. Soc. Med. 65:.687 (1972). 104. Jirasek, L-, Kalensky, J.. and Kubeck, K. Acne chlorina and porphyria cutanea tarda during the manufacture of herbicides. Cs. Dermatol., 48: 306 (1973). 105. Jirásek, L„ Kalensky, J., Kuheck, K., Pazderová, J., and Lukás, E. Acne Chlurina, porphyria cutanea tarda and other manifestations or general intoxication during the manufacture of herbicides. II. Cs. Dermatol. 49: 145 (1974) . 106. May, G. Chloracne from the accident production of tet­ rachlorodibenzodioxin. Brit. J. Ind. Med. 30: 276 (1973). 107. Oliver, R. M. Toxic effects of 2,3,7,8-tetrachlorodibenzo 1,4-dioxin in laboratory workers. Brit. J. Ind. Med. 32: 49 (1975) . 108. Suskind, R. R. The chemistry of the human sehaceous gland. I. Histochemical observations. J. Invest. Dermatol. 17: 37 (1951). 109. Jirasek, L., Kalensky. J., Kubeck, K., Pazderová, J., and Lukás, E. Chlorakne, p o r p h y r i a c u t a n e a t a r d a unde an­ dere Intoxikationen durch Herhizid. Hautarzt 27: 328 (1976) . 110. Ton That, T. Pathologie humain;: et animale de la dioxine. Rev. Med. (Paris): 18: 653 (1977). 111. Rappe, C., Marklund, 3.. Böser, H. R.. and Bosshardt. H.P. Formation of polychlorinated dihenzo-p-dioxina (PCDDs) and dibenzofurans (PCDFs) hv hunting or heating chlorophenates. Chcmosphere 3: 269 (1978). 112. Buser. 11. R„ Bosshar.it. H.-P, and Kappe. C. Formation of polychlorinated dibenzofurans (PCDFs) from the pyrolysis of PCBs. Chcmosphere 7: 109 (1973). November 19S0 113. Buser, H. R., Rappe, C., and Cara, A. Polychlorinated di­ benzofurans (PCDFs! found in Yusho oil and in used Japanese PC8. Chemosphere 7: 439 (1978). 114. Beale, M. G., Shearer, W. T., Karl, M. M., and Robson. A. M. Long-term effects of dioxin exposure. Lancet i: 748 (1977). 115. Ahling, B., Lindskog, A., Jansson, 8., and Sundstrom, G. Formation of polychlorinated dibenzop-dioxins and di­ benzofurans during combustion of a 2,4,5-T formulation. Chemosphere 8: 461, (1977). 116. Kocher. C. W., Mahle, N. H-, Hummel, R. A., Shadoff, L. A., and Getzendaner, M. E. A search for the presence of 2,3,7,8 tetrachlorodibenzo-p-dioxin in beef fat. Bull. Envi­ ron. Contam. Toxicol. 19: 229 (1978). 117. Nagayama, J., Kuratsune, M., and Masuda, Y. Determi­ nation of chlorinated dibenzofurans in Kanechlors and “Yusho oil”. Bull. Environ. Contam. Toxicol. 15:9 (1976). 118. Suskind. R. R. Personal communication, 1978. 119. Hofmann. H. T. Neuere Erfahrungen mit hoch-toxischen Chlorkohlen-wasserstorfen. Arch. Exptl Pathol. Pharmakol., 232: 223 <1957). 120. Thiess. A. M„ and Goldmann, P. Ober das TrichlorphenolDioxin-Unfall-geschehen in der BASF AG vom. 13. No­ vember 1953. In: Vortrag auf dem IV. Medichem-Kongress, Haifa, 1976, in press. 121. Hofmann, M. F., and Meneghini, C. L. A proposito delle follicolosi da idrocarburi clorosostituiti (acne ciorica). G. Ital. Dermatol. 103: 427 (1962). 122. Dalderup, L. M. Safety measures for taking down build­ ings contaminated with toxic material. II. T. Soc. Geneeskd. 52: 616 (1974). 123. Hay, A. Toxic cloud over Seveso (Editorial). Nature 262: 636 (1976). 124. Kimbrough, R. D„ Carter, C. D., Liddle. J. A.. Cline. R. E., and Phillips. P. E. Epdemiology and pathology of a tet­ rachlorodibenzodioxin poisoning episode. Arch. Environ. Health 32: 77 (1977). 125. Committee on the Effects of Herbicides in Vietnam. The Effects of Herbicides in South Vietnam, Part A. Sum­ mary and Conclusions, National Academy of Sciences, Washington, D.C. 1974. 126. Westing, A. H. Ecological considerations regarding massive environmental contamination with 2,3,7.8tetrachlorodibenzo-parn-dioxin. In: Chlorinated Phenoxy Acids and their Dioxins: Mode of Action, Health Risks and Environmental Effects. Ecol. Bull. Vol. 27, Stock­ holm, 1978, pp. 285-294. 127. Meselson, M. S., Westing, A. H., and Constable, J. D. Background material relevant to presentations at the 1970 Annual Meeting of the AAAS. American Associa­ tion for the Advancement of Science, Herbicide Assess­ ment Commission, 92nd Congress. 2nd Session, US Con­ gressional Record 118: S3227-S3233 128. Walsh. J. Odvssev of Agent Orange ends in the Pacific. Science 197: 966 (1977). 129. Axels.m, 0., and Sundell, L. Herbicide exposure, mortal­ ity and tumor incidence. An epidemiological investiga­ tion on Swedish railroad workers. Work-Environ. Health 11:21 (1974). 130. Rappe, C., Buser. II. R.. and Bosshardt. H.-P. Identifica­ tion and quantification of polychlorinated dioenzo-p-dioxins (PCDDs) and dibenzofurans. (PCDFs) in 2.4.5-Tester formulations and herbicide orange. Chemosphere 7: 431 (1978). 131. Hailing, H. M isstankt sam hand mellan hexaklorofenexposition ix-h mts.shildningsbord (Suspected link be­ tween exposure to hexachlorophene and birth of mal­ formed infants). Lakartidningen 74: .5-42 (1977). .1 6 9 8 5 2TJ 132. Hailing H. Personal communication to 0. Axelson (1977). 133. Baughman, R. \V. Tetrachlorodibenzo-p-dioxins in the en­ vironment. High resolution mass spectrometry at the picgoram level. Thesis Harvard University, Cambridge, Mass. 1974. 134. Hardell, L. Maligna mesekymala tumorer och exposition for fencxisyror—en Klinisk observation (Malignant mesenchymal tumors and exposure to phenoxy acids—a clinical observation). Läkartidningen 74: 2753 (1977), 135. Buskind, R. R., and Ashe, W. F. Unpublished reports and personal communication (1979). DOW 1 2 7 1 5 4 6 i I I I I i I 1 * ? I 3 1 1 Ì 1 240 Environm ental Health Perspectives 163B8 24 M r*J *f; National :.r=rc~Farmers Union RESOLUTION on The Consolidated Hearings on Cancellation ot: the E.P.A. Registration of 2,4,5-T and Silvex Herbicides. FIFRA Docket #415 et al To: WHEREAS, Douglas Castle, Director Environmental Protection Agency The National Farmers Union, a national farm stockmen and farmers throughout the United States, together with one thousand three hundred local cooperatives who serve them-, and WHEREAS, the action by the Environmental Protection Agency has been started to cancel the registration of the herbicides 2,4,5-T and Silvex because eight women in Alsea, Oregon reported a coincidence of abortion and spraying the forest. Activist groups who are opposed to spraying pesticides in the U.S. forests have forced EPA to hold this public hearing, and WHEREAS, reputable physicians and scientists haw? now refuted the Alsea conclusions and have reposted on the long time study of mother's mil!: r m n the area; f".n milk does not contain TCDD, the dio:;-.r of 2, ,5-' ’ herbicide, and flQYJ I 0 8 3 9 2 8 organization which represents over two million 2-National Farmers Union Resolution FIFRA Docket #415 et al WHEREAS, currently, EPA registers the labelled 2 , 4 , 5 - ' : ’ a nd Silvex uses as safe and eff icacious. Cri this basis, the herbicides and their use are highly beneficial to the stockmen, ranchers, foresters, rights-of-way users, rice growers and others, and WHEREAS, further benefits include the future of the timber and a reduction in the losses of livestock to poison weeds. As much as 5% of some herds die a violent death, and as much as 8 ‘i of some herds have early abortions and deformed fetus ' caused by eating poison weeds. The poison weeds have esoeso^M O O industry, which depends on vegetation management, been kept under control by using 2,4,5-T and Silvex. Their use is not toxic to the livestock or wild animals, and THEREFORE, BE IT RESOLVED, that the National Farmers Union join the ocher national farm organizations in requesting the U.S. Environmental Protection Agency to step pursuit of its hearings with intent to cancel the register?'.] uses of 2,4,5-T and Silvex, for the management of vegetation in forests, range forage improvement, rights-of-way, poison weed control, ricr. production and other prudent uses. 16988 3-National Farmers Union Resolution FIRFA Docket #415 et al This request is based on findings from data available from universities, research institution:;, industry, and the fact that there is no documented report of damage to applicators, the users of 2,4,5-T, throughtout the area. * * * * * * * * * * * * DOW 1 0 8 3 9 3 0 m e ^ 2423 ! 2421 A Mortality Analysis of Employees Engaged in the Manufacture of 2,4,5-Trichlorophenoxyacetic Acid M. C. Ott, MS.; B. B. Holder, M.D.; and R. D. Olson, 8.S. e r+ ~ lr - « zz. o O' Jr* v*l *Vl CD ►C* O cn ' Only limited epidemiological investigations of em­ ployees exposed to 2,4,5-T have been conducted.5 * In 1971, Poland et al* reported results of a health survey of 73 male employees in a 2,4,5-T and 2,4-dichlorophenoxyacetic acid (2,4-D) manufacturing plant This survey was a follow-up of studies published by Bleiberg et al7 in 1964 on 29 employees in the same plant An important finding in the follow-up was evidence of varying degrees of acne in 48 of the 73 employees. The term tchloracne" was employed to describe the moderate to severe lesions) observed for 13 (18%) of the individuals. No evidence or abnormal excretion of uroporphyrins was found in the follow-up study, in contrast to the findings of the original study. Also, in their summary the authors stated that markedly less evidence of toxicity was found in other organ systems, such as the liver, than was reported in previous studies. Although not judged to be explanatory of differences in toxicity seen from the earlier work, I n 1976 Muranyi-Kovacs et al* published results of a TCDD contamination of the process-starting material. bioassay of 2.4,5-trichlorophenoxyacetic acid (2.4,5-T) for 2.4.5- irichloropheno! (TCP), had been reduced from 10-25 carcinogenicity. The 2,4,5-T, which contained less than ppm to 1 ppm six months before the second survey. No 0.05 parts per million (ppm) of 2,3,7.8-tetrachlorodibenzo- detailed industrial hygiene measurements of 2,4,5-T or p-dioxin (TCDD), was found to produce a significant in­ TCDD levels in the work environment were provided. ^ The present study examines the mortality experience of crease in non-incidental tumors (diagnosed during life or causing the death of the animal) in C3MF mice, but not in a cohort of 204 employees engaged in the manufacture of ' XVII/G mice. Both groups of mice had been fed 80 ppm 2.4.5- T. A review of health examination findings of 2,4,5?T on a daily basis until death. Previously, consider­ phenoxy herbicide workers in this plant was discussed in a able variation between species had been demonstrated in paper by Johnson.' The current survey compares mortali­ the kinetics of excretion of 2,4,5-T.1An earlier screening ty due to specific causes with that of the corresponding . j bioassay study by Innes et al1 was not positive for U S. white male population, and with results of other mor­ I N t u m o r i g e n i c i t y in two hybrid strains of mice fed 60 ppm tality studies conducted at this company location. 2.4.5- T in their diets. The authors of the 1976 bioassay arti­ cle. aware of the kinetic studies and paper by Innes, sug­ History of Process and Industrial Hygiene Measurements gested that additional testing of 2,4,5-T was needed. A The commercial production of 2,4.5-T in the company two-year feeding study in rats was conducted in^Midland, began in March 1950, with the original process being Y.CO 10A Michigan(Kociba et al4). Concentrations of up to.30 mg’of operated continuously until it was permanently shut 2.4.5- T per kilogram per day did not induce^oy ÚUÜ o • uu.aiu . '¡VkJ«’ 1U U k j t ¿ .L i i t r tJ t H A N S -JO A C H IM D O H M E IE R RECH TSA N W A LT 4 Luriui.igstraJ3ö 4 0 8 7 0 0 l.U Ü W IG S H A F E N Tuterfon (0 6 31) 5 1 2 2 5-1 RA O oriineiur. L u d w ig atraS e 4 9. 6 7 0 0 L u dw iQ snafen An Clark, Drummie & Company z. H. William B, Richards Kö*1ton: Pcfitproannt LLjrìwuìuchaian (BLZ 5 4 5 1 0 0 6 7 ) Kto.-Nr. 2 9 3 7 5 6 7 0 D r e s d n e r S A iik L'jdwigal-w»(er< P.O. BOX 6850 Station "A" Saint John, N.B. (BLZ 5 4 5 8 0 0 2 0 ) Wö.-Nf. 1 0 09485 00 S ta d tsu tu k a sB B LuiieriQShafen IQLZ 545500101 Kta.-Ni. 282 33.) Canada E2 L 4S3 Sprechzeiten: rftw iiíremoan^; i _ 22. Februar 1990 Sehr geehrter Herr Kollege Richards, bitte entschuldigen Sie die Verspätete Antwort auf Ihr Schreiben vom 26. Januar 1990. Ihre Frage darf ich kurz wie folgt beantworten: Es ist mir bisher einmal gelungen, ein Gericht davon zu überzeugen, daß der Magen­ krebstod eines Arbeiters auf eine berufliche Dioxinintoxikation zurückgeführt werden muß. Das Urteil des Sozialgerichts Hamburg ist allerdings noch nicht rechts­ kräftig. Die Berufsgenossenschaft der chemischen Industrie, bei der die Arbeiter der Firma Boehringer/Ingelheim versichert sind, hat es mit dem Rechtsmittel der Berufung angefochten. Ebenfalls einmal ist es mir gelungen, die Berufsgenossenschaft der chemischen Industrie davon zu überzeugen, daß die akute myeloische .Leukämie eines Arbeiters der Firma BASF AG, die schließlich zu seinem Tod führte, auf eine einmalige, hohe Dioxineinwirkung zürückzuführen ist. Die Berufsgenossenschaft hat diesen Zusammen­ hang außergerichtlich durch einen entsprechenden Bescheid anerkannt. Mir sind ferner zwei Fälle aus früherer Zeit bekannt, in dem die für die chemische Industrie nach deutschem Recht zuständige Berufsgenossenschaft einen solchen Zusammenhang bejaht hatte. Der eine Fall liegt schon sehr weit zurück. Damals ist aufgrund eines Gutachtens des früheren Toxikologen der Firma BASF AG, Prof. Dr. Heinz Oettel, der Lungenkrebstod eines Arbeiters der Firma Boehringer Ingelheim als durch “Trich1orpheno1-ZerSetzungsprodukte1' anerkannt worden. In jüngerer Zeit ist mir ein Fall bekannt, in dem die Berufsgenossenschaft der chemischen Industrie sich mit einem weiteren Arbeiter der Firma Boehringer, der chronisch d l D X inexponiert gewesen ist^ihm Entschädigungsleistungen zu gewähren. .¿ ih ,* 17000 C L JH 1 U l -U U A l\1 \, im U lW IM I L , cc v^u. u UU U £. - 2 - Ich vertrete weitere fünf ehemals dioxinexpanierte Arbeiter anwaltlich, die an Krebs erkrankt sind, bei denen bisher jedoch noch keine Entscheidung über die Entschädigung,- sei es außergerichtlich oder gerichtlich, gefallen ist. Möglicherweise können Ihnen auch die diesem Schreiben beigefügten Fotokopien weiterhelfen, aus denen hervorgeht, daß die Firma Boebringer bereits 1957 verschiedene amerikanische Firmen vor dem unerwünschten Nebenprodukt Dioxin gewarnt hat. Mit freundlichen Grüßen {Dohmeier), Rechtsanwalt 17001 Cjcj\ i q i ;u_A K t\, UKLüMMlt. & LU. ; 3 -3 1 1 -3 2 5Ut5 459 Ö720;# 7/ 9 ; 3:UZ4M k k L , i 1 3 l An dl« i 1 DOW Ch< m lo a l Company 1714 s etman Bd. - ' Midland, Mioh. / PSA ?> Dr. ff«y/B 11. 2. 1957 Chlorakne. parBtellung von flrlohlorphenol :v»f Sehr geehrte Harren | Vir beziehen une auf don Schriftwechsel ln der oben ange­ führten Angelegenheit, den wir mit Ihnen im Jahre 1955 ftthrten. Sie waren damals so freundlich, une Ihre Erfahrun­ gen mltsuteilen. Da une«re eigenen Arbeiten Uber die Vermeidung der Bildung des Chlorakne—Erregers ni einem gewissen Abschluss gekommen sind, möchten wir Ihnen diese Erfahrungen sugänglg maahen und. tun das durch Beifügung dar kleinen Abhandlung sie Anlage Wir hoffen, Ihnen mit unseren Ausführungen e i n e n B e i t r a g *ur Sicherung der Synthese der grichlorphanonaasigatture gegeben zu haben und nehmen an, dafl der Beitrag auch für Sie ton Interesse Ist. Vir grüßen mit Yorstlglioher Hochachtung C .H . BOEHRIBGER SQHN ppa. : 7 • *• Anlage 17002 ouu ui -0/ a m uiB um : ‘tfi \-,\K ” * 'mi> 30 ^¿T »’'^•TJ u Hüd » ^ v Jf.lU<«*hrn>rjt!< Üc Im1 o*n Rh 4) W e it e r r s r a r b e lt u n g ca r e in e r k r i s t . la a h u n s e re n ir f a h r u n g e n l a t d ie 2 ,4 ,5 -^ r lo h lo r p h e n o i « ö o ig e a u r e e H a t r iu a 2,4,5 T -3 a u re a h lo ra k n .e -e u o lö a e a d e W ir k u n g a u f V e r u n r e i n i g u n g e n d u rc h . N e b e n p r o d u k t e a u r l i c k z u f U h r e n , d l« b e i dom k o a x e n t l o n e l l a n P r o z e ß w enn T rlo h lo rp h a z w lz m tr lu a h e r g e o t e llt , \ E rre ge rn 2,^,5 T r i o h l o r p h e n o x y e s a i g a ä u r e l ä u f t l n c i2 f r l c h l o r b e n s o l ■■ -— ■■ -— > *---- -— u n te r n u r dann e n tste h e n können, bzw . a n d e r s A lk a lia a lz e ro n T r lo h lo r p h e n o l g e r e i n i g t u n d w e i t e r r e r a r b e i t e t w e rd e n und a io h d a b e i R e a k t io n s b e d in g u n g e n e rg e b e n , d l« denen e in e r S a lz o a h m e ls i. n a h « '- o d e r g l e io h k o s u a e n * U n t e r d ie s e m G e s ic h t s p u n k t e r g ib t ste h u n g dea d h lo r a h n e - B r r e g e r a a tu fa n fo lg e n d e s ZU 1 u n d 4 ) Zu 2) « ic h a l t f ü r d ie B ezug a u f d ie e in z e ln e n E n t­ V e rfa h re n s- i Diese S t u f e n s in d , rölllg ungefährlich Bai d ie s e r Stu fe k a n n d e r C h lo r a lc n e - i& r r e g e r e n tste h e n . Zu 2 a) — Ubt die« bei der Autoklaren-Reaktlon au rer— h in d e r n . » is t e in s Ü b e r h it z u n g d e s A u t o k la r e n - m iin lt s ou r e r a o ld e n (Höchsttemperatur 150° 0). und W a lte r d a r a u f au n ah te n , daß ln möglichst g r o s s e r Verdünnung a l t k e th a n o l gearbeitet w ir 1 7 0 0 ^ ^ Hans-Joachim Dohmeier Lawyer To Clark, Drummie & Company attn. William B. Richards P.0. Box 6850 Station "A" Saint John, N.B. Canada E2L 4S3 Day: 22.February 1990 Dear colleague Mr. Richards, please excuse the delayed response to your letter of January 26,1990. I would like to answer your question briefly in the following: I have managed once to convince the court that the death of a worker who died of stomach cancer was caused by a work related dioxin intoxication. The verdict of the court in Hamburg (social tribunal) has however not yet been finalized. The trade association (workman compensation board) of the chemical industry, through which the workers of the company Boehringer Ingelheim are insured, has appealed the verdict. Also once have I managed to convince the trade association of the chemical industry that the acute myeloic leukaemia of a worker of the company BASF AG that finally led to his death was caused by a one time high influence of dioxin. The trade association has acknowledged this correlation by excepting an out of court settlement. Further I know of two cases some time ago, in which the trade association which according to german law is responsible for the chemical industry, has affirmed such a connection. The one case is from quite a while ago. Back then, on the basis of a report of the former toxicologist, Dr.Heinz Oettel, from the company BASF AG the lung cancer death of a worker of the company Boehringer Ingelheim was accepted as caused by trichlorpherol - disintegration product. Lately I know of one case in which the trade association agreed to pay compensation to another worker of the company Boehringer, who was chronically exposed to dioxin. I legally represent five more workers who were exposed to dioxin, and who suffer from cancer, whose cases however have not yet been settled, be it in court or out of court. The photocopies attached to this letter may possibly help you out further, as they go to show, that the company Boehringer has warned different american companies of the undesired by-product dioxin as early as 1957. Best regards, (Dohmeier) Lawyer 17003 To the Dow Chemical Company 1 n i M n ___i____ n J 1 / 1 4 ncitbuiudii nu. Midland. Mich. / USA Re: Chlorine acne. Dr. Wey/B 11.2.1957 Illustration of Trichlorohenol Dear Sirs! We are writing in regard to the correspondence we had with you in 1955 concerning the above mentioned matter. Back then you were kind enough to share your experiences with u s . Because our own research about discouraging the forming of the chlorine acne causing agent has come to a certain end, we would like to share our findings in turn with you, and would like to do so by means of the little report attached. We hope to have helped you secure the synthesis of the trichlorphenoxy acetic acid, with this report, and assume that you would find this of interest. Yours truly C.H. Boehringer Sohn attachments 17004 I l l u s t r a t i o n of t r i c h l o r p h e n o x y a c e t i c a c i d a v o i d i n g t h e f o r m i n g o f c h l o r i n e a c n e c a u s i n g a g e n t s . _____________________________________ ________ Our synthesis of the 2,4,5 trichlorphenoxy acetic acid takes the following steps: 1) 2) Trichlorobenzene -C12Tetrachlorobenzene Tetrachlorobenzene -NaOH- Trichlorphenolsodium a) autoclave reaction b) evaporation of 0H3 Oh c) water vapour distillation of the anisole d) isolation of the trichlorphenols through acidification and following distillation 3) Trichlorphenol -NaOH CH2 CICOONa2,4,5-Trichlorphenox acetic acidic sodium further processing to pure crist. 2,4,5 T-acid 4) According to our experience the chlorine acne causing effects are stemming from pollution through by-products, which during the conventional process can only occur, if trichlorphenolsodium or other alkaline salts from trichlorphenol are produced, cleaned and processed and throughout this reaction conditions are given, that are similar or the same to that of a salt-melt. From this perspective then the following picture for the individual processing steps emerges in regard to the development of the chlorine acne causing agent: concerning H and 4) concerning 2 ) concerning 2 a) : : these steps are completely safe at this step the chlorine acne causing agent may be developing : to avoid this during the autoclave reaction, an overheating of the autoclave contend is to be avoided (max temp. 150*C) and further attention should be given, that the methanol is worked with as diluted as possible. 17005 concerning 2 during the methanol distillation the yellow water in the distillation bubble should be held back, so that the dangerous dry heating of trichlorphanolsodium is avoided. The mud temperature should not be higher than 100*C. concerning 2 c) the water vapour distillation ...... of the trichloranisols must be done in such a way, that no change should occur in the concentration of the trichlorphenolsodiumsolution....... water added. concerning 2 d^ during the distillation of the unprocessed phenol it has to be watched, that no trichlorphenolsodium and no table salt is brought into the distillation bubble and heated together with the phenol. concerning 3) at this step chlorine acne causing agents may also develop. To avoid this the condensation of trichlorphenolsodium with chlore acidic sodium may not be done in a water free medium. A concentration of more than 40% is to be avoided in any case. About the qualities of the chlorine acne causing agent can in short be said the following: As a neutral body it is water vapour volatile, so that it can accumulate in step 2 c) in the distilling trichloranisole. It is therefore practical to forget about using trichloranisole and to destroy it through burning. Since the chlorine acne causing agent shows signs of sublimation already at temperatures of 100*C (even though it has a high melting point), the reaction-product of step 2) and 3) should be processed in completely closed apparatuses and the lab should be well aired. 17006 Re: Chloracne. Illustration of Trichlorphenol Dear sirs i We are writing in regard to the correspondence we had with you in 1955 concerning the above mentioned matter. Back then you were kind enough to share your experiences with us. Because our own research about discouraging the forming of the chloracne causing agent has come to a certain end, we would like to share our findings in turn with you, and would like to do so by means of the little report attached. We hope to have helped you secure the synthesis of the trichlorphenoxy acetic acid, with this report, and assume that you would find this of interest. Yours truly 17007 Dear Mr. Richards, please excuse the delayed response to your letter of January 26,1990. I would like to answer your question briefly in the following: I have managed once to convince the court that the death of a worker who died of stomach cancer was caused by a work related dioxin intoxication. The verdict of the court in Hamburg (social tribunal) has however not yet been finalized. The trade association (workman compensation board) of the chemical industry, through which the workers of the company Boehringer Ingelheim are insured, has appealed the verdict. Also once have I managed to convince the trade association of the chemical industry that the acute myeloische leukaemia of a worker of the company BASF AG that finally led to his death was caused by a one time high influence of dioxin. The trade association has acknowledged this correlation by excepting an out of court settlement. Further I know of two cases some time ago, in which the trade association which according to german law is responsible for the chemical industry, has affirmed such a connection. The one case is from quite a while ago. Back then, on the basis of a report of the former toxicologist, Dr.Heinz Oettel, from the company BASF AG the lung cancer death of a worker of the company Boehringer Ingelheim was accepted as caused by trichlorpherol - disintegration product. Lately I know of one case in which the trade association agreed to pay compensation to another worker of the company Boehringer, who was chronically exposed to dioxin. I legally represent five more workers who were exposed to dioxin, and who suffer from cancer, whose cases however have not yet been settled, be it in court or out of court. The photocopies attached to this letter may possibly help you out further, as they go to show, that the company Boehringer has warned different american companies of the undesired by-product dioxin as early as 1957. Best regards, (Dohmeier) Lawyer 17008 I l l u s t r a t i o n of t r i c h l o r p h e n o x y a c e t i c a c i d a v o i d i n g t h e f o r m i n g o f C h l o r a c n e c a u s i n g agents. Our synthesis of the 2,4,5 trichlorphenoxy acetic acid takes the following steps: 1) 2) Trichlorbenzol -C12Tetrachlorbenzol Tetrachlorbenzol -NaOH- Trichlorphenolnatrium a) autoclave reaction b) evaporation of 0H3 Oh c) water vapour distillation of the anisole d) isolation of the trichlorphenols through acidifying and following distillation 3) Trichlorphenol -NaOH CH2 CICOONa2,4,5-Trichlorphenox acetic acidic Natrium further processing to pure crist. 2,4,5 T-acid 4) According to our experience the chloracne causing effects are stemming from pollution through by-products, which during the conventional process can only occur, if trichlorphenolnatrium or other alkali salts from trichlorphenol are produced, cleaned and processed and throughout this reaction conditions are given, that are similar to that of a salt-melt. From this perspective then the following picture for the individual process steps emerges in regard to the development of the chloracne causing agent: concerning 1) and 4) concerning 2 ) : : these steps are completely safe at this step the chloracne causing agent may be developing concerning 2 a) to avoid this during the autoclave reaction, an overheating of the autoclave contend is to be avoided (max temp. 150*C) and further attention should be given, that the methanol is worked with as diluted as possible. concerning 2 b) during the methanol distillation the yellow water in the distillation pocket should be held back, so that the dangerous dry heating of trichlorphanolnatrium is avoided. The mud temperature should not be higher than 100*C. concerning 2 c) the water vapour distillation ...... of the trichloranisols must be done in such a way, that no change should occur in the concentration of the trichlorphenclnatriumsolution........water added. concerning 2 d) during the distillation of the unprocessed 17009 phenol it has to be watched, that no trichlorphenolnatrium and no table salt is brought into the distillation pocket and heat together with the phenol. concerning 3) : at this step chloracne causing agents may also develop. To avoid this the condensation of trichlorphenolnatrium with chlore acidic natrium may not be done in a water free medium. A concentration of more than 40% is to be avoided in any case. About the qualities of the chloracne causing agent can in short be said the following: As a neutral body it is water vapour volatile, so that it can accumulate in step 2 c) in the distilling trichloranisol. It is therefore practical to forget about using trichloranisol and to destroy it through burning. Since the chloracne causing agent shows signs of sublimation already at temperatures of 100*C (even though it has a high melting point), the reaction-product of step 2) and 3) should be processed in completely closed apparatuses and the lab should be well aired. 17010 17011 GH £ ?' ,* TCDD SILVEX causes SYMPTOM may cause X. X X IN ARM KELOID LUNGS • X X 47. CENTRAL NERVOUS SYSTEM DAMAGE 48. CERVICAL GLANDS ENLARGED 49. CHEMICAL SENSITIVITY 50. CHEST PAIN X X 51. CHEST X 52. CHOKING SENSATION 53. CHOLESTEROL HIGH 54 . CHOLESTEROLOSIS 55. CIRCULATION IN HEART POOR 56 . CIRCULATORY PROBLEMS 57. CLAMMY COLDNESS 58. COLD SORES 59 . CONCENTRATION IMPAIRED 50 . CONJUNCTIVITIS 51. . CONSTIPATION 52 Ì CONVULSIONS 53. - COUGHING (with breathing difficulty, congestion, burning in nasal passages and lungs) >4 . 5RAMPS 5. "CRIPPLED-UP" (unable to move due to general pain) X "RATTLE" • X X X \y X X X (GALLO EjADDER) - X X x X }( X > v • CROUP X X *XX CALCIUM DEPOSITS: X X X 46 . X X X x X > X ) < X BUTTOCK PAIN can > 45. .6 . may cause cannot causes cause C'­ en 03 X X X /;\ x - X .7012 1 /X vj c COMMENTS ON SILVICX A N D T C D D S Y M P T O M S The c a t e g o r y c a n n o t c a u s e h a s b e e n i n t e r p r e t e d as u s u a l l y w i l l n o t cause, s i n c e it is i m p o s s i b l e to s a y t h a t s o m e t h i n g w i l l never happen. S c i e n t i f i c a l l y one c a n n o t p r o v e the n e g a t i v e . S o m e of the g e n e r a l t erms s u c h as e n e r g y loss and a n x i e t y are so n o n s p e c i f i c as to be a s s o c i a t e d w i t h a l m o s t a n y i l l n e s s . Unless t hese are c h a r a c t e r i s t i c of S i l v e x , t h e y h a v e b e e n l i s t e d u n d e r c a n n o t cause. T C D D h a s b e e n t r e a t e d in a s i m i l a r m a n n e r . O n l y s y m p t o m s k n o w n to o c c u r in h u m a n s h a v e b e e n l i s t e d u n d e r c a u s e s . U n d e r m a y c a u s e , m o s t of the s y m p t o m s are t h o s e s e e n in a n i m a l s or m i g h t be e x p e c t e d to o c c u r b a s e d on o u r know-, l e d g e of the t o x i c i t y of the c o m p o u n d in h u m a n s . N a t u r a l l y s y m p t o m s m u s t be i n t e r p r e t e d in r e l a t i o n to the t ime of a l l e g e d e x p o s u r e and a m o u n t of e x p o s u r e . For example, a dermatits t h a t o c c u r s m o n t h s a f t e r e x p o s u r e c o u l d h a r d l y be c a u s e d b y the c h e m i c a l ( c o n t a c t d e r m a t i t i s ) . On ther other hand, chloracne h a s b e e n k n o w n to o c c u r s e v e r a l m o n t h s a f t e r e x p o s u r e . 17013 ■c c c c c b 24 13. ANCIILORHYDRIA X > 14 . A NEM I A X > 15. ANGINA X 16. A NGIO-EDEMA X 17. ANOREXIA X X •X V / K> 00 * X ANXIETY .19. i APPETITE LOSS 20. APPETITE ERRATIC X 21. ARM PAINFUL X 22. A R M STIFF X 23 A R T H R I T I S ; LOWER BACK 24. ARTHRITIS; RHEUMATOID (aggravated) X (new) X . N X X 17014 o ' • '■ caur.es SYMPTOM 25 . "ATTACKS" (simultaneous chest pain, breathing difficulty, numbness in arms/hands, dizziness, paralysis arms/legs, difficulty sleeping) 26. AUDITIVE DISCRIMINATION (decreased) 27. BACKACIJE/PAIN 28. BED WETTING 29. BLADDER INFECTION 30. BLADDER ULCERS 31. BLEEDING NOSE/EARS 32. BLISTERS: cannot causo causes may c a u :iQ BLOOD SPOTS IN EYES 34 . BLOOD SUGAR LOW V / X. \ / > X V > > > X X FACE HAIR MOUTH Crl; Cill X X X X X X FACE FEET CilEST LEGS BLOODY P A T C H E S : may cau3o X X X X 33. 35 . Tcnu SI I,VEX X X X > x X X X X' X x X X X X X BREAST TENDERNESS X > 2. BREATHING DIFFICULTY x X 3. BRONCHITIS X. 1. BURNING SENSATION: 16 . ELURRY VISION !7. BLURRY VISION WITH LOSS OF COLOR PERCEPTION 8/ BOWEL MOVEMENT DIFFICULT 9. BREAST CYSTS 0. BREAST DISCHARGE 1. ("milky") LEGS X X 1701E- > X CO l cc « CO TCDD S 11.VJJX causes SYMPTOM may cause cannot cause causes may cause car car MEMORY LOSS • X >< 181. / MEMORY SLOWED X 182. MENSTRUAL DISTURBANCES: HEAVY PLOW HEMORRHAGING IRREGULARITY SKIPPING 18 0 . \ i 183. > X X X X MENTAL EXHAUSTION x L84 . M E NTAL SYSTEMS DETERIORATING 185. MUMPS 1.86 . MUSCLE CRAMPS 87. MUSCLE PAIN: X > X X X X ARMS BACK CHEST NECK . LEGS X 88. MUSCLE SPASM: 89. MUSCLE SPASM CAUSING BA C K DISLOCATION 90. M U SCLE WEAKNESS )1 . NAUSEA >2 . NEARSIGHTEDNESS X X i3. NECK PAIN (with pain left side of body) X X 4. NECK AND SHOULDER PAIN X X 5. 7ERVE DAMAGE: AREA OF SCAPULA CENTRAL NERVOUS SYSTEM RIGHT LEG x' x ? ARMS BACK CHEST EYES NECK LEGS X V x X * X, X X X ? > a: cz Tcnn SILVEX CO • SYMPTOM 67. CYSTS: cauno:; may cause <7a nno L causes cause ARM BREAST EYELIDS KNEE 1 68. DENTAL CONDITION POOR 69. DEPRESSION 70. DIAPHRAGM AREA PAIN DIARRHEA 72. DIFFICULTY FOCUSING EYES cam O.iU: X X ~ x X X X X X X X X 1 X X ■ 71. may cause X X > -A * vy X X X X 73. DIZZINESS WITH LIGHTHEADEDNESS 74 . DIZZINESS WITH LOSS OF EQUILIBRIUM 75. EARACHE X 76 . EAR BLEEDING A '7. EAR CONGESTION X 8 . EAR INFECTION X X X 9. EAR PAIN X X 0. EA R SHEDDING SKIN X X 1. ECZEMATOID X x 2 . EMOTIONAL DISTRESS X X 3. ENDOMETRIOSIS X X 4. ENERGY LOSS X X 5. ENZYME SYSTEM DAMAGE 5- EYE A-V NICKING 7. 'YE IRRITATION (burning, dwelling, durulent itching) > >< X X X A x X 17017 2 O C c C TCDD SILVLX SYMPTOM causes may cause cannot causes CelUSO Ü mny C Si u :jG C-~ C x - 88- EYE SCARRING 89. EYE SORENESS (with congenstion burning) 90. EYE SPASM A 91. EYELID ITCHING A 92. EYELID SHAKING 93. EYES TURN IN SOCKET (when in pain, shows white only) 94 . FACIAL BLEMISHES A 95. FACIAL GROWTHS x 96. FACIAL SCALES X X X v < X ✓ X / X ' X FATIGUE 98. 99. FATIGUE (with loss of strength in limbs) X V / FEVER A V / \ 100. FINGERNAIL COLORATION (darker under nails) X. ’ 101. FINGERNAIL SPLITTING X 102. FOOT CRAMPS X. 103 . FOOT ITCHING X 104 . FOOT PAIN 105. FLAKING SKIN; HANDS/EARS 106 . FLU & COLDS X X X \ y \ V X \ / V 10 7 . FOOD SENSITIVITY X 10' GALLBLADDER DISEASE X 109. GAMMA (GLOBULIN) LOW 1 110. GASTROENTERITIS X X 1 7018 * ... ...... i )OW ' CO cn Vnr ’ 4 SILVI DC SYMPTOM causes L58 - JOINT PAIN .159. KIDNEY, BLADDER, URINARY T R A C T INFECTION 160. LACK OF MOTIVATION 161. LEAKY VEINS WITH SUFFUSION 162. LEG PAIN 163. LEG SWELLING 164. LEG WEAKNESS 165. LIBIDO INCREASED L6 6 . LIGHT SENSITIVITY L67 - LIPS SWOLLEN L68. LOSS OF AMBITION .69. LOW BLOOD SUGAR 70. LUMP IN TIIROAT 71. LUMPS: may .cause TCDD cannot causes cause may C û U Ijc X X ~ x > X X X X X ■> > X X > X X X. X X > X - X X X X X , ANKLES ARMS HANDS KNEES car *'-a u & X X Xs X X X * X X 72. LYMPH NODE SWOLLEN 73. LYMPHOCYTOSIN ? 74. MALAISE 75. M A NU A L DEXTERITY DECREASE (due to numbness in hands) 76. MASCULAR LESIONS ? — • — 77. MASS, > 78. MEASLES 79 . M E M O R Y LAPSES X X X • LEFT BREAST X X X 1 X > 17019 >< O CE o SYMPTOM 111. GINGIVITIS 112 . GROWTHS 113. HAIR ABNORMALITY 114 . HAIR LOSS 115. HAIR WON'T G|<()W 116 . HALLUCINATIONS ("feels that one is being oaten from inside o u t , l,Y w o r m s ») 117. HAND COLDNESS 118 . HAND CRAMPS 119. HANDS CRACK 12 HANDS SHAKE 121. HAY FEVER 122. HEIiDACHE (sovt'fg^ some last for weeks) 123. HEARING DIFF 1(’(JLTY/LOSS 124. HEART FLUTTER 125. HEART PAIN 126 . HEART SOUND 127. HEAT SENSITIVITY 128. HEELS CRACK 129. HIATAL IIERN.1A 130. HIPS PAINFUL 131. HOARSENESS 132. HYPERACTIVE 133. HYPZRINSULINISM (3 ^) SYMPTOM L34 . HYPERTENSION L35. HYPOCHROMIA 136. HYPOGAMMAGLOBULINEMA L37. HYPOGLYCEMIA L38. HYPOTHÊSIA 139. HYPOVITAMINOSIS 140. ILEITIS L4 1. ILEOCOLITIS L4 2. ILLNESSES EXACERBATED L 43 . INABILITY TO FOCUS EYES .44 - INCOORD T.NATIOH/EQUILIBRJ.UM LOSS .4 5. INABILITY TO ACHIEVE ERECTION .46. INABILITY TO CONCENTRATE .47. INFERTILITY 48 . INFLUENZA ,49. INSOMNIA 50. INTESTINAL KINK .51. INTESTINAL SPASM .52. } INTERTRIGO .53. IRRITABILITY 54. ITCHING .55. JAW INFECTION •s .56 JAW PAIN .57. JOINT DIFFICULTIES causes nay cause _ O ° C7Ï cn CO w TCDD S 11.VEX . o cannot causes cause nay enutif; X X X X ^can: cam X X X X X X X X X X X X > X ■ > > v X X > K X X X X t • X. X X X X X X X X, y X X X • \ / X X • .L7021 X •>< > 1 1 X / • S ILVEX SYMPTOM 196. NERVOUSNESS 197. NEURITIC PAIN 198 . NOSEBLEEDS 199 . NUMBNESS: causes Te n u may cause cannot causes cause X X X ARMS ARMS & HANDS FEET FINGERS & WRISTS LIPS S. TONGUE (with wheezing and epigastric d istress) may cause X X ? Y X 200 . NUMBNESS & PARALYSIS: HANDS & LEGS 20' OTITIS MEDIA X 20 2 . OVARIAN CYSTS X 203- OVARY IRRITATION 204 . OVARY PAIN X X 205. PAIN, BACK OF HEAD & AROUND EYES X 206. PALPITATION 207. PANCREAS AREA PAIN 208 . PARAPHIMOSIS 209 . PARALYSIS OF HANDS (partial) 210. .PARALYSIS OF LEGS (partial) 211. PARESTHESIA X 212. PELVIC INFLAMMATORY DISEASE X 21. PELVIC TENDERNESS/PAIN X 214. 9 PERIDONTOCLASIA ' 215. PHYSICAL EXHAUSTION • * X X X , * X. — X - L7022 r~ ~' c SILV liX causer; SYMPTOM 216 . PHYSICAL SYSTEMS DETERIORATING 217. PNEUMONIA 218. POLYPS 219. PROSTATE ENLARGEMENT/PAIN 220. PURPURA 221. RAPID HEART BEAT 222 . RASH: 223. RHINITIS 224 SCALING IN EARS WITH BLOODY PATCHES 225. SCALP BLOODY 226 . SENSITIVITY TO LIGHT 121. SENSITIVITY TO NOISE !28. SHORTENING OF LIFE EXPENTANCY 29. SHORTNESS OF BREATH 30. SHOULDER PAIN 31. SHRUNK ONE INCH SINCE SPRAY 32. SIDEACIIES 33. SINUSITIS 34. SKIM IRRITATION i telling) 35. SKIN LESIONS: 36. SLEEP COMPLAINTS tcdu may canno t 'causes ma y C iU U iO CJiì IJ : | n C ( U |ü n e:a n > X >< X * > X X V / X > X > ARMS FEET HANDS LEGS X X X X X X X X X X X X X X X X X X X X X (burning, HANDS X 117023 \ / 1 <= c cr: TCDD SILVEX cnnnrjt cjau.'ifif. mny cnusnfi mny cause cause cause ' X SYMPTOM 237. SNEEZING 238. SORE x THROAT-i 239 . SPINAL MUSCLE 240. SPINAL 241. STOMACH CRAMPS X X X 242. STOMACH X 243. STREP THROAT 244 . SUDSTERNAL PAIN 245. SUSCEPTIBILITY TO INFECTION & DISEASE INCREASED STASMS PAIN PAIN 2 ‘ SWALLOWING DIFFICULTY 247. SWAY 24 8 . SWELLING: ABDOMEN BLOATING ANKLES FEET • HANDS LEGS LIPS TACHYCARDIA 250. TANTRUMS 251. TEMPORAL 252. TENSION P AIN * 253. THIGH PAIN 254. THROAT 25' THROAT RAW 256. THYROID INFECTION PROBLEMS * V •X \ / V. / i V X X / \ X X X X BACK • « 249. f'X c: V - X * _ A X V X X X. .... ..... X 'X X X X X — ...... V — ✓ X 4 X X X X _ " r?024 ' ■:il v « •. - SYMPTOM >.51. causes ....... :.. may cause e.lliir 'l cause ..... . causes ‘ W l 1 ray | un •| . cause , > TINGLING SENSATION : FEET & HANDS FINGERS & TOES X v X ’58. TIRES EASILY X : > 25$ . TONS] i.rn S X \ 260. TUBALIC INFECTION 261. TUMORS & GROWTHS 262. ULCERS : BLADDER BLEEDING DUODENAL 263 . A j y y V / X \ / y - UPPER RESPIRATORY INFECTION y V y >\ \ / \ / \ 4 26 5 . UPSET STOMACH y v 266 . URINATION FREQUENT y y !67. URINARY TRACT INFECTION VO VAGINAL DISCHARGE X x y X X • UPSET EASILY 00 26 4 69. VAGINAL IRRITATION (may be followed by bladder infection) 70. VAGINAL ITCHING 71. VAGINAL LUMPS • y y y > y X % / 4 72. VOMITING 73. WARTS 74. WEAKNESS 75. WEIGHT GAIN 76. WEIGHT LOSS 77. WHITE BLOOD CELL LOSS * X y •>< y ■* X 17 325 X > D O W » 1 •reni) S i l v i :;-: s y n rT o n 27 8 . WITHDRAWN EMOTIONALLY 279. WORD TRANSPOSITION : SPOKEN TYPED WRITTEN 280. WORKING CAPACITY IMPAIRED 281. WOUNDS HEAL SLOWLY 282. WRITING D I F F I C U L T Y : HANDS NUMB LACKS CONCENTRATION WORD TRANSPOSITION 283 . WRIST ACHE causo: may cause cannot causo causes may cause y ■VC. V V V < 1 7 Q2 S c s e e > JN 00 w rl (LIMEAD) TRANS. MID. NO. 12»182 NTC. NO. LILLE MEDICAL. LILLE. (1962) V . 7(10)104 Ser.3 (1962) Polyneuritis after usins a weed killer? containing acid 2 f4-D. AUTHOR? Foissac-Gedoux* Phil TRANSLATOR? DATE? Farinas November 1980 REQUESTED BY? U. Mullison* 9001 TRANSLATION NO.? 80-11-34 17027 M oom t r # 2££3T0NH / fo ; o 0t 0 4 4 CO > s m ii S***- / Trans. &>- l l ~ 2 ¥ MID. / o ***> > r ? /g A ' CODEN DOW 1 12182 Record _ 71415 ci Clinical Facts Lille Medical v. 7 (io) 1 0 *1 9 - 5 1 (1 9 6 2 ) POLYNEURITIS AFTER USING A WEED KILLER: CONTAINING ACID 2-*l-D. By Philippe Foissac - Gegoux, Annie Lelievre, Bernard Basin and Pierre Warot. - ‘ ' By 1958, one of us (*) had already drawn attention on the risks involved with the more and the more frequent use of chemi­ cal products In agriculture: two observations were considered at the beginning of this work which concerned the dangers de­ rived from handling organics derived from phosphorus, powerful Insecticides; one of these observations.concerned an agricul­ tural worker who handled, many months before the installation of a polyradiculorephritis syndrome weed killers, sodium and 17G28 2 potassium salt3 of 2 - methyl -4- chlorophenoxyacetic acid; for several reasons, we had eliminated in this case the toxic origin of the neurological troubles..., but we ignored at that time 00W 1 that these products could have a toxic effect. In truth, the cases of intoxication due to weed killers but it is feared that they may multiply: for almost all. the substances destined to stop the development of weeds are dan­ gerous to man. 714156 are rare and are especially known by toxicologists and doctors; Mineral compounds were being used such as chlo­ rates and sulphuric acid: these were three times more incon­ venient with an action often little selective, hence a global destruction of grasses and cereals, of a delicate use (risks of explosion and fire) and of a sure toxicity (burns-methemoglobinemy). The "vegetable hormones", the last commers, make up an undisputed progress. This name is given to chemical bodies whose action is comparable to that of phytohormones elaborated by the-plant itself. In small doses, they in fact stimulate the growth, of young vegetable cells; but in the large doses that they are used they cause "a crazy exaltation of the ma n i ­ festations of growth, a disorderly activity which drives the most deverse monstruosities, the intense consumption of reserves and finally the death of the grass". These "hormones" are oxyacetic derivations of the benzine nucleus and of the naphtalene nucleus of the phenyl, naphtyl and indolacetic, propionic and butylic acids as well as some of their derivatives. One of the most widely used is 2-^- dichlorophenoxyacetic acid (Ac. 2-*l-D.) whose action powerful and 17029 3 selective, is not, hoviever, without inconvenience as the following observation proves. DOW Observation: G... Gerard, 52 years old, farmer, was referred to the sory and motor problems of the lower limbs. This man, without any previous pathological problem, who is not an alcoholic, dates the beginning of his troubles precisely on June 2, 1962. 1 714157 Neurology Clinic on July 30, 1962 by Doctor Chuffart for sen­ On that date he felt, suddenly, an acute pain throughout the entire right orbital and periorbital region becoming weaker the next day making room for (burning sensation) paresthesra and numbness in the same area. Also on June 3 rd , he noticed a (decreased sensitivity) hypoesthesia in the right leg. On June 16 , two weeks.later, / the right leg recovered a normal sensitivity but the numbness was now felt on the left leg; besides, the lower left limb is now "weaker" and cannot move except with the aid of a cane. The problems remained about the same untill July 30 when he entered the service. ' T He now felt a persistant hypoesthesia in the right eye area, with hypoethesia of the cornea, the patient now felt some pain in the same area. The subject is uncertain of his lower left limb where a slight reduction -global- of the segmentary force is noticed. There is no other trophic vaso-motor trouble. The knee reflexes are rather sharp while the ankle reflexes are suppressed. The lower left limb suffers from a global 17030. 4 hypoethesia only deep sensitivity was maintained. The neurological examination of the upper limbs is strictly negative. Besides the general condition is excellent. The blood formula reveals an eosinophilia (8# on Aug 2 and 9# Aug 30). week3 apart show a slight decrease in albumina (43 then 46 grams) and an increase of alpha -2 - globulines (13 then 15 grams per liter). 714158 several Two electrophoretic blood tests, DOW 1 is no albuminuria. There The renal biological exam, the galactosuria provoked, the reactions of floculation do not show any abnormalities. The electrocardiogram is normal. the eye and the E.E.G. results: So is the backside of The electrodiagnosis shows the following ----- proof of stimulation of Aug 2, 1962: integrity of the upper limbs; in. the lower limbs there.is no evident weakness but slight problems of excitability (galvanic hyperexcitability galvanic and faradic hypoexcitability of the extensor of the left big toe ---- high chronaxies of the extensors of the left big toe) witness however a slight neurogenic seizure (Doctor Spy); ------- electromyography of the two frontal tibia on August 4, 19 6 2 (Doctor R a m e z ) : trace of neurogenic seizure of the two muscles examined. The patient leaves the clinic on September 8 , 1962: during hospitalization he was submitted to a daily injection of 200mg of vitamin B1 and 250mg. of vitamin B 6 ; besides 5,000 gammes of hydrocobalamine were administered every three days. aches practically disappeared; The facial the deficiency of sensitivity in 17031 5 the face and the lower left limb was notably Improved; the motor deficiency disappeared and the patient was able to walk normally; the areflexia achilleine persists, there is no visi­ There are still electromyographic signs of neurogenic examined). On the contrary the electrodiagnostic of stimula­ t i o n : ^ August 28 are absolutely normal. The aetiology of this polyneuritis of the lower, limbs with irritative and deficient right trigeminus was suggested to us by the patient himself who was able to relate the begin­ ning of his trouble while killing grass. the last days of May 1 9 6 2 . Made June 1st and Ihis operation consisted of a spraying of two different solutions but both having a base of acid 2-^-D, containing 235 and *110 grams per liters. It was carried out with a tractor which tows the spraying device and which is in a cabin, open in the back; it was very windy when the operations took place and the wind beat the toxic substance in the cabin. These exceptional circumstances, the long exposure to the toxic substance, we had to admit that it was a polyneuritis due to 2-*J-D a c i d . Besides, this observation is not alone in the litterature that includes a certain number of facts of intoxication by these substances, notably In the case of farmers: some hours after inhalation of the toxic substance there Is generally vomiting, 714159 seizure of the right frontal tibia (the left side was not DOW 1 ble atrophy. then subjective sensitive troubles of the type of paresthesis or even pain, then motor troubles, the paralysis of the four limbs or the lower limbs. This sensitive - motor polyneuritis ocolite board picture chart description ----- DOW 1 inconstantly associated with an albuminuria and an interis usually irre­ versible or very slowly and very partially reversible. 714160 The toxicity of these substances is equally proven in the case of intoxication of workers at a vegetable hormone factory: The penetration of the toxic substance through inhalation, but also through the skin; the workers often complained of somnolence, of the lower limbs feeling heavy, gastralgia, loss of appetite, hypersialosis, as well as hypersensitivity of hearing: these troubles are, generally, transient. all of Finally, experimen­ tally, 2-^-D acid administered intravenously or even orally can be fatal: this happens suddenly, either in a neurological stage in the form of a coma with hypertonic of the limbs, or ventricular fibrillation with relatively large doses, but varying according to the animal tested (about 300mg to one gram). To our knowledge, there was no acute intoxication. Bibliography - Assouly M.- Selective weed killers and growth substances. Tecnical survey. Pathological effect on man during the ma n u ­ facture of the ester of 2-^-D. Arch. Mai. Prof., 1951 1, 26. Golstein N. P . Jones P.H. and Brown J.R. --- Polyneuritis after exposure to an ester of 2-^-D acid. 17033 7 Hill E.V. and Carlisle A. ----experimental animals. Toxicity of 2-4-D. for Jour. Indust Hyg. and Toxic, 1974, 29, 2 , 85-95. Paris, 1958. (*) P. Nayrac, M. Fontan, P. Warot, J. Lescut and J. Delahousse: Lille Medical, 1958 714161 Footnote p. 1 DOW 1 Lhoste I. - Chemical weed killers. O.R.S T.O.M., 3, 3, 161-164. 17034 Ç ô - n - i X - \ FAITS curii2 U L l£ v < M i ( t j é d ic a l o ) i o w - n [ î i l 'î ) l'DLYSE\ ItlT E A M E S (SAGE DA S DES H EU HAST : L'A U D E A-.YD. par Philippe Fui^AC-t.'KiMirx. Annie* Lmukyuk. l!<-rn;ii-r. A vrai dire, les cas d'intoxication par des désherbants sont rares et sont surtout connus des toxicologues et d«*s mi'ilecins du travail ; mais il est à «rmindre «pi'ils m* se multiplient : car presque toute» les substances destinées à entraver 1«; déve­ loppement des mauvaises herbes sont dangereuses pour l'homme. On utilisait naguère des composés' minéraux parmi lesquels les chlorates et l'acide suli'nrique : ceux-ci avaient le triple inconvénient d'une action souvent peu sélective, *r«)ù une des­ truction globale «les herbes et des céréales, d'un emploi «lé!irat tris«pies «l'explosion «*t d'incendie) «•t d'une toxicité certaine (brûlures - méthémoglobi­ némie). Les < hormones végétales », dernières venues, constituent un progrès indiscutable. On donne ce nom à des corps chimiques dont Tact ion est comparable à c«*lle d«*s phytohornnuH's élaborées par la plante rlli-mémc. A doses taibh's, «*Ues stimu­ lent en cûct la «•roissance «les cellules végétales .jeunes ; mais aux «loses fortes auxquelles on les emploi«*, elles provo«iucnt « une exaltation folle des manifestations «le croissait«-«*, une activité «lésor«Io i i i k V «pii entrain«* l'apparition de monstruosités les plus «livers«*s, la «*unsommation intense des réserves et finalement la mort au stade herbacé ». J. ( • ) P. N a v r a «-. M . F u s t o .'. P . W a r o t , J . Lus« u t et Di i-.wiocssi-: : IJilr Mcilical. 1958. :l. 3. 161-161. L ille M éd ical. 3' S é rie . A nnée 1962. T o m e V U , N • 1«) ( ’«•s « hormones » sont «les dérivés oxyacéthpics du noyau benzène et du noyau naphtah'-iie dits acides phéiiyl, naphtyl «*t iiulolacétiipn-, propionique et butylique. ainsi que de ci-rtains «h* leurs dérivés. I/iiu «les plus employés est l'acid«. '2-4«lichhirophénoxyscétiquc fAc. 2-4-1).j dont l'action, puissant«* et sélectiv«*, n ’«*st c«*pen«lant pas «léniiée «le tout inconvénient ainsi «pte I«* prouve l'observa­ tion suivante. DOW 1 7 1 4 1 6 2 Déjà en liifiS. l'im d'entre nous (.*) avait attiré l'attention sur 1rs risques que ('«importait l'u tili­ sation «lr plus rn plus fivqurtito en agriculture de produits chimiques : deux observations étaient à l'origine «le ce travail dans lequel l ’aeccnt avait été mis sur 1rs dangers de la manipulation des dérivés organiques du phô.sphore, insecticides puis­ sants ; l'utir «le r«*s observations concernait un ouvrier agricole ayant manipulé, plusieurs mois avant l'installation d'un syndrome de polyradiculonévrite. des désherbants. s«*Is sodique et potassique de l'ae'ulo 2-métbyl-4-ebloropbén«)xyacétiquc ; pour plusieurs raisons, nous avions éliminé dans ce cas l'origine toxique des troubles neurologiques..., mais nous ignorions à I époque que ces produits pou­ vaient av«iir une action toxique. O ü S K lt V A T lO N : Ci... ( it u a iil. 53 ana. a g ric u lte u r, est adressé à la C lin iq u e Neinologi«;«». le 30 Ju illi-t 1962, |ia r le D octeur C u i rru - .r pour «l«-s trn u lili-s s e n s itifs «s m oteurs «l«-s meml:r«-s iin é r ie m s . O l hom m e, sa n s antecédem s |>:«fliolo g iqucs no tables. q u i n'est [>as é th y liq u e , s iin e très précisém ent le début de s«-s troubli-s au 2 ju in 1962. I l iT S se u tit ce jo u r-là . brusquenn-nt. un.- douleur v iv e d an s toute la région o rb ita ire et p é rio rh ita ire d ro ite, s'a tté n u a n t dès le le n d e m a in p o u r fa ire place à des p a re s ilu;.si«*s et à une a n e s ilié s ic ««•cupuiil le nu'n<- i -rrilo i re. L e 3 ju in ég ale m e nt. il note i'^ p p ariiio n «l'une li> poesihêsie de la ja m b e d ro ite . L e 16 ju in , so it « liu x si-m aim -s ap rès le débin. la jam b e d ro ite a ré cu p éré une s e n s ib ilité n o i: .«le n ia is l'an e sth é sie , «lui p e rsiste à lu face , a gagné la jam be gauche ; d'au tre p a rt. 1«; nn-mlir«* in fé rii- ilr gauche «*sl ■ s plus fa illie .> et la m a rch e n'est possible qu'avec l'aid e ■l’ une canne. L e s tro u b les re ste n t sen sib le m e n t iilr iit iip c s jus«iu'au 3i) ju itle r. «late de l’e n tré e «lans le servie«'. On constate a lo rs la p e rsista n ce d’une iiypoest hüsie «lans le te rr.to ire de l ’o p lu a Im iq n e d ro it, avec liyp o e srh é sie corné-unt* ; le m alade accuse enco«-e d an s ce même t e rr iio ir e quolques épi.MJth-s «lo uliiuri-ux tr«'*s passug.-rs i-t «l'iiit. u s ité ' modérée. L e su je t s«* «lit in c e rta in do sou im n il.re in fé rie u r gaueli«. an iiiv<-an iliu p iil on coust.-u«- un«. h-gè«»- «liminui ion — globale — «1p la fo rte seg m en taire. i i n 'e xiste au cu n tro uble tro p h iq u e , au cu n tro u b le v.isu-umiéui-. L e s ré lln x cs lo iu lie u s so nt p lu tô t v if s ta n d is que les a c b lllé e n s sont a b o lis. L e m em bre in fé r ie u r g a u ch e 'e st le siègi» d’ une hypo<-sthésie glo b ale, .seule la s« lisib ilité profonde étant co n servé e. le 19 17035 L Y x a m e n ncui ologiqiip d is m em bres su p é rie u rs se lévèio stricte m en t n é g a tif. D’a u tre p a rt, l'é ia t g é n éra i est e x c e lle n t. II n 'y a pas d 'a lb u m in u rie . I.a fo rm u le sanguine ré vè le un*» é o sin o p h ilie ( S ' , le 2 août .»t ' J' , le 30 a o û t). Deux exa m en s électro p ho rétiq u es sa n g u in s. A p lu sie u rs sem ain es d 'in te rv a lle . m ontrent une baisse légère de ralbum in*» (13 p u is -10 gram m es j et une aug m entatio n d is :il|d ia-2 -g Io h u lin fs (13 p u is 15 gram m es p a r lit r e ) . C es circo n sta n ce s e xcep tio n n elle s, la longue durée d 'exp o sitio n au to xique, nous ont fa it ad m ettre qu'il s ’a g is sa it vraise m b lab le m en t d’ une p o ly n é v rite dite h l'a rid e 2-l-D. L e b ila n biologique ré n a l, la g a lu rto siirie piiivn<|uée, les ré n ciio n s de llo eu la tin u ne m ontrent pas d 'an o m alies. L ’électro carriio g ram m e est n o rm al. 11 en est de même 'lu fond d'flcil et de l' E .E .G . L'é le c tro d in g n o stic donne les renseign em en ts s u iv a n ts : — épreuve de .stim u la tio n du 2 août 1962 : in té g rité des m em bres su p é rie u rs ; a u x m em bres in fé rie u rs , il n’y a pas de ré actio n de ra le n tisse m e n t évidente m a is les légers tro ubles de l’e x e ita b ilité (h y p e re x c ita b ilité g a lv an iq u e • h y p o e x c ita h ilité g a lv an iq u e et fara d iq u e de l'e x te n se u r propre du g ro s o rte il gauche ■rh m n a x ie s élevées îles e x te n se u rs il il gro s o rte il g a u ch e) tém oignent cependant d’une légère a tte in te neurogène (D o c te u r îjr x ) : La toxicité de ees .substances est également prouvée par !»-s cas d iutoxieatiou chez les ouvriers travaillant à la fabrication îles hormones végétales: la pénétration tin toxique s<- ferait par inhalation, mais aussi par voie cutanée : les ouvriers se plai­ gnent souvent de somnolence, de sensations île lour­ deur des membres inférieurs, de trustrallies, (l'ano­ rexie et d'Iiypcrsialorrliée. ainsi que d'une hyper­ sensibilité de l ’ouïe: tous ees troubles sont, dans la renie, fucaci's. Knfiii. expérimentalement, l'acide '2-4-I\. administré par voie intraveineuse ou même par voie orale, petit entraîner la mort : celle-ci survient, soit dans un tableau ncuroh »trique sous forme de coma avec hypertonie des extrémités, soit par fibrillation ventriculaire, et ce pour des doses relativement élevées, mais évidemment varia­ bles suivant l'animal en expérience (de l'ordre de 300 mg. à un ¡rrantmo en une prise). A notre con­ naissance. il n'a pas été effectué 'l'intoxication subaiiruë. — électro n tyn g rap h ie des deux ja n tb ie rs a n té rie u rs du 1 août 1962 (D o c te u r H . i J I i /.) : tracé d 'atte in te neuro­ gène des deux m u scle s exp lo ré s. L e m alade q u itte la c lin iq u e le 6 septem bre 1962 : d u ra n t l'h o s p ita lis a tio n il a été so u m is à. une in je ctio n quotidienne de 2uo nig. île v ita m in e B t et 2âû m g.. de v ita m in e B 6 ; en o u tre , l ’h yd ro co b a lan iin e lu i a été a d m in istré e à la dose île 5.uuo gam m as tous les* tro is jo u rs . L e s alg ie s fa c ia le s ont p ratiq u em en t d isp a ru ; les tro ubles s e n s itifs d é fic ita ire s de la face et du m em bre in fé rie u r gauche se so nt n otablem ent attén u é s : le d éficit m oteur a d isp a ru et la m a rch e est redevenue n o rm a le ; l ’a ré fle xie a c h illé e n n e p e rsiste ; aucune atro p h ie ne s ’est dessinée. I l p e rsiste des sig n e s é le ciro m y o g rap h iq u e s d’a tte in te neurogène du ja m h ie r a n t é r ie u r d ro it (l'e xa m e n n'a pas été p ratiq u é du cftté g a u c h e ). P a r co n tre , les réponses à l ’é le ctro d iag n o stic de s tim u la tio n , en date du 28 ao û t, so nt ab so lu m en t n o rm ales. a’ L ’étiolo gie de cette p o ly n é v rite des m em bres in fé rie u rs avec a tte in te ir r it a t iv e Pt d é fic ita ire trig é m e lla ire d ro ite nous a été suggérée p a r le m alad e lui-m êm e qu i n ’a pas manqué de fa ire le rap p ro ch em en t e n tre le début de ses troublps et une o p ératio n de désherbage effectuée le B IB L IO G R A P H IE 1 " Ju in et le s d e rn ie rs jo u rs de m a i 1962. C elle-ci a co n sisté en une p u lv é ris a tio n île deux so lu tio n s d iffé ­ rentes m a is toutes d eu x à base d 'acide 2-4-D. et en contenant 235 et 110 g ra m m e s p a r litr e . E lle s’est effe c­ tuée g râce à un tra c te u r q u i rem orque le p u lv é ris a te u r et qu i est su rm o n té d'une cab in e, o u verte A l'a rriè re ; o r. les o p é ratio n s se sont déro ulées p a r vent vio le n t et celui-ci ra b a tta it d an s la cab in e le nuage de su bstance toxiqup. 1050 DOW 1 7 1 4 1 6 3 Ad l'est t». celle observation nY-d pas isolée dans la littérature t|iii comporte un certain nomlire de faits d'intoxication par ees substances, iiotainmcnt fiiez des agriculteurs: quelques heures après l ’in­ halation du toxiipii- surviennent hnhitur!h-im-nt tics vomissements, puis des troubles sensitifs subjectifs à type de paresthésies ou même de douleurs, puis îles troubles moteurs, l'atteinte paralytique pou­ vant intéresser les quatre membres ou les membres inférieurs. Cette polynévrite sensitivo-motriee — incuusfammcut associée à une albuminurie et à un tableau d'entérocolite — se révèle habituellement irréversible ou très lentement et très partiellement réversible. . A s s o c i a M. — D ésherbants, sé le c tifs et su b stances d» c ro issa n ce . A p erçu technique. E f f e t pathologique su r l'h o m m e au co u rs de la fa b ric a tio n de l ’ester du 2-l-D. Arrh. M"l. Prof.. 1951. 1. 26. Gi u .s i k i x N .P ., J o skn P .H . and n iio n s J . R . — P o ly­ n é v rite ap rès e xp o sitio n à un e s te r de l ’acide 2-l-D. In Arcli. Mal. prof.. 1969. p. 381 (a n a ly s e ). H i l .i . E V . and C ak i . i s i .k A . — T o x ic it y of 2-l-D. for e x p e rim e n ta l a n im a is . Jour, huluxt. lluo. o»U Torir. 1947. *2il. 2. 85-95. L iiostk I. — /.*•* ilrxh,,rlnintx rlihiii'iti' i. O .ll.S T .O .S L P a r is , 1958. L i l l e M éd ical. 3' S é rie . A nnée 1982. Tom e V I I . N • 10 17038 . . I.' i . un M .K . a n il N o i:m i.\ I l . T . — E ffe c ts of 2-1 d lc h V ■ >. I)!it n o \ y a c " tic nci.“»il. taudis que •'!!<') nouveaux cas l'étaient ,1e l il.",!I à i:>.',7. \ Sans doute le i»t*ti*rit>l,»jrit|Ue est-il fait plus souvent qu'aul rcl’oisV: «un passe souvent à côté du diagnostic bnclériologispic parce t|ue l'un écarte trop vite, sous l 'appcllatiutv.île facilite de « cuutumiiiants diplitériniorphcs » tlesHuieilIcs (7ram sitif isolés d'hémocultures, de liqtiiHe céphalo. -.eliitlieti ou tle tout autre pruduit e t \|ti i sont il 'authentiques listéiia» il..u,i:\»'ONXtE). \ l a i s il est Mrs vraisemblable aussi que la diffusion, \ceonnue, de riofei-tiuu dans le résilie animal eut ruine In niulliplieatiou îles transmissions accidentelles^ à l'homme. \ Il est rare que le clinicien fasse le diagnostic tle listériose tri en demande continuation au hiolutristc : rien d'étounaut à cela si l'on considère qu'il s'agit d'une infection de connaissance récente et dont la fréquence est d ’ailleurs toute relative : lu littérature française ne comportait en effet, en 10.”'). que " ïi observations. D 'autre part, les listé­ rioses se présentent sous des aspects cliniques extrêmement divers : l'im portante statistique de S i :i .ix<:i :k . portant sur les .'»44 cas publiés dans le monde eu lîJûti, relève KiO étals septicopyobémiques du nouveau-né. 100 méningites purulentes avec ou sans eiicéplialite, 4] formes sanguines à type de mononucléose infectieuse. 10 conjonctivites gratinloinateiises. les autres cas coucernaut îles locali­ sations viscérales diverses : endocardites, myocar­ dites. méll'ites. etc... 1)t juctii Tout au plus peut-on parfois soupçonner l ’ori­ gine listérienne d ’un état septicopyohémiquc du nouveau-né,' ou d'une méningite purulente de l ’enfant ou de l ’adulte, parce q u ’il s'agit là des manifestations les plus frequentes de l ’infection. .Mais, le plus souvent, le mérite du diagnostic revient au seul bactériologiste... et ce n'est qu'a posteriori, lorsque le germe est identifié, que le clinicien mettra l'accent sur quelques nuances séméiologiques qui auraient dû faire évoquer la listériose, mais dont 1a signification lui avait échappé. BOW 1 7 1 4 1 6 4 MHS! SU IT E em p lo is en u c r ic u liu iv des d ésh erb an ts s é h c iit s ••I ih s rc K iilttris a te u is i!*1 vég étatio n. Ayriculturr F n n i\'ti\r , 1956. 111. 17'i. 45-5-t. ("est ainsi que les choses se sont passées dans l ’observation que nous rapportons d'une ménin­ gite purulente de l'adulte, inquiétante d'emblée a n s, m écan icien, sa n s an técéd en t patholo g iqucN otiiuhle. présente, le 17-3-1962. trè s b ru talem e n t, v e rs 12 h e u re s. un état in fe ctie u x d 'a llu re g rip p a le , avec fiè vre à 3 yV c o u rb u re s, m a laise g é n é ra l, qui l'oblige à s 'a lit e r . C t \ tro u b le s s’In ten siA en t le s jo u rs s u iv a n ts ta n d is qu'appaiN ilssent céphalées de p lu s en p lu s in ten ses c i v o m isse m e n tA L e 22 m a rs est constatée une ra id e u r m éningée et le ma Inde est a d tv .-^ à la C lin iq u e N eu ro lo giq u e. I l est a d m is au début de Ism -fs-m id i. L 'u n d’e n tre nous cons­ tate a lo rs un s y n d ro m X méningé fra n c , un éta t d'obnu­ b ila tio n in te lle c tu e lle ;Na-c légère a g ita tio n psycho­ m o tric e : la te m p é ra tu re cm à 39-5 ; le m a lad e a un hoquet p e rm an en t ; l'examcW neuro log ique ne révèle au cu n s ic n e p a rtic u lie r. L e liqu id e ra c h id ie n se révèle L ill e M édical. 3' S é rie . A im é e 19>»2. T o m e V I I . N “ 1" 10? I 1703? m m ^v 4 ’; r w '«»J S' r .\'vï’■ . I 1 -i S ellers, Conner ASHLEY SELLERS (19 0 2-19771 GILBERT A. CUNEO (1913-1876) O c t o b e r 29, 1980 MAX GOLOCN” ALBERT L. RE CVES j OCL p. S he do OF COUNSCL WILLIAM j, SBBIGGS COWARO L. wCIOCNFELO BUEL WHITE Cha RlCS C. YOnh CRS TELEPHONE (202) 7 6 8 - 7 SOO JEFFREY P. ALTMAN JCO L. |A |« IN JULIC FOX BlaC kS maw JEFFREY A. BOCCACR JANlS A. CHERRY JOHN C. CONNER. JR. JOHN a. COuR* mauREEn Oui Gnan LAWRENCE S. CBNER Lawrence m. Farrell O. MICHAEL FITZHUGH alien a. gre en ROBERT c. GREGG C. SANOERSON HOC JOE G. HOLLINGSWORTH THOHAS w. HUSSEY MICHAEL T. JANIK MICHAEL T. KAVANAUGH" STEPHEN O. ANIGHT FREOERIC M. LEVY ROBERT M. L’NDOUIST LOUiSC WISE LUCAS LANE MCVEY MARILYN LYNG O’CONNELL THOMAS C. PAPSON MITCHELL H. SEGAL DEL STILTNER CHRISTIAN VOLZ KENNCTH w. WEINSTEIN BARBARA G. WCRTHCR TWX 710-62 2-01* 8 CABLE: S CLCOn Cu TELECOPIER BY HAND (202) 7 6 8 - 7 S 6 * WRITERS DIRECT OlAL NUMBER (202) 7 6 8 - "NOT AOMITTCC In CXC. Di r ect or , S pe ci a l P e s t i c i d e R e v i e w D i v i s i o n Of f i c e of P e s t i c i d e P r o g r a m s U.S. E n v i r o n m e n t a l P r o t e c t i o n A g e n c y 401 M Street, S.W. W a s h i n g t o n , D.C. 2 04 60 Attn: Re: D e a r Ms. Ms. Patricia Formation Cohn: (TS-791) Cohn of 2 , 4 - D T a s k F o rc e Research Da t a . This le tt er is to advi se y o u of the f o r m a t i o n of the "Task F o r c e on 2 ,4 -D R e s e a r c h Da t a. " The p u r p o s e of the T a s k Force is to develop j oi n t l y , p u r s u a n t to the p r o v i s i o n s of § 3(c)(2) (B) of FIFRA, the a d d i t i o n a l data i d e n t i f i e d by E P A in its Ord er a n d Not i c e of A u g u s t 29, 1980 to r e g i s t r a n t s of p r o d u c t s c o n ­ t a i n i n g 2 , 4-D. The C h a i r m a n of the T a s k Force, J o h n E. Davie s, n o t i f i e d all re g i s t r a n t s w i t h m a n u f a c t u r i n g - u s e p r o d u c t s of the Task F o r c e ' s f o r m a t i o n (as i d e n t i f i e d in A p p e n d i x E to E P A' s Ord er and N o ti c e of A u g u s t 29, 1980) and i n v i t e d such r e g i s t r a n t s to p a r t i c i p a t e in the T a s k F o rc e and a t t e n d the T a s k F o r c e ' s o r g a n i ­ z a t i o n a l m e e t i n g h e l d on O c t o b e r 21, 1980. P a r t i c i p a t i o n on the T a s k Force is op en to all r e g i s t r a n t s w i t h m a n u f a c t u r i n g - u s e pr od uc ts . At the T a s k F o r c e ' s o r g a n i z a t i o n a l m e e t i n g c o m p a n i e s i n d i c a t e d t hei r d e s i r e to p a r t i c i p a t e •Fo-rce : the f o l l o w i n g on the Ta sk CCW06 I 5 5 8 4 C. STANkCY DECS HERBERT L. f E n STER RiCharo a. FLYC jam CS j . Ca u a G mcr ROtCBT A. MAN&Ruh CharlCS a. O'CONNOR. ZD JOHN S. PACHTER THOMAS L. RATTEN RatmONO s . c. rusmxar ncii . h. ruttcn scr c marvCT o . SHCRZCR RICmarO c. SOIISARHC’ • SO h Qa n Oa n t l ' w 0 0 .1 1 0 0 Cuneo ATTORNEYS ANO C O U N SE LO R S IS 7 5 CYE S T R E E T . N O R T H W E S T W A S H I N G T O N , O. C. 2 0 0 0 5 JO^N o. CONNER WILSIC M. AO*HS. j R ROeCOÎ A. ANTHONY JTCvCN L. BHiCCCBman WILLIAM M. auTTCBflClO & Director, S pe ci al Page 2 'October 27, 1980 Pesticide Re v ie w D i v i s i o n (TS-791) The Task F o r c e w o u l d a p p r e c i a t e E P A a d v i s i n g it of any c o m ­ pan i es that s h o u l d be a d v i s e d of the f o r m a t i o n of and i n v i t e d to p a r t i c i p a t e on the T a s k Force, in a d d i t i o n to t h os e co m p a n ie s "listed on A p p e n d i x E to the A g e n c y ' s O r d e r and N o t i c e of A u g u s t 29, 1980. The Ta sk F o r c e looks f o r w a r d to w o r k i n g w i t h E P A in r e s p o n d ­ ing to its O rd er and N ot i c e of A u g u s t 29, 1980. S h o u l d y o u ha v e any qu e sti on s or co m m en t s , p l e a s e feel free to c o n t a c t me or Joh n Conner, Jr. T h a n k y o u for a s s i s t a n c e in this matter. Very truly y p u r s , J o h n D. Con ne r ..Counsel fo r T a s k F o r c e /das cc: John E. D a v i e s R h o n e - P o u l e n c C he m i c a l Co. 17039 CCW06 1 5 5 8 5 BASF Wyandotte Corporation Diamond Shamrock Corporation The D o w C h e m i c a l C o mpa ny PBI-Gordon Corporation R h o n e - P o u l e n c , Inc. Vertac Chemical Corporation a d .c^iiiv^Xyybuiwii? thn.' tru^fitiarjs (ll c ao I n f a s m a t l o s £ . ^ ‘ ^ t, ¿«ot^kfC copy of theto.vicoio^icai i n f o z n & t X ^ & t '3' ^ """ ‘ -■f-.-ifi.- - -■' -Jt4 l| copy o f a recant reloaao from, fcha:ffotlc yJ : I*-■ & •■ .•*'•.*}■ .»v»y^, > ? K '- v+'i* ■ « ¡arir*-t« i? 4 An-' 1 1 \ ' n tirm i1 ' im»i:s>i»v ■•• ' J t ; ...!v v ,0 tr.a • a ’'«aa iii u ui. • it1 U»a unsiiiiigoiw axt'jnalv«* field tasting -rod tha ‘ by .many poodle and fig^ncid3 , and If £fFi”-'«, 'J. \ ‘A^ . ' .y i o ' - i h . '. : - * . ‘‘¡f r : i i • : •S *. rV-i ti i f! te Oil D.O ¿ ' j l ' j l o vj A Tl ; M ii >. O X V A r . X T I C i ' R O i - . l C t i L O R I.' f A 8- d-D ; 1 ; 1>t r. o . s i \\ i d o l ' / A C IDS i \i C i - V } > .1*) ^' _ T ; •'■■nfi r e l a t e d c o m <-l a v . L u a i l y t o : '■111 Î f'l m a t t e r o i t u : ; t r o - l i e r IjL'.' i d e S a m A 1‘. u t h e r t. ~ n o t tlu-s«. j f i ; ■*...., 1Vi s . '■d c i vm kiv;. »o CJV 00 O O t o d , i - i ), ■ : - i i . ’- - K . • r Hy w i l l ; ' 11i : n • : • ' i **r ¡ n i v a l - . a r i.* u s t . < l as. i r do*.b-. . ft,.,-;- n • r ■- p ,; ■li-i’. i y u . -,(■>■! ni.-; h c i i ' e : i •. -,,. t r r ; i ■■11 ' r *■L*r\‘.’ f . • »: ! '. : i : f>L; i ’ - p : i * .* 1! . i . ' h t i ! l S p a t e if: i s . i i ’«< l 1■- : i • *“ ole. y* : .. :• r t l . : r . e hi- f o r - , • sit:: , ■< i . ' .i r s i u a y a r d v. n : ■ ;i ..•*.<: b T U « iié.xïXh'iy n o t h i i*I^ »i . t• : ,ii ed> :i : ■ t m ■ . s .v e i l i n g (Ji ¡l...- . n.L r.u.c--, ^ 1 -■*l'J r : n e e . i ly ■ g*-ue r n l i ¿ e d e r y t h e m a ot •.. te i n a L n i u i . e u s i n f l a m m a t i o n oi the in 'm th , ..tuii o i i - ¿ a r i i t . to s a i o i d o i n a - 1 8 -, c a r - o l d a Ti / ' i. / . v wl t i l e C i «: a r l n g : j ( *u s I.*1 s rL*[j‘; f Ln v. n s m a d e . ~ - i , nd O i La o p r •y r ...i ¿ l i g h t s . v . c l l i n g o f l i p s a n d ..•:e : :j l o.' a. f a t a l e a s e i . i s t o r y d u e e., . 1: : %' i 1 1! . ». •- j ; ii 1G J' y-; -Vv j !; . p o i v--A op.. .** ; .. r - t i. i tin.- C i a a r i r. g h o u u !:as r e c e i v e d se*. e r a l C onnecticut Iii Lin.* p a s t t h r e e r e p o r t s o! pe r ip h u r a l n e u r i t i s U t n rüT-i: f o l l o w i n g e x p o - . u r e t o t h e ¿ e p r o m u . i , , in a d d i t i o n to t h o s e ! in- -ni v uitud . f~-.,:., 'm p to rr W ItiV '-s tr ot w e r « a s 3 o< i i t c i «: r v : • ' . V : o k : v. i t : !. : • - l : . A l of : f ; r i a : le t :. • r g y w i t h p n . . r n - i ■■ i d i . r i If.* ■ 1: ■*. . •i ■ ‘ . i i . ' -; : .;i r v ! :■ m .■ ■.. v ; . !.lo r m e t e : : piii.'i.oxyi.u r t u 1-:- 1 -.Oi i t>*ci W ith p i:■': Il iO 1:1'I \ \ j r o 1 1h ■r s w i t h a t a x i a , • i:.,i i',;v, i;•. r ■ •• . d : -, : • ¡ ¡ a ft i• or '1■■■ r>■ < ■•■ . . ■l ; . : L •. •• t . I : ■■ : :, t, • - i' i1 . : .. . I. .!1 1 ! 17041 2 , - l - D a n d i t s de r:v a tiv S e r v e ns a ban.: m i l r r : 1 t i nt . > I . l l I « - . I - i ' . l c s u r i a n d s a l t s an." p r o d u c e d . T h e LD5U oi ! p r . - d m t- : - nu- i n 300 to 7 0 0 m i l l i g r a m s p e r k i l o g r a m o r a l l y . m a y product; d e a th . F o u r o a s e s h a v e b e e n ue.-c b.-u th e l i t e m a p p r o x i m a t e l y 20.% 2 , 4 - D a n d -10% 2 , 4 , 5 - T , Witi:in an h o u r , lie b e i n m e n a u s e a t e d a n d b e g a n to v o m i t . A p p r o x i m a t e l y o n e h o u r n i t e r d ie i n g e s t i o n lie w a s fo und in a c h a i r c o n s c i o u s b u t in a d a / . e d c o n d i t i o n , lit.- w a s . . d m i t l e n to t h e h o s p i t a l a n h o u r ancl a h a l f l a t e r , s t i l l c o n s c i o u s , b u t d i s o r i e n t e d . On h is s e c o n d h o s p i t a l d a y he w a s on the h o s p i t a l c r i t i c a l l i s t b e c a u s e h is g e n e r a l c o n d i t i o n w a s g e t t i n g w o r s e . H i s t e m p e r a t u r e w a s 104° F . , h i s blood p r e s s u r e 7 0 /5 0 , and a lth o u g h h is u r i n a r y output w a s d e s c r i b e d as good, h i s B U N h a d r i s e n f r o m 16 m i l l i g r a m s p e r c e n t to 4 8 . He w a s h y p e r v e n t i l a t i n g and had b a s a la r r a l e s , L a t e in t h e s e c o n d d a y o f h o s p i t a l i z a t i o n t h e p a t i e n t ' s b l o o d p r e s s u r e .vas v e r y l o w d e s p i t e l a r g e d o s e s o f A r a m i n e a n d a t r i a l on L e v o p h e d . H e h a d s i n u s t a c h y c a r d i a (150), a c e n t r a l v e n o u s p r e s s u r e of m i n u s 3, t e m p e r a t u r e o f 10 4° F , h y p e r v e n t i l a t i o n , b l o o d P H o f 7 . 4 3, a n d . a n u r i a . H e a l s o h a d a generalized ery th e m a. T h e p a t i e n t d e v e l o p e d s c a t t e r e d c r e p i t a n t r a l e s in t h e r i g h t l u n g a n d d i e d o f c a r d i a c s t a n d s t i l l ( n o v e n t r i c u l a r a r r h y t h m i a s w e r e n o t i c e d ) e a r l y in t h e m o r n i n g o f h i s t h i r d h o s p i t a l d a y , a p p r o x i m a t e l y 46 h o u r s a f t e r th e ingestion. T h i s c a s e h a d s e v e r a l s i m i l a r i t i e s to th e c a s e r e p o r t o f p o i s o n i n g b y M C P A (2 m e t h y l - 4 - c h l o r o - p h e n o x y a c e t i c a c i d ) . V o m i t i n g o c c u r r i n g s h o r t l y a f t e r i n g e s t i o n a n d u n c o n s c i o u s n e s s a p p e a r i n g in a f e w h o u r s . B o t h h a d l o w e r e d b l o o d p r e s s u r e b u t in t h e M C P A c a s e i t c o u l d be m a i n ­ ta in e d w ith i n e t a r a m i n a l . H o w e v e r , none of the n e u r o l o g i c a l s y m p t o m s (fa c ia l tw itching, c o n s t r i c t e d pupils, d e c r e a s e d tendon r e f l e x e s , clonic s p a s m o f l i m b s ) w e r e m e n t i o n e d in t h e p r e s e n t c a s e . E a r l y d e a t h s in a n i m a l s by l a r g e d o s e s o f c h l o r i n a t e d p h e n o x y n c e t i c a c i d d e r i v a t i v e s w e r e a t t r i b u t e d to v e n t r i c u l a r f i b r i l l a t i o n . In d e l a y e d d e a t h s , t h e r e w a s a d i s i n c l i n a t i o n to m o v e , p r o g r e s s i n g to r i g i d i t y of s k e l e t a l m u s c l e s ( m y o to n ia ) and a t a x i a . T h e s e v e r e c a s e s had p r o g r e s s iv e - a p a th y , m u s c u l a r w e a k n e s s of the hind l i m b s , p a r a l y s i s , c lo n ic s p a s m s and finally corn a . 17C42 I n g e s t i o n s o f th e so h e r b i c i d e .. a s y m p to m a tic and su p p o rtiv e t ' ap\ Cl: P r o d u c t s r e c o m m e n d s Quiniu. S>.:f; e v . - r y tw o h o u r s f o r th e f i r s t j ~ , a n d to s u p p r e s s , v e n t r i c u l a r c u c a r d ia c m o n ito rin g w ith d e l i b r u i-Y-vcr s h o u l d b e t r e a t e d u s i n g ph y s p o n g e s ) s i n c e a n t i p y r e t i c s m a y be in.- . a l l y , d e f e r o x a m i n e w l i l Thus, w o u l d b i n d 85 m i l l i g r a m s o f f e r r i c the i n i t i a l r e c o m m e n d e d dose i r o n a n d th e m a x i m a l i t - h o u r th.e e q u i v a l e n t o f TP^O. T h e m a n u f a c t u r e r h a s o f f e r e d to s u p p l y on its u s e and c a u t io n s I lu and, p r o d u c e - a d o s a g e o f 6 g r a m s w o u l d b in d o v e r o n e - h a l t u r a i n o f i r o n , 2 1/2 g r a m s o f F e S O ^ . f e r r i o x a m i ne e n te r i n . ' . into f u r t h e r i L e m h . .d r e a v tiot.r . b i n d H . 5 u/o o f i t s - w e i g h t o f f e r r i c of 1 g r a m re­ t r e a t m e n t o f an i n d i e id u a . c a m . : . and u n t il the M a n u f a c t u r e r c a n i o m p le t o s o lu b le in w a t e r , c h a ra c te ris tic ■ . •¡ a T i n - n - : o r--, a l a r g e r n u m b e r o f o o s e rv n t i o n s D e i t -r oxi .' i 11 ti f o r d i s t r i b u t i o n pa< k a g o in se rti­ to a l l o f t h e p o i s o n c o n t r o l c e n t e r s . H enry John J . 1. . Y e r h o i ~t . D i r e - l . , . r Cr -. »t l y , .M.D., ih r r . t.a M ..., - THE MIDLAND. -7. M a r c h '20, 1959 D OW c h em ic a V com pany , . 0 04 4 S5 J A-.. or CJl i&>.*-r M»rk Wolf . Btbchera Research Lab .634 Building V ' / >: > w ••": . MAR 23 1953 Biochem, Res. Lab. ¿ k :i' ' M r ; h -^ CD JO <1 o Dear-Mark ■, ; i.-i . ; . By review of our conversation this morning (March 18) • regarding the relative toxicity, of 1. l/2 to 2 gallons of Forron 245 in 100 gallons of water or Forron Brushkiller • at t h e 'same concentration in water, as compared with Esteron Brushkiller O.S. in an oil-water emulsion, we would like, to outline the field situation and our needs as we see it. ,. Vai ro CD o It is a :common practice on the utility right-of-ways to ; use 1 gallon of Esteron Brushkiller O.S. or Esteron 245 O.S. plus 10 galons of oil-; this oil could be either ' No. 1 or 2 fuel oil or kerosene in 89 gallons of water 7 for a total of ICO gallons of mix. This mixture is used because it gives quick, uniform knockdown, does a little better Job on conifers and actually has been promoted by some companies because it Is dramatic enough that It is easy to sell. .^Nonetheless it is being .used very commonly and our products are used In this manner when the customers decide they want to use oil. The ,use of this oil has a number of problems; in the first . place it costs money, it is difficult to mix with Esteron O.S. and water, it is messy to handle, it is hard to obtain, and It requires additional trucking facilities to handle the large volume of. raw material to be imported. We have been shooting at a formulation which would essen­ tially give the early uniform brown-out and kill of the oll-Esteron Brushkiller mix without having all of the disadvantages and handling problems of oil. These formula­ tions which Chem Engineering Lab has come up with are Forron Brushkiller and Forron 245. You have indicated to us that Forron formulations used In this manner are, somewhat more toxic to the handler than., the Esteron 245 or Erteron Brushkiller formulations and the question naturally comes up a3 to w h a t .is the relative .*■ * 1 _ l 1. a • a .m ' i i .. . .n ^ i. j ¿»U 4- U — - . 4 *i . i- L ..J.; . . ^ r v . v . v f *. .17045 >c At* Mr. Mark Wolf March .20, 1959 Page " .'/ ¿ A v; >n - — /«4 It* #..*% i4 1 4 1» a 4* ~ ........... ..............V o p c u u i g a n j * n c w y u iu x ih c xjkj i u i u v n n ilid u comblnatiuna« the relative handling hazards are -of 1 1 / 2 or 2 gallons of Forron 245 or Porron Z^shkiller.-per 10 0 gallons of water or as compared with 1 gallon;; Esteron Brushkiller O.S. or Esteron 245 0,S. plus 10 gallons, of one of the above oils, ..plus 89 gallons of water. This should, of course, include skin irritation, eye irritation, possibly inhala­ tion and any other tests which you .think might be pertinent. : r .....■ ■ ' V'« I- ■■■■■■. : ••■. ■ CJ1 cn ■ u.. cn to 00 it •' ■ •This information can be important|to us in furthering ■our Forron program and in counseling our customers proper­ t y -iii the use of oil-water mixtures with our present brush'killer formulations. We would appreciate your checking this out for us. Yours very truly, V- L. L. Coulter . : Agricultural Chemicals Development ; ; :TI; wb ' '<* " . if. y 17046 W ■& / ? . & # ¥ , -.-I: ;■ « V '.; Vi - I'l.-* *«C - {I A ? - ..II. L. OlaoiC/H-i.itw! D. B. M o C a s key .R .!•!. Fi l e ' \! \ ! DOW CMGMICAL ' ' BM TE Ea-A lM C H I C A N CABLE: D O W PA N A M 1 /. 0 0 4 4 S Ü LIMITED 1714 E A S T M A N R O A D M ID L A N D . M IC H IG A N O.3.A. April 21, 1953 (Diet. 4-16-53) Ccm¿:anhia Swift Do Brasil S.A. Rua Formosa 3 6 7 Sao Paulo, Brasil Attention: Mr. M. V/. Irwin Gentlemen: Your letter of April 10, 1953 about our E3teron Brush Killer causing nau3ea among the men applying it when it was used as a spray was very interesting to us. Our Esteron Brush Killer lias been used widely in thi3 country for the past few years, and this is the first instance of this sort that has coma to my attention. It has been used widely as a spray as you are using it, and with no adverse results reported in this connection until now. I am at a complete I030 to explain this, particularly so since the product used in the DuFont formulation Is.chemi­ cally identical with .that usod In our own. Thi3 makes me wonder if this.may.not be ono of those cases when soma other factor has brought thia about, and by chance it concured with the m e n ’s u3eagQ of this product. I would therefore, suggest that this material be used again a3 a spray since since i t ’s so much more econoraical and that a close check be maintained for other factors that might bring about this result. Very truly yours. W . R , Mull Ison Assistant Technical Director Cl Cl rf*. 00 T H E D (pW CHEMICAL COMPANY 30 ROCKE. F E L L E R PLAZA NEW Y O R K SO N S W YORK Biochemical Research Licland, M i c h i g a n cci or cn ►£00 ÎO Department John A. Gird, Ilion, he?. York MN07 32 8o \ S u b j e c t ne r s o n iraa e m p l o y e d by John A . Gird, c u s t o m cornyer, R. D. f * 2 , I] Ion, Hen York, w h o nnrayed crush this cast summer w i t h Don Este r o n brush killer. I u n d e r s t a n d that Dr. ' I . C. H u t c h i n s in Albany, N.Y. has tried to d e t e r m i n e the cause of ?/r. S t e r l i n g ’s illn e s s and th i n k s nerhnos that part of it may hav e been ca u s e d by th e c h e m i c a l s in the brush killer. P l e a s e k eeo thi3 le t t e r on file in case either I/.r. Gird or J/r. S t e r l i n g or Dr. H u t c h i n s w rite to you c o n c e r n i n g the m a t t e r s i n c e we have i n f ormed t h e m that any ir.fuSriea r e g a r d i n g the n a t u r e of the t o x i c i t y of Don Esteror. Brush K i l l e r should be d i r e c t e d to your attention-. Very t r u l y yours, ïï. L. C o r b i n Agricultural flLC iacr Chemical Sal e 0 0 4 4 b' 3 > cn or L A T <_n I O ro N 00 Va I —o i 5 A ft £ : > . i t c 369 LD C HILLARD SMITH 0 M M U N ( c / 'i AG CHEM SALES i RECVD A LETTER FROM H Y BRYAN, WESTERN MERCANTILE, ADVISING ONE OF THE TELEPHONE COMPANIES HAS A SUIT PENDING FOR THE DEATH OF TOO COWS. c > c PLAINTIFF CHANGES THAT THE DOWS DIED FROM CONSUMING OUR ESTERON BRUSH L A KILLER. THE DEFENSE ATTORNEY HAS ASKED THAT HY FURNISH HIM WITH THE AMS f ; , ..j ^ H i f.-4' ' THANKS. M fi U "N I u r C A T c o M M U r ') c 0 M b c C; I O N v •17049 N • • :..V. • S ooa c h b m c o UNANCH S A L IS O FF IC E S N r «V Y OI1K C i* * t> *N F H « fiC I5 .C O • T u ie I ü ) ö ^ Ü H C L i i C A L M IDLAN D • C o w l a u y 0 .0 - 1 'IO L • DOW M ICH IG A N PH IL A D E L PH IA LOS A N G ELE9 W A S H IN G T O N SA IN T L O U IS C l ¿VELA N O HO USTON C H IC A G O July 27> 1951 ATLANTA SEATTLE BOSTON Ol en A. E , V /cil Acriculturai Chemical- Division ►£St. Louia Office ce: VJ. U. Allen CO II. L. Smith G. J. Williams Ben Branch Larry Southwick SUBJECT: Esteron Brush Killer: Sprayed Area Reported to have Caused Polaoninc of Cattle near Carthago, Illinois en 1. I wish to compliment you on your letter of July 9 in which you give a detailed account of your investigation of the subject case. It is one of the best reports from the field I have ever seen. 2. After looking, this report over, I could come only to the conclusion that the brush killer was not responsible for the death of these cattle. It does not seem likely to me that spraying on Juno 6 would havo any effect on cattle in open paoturo on June 26 . We have evidence, as you know, that the sprays them­ selves are not poisonous and insofar as wo know, the vegetation which you list in your letter as being found on the sprayed rightof-way aro not known to have caused poisoning ir cattle. Hee d ­ less to say, we wish va had an explanation for this Incident, but at the present time I am afraid we have no explanation for tho death of these-cattle. 5. X rocoivod tho samplo of M o o r m a n ’s Hog Minerals and have sent it in to the Main Lab. for analyses, A chock for fluoride did not reveal any. Analysis £or mefc/ila did not reveal anything suspicious. Sincerely yours, ■. be 1 17050 V, K. Rowe Biochemical Research Department r Ï 2 .3 0 -1 3 -2 0 004480 THO E>©rj CHEMISAI. C O M P A W Y M ID LA N D «Iu j ;c o î? 1 0 rJ 2 en en M N073280 ORIGINAL o"> Hr, Dan Sanford Ar^Li.£í Iv a * ; ' ••iVV’g .. r & i X f i ✓.< Äfci« ?» "H Ä ■ ^ é^ ¡ü » rp er$ ci^ ¿ rá » ^ ^ ' íj^ ^ ?j:p jt» ru a n . w l x i o t ^ í o c ^ w ir o e i b u o ó * m 1 t 6 c d a y s «^^QiiAt h e ^ t liÍr < t d a y - >. ■r-r» o eaed .'to >,Iw cJlowed¿ • oaewhat ¿¿«ndth« anlna l:.gay» 'th© > ......... .... - fàôï^è-iàïifegœK^SÉ '* “^ Á* v• . » • a jé* " • ' " • <(v r * * r . —f • ^ ,v^ * * ^ i- y r y y ¿ ¡! 4«. * ,/ ’ w ■ v ___ . >•■ V^-^íár g e n e r a l appearsn«® v t BQHe u.eproBBioii« ^T ne ttJi7 r o ü o w in g th e ;V- j ^ f H h l r d do« a t h e a n l « a l « a a n o t a b ly o f f - f é e d r ;g e n e r a l la s s lt u d o n ó te d « 3 id .;r u ^ B a tlo a :h a ¿ p 0 6 a 8 e d ^ .S e iB p er a titr e « a s ; B t i l l ^ ^ ^ ® * d ,s eeon d vd ay tá ^ ew ln g j t h e ;j!Iast-;d o s e - In e o o r d ln a tió n " l^ra^noted^ e r * / wi b ;- g ligh tl^ i**™ rer th a a 'a o ra a l'^ l& iw e^ n a s^ ira and; g e n e r a l *-;h £_. -sr(fiaví J la B S ltu d e :To f *t h e "«iiln&l^^TheV'heart^TBeat.: s e e a e d t o b e * , l i t t l e % . -tf'gr^^B low ed /and? iioáew liiát^ irécU céíiéd^ ^ SéB plratlon :;«as';' a eBdrh& t; labor^T $¡ ■ ^ jil^ ^ B d ^ fiaaú n átioaD t. had::.9 e a a e d ¿ ^ ^ a ^ tta lr d > ;d a j:fo lle w ln g ^ th e . ' ; ^ ^ ^ t ^ « « V o í . < ? B t e r c n - . - 1 ü i e ¿ i t e e ^ ^ p é t m b e d v l n ' a ; . r e r j - / q i i l e t #:' 'g é n t le ;::0 ^ 5 Ig n '.o í^ -p a ln -e r /a t r u g g lln g r ,t h e JnBt: ieéneC rt'é^getV pcrbgreB B lT elx-'nore d e p r e s s e d , r e s-^ T í? * 4^ '^ ir a t lo n iaaB n Q tlo iea to ly :elo w er* ;h earh r a ta ; « a s © ó n sld era b ly . slo w e d and weak o o n tln u e d vto d e e lln e .freía th er W m *n \*a l i& c ^ d a j ■/ A & L a h t llid e a t h ; 07 ío ra e d o r r«xoepiion->i is p e a r « íf e f v g e n e r a lg £« as1 ^F>5r ■V»« esá é lsl M M :B e e ra -'ire íé 'Á '«hraxticenv :darle; rere* ro n a e e l tesearch ^ efe ■ v p ■i°tv'i£a :W ¿M m $> * ¡ m Ssyffi fT -O óH . - a rS ;;.■ • .V .1/ ; ■•í.-lS’ i . ¿d*.w-.'i.l ■J¿S*j1¿\!ú ;■»*»*i-«. 4945 • ' *». •l’.V.*>V •■«jJJi» •. » -4<. '■*'■>■.'.i--1r-. . *» -X 4 g 4 4 T2.30-Xj • 0 z o o vO To: V. K. Rowe, BRD Subject : "Ni <*G vO HISTOPATHOLOGIC IMPRESSIONS OP STEER FED DOW ESTERON BRUSH KILLER O O Lung: Normal Hea r t : Normal <1 cn Moderate pathology characterized by areas of focal hemorrhagic necrosis surrounded by areas of moderate fatty degeneration. ^ L i ver : 1x3 , Kidney : Very slight interstitial edema and congestion _1 __ In the medulla and cortical medullary region. Spleen: Normal Adrenals : Normal Pancreas : Normal Testes : Degenerated and non-spermatogenic . Thyroid : • Normal Lymph N o d e : Normal Thymus Gland : Normal Bladder : Normal Rumen, Reticulum, Omasum, and Abomasum : Conclusions : » yA) J * * U S**** Mucosa, submucosa, and muscle layers appeared normal with no evidence of congestion, hyperemia, nor edema . The lesions in the liver are characteristic of toxic necrosis. F. Oyen 2-18-54 Jew 17056 C Jo SLIDES FILED. CAGú . MARK. BLOOD COUNTS ( BIRTH DATE: BONE MARROW COUNTS ( AGE IN DAYS? STARVED? X/ c + ) j BIOCHEMICAL RESEARCH DEPARTMENT ------ animal NO, , MATERIAL? TISSUE EXAMINATION FILENO. T 3 , - EXPT.NO. J a - J 3 RUN NO. DIED -y * a DAYS GROSS EXAMINATION DATE? / / - ¡¡¡7 S 3 Da t e rem oved from f ix a t iv e . r'J GRAMS / ¿ — j ~ s r ? SECTIONED BY 'i . (7 T = r ____________ STAINS? HEMATOXYLIN AND EOSIN ( O ' OR EXAMINATION OP ORGANS?. _____________________ y ~ " r WT. • 752108 EXAMINATION OF SECTIONS? APPEARANCE OF VISCERA? LUNG..N ••• ’.*v. ~r , jU-O ?ui : mi 2 •V <■« .¿V • ' . «• \\i' rv- •Ul o <■ Ul oc . uo i .• o ■- ■ ... :XÍl%: ’ * ‘- y DORSAL 7 ' VENTRAL ‘ . f v “.s' V.-.'í' ¿ ’■i.;>-;öj;ÄY irY> ’v '^ 'r i: Y HEART LIVER? *•*•'*".5* heart. * V**. pí.'-fl-.-C«*.S¿' . “I u,.^ T • 1 o“i • ' 1 * ' klDHEVSt; •' . i . t *1 '• ‘A - .- .? ■•?■' •■ 0 • ■■■f - , r NG LU im a. *. •••; .1; •Slf.'v a n 3 * <£=> : JT' r*. : • -■V~rv “S ‘ OUl °u.* a o UI a . :ui u.. o o ) TTT EMBEDDED? PARa FF1N( f ^ ío R . KILLED BY DECAPITATION ( •- .*«. .w:.* . ( KILLED ( ' FORMALIN! A O O R._______ _ BODY W T,_ R & MICROSCOPIC EXAMINATION? CONDITION? O £ y < • ‘ 7-*. i\ ” ' - '■ : vr' ?v ,L ) j £ . .v .♦► ‘•jCr- //• v ,:¿y.v< ADRENALS? r ;■'!: .• ■ ■•_ - " » y j f: pa n c rea s ? T ■VAy; E S T E S ? 1V'*'V-7*5 BORE MAHROBÍ?'' ? ’. ••• 7v'‘I',* f . ■ •- r ^ >• y ■■■ ■ '-*• ' . Á.7-.. V c • . - . áfafa'rt* ■? .11 . '■ . SIGNED' DATED • ‘ ' •: . 1 r. • -1.. 5; . -C Ür ' « * .!*<; til*-*- vV .»r'-; ■. f .i A•'» ~'^-+S- *1 ^ j . ,;v- •. n in a 11 a l l ..... DATED 1 ■ ■■■]^’ SIGNED . / /? 4947 \í^ / /; M N O 69799 Biochemical Research Department The Dow Chemical ComDanv BC T2.30-66 -(0 s '] RESULTS OP RANGE FUNDING T O X I C O ­ LOGICAL TESTS ON M -6 9 7 (ESTERON BRUSH KILLER-TYPE FORMULATION) Signed -Checked Date Date ------------ File T 2 .30-66“ / Sample N o . 1 Chg. 1219-2 Rept. By T. R. Torkeison 'y*H~ / 3 . C THIS REPORT IS THE PROPERTY OF the DOW CHEMICAL COMPANY PROBLEM This material is a proposed formulation for use as a brush killer. What is its toxicity and what handling precautions will be necessary? How does' it compare with E 3 teron 2^5T and 24D brush killer? CONCLUSIONS This material has a low acute oral toxicity. There is no problem from ingestlcvi incidental to the handling and use of this substance. The undiluted material and a 5$ solution of kerosene may be expected to cause a moderate response on the skin. Precautions should be taken to avoid prolonged or repeated skin contact. Protective clothing may be required. A 10 and 1$ emulsion in water caused only a slight response upon the skin. Precautions should be taken to avoid repeated and prolonged contact with such dilutions. The material7its emulsion (10$ and 1$) in water and a 5$ solution in kerosene cause only a slight transitory effect (Continued) c i. t Biochemical Research Department T2.30-66 Page 2 upon the eye. Safety glasses should probably be worn to avoid DOW (CONCHJSIONS CONTINUED) the pain and discomfort that results from contact. formulation reported in T25.14-86-1. They both have a low acute oral toxicity and cause slight skin and eye Irritation. For 752078 M -6 9 7 is very similar in toxicity to the brush killer practical purposes the two materials should be handled the same. These conclusions are based upon range finding toxico­ logical tests and are limited to precautions for industrial handling of the material and its use as a brush killer. De­ velopment of this or other uses may require consideration of the ' health problems presented and of the need for further toxicolog­ ical studies. HAZARDS, TRECATJTTONS' TOR SAFE HANDLING, AND "FIRST ATP MEASURES Ingestion The material has a low acute oral toxicity. There is no problem from ingestion incidental to the handling and use of this substance. If large quantities are swallowed, accidentally or willfully, some injury may result; the likelihood of serious injury Is remote. Containers of the material should be labeled so that accidental swallowing due to mistaken identity cannot occur. 17059 Biochemical Research Department T2 . 30-66 Page 3 The undiluted material causes a slight effect upon-'the eye. DOW Eye Contact Pain and conjunctival irritation persists for several days. Safety glasses should provide satisfactory protection. If the eyes are contaminated, they should be flushed immediately with copious amounts of flowing water for at least 15 m i n u t e s . Med­ ical attention should then be obtained. Emulsions (10$ and 1$ in water) and a ,5$ solution in kerosene have a very slight effect upon the eye. Contact is but very slightly painful and irritating and may cause transient irritation to the conjunctival membranes. It seems advisable to prevent contamination of the eyes simply to avoid the discomfort which may result. Minimal eye protection should be satisfactory. If the eyes are contaminated, they should be flushed with copious amounts of flowing water. Skin Contact - Irritation The undiluted material has a slight effect upon intact skin. occurs. Several exposures are needed before definite response The undiluted material is not likely to cause appreciable irritation unless exposures are quite severe. cleanliness should be exercised. helpful in preventing contact. Good care and Protective clothing may be Any injuries or irritations which may develop should receive medical attention. A 10 and 1$ 17060 752070 Precautions should be taken to prevent contact with the eyes. Biochemical Research Department T2.30-66 Page 4 emulsion in water cause even less irritation upon the skin than does the 100$ material. avert irritation. Reasonable care and cleanliness should a o Any injuries or irritations which may develop should receive medical attention. •vj The 5$> solution in kerosene, however, causes a moderate response upon skin. A single exposure for 24 hours to a 5$ Vi ¿0 solution in kerosene is capable of causing slight irritation. Q Repeated prolonged contact over a period of several days may result in blistering and a superficial burn. causes a slight folliculitis. prevent skin contact. The material also Precautions should be taken to Protective clothing, impermeable to the material, should be worn as required by circumstance. Contam­ inated skin should be washed with soap and plenty of water. Contaminated clothing and shoes should be removed and not re-used until thoroughly cleaned. 17061 Biochemical Research Department T2.30 -66 Page 5 SAMP IE INFORMATION C.R.I. Name: M -6 9 7 Common Name: M -6 9 7 (Esteron type formulation brush killer) George Scoles R e f .: WS B6P53 M.P. : Below 0°F. Sample N o .: 752081 Source: 1 Date Request Received: 11-29-55 Date Sample Received: 11-29-55 Physical State: Sol.: Light amber solution Kerosene, xylene, Emulsifiable with water Composition: 35.1# 32.5# 2.5# 2.5# 27.4^ Dowanol 97B ester of 2,4,-D Dowanol 97B ester of 2,4,5-T Dow Polyglycol 59-1 Caryly base 137B Penóla heavy aromatic naphol 17062 Biochemical Research Department T 2 . 30-66 . Page 6 SUMMARY OF RANGE FINDING TOXICOLOGICAL DATA Acute Oral Toxicity Preparation Fed Dose (g./kg.) No. Died No. Fed. Male Rat 20# emulsion in water 3.0 2/2 Male Rat 20# emulsion in water 2.0 1/2 Slight cloudy swelling in the k i d n e y s . Male Rat 20# emulsion in water 1.0 0/2 Slight cloudy swelling in the k i d n e y s . Male Rat 20# emulsion in water 0.5 0/2 Essentially no effect. Male Rat 20# solution in kerosene 2.0 2/2 — Male Rat 20# solution in kerosene 1.0 0/2 Pathology essentially negative. Animal Response-Remarks — Eye Contact - Rabbit Material Treatment Response-Remarks 100# Unwashed and washed with water. Slight pain, moderate conjunct ival irritation, very slight iritis which healed In 2 days 10# emulsion in water. Unwashed and washed with water. Very slight pain, slight conjunctival irritation which healed within 2 d a y s . 1# emulsion in water. Unwashed and washed with water Ve r y slight pain, slight conjunctival irritation which healed within 2 d a y s . 5# solution in kerosene Unwashed and washed in water. Ve r y slight pain, slight conJunctival irritation'which healed within 2 d a y s . 17063 Biochemical Research Department T2.30-66 Page 7 o Skin Contact - Rabbit Material Condition of Skin No. of Appi. Site Response 100# Intact 10 Ear Slight hyperemia, slight necrosis and .slight exfoliation. Slight folliculitis after 10 applications. - Remarks < c, t\ cr Oc J ^ 100# Intact 10 Belly Slight hperemia, sligit edema, very slight necrosis, and moderate exfoliation. 100# Abraded 3 Belly Moderate hyperemia, slight edema, very slight necrosis. 10# emulsion in water. Intact 10 Ear No response. 10# emulsion in w a t e r . Intact 10 Belly Very slight hyperemia, slight exfoliation. 10# emulsion in water. Abraded 3 Belly Slight hyperemia, very slight edema and necrosis. 1# emulsion in water. Intact 10 Ear No r e s p o n s e . 1# emulsion in water Intact 10 Belly Very slight hyperemia, slight exfoliation after 5 exposures. 1# emulsion in water Abraded 3 Belly Slight hyperemia and slight exfoliation. 5# solution in kerosene Intact 10 Ear Slight exfoliation and slight hardening and folliculitis of the ear. 5# solution in kerosene Intact 3 Belly Moderate hyperemia, slight edema and moderate necrosis, moderate exfoliation with scab and scar formation. Biochemical Research Department T2.30 -66 Page 8 DOW Skin Absorption d There is no indication from the skin irritation tests conducted, that this material is absorbed through the skin in 752034 toxic a m ounts. I 17065 Biochemical Research Department T2.30 -66 Page 9 -UNIT INDEX CD CD Effects resulting from ingestion, eye contact and skin contact are given. Hazards precautions for safe handling, and first aid measures are discussed. INDEX HEADINGS 4 C.R.I. Name: M-697 (Esteron type formulation brush killer', Esteron 245T Esteron 24D Brush Killer DISTRIBUTION "Director of Research - R. H. Boundy Central Research Index Western Central 'Research Pile Texas Central Research Index Medical Department - Dr. H. H. Gay Texas Medical Department - Dr. D. J. Kilian Safety Department - S. M. MacCutcheon Texas Division Safety Department - R. L. Allinson Western Division Safety Department - D. Elshere Legal Department - W. W. Sunderland E. C. Britton Research Laboratory - E. C. Britton Technical Service and Development - A. Hart East Main laboratory - E..N. Luce West Main Laboratory - L. M. Greene Special Services Laboratory - A. W. Beshgetoor Spectroscopy Laboratory - N. Wright Agricultural Research Laboratory - D. Martin, Seal Beach Chemical Engineering laboratory - G. Scoles Agricultural Chemical Development - L. L. Coulter ■"<1 ' ~ - X . i l . ¿»■'O-' B. J . P o r te r - F aine a v i l i e Dr« Kodszus o f B ceh riu g er wan. h e re l a s t week to dLscnss th e a c q u is itio n from Diamond o f our know-how f o r th e p ro d u c tio n o f penta*c h lo ro p h e n o i. He asked s p e c i f i c a l l y i f we had observed any in d ic a tio n s of- chloracnegene in o u r p ro d u c t. I t o l d h-im t h a t in th e work t h a t A1 a i r sen and I r v in g Sosen had dene s e v e r a l y e a rs ago and th e more re c e n t work dons by Jac k Jenney in th e la b o r a to r y and by ¿-1 lew is in th e p i l o t p la n t we had n o t been s c ru p u lo u sly c a r e f u l t o av o id c o n ta c t, b u t a t th e sane tim e had haH no l-nrH/»a-fclnTT. o f c h lo ra cn e tr o u b l e . He th e n asked i f we had re c a iv e d h is r e p o r t on th e s o lu tio n to th e c h lo racn e problem which a t one tim e had fo rc e d th e shutdown o f th e B oehrlnger tric h lo r o p h e n o l p l a n t . I t o l d hlm I d id n 't th in k we had seen i t . He promised to send o v er a copy. 'ScP 1 9 : id e n tif ie d a s an ex trem ely tm H e m a te r ia l and p ro b ab ly tilS C3.USS u i SCutt o f th a ch lo racn e d i f f i c u l t i e s . T h is m a te r ia l i s n o t farmed i f th e t r i c h laro p h en a l a u t o d i r e te n p e ra tu re i s k e p t below 255 *C and i f th e d rie d T C P-caustic crude m ixture i s n o t allo w ed to exceed 120" C. In view o f our problem s w ith ¿xLaracna in o ur tric h lo r o p h e n o l p l a n t , i t would c e r­ t a i n l y seem In o rd e r t o check th s s« obs e r va t io n s , i f p o s s ib le , in t r i a l p la n t m s , I t l a q u ite l i k e l y th a t by d ropp in g o u r re a c tio n te m p e ratu re 15" o r more from what I u n d erstan d l a o u r c u rre n t l e v e l o f o p e ra tio n of about 170* C , we may s u f f e r a s i g n i f i c a n t d ecrease i n re a c tio n r a t e and p ro lo n g a tio n o f our re a c tio n c y cle tim e . I b e lie v e Hay G uidi has had a good b i t o f ex p erien ce in co n tin u o u s e a u a tlo chlorobenzene r e a c tio n s and I would guess t h a t we might be a b le to conve r t our e x i s t i n g autoc&lve t o a continuous u n it by p ro v id in g a s l u r r y charge pump, a r e f lu x co n d en ser, and a TSKartoff c o n tr o l v a lv e . S in ce com plete conver s io n would n o t be a s s e n t i n i , i t should be p o s s ib le t o o p erat e such a u n it a t th e p o in t on th e a u to clav e curve a t which th e r a t e o f re a c tio n should be f a i r l y g re a t and we s i g h t be a b le to a f f e c t an a c tu a l In c re a s e i n our p ro d u c tio n c a p a c ity and a t th e same t i n e e lim in a te ch lo racn e p ro b lem s. . D. J . P o r te r D J2;s.ja DS 000L74L5 7~3T'.Lakea / H . C. S u tta r-C le v e la n d fwG 13 1- u ». ». o.c w. •L * m. t. w . C. H. BO E H RI N G E R S O H N S¿ - ± ftu ! otrrwoT C H E M I S C H E FABRI K. N itu n k ilh i A. I. is litlili J Mr. J.A. Borroy c/o DIAMOND ALKALI COMPANY TfT Mn m Al* C M 0 ia I k h H i.lM ■i TiuUm (M^i| KrJIU J knZckWa k n W»Mtk (httn NwfirVfa om, zdd« ' Dr .Mz/FÍc GC/Sg . - kttrifc @ Ingelheim am Rhein August 10, i960 Dear Mr. Borroy: Recently we received a letter from Mr. J. Burton, dated June 22, i960, addressed to Mr. Doll, Managing Director of CELA G.m.b.H. Mr. Burton requested to .have the answer addressed-to.you. Unfor­ tunately his letter was sent by surface mail which meant a several weeks1 delay. We therefore hasten to let you have an answer and the desired .information. We thank you, also in the name of CELA, for the information * regarding your process for the production of 2,A,5-Trichlorophenol from 1,2,4,5-Tetraeklorobenzêne, as well as for the description of the explosion which occurred in your Factory. It was very interesting for us to read that in your laboratories you are presently working on a modified method according to which the autoclave is at first loaded with the full quantity of Tetrachlorobenzene adding slowly the solution of caustic soda. We have had good experiences over long years with a principally equal process which in our opinion offers a great operating safety if working below certain temperatures.- Here below we are outlining our standard process r _¥e ¿re loading the autoclave of 7^00 Litres with 1^00 Kg 6,5 K g Mol; cold symmetrical Tetrachlorobenzene, suspended . ihrlOOO. Litres- Methariol, and dilute therein with.another _2500 Litres Methanol. This amount o f Methanol is regenerated .from former batches- and. has. a content, of 95$É- »w«. Í2J-; ~ 2. • DS 00022020 ■ ■ ttr - 2 Boefvinger Soiin Mr* J.A. Borroy, Diamond Alkali Co. USA 10 -8 -1 9 6 0 .The autoclave la then locked and heated to an internal temperature of 1 3 0 - 1 3 5 °# the pressure thus reaching 9 attl. The steam is shut off and over a period of 5 hours 730 Kg of aqueous caustic soda solution min'iimim 49$ are injected .(« 18,24 Kg Mol 100#)* The heat thus developped brings the contents of the. autoclave, to a temperature of 15 0 -1 5 3 ° within one hour* Generally a 'further increase, in temperature in the course, of reaction of 12 hours will not take place* By the end of reaction it is necessary to add some heat in order to maintain temperature at 150°. 8 hours after having finished the injectionof caustic soda solution a pressure of 20 attL is reached, which rests constant until the end of r e action* ... How the contents o f the autoclave is cooled down to 105° •- and filled in a distilling apparatus of 7000 Litres in order-to distill off the Methanol. Following the evaporation 'of the Methanol during which the temperature must not exceed 115°, and after adding 300 Litres of water by blow­ ing in steam (3 * 5 attl), the formed.Trichioroanisol is distilled off. It remains a solution of about 3656 2,4,5TrichlorophenoL. in surplus caustic soda solution, for onward processing into Phenol* He consider it especially important that whilst evaporating methanolic or aqueous solutions of Trichlorophenolate •solutions a concentration of 4o£ is. not exceeded because i otherwise there exists the danger of a sudden exothermic formation of chloride acne-active substances which, as you know, has led to a severe damage to the staff of an important European Factory* In a letter dated September 20, 1957* addressed to your Research-Center, Painesville, Ohio, we described oxtr own experiences in.this connection. ' ' He- should be pleased if you - in supplement of your- letter, dated June 26, i9 6 0 — would tell us how you elaborate the /-"Vreaction:. product- of the autoclave to Triohlorophenolate. . -:The information regaining yoiir process-will, of course,— be; treated strictly confidential and we sincerely ask you '--'v.'Vto.-'act-.accordingly with regard to our indications*. /\ The acne cure announced by Eoshringer in Cher,> VJsek for June 20, 1959 is confirmed as inactive for chicracne. Boehringer has had no new cases of chloracne in 3-5 years. They did this by discovering the compound which is the bad actor and eliminating it as a by-product. After they accom­ plished thi3 processwise, they then cleaned up their factory in a major fashion before-reopening - it was closed a year. Dave Porter«s memo of September 18, 1957 to you and -yours to me of July 28, 1959 set "forth substantially the require­ ments. As Dave points out, the bad actor is a tetrachlcrcosnaodioxime. As you pointed out, certain conditions of temperature in the nrocess can cause the trouble. In addition, even though Boehringer is sure it has no more dioxins in Its process, it ventilates its plant with great care, issues clean work clothes every day and continuously checks its triclilorphenol on rabbit ears per the test described in tho Dermatologies.paper (Derm. 115, 5k0, 1957) copy of which you 3ent me. Kudssus has reneged on sending out the report he pro­ mised Dave - says the dioxime is so active as to be a chemical warfare chemical. But we have all dope orally. Do you distill TCP? This i3 said to be a most danger­ ous step. In distillation, if any alkali or salts are present, oxime forms very rapidly. Recommend that alkali and salt be washed from crude TCP before distillation. Referring to your points 1, 2 and 3 in your memo to me of July 28, 1957 (H. S. V/einer has a copy): DS 00017413 17071 j. 3 - r to n .~:e: 2- Scshringor - Chlcracna Prcfcl ad“ is 3 •S e p te m b e r 50, 1 9 5 9 1. After dilution wit h methanol, the reaction mass ie only dangercua over 170° C. 2. Distill out m a j o r portion of methanol under 110°, then strip out r e m ainder of methanol with 3taam prefe r a b l y at 100° (120° C., cited b y you 3aia to be dangerous). Boahringer offers to O'l > ¡7 *.i r> -•JJ---- { evlev your process conditions and • - ■? r" keee ideas don <•: do the job. Pinally, after Boeliringer did all the above, they tore out p i a s t a r walls, floors and similar parts of buildings u ntil no remaining structure gave p o s itive rabbit eer test. This done b y c a r e f u l l y protected x:orkmon. Cnca clean and following above p r o ­ cess steps, they have enjoyed good experience. Be t t o r try a fe w rabbit ears cn your joint if y o u are still having trouble. Oil, yes, Bcehringer liver damage cases are still on compensation after more than five y e a r s i T h o rnton P. Hoid-sr ■ W E :s jm 1 0 /5 /5 9 DS 00017414 17072' T H E D O W C H E M I C A L C O M P A N Y M IDLAND, 'Michigan M a r c h 2S, 1 9 ^ 5 & f ] / , Mr. K. Rowe ~ Biochemical Research Laboratory 1701-Building cc: J. C- Tuc k e r J. W. Harris H. W. Feinauer E. C- Staehling C. E. Otis K- Y. .Hansen R. C. H o f f W. J- M c C o y J. D. Doe d e n s K. C- Bar r o n s H. R. Hoyle B. B. Holder, .M-D. S. E. Sadek P- H. R i l e y R. N- Smiley L. B- Grant C. 0- Hutchenreuther P. C- Amstutz W- P. Palsey G. E- L y n n ' ■ W. M. Gill M. G. Wiltse D. E- Fletcher W. L- Corbin D- D- Irish J. E- Peterson REPORT ON THE CHLCEACNE PROBLEM MEETING ON 3 / 2 k/65 Present: Dr. J. Wilkenfeld and Mr. Raymond V e r h o e z e / H o o k e r .Chemical C o r p o r a t i o n Mr. Francis K e n n e d y and Dr. Ed Chandler, Diamond A l k a l i C o m p a n y Mr. C. L- Dunn and Dr. John p. Frawley, Hercules P o w d e r C o m p a n y V. K- recapped the Dow situation in terms or the p r o b l e m and the Initial studies b y Toxicology and E n v i r o n m e n t a l Research Laboratory regarding the in-plant situation. He expanded this in general terms to the st u d y of end products, ours ana other peoples. He made reference to s y m m e t r i c a l tetrachloro-p-dibenzodioxin. He referred to the ev i d e n c e for unknown acnegen3. There were some questions f r o m the group about the unknowns. We (Dow) were not able to a n s w e r these questions except to review the evidence Tor their existence in the process samples and end product’s ,! . r\\3JÜCT TO iNjb'NCnC' MF’ .USm k .v- w_/£PA CON D.C. EX H IBIT 18 . 17073 Dr. Holder reviewed the medical side of the Dov; experience; he said that we now have approximately 60 to 7 0 cases o f individuals w i t h chloracne ranging from two severe cases to some very mild cases that were difficult to diagnose. He showed slides of the more dramatic cases. The slides w e r e exclusively views of the faces of the individuals afflicted. He described in fair detail the appearance of the I n d i v i ­ duals mentioning the blackheads specificallyH e then reviewed the clinical studies that are being made on these people with emphasis on the liver function tests- H e m e n ­ tioned the single liver biopsy that has been taken and studied in w h i c h the liver was normal although the m a n h a d a r£ther pronounced case of chloracne. Dr. H o l d e r a l s o mentioned the incidence of fatigue among the arrxicted ~g^ople as" being the only ocher significant b i n d i n g in these folks. He touched b r i e f l y on treatment indicating that various topical treatments were not particularly effective. He descriDea the cycling or this disorder in individuals w h o had been completely removed f r o m exposure. He ment ioned that some fellows are approaching the end of their t r o u b l e two or two and one-half years after onset of the skin d i s ­ order. He also described "acute chloracne11 w h i c h is a n a c u t e inflammatory condition that appears considerably sooner than, the normal chloracne in individuals and appear? after p r o ­ nounced single exposure. The acute chloracne shows up w i t h i n a few days of exposure. Dr. Holder mentioned five to eight days specifically.. There w a s 'considerable discussion b y t h e group on the skin d is order Itself. The Hooker repr e sentatives related experience of skin condition thirty years a f t e r exp o ^sureT T h eir, cases were more similar to the Dowicide bumps which Dow h a 3 experienced in that there were large boils or • . large Dumos rather than m e multitude of small b lackheads and eruptiohS Willch~I)ow is seeing m the "current cases" Dr. Sadek showed slides of ears and livers of rabbits t h a t h a d, been ex p o s e d " ^ ' tne symmetrical tezrachloro-p-dibenzodioxi He "discussed the pathology in detail w h i c h X w i l l not a t t e m p t to summarize.. — — V. K. mentioned the studies in wh i c h the rabbit ears h a v e been treated w i t h TC3D in benzene or corn oil and then washed w i t h soap .and water at various time intervals later. If exposure occurs for very long, w a s h i n g does little gaod. H e also bri e f l y mentioned the oral studies but w i t h o u t detail. Silverstein described the plant study on w a s h i n g of contamination from tools and surfaces. This study indicated that benzene, acetone and Chlorothene N U w e r e effective in removing the contaminant from tools and also that detergent and water with scrubbing action.could c l e a n up tools and equipment. Some discussion ensued on the use 17074 V. K.. « o w e - 3 - March 29 , I 955 of detergent -and water and the point was made a g a i n tha.t strong scrubbing action was necessary Tor this a p p r o a c h to be successful. . .* Harold Gill then discussed the analysis for t e t r a c h l o r o - p — . dibenzodioxin b y vapor phase chromatography. H e listed the limit of-sensitivity on various process material s . H e mentioned the oil which he defined as a non— s a p o n if i a b l e mixture of chloro anisoles, tetrachlorobenzene and t r i ­ chlorobenzene; the limit of sensitivity for T C B D i n t h i s material.is 10 ppm. The limit is 1 ppm for 2 , A-,5-trIehlorophenol, and f o r 2,4,5-T Acid, either acetic or p r o p i o n i c . Gill then defined 1 p p m as a very discernible, peak.- ' H e m e n ­ tioned that he-might estimate 0.5 p p m in 3 one i n s t a n c e s b u t -to be conservative the analyst reports <1 p p m i f the p e a k does hot measure up to the quite identifiable level o f 1 • ppm. The analytical problem has not yet been solved f o r the .T-Acid esters. The general procedure used f o r the T - A c i d s is to extract the sample (arbitrarily about 20 grams) w i t h chloroform (about kO milliliters), filter the'-chloroform to remove solids and w a s h with an equal volume o f N /lO caustic to remove any acidic materials* The chloroform, extract then is concentrated b y evaporation to"'one-tenth the original volume; thus, 'the concentration, of the d i o x i n in the chloroform will be ten times higher than in the original sample- When the analysis is conducted on t r i — . chlorophenol, the material is dissolved in N / l caust i c t o the extent of 10$», and this solution is then extracted with the chloroform and handled as indicated above. A question was asked about the utilization o f d e t e c t o r s other than the flame ionization w h i c h is specified i n t h e Analytical Laboratory write-up for this analysis. Gill has .'not tried the micro coulometric detector bec a u s e h e is not set up to do so, but he has experimented w i t h electron capture. He stated that theoretically this u n i t should not. .provide any greater increase in sensitivi t y . In actuality he found a slight increase in s e n s i t i v i t y b u t there are usually too m a n y chlorinated species p r e s e n t w h i c h m a y saturate the electron capture cell w h o s e r e c o v e r y is too slaw to be of practical use. He summarized b y s a y ­ ing that the slight -increase in sensitivity' is n o t w o r t h the effort -to switch f r o m flame ionization to e l e c t r o n capture. A question was asked about how' the e x t r a c t i o n ± 3 performed. Gill stated that it i3 performed in a w i d e mouth bottle on a shaker for one hour. (It w a s m o t m e n ­ tioned, but it is the case that this is done at r o o m temperature.) He mentioned that spiked samples have b e e n 17075 v- uawe March 4 29 „ I 965 run this w a y and the recovery ranged from 9 0 to 100 p e r cent- The ratio of solvent to the material being extracted on this step is not critical according to Gill. -Their , standard .procedure is 20 grams of sample'and 40 m i l l i l i t e r s of chloroform. On trichlorophenol samples specifically, 20 grams of phenol is converted to phenate — about 10 p e r cent concentration in water. The phenate solution is extracted with 20 milliliters of chloroform in a single extraction. The chloroform is then concentrated so that the c o n c e n t r a t i o n of the dioxin w i l l be ten times that in the origina l s a m p l e . The question of volatility of dioxin came up and H a r o l d G i l l .stated that he-found he can distill o-dichlorobenzene av/ay from tetrachlorobenmodioxinJ ’He said that i n his o p i n i o n the secret-was to avoid distilling to dryness. • • A m e mber of the group asked if samples of standard T C B D w e r e available. ’ T h e answer w a s yes and 100 mg samples w e r e p r o ­ vided to one of the representatives from each company(a sample had previously been given to Dr. K e l l y of Monsanto.) A question of laboratory safety in the analytical w o r k came up and the basic precaution of v/earing vinyl gloves w a s mentioned. Information relative to the gloves_we used was provided to the group. Disposal of contaminated laboratory materials and pl a n t • materials was discussed. V/e mentioned that D o w b u m s some small amounts of x*aste. Harold Gill stated that his l a b ­ oratory study of- combustion showed that 9 9 -9o per- cent of *' .the dioxin sample was burned at 800°C. V/e described w h y w e felt that our practice of burning small amounts of dioxin was a. safe one. V. K. then outlined the project in w h i c h plant samples and • products (not mentioned b y name) were spiked w i t h known, amounts of the TCBDThe spiked samples w e r e split f o r the purpose of checking our analytical procedures f o r r e c o v e r y and correlating these results with the bio-assay m e t h o d . The question of specification, quality control s p e c i f i c a t i o n that is, was raised and w e were asked if w e could g i v e l e v e l s of dioxin contamination w h i c h were permissible limits. V. K. mentioned that at present v/e a r e using zero w i t h a confidence of 1 ppm in process samples. There w a s s o m e discussion on the* problem of customers using finished p r o ­ ducts under far less desirable conditions of h e a l t h c o n t r o l than we can provide our workmen in our own plantThere seemed to be agreement among the group that w e could n o t afford to sell contaminated products. 17078 V . K. Rowe - 5 - • fla rch 29 , 1965 Jack: Peterson, then discussed the data from animal e x p e r i ­ m ents using pure symmetrical tetrachlorobenzodiaxin-' D o s e s ranging T r a m 2 parts per billion to 1000 parts p e r m i l l i o n or tetrachlorobenzodioxin in benzene had ,been administered to the rabbit ear. Dosage in most cases was 0.1. m l p e r day. Both single and multiple exposures have been studied and multiple exposures administered on a rive days p e r w e e k • basis'. The significant factors in the study are dose, t h e number of applications and- the days on exposure of the a n imals. The r e s p o n s e which is reported in the gross o b ­ servation of the condition of the rabbit rs ear b y the toxicologistsThis does not include pathological f i n d i n g s there is not enough .data in this area to discuss. The .level. — response ranges from none through v e r y slight, slight, slight to moderate, moderate," moderate to-severe, severe, and extremely severe. Jack indicated *to the group that there i s not a sharp definition between these catego r i e s o f response and indicated also that there is some d i f f i c u l t y in graphing this type of response. He.described the r e s p o n s e from single applications to the rabbit ear first r at 100 parts per mill i o n there was a severe response i n eight days; at 40 parts p e r million there was a slight response in eleven days; a t ’20, 10, J and 4 parts per million there w a s no response. These tests were run on s i n g l e .rabbits and ■without w a s h i n g the material off. J a c k then discussed the .multiple application data which he took from his m a j o r graph of this data. The important points that h e m a d e f r o m this data were first that a t the limit of.VPC s e n s i t i v i t y a severe response m a y be produced. I n other words, e v e n if. the VPC does not detect TCBD, an a n i m a l .response m a y s-till occur. His. second important point was that the I n d u c t i o n period for response averaged about t e n days o n the a n i m a l s in the studies. There was a brief discussion then about the air samples'’t h a t were taken in the plantSilverstein mentioned t h a t some air samples h a v e shown activity on the animals. The degree of response Is slight and the number of samples t h a t show activity is small out of the total nu m b e r taken and the amount of air that must be sampled is very much l a r g e r t h a n the amount a man. normally breathes In a n eight h o u r day. The meeting was 'ad JournedThe group then proceeded to t h e Toxicology Laboratory to view some of the test animals. They were shewn responses of varying intensity and these w e r e described. This demonstration appeared to have cansldej/able Biochemical Research Laboratory 1701 Building LGScsJl 17077 V • iV. * • « w * v. - o Postscript All participants seemed to appreciate w e l l the p r o b l e m a n d all indicated that they would return home and attempt to c o n v i n c e their management to institute safety specifications ( r e a l l y quality control) for their various products in this a r e a - ~All agreed that the industry should meet its own responsibility. All were very appreciative of Dow's effort to steer t h e m a w a y from a danger area. Time will tell w h e t h e r - w e a c c o m p l i s h e d our mission, but as of now I feel satisfied w i t h our e f f o r t and the reception it received. . VKH. % 17078 THE DO W » r*i ' July 30, CH EM ICAL C O M P A N Y ’ MIDLAND« 1964 MICNIOAH Mr. H. R. Hoyle _ Environmental R e s e a r c h 1701 Bldg. _ Subject: 4 M A O Z 0 ^ M ANUFACTURE OF T R I C H L O R P H E N O L A T 199 B L D G / -' • • • *. y m • „ We started m a k i n g 2 , 4 , 5 - T r i c h l o r p h B n d l - i n 199 I n m i d 1946.. W e dissolved flake (anhydrous) caustic in si/ne/ N L ^ Q a n d u s e d e n o u g h of this solution to supply, of c a u s t i c p e r m o l e of t e t r a c h l o r benzene. This r e a c t i o n w a s r u n in b a t c h (tumbler) reactors u n t i l late 1 9 5 2 . • ' :y I n late 1952 we started t o r u n this same r e a c t i o n i n a c o n t i n u o u s co: reactor. We us e d the same c h e m i c a l s a n d the same mol e ratios. Reacticn time and temp e r a t u r e s w e r e s i m i l a r to those of the b a t c h reacto: I n April of 1 9 6 2 we s t art e d a d d i n g w a t e r t o the caustic-. ' solution. We added e n o u g h H u r o n wat e r to be e q u i v a l e n t to 7 3 ^ c ' caustic which we h o p e d to e v e n t u a l l y s u b s t i t u t e f o r the f l a k e caustic We used the same a m ount of \ a n d t e t r a c h l o r b e n z e n e a s w i t h the - aqueous caustic and ma d e a l o n g t e r m p l a n t r u n to stu d y the e f f e c t of w a t e r on this reaction. Th e t e m p e r a t u r e wa s a d j u s t e d u p w a r d t o gi v e the same conversion. Y i e l d a n d q u a l i t y w e r e as g o o d or b e t t e r t h a n w h e n v/e used anhydrous caustic, bu t we sti l l h a d a ll of the mechanica. o perating troubles c a used b y the I n s o l u b l e s o d i u m chlo r i d e f o r m e d i n . the r e a c t i o n - We o p e r a t e d this w a y u n t i l J u l y 1, I 9 6 3 , e x c e p t f o r a short pil o t plant r u n m a d e i n S e p t e m b e r 1 9 6 2 . uuuo I n Sept e m b e r 1 9 6 2 we m a d e a t w o iveek p i l o t p l a n t r u n u s i n g p i p e line caustic (app. 32J$ NaOH) d i l u t e d w i t h H u r o n w a t e r t o app. caustic. The same amount of j and tetrachlorbenzene were again used. The temperature was r a i s e d to g i v e app. th e same conver s i o n , t h e yie l d and q u a l i t y were good. In f a c t there wa s a slight d r o p In t h e I m p u r i ­ ties w h i c h the I n f r a r e d Lab h a d l o n g r e f e r r e d to as A a n d B. The caustic insoluble oil ma d e d u r i n g this r u n w a s s t u d i e d b y t h e B i o c h e m Lab, R e p o r t No.. T 2 - 1 1 3 - 1 d a t e d 12-20-62. The sodium chloride f o r m e d i n the h ydrolysis w a s s o lu b l e in this r e a c t i o n m i x t u r e so th e c o i l p l u g g i n g f r o m salt has b e e n eliminated. W i t h the old process, m o s t of the. f^me we had b e e n able to w a s h the coi l s b e f o r e they p l u g g e d , but often t h e y did p l u g . a n d this u n p l u g g i n g o p e r a t i o n was a l w a y s a s e r i o u s safety hazard. • -fcQEMIiAiate September 1 9 6 2 and July 1, 1 9 6 3 we designed and built equipment to increase our capacity to hydrolyze tetrachlorbenzene .re caustic method. During this time we ran the plant again j-t Oron. f-lgke caustic diluted to 73?» caustic equivalent. The plant was _ ” PreShntiatiibtjm 7-1- 6 3 for I n s t a l l a t i o n of t h e ' n e w e q u i p m e n t . MDL N? f el .. < u ^ • 17079. -2: K :- . * • • [ “ ’ The plant was s t arted up In late July 19^3* We had some s t a r t u p difficulties but not serious, and b e c a u s e o f . a tetrachlorbenz.ene* shortage we ’ w ere net p u s h e d . Most of ou r t r o u b l e was caused b y a small amount of p a r a d i c h l o r b e n z e n e in the t c t r a c h l o r b e n z c n c receiv f r o m 466 B l d g . — 4 6 6 Bldg, started m a k i n g a l l of t h e i r t e t r a c h l o r b e zene f r o m p a r a d i c h l o r b e n z e n e app. J u l y 1, 1 9 6 3 , b e f o r e -this t i m e t u s e d rconochlorbenzene or o r t h o d i c h l o r b e n z e n e . Part of this p a r a d i distilled over w i t h our r e c o v e r e d \ a n d w e could no t k e e p i back. This p a r a d i chi or then s e p a r a t e d out in the caustic-\ solution and c a u s e d p l u g g i n g of l i n e s b e c a u s e of freezing. W e got extra exposure b e c a u s e of this p l u g g i n g . E v e n t u a l l y w e go t a l l - 1 1 traced and covered but t h i s h a d n e v e 3 b e e n a p r o b l e m before. In November and D e c e m b e r 1 9 6 3 a n d J a n u a r y a nd F e b r u a r y 1964 w e w e r r u n n i n g at the lim i t of ou r h y d r o l y z i n g capacity. T h e c a u s t i c ins uble oils were r u n n i n g h i g h e r t h a n n o r m a l a n d b e c a u s e our. d e c a n t e r small v;e were d r a w i n g off oil (which goe s to t h e bur n e r ) e v e r y da y we have done f o r years.^ B e c a u s e . w e w e r e p u s h i n g the e q u i p m e n t and h a v i n g trouble w i t h the * p r e s e n c e of p a r a d i c h l o r b e n z e n e we h a d m o r e exposure than normal. 6 I About Feb r u a r y 1, 1964 we n o t i c e d th e f i r s t t r o u b l e w i t h c h l o r a c n e Two supervisors, three t r i c h l o r p h e n o l o p e r a t o r s a n d one l a b o r a t o r y e m ployee started to ha v e a r a s h on t h e i r f a c e s . We call e d the. Environmental Research group almost Immediately. A l s o we Installecapacitance p r o b e (app. 2-10-64) in the oil d r a w - o f f line so t h a t operators do n o t h a v e to b e expo s e d to v a p o r s w h i l e t h e y w a t c h th e separation. The oper a t o r s s t a r t e d 'wearing an a i r h o o d w h e n t h e y l o w e r e d the oil d r a i n p i p e into the d e m p s t e r box, or took raeasureme etc. We thought the m o s t expo s u r e came f r o m a r o u n d thi s oil draw-c and v/e kn e w this oil ha s always b e e n bad. -Starting in the m i d d l e of F e b r u a r y 1964 P h o e n i x c o n t r a c t o r s m o v e d 1 199 Bldg, to i n s t a l l a 10" s t e a m line, a n a d d i t i o n a l r e a c t o r coil, l a r g e r oil d e c a n t e r a n d r e v i s e d w a t e r l i n e s t o the\ . column condensers. T h e i r w o r k was all in t h e a r e a o f t h e t r i c h l o r p h e n o l p f r o m the roof l e vel to the floor. T h e y did n o t m a k e a n y t i e - i n to caustic i n s o l u b l e oil lines. V/e s t a r t e d to u s e the r e a c t o r c o l l ar. n e w oil d e c a n t e r in ear l y A p r i l a n d the c o n t r a c t o r s .were f i n i s h e d b 4 - 1 5 - 6 4 w h e n they left this area. 17080 The r e a c t i o n p r o d u c t f r o m our r e a c t o r go e s d i r e c t l y t o the recover?/ column. (See a t t a c h e d f l o w sheet- a n d e q u i p m e n t l a y o u t ) I comes off e c- o•v e r^y —c— o— l u m n —a n a t he \ w w * ^ the top of the •w - rww p h e n a t e and c a u s t i c ins o l u b l e oils off the b o t t o m . The bottoms go t h r o u g h an oil d e c a n t e r a nd then to the top of th e s t e a m s t r i p p e r t ------ *^he last traces of caustic i n s o l u b l e m a t e r i a l . The s t e a m a n vol'atiilc-n a tWWl c r l a l s *have s g o n e to We *V Uiu tu VW a l w a yW ww the •air. ••• w " w never had any trouble w i t h this ve n t u n t i l a b o u t N o v e m b e r 1, 1964, then, a t incre rilst star t e d f a l l i n g out a r o u n d the p h e n o l t r e a t i n g S e " Pr^feiS«iinPt c " A d e m i s t e r i n s t a l l e d in D e c e m b e r 1 9 6 3 s t o p p e d t h e caus gTtion, but t h e n p a r a d i c h l o r b e n z e n e s t a r t e d f a l l i n g out as w e t sno w h i c h c ollected on roof and on above" r o o f s t r u c t u r e 'pv.i - J probably a bad source of co n t a m i n a t i o n . * • The Phoenix crew w o rked in this area p a r t time fo r a f ew d a y s . On . 5-12-64 we installed a line t a k i n g the tops^ (vent) f r o m the strippi column and. put it in the b o t t o m of the / " column» T h i s volat material should~now Join the s t r e a m of oil removed by the o i l decanwhich gees -to the burner. S i n c e e a r l y Apr i l 1 9 6 5 we have h a d the larger oil de c a n t e r and hav e o n l y d r a w n off oil twice a w e e k instea of daily as we h a d d o n e f o r s e v e r a l y e a r s . • • • Summary ---------------------- • - 1. Started m a k i n g t r i c h l o r p h e n o l in 1 9 9 Bldg, in 1946, caustic and b a t c h react o r s . 2. Started u s i n g a c o n t i n u o u s coil r e a c t o r in. 1952, and rates. u s i n g anhyd with same chem Used T 5 % caustic Apr i l 1 9 6 2 to J u l y 1 , 1 9 6 3 . in S e p t e m b e r 1 9 6 2 , usin£ 4. Pilot pla n t run, of tv/o w e e k s duration, pipe line caustic d i l u t e d to 2 2 % NaOH. 5. Plant started on 2 2 % c a u s t i c 8 - I - 6 5 . 6. N o v e m b e r - 1 9 6 5 p u s h i n g e x i s t i n g p l a n t to limit. 7- December 1 9 6 5 demister installed. 8. F e b r u a r y 1, 1964, s i x c a s e s of c h l o r a c n e t r o u b l e r e c o g n i s e d . • 9. F e b r u a r y 10, 1964, i n s t a l l e d oil d r a w - o f f probe. € - 10. E a r l y April 1964, n e w c o i l an d l a r g e d e c a n t e r Insta l l e d . 11. M a y 12, 1964, ve n t f r o m t o p of s t r i p p i n g c o l u m n to b o t t o m of [ ___ column. • • A&G000087 Ray Holmes 199 Bldg. «PS ■ CONFIDENTIAL Disclosure Restricted Pursuant To Court Order. "Agent Orange" Product Liability 1 7 0 8 1 L*t'eaiion’MDL No’3S1> April 6, 1566 Mr. J. 0. King Mr. J. C. Kelly Dow Chemical Co On March 21, we directed a sample of our Technical 2,li,5-T Acid to subject account. 2h talking with Ken Hanson cm April U, he advised that they would not be in a market for our material. Apparently, they feel that our material could conceivably re­ create a chlor-acne prob lem at Midland and, as such, would not entertain the purchase nf our present pro­ duction. j/ * JCK/ia cc. / / Mr. F. E. Kennedy - Kevark Jfr. R. A. thiidi / . /' /./ H / ' / 17082 f Diamond Sham rock Chem ical Company Fine Chemicals Division / 60 Park Place / Newark. New Jersey 0 7 1 0 2 / Telephone (201 ) 484-8400 September 2A, 1973 Chemicaland Corporation c/o Cloray, N. J. Corp. 80 L is t e r Avenue Newark, New Jersey 07105 A tt.: Hr. W illiam Mitchell Dear Mr. M itc h e ll: I t was a pleasure to meet you on my v i s i t to your place on September 11, 1973- As I sa id at that time I w ill do what I can in the time a v a ila b le to a s s i s t you and your personnel in the sta rt-u p o f 2, A - D operations. Per John Brennan's request I delivered two copies each o f the fo llo w in g on my v i s i t : MCA operating in stru c tio n s, W. Tobin 7/15/63 DCP opera 11 rig In s tr u c tio n s , V. Tobin 7/15/63 MCA process flowsheet, drawing no. MF-200-3 DCP process flowsheet, drawing no. NF-200-A Enclosed are two copies each o f the follow in g items that you requested: » 1. Product s p e c if ic a t io n s for 2, A - D acid M u ria tic acid 2, A - DCP k ? Dimethyl amine - D 6§ Dimethylamine - D 2 . t 2, A - D operating in stru ctio n s 2, A - D Condensation Reaction, W.A.Goodloe/J.Mattts, Jr. 12/19/69 New "D " Melt Unit, F.G.Steward 10/27/67 Prep o f DCP S o l 'n for 0 Reactor Revised 2, A - D A c i d i f i c a t io n Procedure, V/.A.Goodloe 1/16/69 *T3. Monthly Operating Data August 1968 - July 1969 DSOOOIH b5 3 17083' A Unit of Diamond Shamrock Corporation Chemiealand C o r p o r a t i o n 4. S e p t e m b e r 24, Page =2 1973 Chloracne Inform ation 2 menos r e p o r t i n g a m e e t i n g w i t h r e o r e s e n t a t i v e s o f Dow, H o o k e r , H e r c u l e s a nd Di amond r e g a r d i n g chloracne. The r e q u e s t e d d a t a on la b t e s t s run on the p r o d u c t s and n e c e s s a r y lab equipment is not y e t a v a i l a b l e . I t w i l l be f o r w a r d e d a s s o o n a s 1 can ge t i t to g e t h e r . Very truly yours, DIAMOND SHAMROCK'CHEMICAL COMPANY 7, cf F. G or d on S t e w a r d , P ro d u c t io n Manager No p co C h e m i c a l D i v i s i o n F GS: bk c c : Mr. F. R. Kennedy Mr. M. C. H e i s e l e jjsOOO UbSH 17084 ~ ■ 3/25/65 JOHN GOHT, JR. S, L. CHAHDLM1 CKLOROACHB - DOW MSKTIMO * /' cc« t. R* JCcnaody - Hgr,, Newark plant x' J T 0. Kins M. F. Wilkerson ¿p On March 2U, KikB !C*nnscíy and I nyt w ith two p e o p le f r o a iiooker Q is a io a l C o ., two f r o a H arcu lo * , and w ith th e Dow group t o d is c u s s th e to x ic o lo g ic a l im p u r itie s fi) a s s o c ia te d w ith 2 ,U ,5 triC h lo ro p fa e a o l .and r e l a t e d » a t e r í a i s . % Dr. Roce of Dow C h s a lc a l opened th e mealing by s t a t i n g t h a t th e y had o p e ra te d for 25 year* w ith o u t t r o u b l e ; b u t , in th o l a s t y e a r , th e y hod 60 to 70 o a s e s of h ohlcreasie. Ton of th o s e were m o d e ra te , and f i v e t o ton were e x tre m a ly s e v e r e . Thair approach vas a q u a l i t a t i v e one a t f i r s t . They wanted to f in d th o c a u s a tiv o caterial, l e a r n how t o i d e n t i f y i t , and t r y t o av o id c o n tin u a l tr o u b le v i t h the ifi) unkneun. They t e s t e d v a rio u s m a ta r ía is from t a r f r a c t i o n s and f r o « , a s th e y pet it, “gunk", e t c . Ttiay found t h a t t h e r e a r e a number o f suspect m a t e r i a l s , prcbcbly 26 or 27; but th e major “b a d a c to r " t h a t th e y i d e n t i f i e d and which stsy tsd to consistently cau se th e problem was 2 ,3 ,T ,B -T e tra c h lo ro d ib e n z o p-Dioxia ( o y c s a t r i c a l ) . ,A -p A\ i ¡I . . « \\ \ 0A r ~f ^ j 7, p- f ~f~& T~fi.fi C H u C f l O 0 l i 8 £ Dio*-/*' r« C S y • 'l f ii e T f i/ c . / * ' - ) This incidentally waii previously listod as a suspect material by'Cy PerldjS3 of otar oesrpeny. A similar material ia the unsytsmotrloal l,3»7,8-TCUUDf also nocartirtas listed as 2,3*7,?-“CE33. \ The Dow people used the white glove approach and found this contaminant cn tool hnsdlcs, benches, Instruartnta, end other fora.ites. In test animals, they could consistently cause the oyraptexs to appear. Dr. Holder of Dow, orus of thoir radical doctors, fcnd excellent color 3lidcs of the various 7>attents, The difficulty sioris with cultiple blockheads resulting in closed cystic structures which make the patient look like hs needs to wash his face. Trio disease develops slowly, not appearing until six weeks to two months after did exposure but appearing in five to oovea days vith very heavy exposure. Ooo bench chealst has bean under trostennt for two years and hio face is starting to show signs of elecring. Dr. Holder says that he believes this inn’s problems will be solved in another six rrmt-hs. Cr. £*dok, who does their d c r o eooplo work in connection vith their caical lebcrsfcor/, showed photc micrographs of the cysts as thay form 3d in the ccrc of rtbbits. Tho cysts coirelattd with those found on the faces of the n=m. JJSOOO I H 5 5 17085 ChJaroaone - Ba« Meeting ' ) -2« ftarch 25, h$65 Basically, thare i* » ~ntlfiold deposit In th« hair follicles end oil drrrts In the fees, Tbcao eventually go iron the blockhead eta^o to fera a closed, heavy oar* deposit. Too onctrLcol cannot bo round In the facial tissues or in th« cores, but the problea still persists after scpceure. Tha best description of the acuta stag« la, that tha facial tissues reaczzble tho exaggerated aurfaae torture of cn orec^o^ rather glased and warbly with the «m*Io2sd bard core deposits. A secondary oyepbon, vhich does not correlate directly with tho eacruzrt of facial damntitia, la a fatigue reaction whore the criplaycs Is ccnplotoly listless, tired out, cr.d crt-sly isc^.eacitsiei. A ccnplote biopsy of liver, kidney, etc., ebsrs no daecnsrctica of cajor erg» a. A ccsplste clinical examination of tho patients shoved no jesasuruble affect on ho art, blood pressure, respiration rate, blcod ov.^^r, etc. The fatigued patients aotuwd to bo helped by heavy doses of vitaaiiu, perhaps related in ecae way to the carotene uztabolisu of tho body (involving vitcrln A, etc,) y An oral dose of 17 teicrograus ijossdiately killed the test animals. Tho Osar people did not lower this dosage to obtain an but decided that, when thoy can detect this cofjpoiBTd, it should rot be in the product. They found that, after fsrpesure to the material, washing within 15 minutes did not help a groat deal, but did clow down tho speed at which tho syrpicnj appeared. Meshing after css he;? was of absolutely no help whatsoever in reducing total derantitls or speed of appearance cf the reaction, Moderate scrubbing vith detergent does not recove this material. . Csircsnly hard scrubbing can acconplish the task or tho use of solvents, ouch es l,l,l-trlchlaroflth£ii3. "ZT\ Dev has developed a nev a n a l y t i c a l i:*rfchod i n w hich th e y have o c a fid s n s o in M I t h e i r s e n s i t i v i t y t o 1 ppm. They can o n ly tit a t e in l e v e l s below t h i s t h a t c c n s c a y * — y bo p r e s e n t below th o 1 ppx. Thoy s t a t e d t h a t th o y hav e n e t used n ic r o - c o lc r ir c r f c r la c s t h o d s , and t h e e l e c t r o n c a p tu r e t e c t a t h a t th e y r a n node o n ly a v e ry s l i g h t . , l e p ro v e ag n t In s e n s i t i v i t y w ith t h i s c expound. T h e ir a n a l y t i c a l c h c a is t s t a t e d t h a t J t h e e l e c t r o n c e l l s a t u r a t e s b e ca u se o f th o p re se n c e o f o th e r m a te r ia ls i n h ig h c o n c e n tr a tio n ooap&reo t o th e dioxin. Thia Eatcrlal has sooa otrango properties. It has a fairly high vapor pressure but nevertheless Is quite persistent ss a contaminant. It con be separated iron benzene by boiling if it is not carried down to dryness. The Dow poopio cro extremely careful in all of their work with this cocpound. They toe PVC thrcw-ocry glares, end all ecrplca aro burned in a special furonce which operatea eij QGCPj?. These saxplua are sealed before going to the burner. They use bioassey nsthods on rabbits far qualitative checking only. The Sow people stato that they intend to set a limit of soro with sensitivity of plus or sinus 1 ppa on this notarial. They hove analyzed materials from other oospraies. Including our cccpaoy, end have found eaounta as high as 10 ppa in 2,U,5-T o d d end 20 to 30 ppa 1a phaaatea. They have m d p a single application to the oars of teat rabbits and found that 20 ppa will not givo folliculitis.. Forty ppa doec give a slight effect, end 100 ppa la severe. They have node repeat applications of iron 10 to 100 prb, end 25 of these trcatrrsrto do cot cause a reopenso; hewovor, 1000 ppb (l ppp) gives a slight response with nine applications cad a oarere rocsticn with 11 applications. They conclude, therefore, that 1 ppn with repent exposure oen create a prtblca. Bow's people eutllnsd a rothad fer ccxtracting end running ccrcplcs cn • 2,U,5-?j 2,h&+?i ctd phenols. It involves a ehlcrofora entreaticn, follcsred by j>S0 0 0 11> b 5 b HHSXEG HELD GF H E EESEIT KCElïŒDu, i&ftCH S k } ly b 5 A5 Dia»í3 ?X^-Cn^S?g.\¿ gE3S&aCH LfU5gaaTCfiC3« HSSLftJTP* Iü ÇïZ C&û Otirsr Ylcitas3 to tha esotins lnclrdLsd lêr. Dcàâa, vho cecccptaiad Dr. Prcrlcy fïrca Earcules Fardo?. Dr. Rally fren nemunto àid cet attend, but and vieited vith Der? ths gfgvicua voek. Tha Dsv psapla ai iha coot-» I25 ^cre Q3 falloua: Y. R. Eevo, Assistant Dimeter - Bis«Chemical Et-' casrch Lnbj Dr. Holder, M.D., Phyniaina roaponsiblô for troatsoct of patiente) Dr. Sedoh, Pathalogiat;-K. Silveratein, Chaulât; J. Potercca, CbgfflAcal EaglTiggg handling stetistles, end Eevard (?), Chenist racpon3ible fctr tha dsvalcpcant of tbe gus chracatograoh eethcd of euulynlo. Dr* Solder epsaod tha œeetlrig vith colorad aliñas of Dow patienta taies treataà as a recuit of ccçocurs in I5S3 . The picturoa ebered a typicrl bleskhccd fGreaticn agoued ths cyce and forehasA. The éruptions picturad esra cash cera jateaos than onything I paroccally hâve eean at aur FlnnS* V . "K. Rena be-d eaid thsy had > to 10 crees, but this statsrazrt -sa3 cpalekliz carrested by Dr. Haider, to 70 te75 casco. Düring a question and entrer r guried, Dr. Solder àeccrlbod tha preseros cf couedocae end ccrbunclaci ccrcc. tha chculêer bledos, bcak crd butteehn areas. U? vintil thia point, 2 vrcu> dored if thoro mro tuo ccparcto typas of chiurecna va verc dicouaeinig. Eo claiaa tkat 2»1/2 peurs out of tha centast arco is ci¿21cieat to clcar û patient of eynytona. Thia dosa rot cesa possibla, eines 2-1/2 yuur3 haro E3t elnpred. Ho claies to bave cortad fatigua as a crzryicn also. Fíyo cf tinIr care sovero caso3 rrere cubaitted to crtecnive tcatirg, mich imludad epen (7 ) livor hispa7 ;■pcrphyrirs; standard dtabolic testa; kicrny thyroid, lurg erd. harrt funotienn. la all caces, all cf tiesa tasto ohcrrd n r ral frmrticairg of .tha cerrera irval“ d, Slia bicarias trinen ¿id r.tt ~'_~v r.h 2rr.s-ccrlG tic ir o r c a o a ?N O *s ^ « :i U C -Î'. <-- - - o have n o t e s ■ b a s ic . t a c t ,, js r b e re They ca a s c e r t a in e d e v e ry 't d n t k r r e a p c s u r c r o a e o s n b ly p o s i t i v e case la th a t it la th ro u g h la c o t ca u se d a? tv ~ ~ ia la sys- d ire c t can- by b i- la t s r e l. Conteory to sacs of our feelings, they put little stock la natural lonunity cad a r jp a r ic n c e d if f e r e n c e eo la G k ln ty p e s . D r. H o ld e r caeca 02 p a r - to i dialing tha trestnani vork decs by Dr. Bielcar3, that cf treating tho eycptoiss by blackhead oca ccuedons renovd and tbs edalalstratlcn cl vitaains, particularly vitoain A. Tha e n t ir e D ew g r o u p a re c c u g le t e ly d i c h l o T o - q ib - n c o ^ p - d io n r ia . a re p o rt to Jn s k h o rro r 1 , 3 / 7 /^' ” t h is has c e t r ie d . In t h e ir eeno^ n in c a p th d e n e not e l id ra te d in it s T h is Is o n Ju n e £7 , &CSES a c t i v i t y , s t u d ie s , v ip e c a n p lc s in th e i n t e r e s t i n g .c o t e t r ill P la n t «= t h e £ z n o 3 c h lc r c s n e . a fte r a p p lic a t io n . v a a b J-n g s e v e ry in T h e re fo r d ic s in cam ano . and a s a th e fa r In th e y v a n n e d Tba c u e - h a lf , r a b b it ’ 0 e a r b c c a c e up to k t in e t if it of th e d ib e n z e a e - f t ir e c i, t h e ir t h is s p v :- a knavn c c a p o u rd , b u t hod is le s s th a n u se d to e n tra n t r a b b it o f c o n ta c t o f f v it h a ffe c te d in a n \ a 1270n n t r i c a i i s a r o r e o lu b ilit y s h o rt case , Is B a n n e rs v a n c a r r ie r 2 , 3 , 6 ,& - c h lc r a s r a g e a s u g g e s te d b y C y P e r k in s c o t f in d s ig n if ic a n t ly one th e n o t a p p ro a c h T h e y d id The th a t cc^ p o u n d 19 6 0 . lo o k e d p r o d u c t io n . e t h a n o l e n d a b o u t hCO p p n th e b u t does th e y p o s s ib ilit y . c o n v in c e d in 10 ra n te s ts . Con n e c e s s a ry d l r c - in s p it e 15 th a t c la a la s o f c o n t ia a u s h o u rs . Dr. Croak ohevad d i d o s of call stnructurc vbiei: is in the skin cf rabbit ears, vith d i d had covers cases cf chlcracac. bssyond ny coupmbension. cases. Moot of ids prccontaticn a Tbo rabbit suntr.lmd liver ¿snags in d a c s b ell This dosage (necrosis?) occurred very close to the bilo dost. S o l ok s t a t e d t h a t i n c a t t l e , 1“ ~r-t\r: 7t o 3in e r r m ln h r .i v a t t Dr- ,---- ,1 — --1-U T) s n f: n i ¡.i ^ - ■" - 3 - vi+-.»>-**«• * r~ c vcry sic? prcccs:!. ria w-uJ-uL'^v? of Yitaoic A in tri b l c d ctrcrsi la a Tri eccunt ci vcrd corsa by tri Eio-Crirriccri Ss-riicn vaa thcjciigh soci crrinaaiva. Tenta ci o errali dece ci 20 ¿ree shered cc rocpcnco. kO ppa dcrclo^cd a aligeri folliauiitia le 11 dopo. ci ICO jrrn coarod a severe ree— ico le S èars. A CI3 3 I0 ¿eco Dee ucas a -ceri cecia ci S tersa, vcorilcg iroc ^ .'0 r-cccccce!' to **7cr7 Savore1', gc tìnt iriorprotir« tìcn ci re culto la conicaie^. Ca a multiple appi lece Ica oi 1 ppn, a ecd® arata resecare vas ¿Lstcctod aitar > applicati eoe, ari. a coverò re crocce aitar 11 esplicatisi;. 2j applicatlcr.a caca oi 10, 20 ari. 100 ppb alicrcd co oiieet, Aa pcrt ci triir procrea, t-riv ocsted catrplea fresi all carpare itera eri vere U r i ensugh ta soni ero resultò ci tri ir firiioga psrscriLiy to co ri tri Pieri. Trias ai cur T«=acid aarpris producati la Septaobar ai 1961 abtvcd allght raoprare aitar 13 ¿aro ca tee rabbìts, ari 2 of tri sanraLeo ehrrrvd 5 cri 16 £po ccalTticaily. Ci rio acenriu ai trlchlcrrorrirete, erta ddcved a oliglit to eriarcri reeversa ri Gprrse ri 25 triyo. dayo, ornila tri otrir orivcd ri re® lei tri? of trino cc_rplc3 vere aràlyted by ericca risieri, Àt tdia tiri, tri crriupri ci tri orisric csvriloa ria eri tesa ririrvirri. Udita rata aro cct oc ed far tiri ’rp: ci alia test becauaa triy do rat io® epuri prcparly ( 7) ; do tot it vaa dottrrized that the dl oxi n dsccupcsss at Ccv has a very Inrya Industrial vaste burner vith Arrears tei.j T H E D O W CHEMICAL C O M P A N Y Subject TOXICITY OF 2,4,5-TRICHLOEOPKEJOXY ACETIC ACID, ^' ‘ y , $ ¡CONFIDENTIAL . S'<- >—T m e w c Fa. T23.14-23-1 < ch,. 121QA ^ R.c’d 3-15-45 J*? Fin’d 8-8-45 Worb By C. G eisel y— k au a c .e d .*. ENT 9-79 ^ To Tech. Service & Developcheck W . W . Allen W. R. V e a z e y R«pt. Br ^ ./C. Problem - What are the handling hazards to be associated with 2,4,5-trichlorophenoxy acetic acid? Material Name - 2,4,5-trichlorophenoxy aoetic acid - K4568-2 Formula - Cl Structural - 0 Cl < O - 0 - < ? - C - 0 - H Cl ! Empirical - CgHgOgClg Source - Organic Research Lab. - L. Begin Ref. - #410-5-258 Experimental Results Acute Oral - Weighed doses of the acid were emulsified in 5-10$ gum arable solution and fed to cavies in single oral doses by means of a stomach tube. The material as the sodium salt, ad­ justed to pH = 10,was also fed. ' The results are given in Table I Table I The-Acute Oral Toxicity of 2,4,5-Triohloro-phenoxy Acetic acid and its Sodium Salt for Cavies. \ Material 100$ Survival Dose s«As. 100$ . Lethal Dose s»Ag. Acid 0.3 1.0 • Salt - pH 3 10 0.3 0.5 / THiS REFORT 13 THE PROPERTY OF \ • 1219 25 25C 1144 17135 * ? v w O ) ^ Theâe figures indicate that the subject material is moderately toxic when given in single oral doses. No information upon the 032715 rage 2 effect of repeated administrations was obtained. It was noted in this acute oral work that the animals did not exhibit the nervous symptoms caused by 2 ,4-dichlorophenoxy acetic acid, sodium salt. The animals fed large doses of this latter material exhibited paralysis of the posterior portion of their bodies. Skin Irritation - The acid as a 1 C solution in butyl carbitol acetate v/as applied 10 times in 11 days to the ear and shaven belly of a rabbit. A very slight irritation developed on the ear and a slight to moderate irritation appeared on the belly. A 1ia aqueous solution of the sodium salt failed to pro­ duce any significant irritation on the ear even after 20 exposures in 27 days; similar exposure on the belly resulted in a very slight simple irritation. Conclusions 2,4,5-Trichlorophenoxy acetic acid has a moderate acute oral toxicity and is slightly irritating to the skin of rabbits. We conclude that excessive exposure to thé dust of either the free acid or the salt would be likely to cause skin irritation as would exposure to concentrated solutions for prolonged periods of time. Exposure to dilute solutions such as those used in practical application would not be expected to cause trouble except among those who persist in spraying themselves or who do not take the necessary precautions to prevent prolonged contact with the -material. Reasonable handling precautions which will prevent In­ gestion and prolonged skin contact with the material will suffice to prevent serious trouble. jf-5 copies. 17136 Q V. BIOCHEMICAL RESEARCH LABORATORY Test on r 2 = - . ----- '-/ E*±t, Cavy Prob, T ¿ 2 . S . S * / Acute oral toxicity, Date 3 > - 2 h t/ S ' ¿g -r-S z J Weight kg. Dose gm/kg Dose •gnu ¡2 £ > 3 * 7 ¿T7^ o . / .o S ~ 7 2 .£ £ o ° 7 /¿7* 0. / . o< £7 411 h /& 7 c r j S"% * £ ¿?. 3 .//« & S L 3/xz ^ipljemarks £ 2.7 M l \ Ì ./ s 0-3 . 3-*/ . .S'*/ /• * .5"2>/ ! • J T 2 <7 /. a . 3 ^ /* ! ? < + ..rs'S"' 3 . o /.¿ ¿ < r A o ^ -z^ r9 3 O /e r f t .¿ 3 7 3. * /. / 7 / */* *éé> 7 /< A O ¿ .¿ 7 •S " 7 7 Jo. O ¿ r .y ? /7 7 f *1 • £& J H iL U J \s * 3 0 ~ ¥ ....... J ¿ ,7 0 . l wt ; u jtr Animal # Dose cc. - U 7 U £L J 3-^*1- — 'A tT ' -3 - *3-X - ’• £ 35 7 J.3 .1 0 7 / I° > H £ ** JL/a - 3 3 0 0 .3 .0 -u -^ r C JS L - O .l" ,-3?f 1^ ^ ».nwti / - '•!X?’ j - •• ... ■. ...,. ■ • ■' • ■ : -■; -■■.' . ■ 1 (; • .• ... * t.’ .... ■ 1 ! 1 1219—43—5C—642 ■a i O Q I e 1. o c> ^ Test on RESEARCH LABORATORY /f $ 0 7 Skin Irritation ¿¿¿¿¿it ^ No. of Applications ¿ZcL^/} — X-''¿? ' •r A A O n BIOCHEMICAL & .C .C L . L. r Quaj^tUrte-trtv* Ht; Ear ~> Rabbit ft 7* f-/ 72. ¿J-y * Afeetoaao— A /Â^ C^A-A-LstC Cage Prob. T S.sy'-ï 3 - / ' BIOCHEMICAL R E S EARCH L A BORATORY 'Test on /f ¥ * 7 o S~Za ~ _____________________ Skin Irritation /O No. of Applications Qaa~:it-j.ta >c y"- ^r*T /7 /..^ /te. / ?sAlAAs<^&/* 77- ,-. _ /L-f-.■— .-OsA ^A-*Al. 'Z+~~*./2-x) ^ ^ c^ £ c^ -. '/¿> t? r XL ^ 7- -* t «-*» -,___ / ^ ^ - 2. 3 * *f S" X (¿l x ) ^ A 7 <* J> < / - 4 - ¿ s ~ < 2 4 z- / V ( .tV-<>. ir~. ]*£•: • ■:• -'■■• . •'•■'-* ■ ■■ " ' -X ’. .. . - ■ 1213-20— 1M— 1^5 . x, / / f c-^' /J¿. BIOCHEMICAL ¿ LABORATORY ^ '*£*. • S* -t / ~ frati ye Ear _____ d 5- y~- '~Z cJ& ~ 2c¿* > ¿L- Y -/ ? /) Rabbit ¿r Day # Date ¿>T~~ Z ltJ j - 3 - S s - * /tf- f ù - Y s ^ u . * s ~ it y it ^ // — . . . . . & 7 // /•2— - ~ u ¿ d _ .. " . ... (/ •i J2.Ö • > < _.■■ - •« --. -. ■ • ■■■■••■■ « Ri (7. i/ -î. 6 ... C 1 2 1 9 - 2 C — 1M-1Ì+5 iri -;t BIOCHEMICAL 'T 2 St *On / f C jT S RESEARCH LABORATORY ' 9 - fa Ear S 7Z~L Rabbit £ ? - / f ö O—h Day £ Date Prob. T 3 ./,Ö J^ _______Z^-.x.) ß ■ //& 2.33 7 - /-r" / a - ■S*SAb-~~._____ •: ■/-¿-/-S' ¿7- y// / . d 2 - ~ ~ ~ --- - / 6 - X ) n J << /,/. o *2 ,•£”•? /« - y. _y / y /_r // /3- 1 /3 ¡S f y - //- y y yC_/5^/ -/ / -7 y 2 Reaction £ Cage £ — Si y Abdo m e n Exp. £ ¿2 > 3 0- ^ r / It ~~ v* C>->3 L\ 2--Ö Mo. of Applications U 0 L, i Skin Irritation i --— Z / 1' ^-r y -'/S ' / f / / /S~ / £> ,1. / '/ _ *+-*'+X>-*/ 'S /7 sT" f t V- ^ / L _ cvo A7, > 3 / / — . JW y 1 - - *.. 3.0 V ^ fi (f ? r Z a — - *y -Z. 6» - yh-i ... .../ ---------....•- . ■-. :■ ' # \ • ' 1213-2C-1M-14-5 . . . . ■ .■ . BIOCHEMICAL R E S E A R C H L ABORATORY T 8 3 t ' o n / i r X 6 9 - z . I M j r ?s, 2Z & L^o Mo. of Applications Eh t ÍU&»í4-^3^irV e ■ a -i ¿L Cage £ 3 f ? ~ / f ó Q~h Date Day Exp. # # e> br- 3.Sy - ¿ 3 - / Reaction /t*& ^ “ / y ' £ . £ $ /^. J*£o. t f \ .a«A^^c-íT7-"-i— - -^-3 > 3 T . /// // J . /* 'f-'í V ' /f // aíT V / & - */£~ JW d* 'Á f - 4 f .1./ *¿’•*■*5*9 *y ■s 2.-2-. / 7 y- 3 S -^5" i- £» f t V. z.//, *0 / i y-xsr^yV’’'’ Prob. T 2 «> > 3 o - ^ Va— -7 ■«/- ¿ -*/s~ ■ ir ¿J-9// y1 - /3- /-r" /=y- /y - y s " y-y /_ - L /-/ /jT y-/s-yy d ^ /4 -< i< r /-r C c r Abdo m e n U Rabbit $ J .) V T Skin Irritation Í? ^ XLs^JÍZ---*' ^ " >o 3.n y ■ r. ,. ^TT. —v n . f S ? ' ^ --- V/ i -Z. Éa -y ¿ • ■* • ■ ■- -•■■■'" . \ ■ '■ ... ■ ' -‘ - ••• .1 :•: fl U. THE LANCET Vol 338 Saturday 26 October 1991 No 8774 Cancer mortality in workers exposed to chlorophenoxy herbicides and chlorophenols R odolfo Saracci M anolis K ogevinas P ier -Alberto Bertazzi Bas H. Bueno de M esquita D avid Coggon L ois M. G reen T imo Kauppinen Kristan a . L ’A bbE Margareta L it t o r in Elsebeth L ynge John D. M athews Manfred N euberger J ohn O sman N e il Pearce Regina W inkelmann Epidemiological studies have revealed an increased risk of cancer, notably soft-tissue sarcomas and non-Hodgkin's lymphomas, in people occupationally exposed to chlorophenoxy herbicides, including those contaminated by 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (T C D D ). W e report here a historical cohort study of mortality in an international register of 18 910 production workers or sprayers from ten countries. Exposure was reconstructed through questionnaires, factory or spraying records, and job histories. Cause-specific national death rates were used as reference. N o excess w as observed in all-cause mortality, for all neoplasms, for the most common epithelial cancers, or for lymphomas. A statistically non-significant two-fold excess risk, based on 4 observed deaths, w as noted for softtissue sarcoma with a standardised mortality ratio ( S M R ) of 196 and 95% confidence interval (Cl) 53-502; this was concentrated as a six-fold statistically significant excess, occurring 10-19 years from first exposure in the cohort as a whole ( S M R = 606 [165-1552]) and, for the same time period, as a nine-fold excess among sprayers ( S M R = 882 [182-2579]). Risks appeared to be increased for cancers of the testicle, thyroid, other endocrine glands, and nose and nasal cavity, based on small numbers of deaths. The excess of soft-tissue sarcomas among sprayers is compatible »awith a causal role of chlorophenoxy herbicides’ but the excess does not seem to be specifically associated with those herbicides probably contaminated by T C D D . Lancet 1991; 338:1027-32. Introduction Chlorophenoxy herbicides have been used extensively since the mid-1950s for control of weeds and for removing unwanted brush on non-crop land.1 In the 1960s an equal mixture of 2,4-dichloro and 2,4,5-trichloro phenoxyacetic adds (agent orange) was heavily used in South Vietnam and Cambodia for defoliation by the US armed forces. Since 1969 in several industrialised countries, production and use of some compounds, and especially of 2,4,5trichlorophenoxyacetic add (2,4,5-T) and its derivatives have been reduced or banned. Chlorinated phenols are ADDRESSES: U nit o f A nalytical E pidem iology, In te rn a tio n a l A gency f o r R e search on C a n cer, Lyon. F ran ca (R. Saracci, MO, M. Kogevinas. PhO, R Winkelmann. M A ) ; U niversity o f M ilan, Italy (Prof P. A. Bertazzi, M O ) ; N atio n al In s titu te o f P u b lic H ealth and E nvironm ental P ro te c tio n , B ilthoven. N e th e rla n d s (B. H. Bueno de Mesquita. M O ) ; M edical R esearch Council E nvironm ental Epidemiology Unit, U niversity of S o u th am p to n . UK (D. Coggon, M0); O n tario H ydro, T o ro n to . C an ad a (L M. Green. CPH); In s titu te o f O c c u p a tio n a l H ealth. H elsinki, Finland (T. Kauppinen, PhO); D e p a rtm e n t o f P re v en tiv e M e d icin e and B io sta tistic s. U niversity o f T o ro n to . C an ad a (K. A. L'Abbé, P h D ); Lund U niversity, S w e d e n (M. Littorin, MO); D anish C a n c e r R egistry, C o p e n h ag en , D enm ark (E. Lynge, PhO); M enzies S chool o f H ealth R e search , C asu arin a. A u stralia (Prof J. 0. Mathews, M0); I n s titu te o f E nvironm ental H ygiene. V ienna. A u stria (Prof M. Neuberger. M0); H ealth an d S a fe ty E xecutive. B ootle. M erseyside, UK (J. Osman, MO); W e llin g to n S ch o o l of M edicine, N ew Z ealand (N. Pearce. PhO). Correspondence to Or Rodolfo Saracci, Unit of Analytical Epidemiology, International Agency for Research on Cancer. 150 cours Albert Thomas, Lyon 69372, Cédex 08, France. 17145 1028 VOL 338: OCT 26,1991 THE LANCET intermediates in the production of these chlorophenoxy herbicides and are also used directly for wood preservation. Both groups of compounds may be contaminated during the production process with polychlorinated dioxins and furans, including tetrachlorodibenzo-p-dioxin (dioxin, TCDD), which is a widespread contaminant of the general environment.* Studies of cancer risks have revealed excesses for soft-tissue sarcoma and non-Hodgkin's lymphoma in populations exposed to chlorophenoxy herbicides, chlorinated phenols, dioxins, and furans during manufacture and spraying or after accidents.1-“ In 1987 an International Agency for Research on Cancer (IARQ working group concluded that there was “limited” evidence of human carcinogenicity for chlorophenoxy herbicides and chlorinated phenols.27 A recent paper,*6 focusing on exposure in chemical plants to “dioxin”, reported excesses for cancer of the respiratory tract and soft-tissue sarcoma, but could not exclude the contribution of smoking and other exposures in the workplace. We present here the first detailed mortality analysis of a large international cohort of workers (the International Register of Workers Exposed to Phenoxy Herbicides and their Contaminants) set up by the LARC in association with the US National Institute of Environmental Health Sciences (NIEHS). Results for some cohorts in the register have been reported earlier***-9-13but for different follow-up periods. Material and methods Study population T h e register incorporates information on 17 372 male workers, 1337 female workers, and 1 o f unknown sex, distributed among twenty cohorts from ten countries (table l). Since publication o f the register population“ m inor corrections have led to the exclusion o f 62 workers found to be ineligible. Workers from one British company w hich both produced and sprayed herbicides have been scparatedhere into two cohorts (14 and 20). T h e register includes workers ever employed in production or spraying, accept in the cohorts horn Australia, Canada, and New Zealand, in which minimum employment periods of 1 year, 6 months, and 1 m onth, respectively, were specified. Eligibility of cohorts depended on the completeness at company level o f records identifying workers and on the ability to ensure tracing rates o f 95% or mote. Follow-up for mortality was based either on computerised national record systems or on active follow-up procedures. Additional information on cases o f soft-tissue sarcoma and non-Hodgkin’s lymphoma cases was sought horn medical records and cancer registries. Denmark, N ew Zealand, Finland, and Sweden provided incidence data horn population-based cancer registries. Person-years at risk were calculated horn 1955 onwards since only from that year were cancer-specific mortality rates available for all participating countries. Excluded from the analysis were 220 workers who either died or were lost to follow-up before 1955, 105 workers with unknown year of first exposure, 131 with unknown year o f birth, 1 with unknown sex, and 63 with other missing information. T h e 18 390 workers included comprise 16 863 males and 1527 females, and 307 488 person-years at risk were accumulated, with an average follow-up o f 17 years. Workers lost to follow-up constituted 5% o f the total cohort, and in no individual cohort did this proportion exceed 10%. Exposure assessment Questionnaires were constructed for factories producing chlorophenoxy herbicides or chlorinated phenols and for spraying cohorts. T hese were completed with the assistance of industrial hygienists, workers, and/or factory personnel. Industry and other production records were also used. Job histories were examined when available. Workers were classified as exposed, probably exposed, exposure unknown, or non-exposed: TABUE I—DESCRIPTION OF COHORTS IN INTERNATIONAL REGISTER Cohort Period Type No at of of risk subjects cohort Sex s 1, Australia 2, Austria 2177 159 3, Canada 4, Denmarfc* 1222 3843 s p M B 5, Denmark 6, Finland 7, Italy 8, Italy 9, Netherlands 10, Netherlands 11, New Zealand 616 62 325 81 1167 1143 1038 p p p p p p p B B B B B B B 12, New Zealand 13, Sweden 780 270 s p B B 14, UK* 15, UK 16, UK 1531 145 1147 p p p M M M 17, UK 18, UK 353 275 p p M M 19, UK 528 p M 20, UK 2013 s M PC M B Main chemicais sprayed or produced 1955-83 2,4,5-T/2,4-D 1971-88 2,4^-T/2,4-D MCPA/2.4.5-TCP 2,4-DCP 1955-82 2,4,5-T/2,4-D 1955-82 MCPA/MCPP 2,4-DP 1955-82 2,4-DP/MCPA 1955-85 2,3,4,6-TcCP 1970-86 2,44-TCP 1967-86 2,4-D/MCPA 1955-85 2,4ï5-T/2,4,5-TCP 1965-86 MCPA/MCPP/2.4-D 1969-87 2,4,5-T/2,4-D MCPA/MCPB/ 2,4,5-TCP 1973-87 2,4,5-T/MCPA/2,4-D 1965-86 2,4-D/MCPA/MCPP 2,4,6-TCP 1955-87 MCPA 1960-85 PCP 1973-87 2,4-DB/MCPA MCPP/2.4-D/2.4DP 2,4,5-T ..t-87 MCPB/PBA 1969-87 2.4-DP/2.4-DB MCPA/MCPP 1969-87 MCPA/MCPP/2.4-D 2,4-DP 1955-87 MCPA s - sprayers; p-production: PC-chloracne cases in production. M - mates: B » both sexes. 2.4-0 2.4-dichlorophenoxyacetic acid: 2.4*0P‘" 2-(Z 4-dichlorophenoxy)propanpicacid: 2.4-08» 4-(2.4-dichtorophenoKY)butanoic acid: 2.4,5-T - (2.4.5tr¡chlorophenoxy)-acetic addL 2.4.5-TP»2-(2.4.5- 0(0-878)/o; 144 (30-422) (3) 0 (0-3689) (0) 114(31-293) (4) 89 (18-260) (31 40(5-143) (2) 0(0-444) (01 56(7-202)/2; 3 5 (1 -1 9 7 )//; 86(18-250) (3) 0(0-1230) (0) 0 (0-1942) (0) 153(50-357) (5) 178(48-455) (4) 0 (0-332) (01 160 (19-578) (2) 88(18-256) (3) 317* (103-739) (5) 99(84-116) (162) 106.(69-156) (25; 108(77-146) (41) — ( I t ) ------- • p < 0 *0 5 . maintenance and cleaning, 1665 other, .1907 undassifiable). A substantial number of workers producing chlorophenoxy herbicides may also have exposed to chlorophenols (eg, p-chloro-ocresol) which are used as raw materials in the synthesis of chlorophenoxy adds. Exposure to the most toxic dioxin congener (2,3,7,8,-TCDD ) may occur during production of 2,4,5-TCP and 2,4,5-T, and during spraying ofherbiddes containing 2,4,5-T or its derivatives.1Facrories4,5,6,8,10,14,15,17,18,and20(n=6845)had other not produced 2,4,5-T or had produced very little of it (around 10 tonnes per year during the study period). Workers in these factories were exposed to various chlorophenoxy herbiddes, chlorinated phenols, polychlorinated dibenzodioxins, and furans but were probably not exposed to TCD D . Thus within the register population it was possible to differentiate workers probably exposed to TC D D and workers probably not exposed to TCDD. Production acddents were known to have occurred in two cohorts (factories 7 and 9), 319 workers being exposed. There were 181 chloracne cases among workers in the cohort, 128 of whom came from cohort 2, which incorporated only workers diagnosed with chloracne. 9 production workers with a history of chloracne from exposure to polychlorinated dioxins in 1971-73 had a median levd of 340 pg TCD D per g blood lipids (range 98-659), higher than 4 unexposed workers from the same plant (median 18, range 8-28 pg/g) and 17 external controls (median 16, range < 5 to 23 pg/g) (M. Neuberger et al, to be published elsewhere.) Statistical analysis The person-years method was used to derive standardised mortality ratios (SMR) with 95% confidence intervals (Cl) based on the Poisson distribution.” An excess or deficit of an SMR is regarded as statistically significant at p < 0-05 (two-tail) when the C l does not include 100. The WHO Mortality Data Bank was used to compute national mortality reference rates for sex, age (in 5-year age groups), and calendar period (in 5-year periods, except when such a period coincides with an ICD revision). Duration o f exposure was treated as a time-dependent variable in the allocation of personyears at risk. Poisson regression analysis was applied for selected sites.” Coding Coding of underlying cause of death was done nationally. A conversion table has been prepared in 1ARC to allow the pooling of results over different ICD revisions.31-“ About 40% of soft-tissue sarcomas (one of the a priori neoplasms of interest) develop in parenchymal organs3* and are not coded under ICD 171 (8th and 9th revision, “malignant neoplasms of connective and other soft tissue”). Histological diagnoses were not generally available and reference mortality rates are not available for sarcomas not coded as ICD 171. SMRs for soft-tissue sarcoma therefore relate only to sarcomas coded as ICD 171. Information on other sarcomas, identified from medical records and cancer registration, is presented but no statistical analysis was done. Results All-cause mortality was lower than expected from national rates (SMR=95 [95% Cl 91-99]). Among exposed workers, this was mainly because of low mortality for circulatory and respiratory diseases (SMR=90 [84r-97], SMR = 72 [60-86], respectively). Workers with unknown >3 if ,'•5 --t 1030_________________________________________ T H E LANCET_______________ __________ VOL 338: O C T 26, 1991 TABLE 111—MORTALITY FOR ALL MALIGNANT NEOPLASMS ANO FOR SOFT-TISSUE SARCOMA ANO NON-HOOGKIN'S LYMPHOMA se p a r a t e l y , b o t h s e x e s All malignant neoplasms & A •» r-, à a n- _i ;} 3 • * ! • ¡ 1 : > « T ■1 - Soft-tissue sarccmas Non-Hodgkin's lymphomas CliO (3070 /ACf t/V/**1iij Exn sjivtn Obs Exp SMR (95% Cl) Obs Exp SM« (95% Cl) Obs Exposure Exposed and probably exposed Non-exposed 515 100 508-85 101-08 101 (93-110) 99(81-120) 4 0 2-04 0-42 196 -53-502) 0 0-678) 11 ■ 4 11-64 2-25 95 (47-169) 178 (48-155) Type o f cohort* Production Spraycn 253 262 258-91 249-94 98(86-111) 105(93-118) 3 1-03 1-01 973-541) 297 "41-868) 8 3 5-36 6-28 149 (64-294) 49 (10-140) Chemicals produced or sprayed* Both Phenoxy Chiorophmols 112 384 19 106-70 385-28 16-82 105 (86-126) 100(90-110) 113(68-176) 1 3 0 0-48 1-50 0-06 208-5-1161) 200 41-585) 0 0-6148) 4 7 0 2-37 8-96 0-31 169 (46—132) 78(32-161) 0(0-1190) TCDD exposure* Probable Unlikely 236 279 215-12 293-76 110(96-125) 95(84-107) 2 2 1-00 1-04 200 24-723) 193 *23-695) 5 6 5-76 5-88 87(28-203) 102 (37-222) Years since first exposure * 30+ 20-29 10-19 0-9 74 171 170 100 88-60 159-19 166-49 94-53 84(66-105) 107(92-125) 102(87-119) 106 (86-129) 0 0 4 0 0-24 0-52 0-66 0-50 0 0-1537) 0 0-709) 606 165-1552) 0 0-738) 2 3 5 1 1-68 3-38 3-94 2-67 119(14-430) 89(18-259) 127 (41-296) 38(1-209) Duration o f exposure* (yr) 20 + 10-19 1-9 <1 36 74 234 168 4217 76-16 230-54 155-68 85(60-118) 97(76-122) 102(89-115) 108(92-126) 0 2 0 2 0-15 0-29 0-89 0-59 0 0-2459) 690 -54-2491) 0 0-415) 339 -41-1125) l 1 3 6 1-02 1-81 5-36 3-35 98(3-546) 55 (1-308) 56(12-164) 179(66-390) Department* Production Maintoiance Other exposure Unclassified 62 40 42 107 60-38 42-02 39-65 114-10 103 (79-132) 95(68-130) 106(76-143) 94(77-113) 0 0 1 0 0-29 0-15 0-16 0-35 0 0-1272) 0 0-2459) 625 '16-3482) 0 -0-1054) 2 1 3 2 1-40 0-91 0-90 2-08 143 (17-516) 110(3-612) 333 (69-974) 96(12-347) 'Exposed and probably exposed workers are grouped together. Í’ ‘'•! i . M '. a ¥ ' j. ! 'I ! 1 exposure status had high all-cause mortality (table II), especially for accidents, poisoning, and violence including suidde(SMR=319 [182-518]). Table II gives SMRs (and 95% CIs) and observed deaths for major causes of death and for malignant neoplasms by site and exposure for both sexes combined since only 10 deaths from cancer were available for analysis among exposed females. Significant excesses were observed among males for malignant thyroid and benign and unspecified neoplasms in the exposed category, malignant neoplasms of trachea, bronchus and lung in the probably exposed category, and malignant neoplasms of unspecified digestive organs and benign and unspecified neoplasms in the non-exposed category; significant deficits were observed for malignant neoplasms of skin and of brain. Exposed workers had SMRs above 200 for neoplasms of unspecified digesdve organs, neoplasms of the nose and nasal cavity, soft-tissue sarcoma, breast cancer (in males) and for neoplasms of the testis, other endocrine glands and thyroid. Table III gives combined SMRs for exposed and probably exposed workers of both sexes, for all neoplasms, soft-tissue sarcomas and non-Hodgkin’s lymphomas. The pattern of risk for all neoplasms by time first exposure did not indicate a strong healthy worker effect, and mortality did not vary substantially between the groups examined. to be increased among sprayers (3 deaths, SMR = 297 [61-868]). All deaths occurred 10-19 years after first exposure, giving rise, for this rime interval, to a six-fold excess risk in the cohort as a whole (table III) and an even greater excess among exposed sprayers (3 deaths, SMR = 882 [182-2579]). No differentiation in risk was observed in relation to duration of exposure or probable TCDD exposure. 5 additional cases of soft-tissue sarcoma were recorded in cohort members who were alive at the end of follow-up or who had died with a certified cause of death other than ICD 171. These included 1 non-fatal case in the non-exposed group. Details of all 9 cases are given in table IV. M alignant lymphoma 14 deaths from non-Hodgkin’s lymphoma (ICD 200, 202, 8th and 9th revision) were observed among men and 1 among women; 11 deaths were in exposed workers, all men. Mortality for exposed/probably exposed workers was close to expected (SMR=95) with production workers having a small statistically insignificant increase in mortality (8 deaths, SMR = 149) (table ill). 10 out of 11 deaths occurred more than 10 years after first exposure. 6 deaths occurred among workers exposed for than a year, and no difference in risk could be seen in relation to exposure to TCDD or type of chemical produced. The highest SMR among production workers was for those in “other jobs” (transport/storage, Soft-tissue sarcoma laboratory workers, plant supervisors). 4 deaths from 4 deaths were observed, all among exposed male workers . non-Hodgkin’s ly m p h o m a were observed among nonexposed workers in one Danish factory (cohort 4). Mortality (table III). No increased risk was observed among for non-exposed workers was higher than that of all exposed production workers (1 death), whereas mortality appeared m e t ■1?/4$ THF. I.ANCHT un: k> T ( 'D O . O il hi; i iKldiium;il registered cases o f soli-tissue sarcoma, identified from oilier morbidity or mortality records i 3 production workers, 1 sprayer, 1 noil-exposed) 1 was in j worker probably exposed to T C D D . A small, non-significant increase in mortality' from non-H odgkin's lym phom a was observed am ong production workers, most deaths occurring more than 1.0 years after first exposure. 6 out of the 11 deaths were in workers exposed for less than one year. O ther stu d ies1JJ' have, however, shown risks associated with exposure to ehlorophcnoxy herbicides higher for non-H odgkin’s lym phom as than for soft-tissue sarcomas. T h ere was no increase in mortality from Hodgkin's disease, and the evidence for an association of with exposure to ehlorophcnoxy herbicides has been weaker than that for non-H odgkin’s lymphoma. W e found increased risks for some uncom m on neoplasms but these results are difficult to interpret because o f the small numbers. Neoplasms o f the thyroid and other endocrine glands have not been previously linked with ehlorophcnoxy herbicides in man but exposure to T C D D and chlorophenols have been a s s w jie d with neoplasms of the thyroid and the adrenals tn mice and rats. " Interpretation of our findings will be easier when follow-up of this large cohort is longer— ie, when the num ber of recorded deaths is greater. T h e pattern so far indicates no increased mortality for neoplasms in general for the most com m on epithelial cancers, and no clearly detectable excess for non-H odgkin’s or for H odgkin’s lymphoma. T h e significant six-fold excess o f soft-tissue sarcomas occurring in the period 10-19 years since first exposure in the whole cohort, rising to a nine-fold excess in sprayers, is compatible with a causal role for chlorophenoxy herbicides, though not specifically for those probably contam inated with T C D D . Supported by grant No l-ES-95276 of the US National Institute of Environmental Health Sciences. We thank line Johnson for his contribution ‘m semng-up the register and David H o d for support throughout the project; Hciko Beeher, M anlyn Fingerhut. and Paolo Boflecta for constructive comments on an earlier draft; David Marlow and William Parsons for help with planning the industrial hygiene investigation; Gilles Ferro for assistance tn data management, and Agnes Hanss-Cousseau lor manuscript preparation. K.A. L A. was in receipt of a research fellowship from IARC during pan of the work on this study REFERENCES i \ i 1 International Agency for Research on Cancer. Some halogenated hydrocarbons and pesticide exposures. In: M onographs on the evaluation o f the carcinogenic nsk of chemicals to humans; vol X L l. Lyon: [ARC. 1986; 34b, 395. 2 Kcnazzi PA. Zocchetn C, Pcsaton ACL Guercilena S, Sananco M. Ten-year mortality study ot' the population involved in the Scvcso incident in 1976. A m ] F.pidtnnol 1989; 129: 1187-200. 3. KondCiG. W enersirocm N H . R oushG J,M cLaren EA, L ippsT E ,C ook RR. Cause specific mortality among employees engaged in the manufacture, formulation or packaging of 2,4-dichlomphcnoxyacetic acid and related salts. Br J hid M ed 1988; -15:98-105. 4. Coggon D , Pannett B. W inter PD , Achcson ED, Bonsall J. Mortality of workers exposed to 2 methvl-4 ehlorophcnoxy ace tic acid. Scatu! J IVGrfr ¡'.minm Health 1986; 12: 448-54. 5. Cook R R .B o n d G G , Olson R A ,O n M G .G ondck M R Evaluation of the mortality experience o f workers exposed to chlonnated dioxins. Chemosphere 1986; 15: 1969-76. o. Eriksson M , Hardell L.t Berg NO. Moller T , Axelson O Soft tissue sarcoma and exposure to chemical substances a case-referent study. Br J bid M ed 1981.38: 27- 33. 7. Eriksson M. Hardell L, Adami HO Exposure to dioxins as a nsk factor for soft tissue sarcoma: a population-bused case-control study. J S a il Cancer fntt 1990; S3: 486-90. . l.ynge E. A follow-up study of cancer incidence among workers m manufacture of phenoxv herbicides in Denmark. H rJ Cancer 1985; 52: 259-70. 8 VOl. DX: o c r 26, llWI 9 Green LM . A cohort mortalitv >iudv ol t«»rcMry wnrkers excised to phenoxv acul herbicides. Hr 7 hut S Ud ll*oi ; 48: 2 3+■ 3s 10 Hardell !.. Sandsirnm A. ^use-control studv Soli-iissuc sarcoma and exposure to phenoxv acetic acid'- or chloniphenols. Hr ^ ( .amer I97ntrol Preliminary report; 2.3.7,8ictrachlorodiben/o-p-dioxm, exposure to hum ans— Scvcso, Italy ill.U irK 1988; 48: 733-36 19 Pearce N E, Smith AH, Howard JK. Sheppard RA, Giles H J, ‘League (LA. Non-H odgkin’s lymphoma and exposure to phenoxv herbicides, chlorophenols, fencing work, and meat works employment: a casecontrol study. Hr J hui Med I98r>; 43: 75-8 3 20. Persson B, Dahlander A, Frcdnksson M, Krage H N . Ohlson C -G . .Axelson O. Malignant lymphomas and »«ecupacumal exposures. Br J hid.W ed 1989; 46:516-20. 21. Smith A H , Pearce N , Fisher D O . Giles H J. l eague CA, Howard JK. Soft tissue sarcoma and exposure to phenoxv herbicides and chlorophenols in New Zealand. J S a tl Cancer lust 1984; 72: 1111-17. 22. Vincis P. Terracini B. Cïcconc G . Cignetu A. Colombo E, Donna A, Matli L, Pisa R, Ricci 1?, Zamm U. (tomba 1*. Phenoxv herbicides and soft tissue sarcomas :m female rice weeders: a population-based » •' case-control study. Sc^nd J U“«»r/c Htmron Health 1987; 13: 9-17. 23. Wigle D T . Semenciw R M , Wilkins K . Riedel D . Rirtcr L .M o m so n H I, M ao Y. Mortality study of Canadian male farm operators: nonHodgkuPs lymphoma mortality and agricultural practices in Saskatchewan;^ N*i(I Cancer lust 1990; 82: 575—82. 24. W iklund K , Dich J,^4olm I.-E . Eklund G. Risk of cancer in pesticide applicators in Swedish agriculture. H ' J Ind Sied 1989; 46: 809-14. 25. Woods JS, Pohssar L, Sevénson R K , Hcnser LS, Kulander BG. Soft tissue sarcoma and non-H odgkin’s lymphoma in relation to phenoxv herbicide and chlonnated phenol exposure in western Washington. 7 X ati Cancer Inst 1987; 78: 899-910 26. Zobcr A, Messerer P, Huber P T hiny-four-year mortality follow-up of BASF employees exposed to 2,3,743-T C D D after the 1953 accident. hit Arch Occup Ihnirtm Health 1990. 62: 139-57. 27. IARC M onographs on the Evaluation of Carcinogenic Risks to Humans. Overall evaluations of carcinogenicity an updating of IA R C Mouogr 1—42 'suppl Lyon: [ARC, 1987. 28. IARC Working Group. Phenoxv acid herbicides and contaminants description of the IARC International Register of Workers. A m J ind M ed 1990; 18: 39-45. 29. Coleman M P, Hcrmon C, Douglas A. Person-years 1PYRS): a Fortran program for cohort study analysis W H O IARC internal report no 39 0061. Lyon; IARC, 1989. 30. Checkoway H, Pearce N E, Grawford-Bmwn DJ. Research methods in occupational epidemiology. New York. (Oxford University Press, 1989 31. W orld Health Organisation. Manual ol the international statistical classification-ot diseases, iniunes and causes of death , 7th revision conference]. Geneva: W H O , 1957. 32 W orld Health Organisation. M anual of the international statistical classification of diseases, injuries and causes of death i8th revision conference;. Geneva: W H O , 1967. 33. W orld Health Organisation. Manual of the international statistical classification of diseases, injuries and causes of death -9th revision conference:. Geneva: W H O , 1978 34. Fingerhut M A, Halpenn W E, Honchar PA, Smith AB, (jro th O H , Russell WO. An evaluation of reports of dioxin exposure and soli tissue sarcoma pathology among chemical workers in the United States. Scant! J Work Hminm Health 1984, 10: 299- 30 3 35. Hull" JE. Salmon AG, Hooper N F . /e ise L. U m g-ierm carcinogenesis studies on 2,3,7,8-teirachlorodibcnzo-p-dioxin and hexachlorodiben/.o-p-dioxin. ('ell Hud Toxicol 1991; 7: Ö/-94. to g e t effectiv e c a lc iu m a n ta g o n is m w ith m in im a l sid e-effects ! C A R D K N E * A b b rev iated I'rry nbin): in fo rm atio n U ' e t : C h r o m s s ub ís - l u c m . i -inl.i :•> n . - J i t m 1i \ p c M i i i M O i i D o l a r e • " r vn < n s -,,hi >i irmiv: .loss .>i .‘" m e : i .! :it: n i n e upv\.if«U t o .1 in. iMititiin «>1 Ms ;>s ris'ii 'U»n .1 i n m i l s ' : ....... ... i. n«-M s! i. i. /n /j ■>1 *i: rv' 0 ' -It » m e 0 . 1 .in./ •• -i.:,', 1•up.; i, I i mu. i ll s I 1 si .ion M Ut IN H Y P E R T E N S I O N ^ i iij 1111 m. l : 1 si In b e s i m .I . n i s s ........t f o l o ( h e n s .iff Mil t ut. it i o n V 1 ■». 1-. ■ :ti. ;l!) ,1 I mu.ills M i n e :• si t . i n ' n l k i il l. uc m J i n i . m i m i i l ' s i >. lissluis 1 U ii.lt." V . f t 1* . •iiiiiiriisl<-.{ siii.li r i > s . i : . M i s N ' :i»i\i ss l u r e i ' t n . i l k ssilli l>s I n i‘lo. Vs i> C " o n i r a - i n d i c a t i o n t : l ' i s e n n : . s m . i ' i. u u o m I K p e r ' C i i m i i v i t \ is> ifsl ip ii u •isv: :o , nlo1 i, i>i,. t«m s .l . i . s itu k i . i - H w U , >!,**■ .s - *11111 l »» i n m u t o M .r ( A K I 'l.M >>l 'l . i M t n c ills '! i;**. - ‘ f Cardene m m o \ s .-Isl ss sis nil. !'.s '.• •• lists>11 HI pJI U III* 'Mill 1 l t l ' l o f \ >■: >:r..ks ^ 'S 11: -.. ■ p o o f . Ifsll.ls rCssTW Of lllip .tll S .! ‘Is }'.Ills ol . .11 _ ': C>- s 111 . 11I1. Ilslllis . .nisi iil.issllis. . ú . n i s pin« .¡. iiimj ; In i.l.i. :n p s : ipli. 1 .s .Is • •• «.»MM.........11 ¡ 'il l s 'l l l. s s u li . I.'sli.,, i n I nos ........ M . . ; | . | . . ( ;• ills ni: . ol.». iss r> S i d r - c t l c c t s . 11.ip : -.s. . 1 i 1s ii ........ . I \ ' l b Ml. . s o : , . o r . n r m us p n.is n il. ■■ is 1 101«. 11 ri. . '»► >• -I.......... Ii.: K 1: ¡v n u t.: ills r e ....... I m e ( NS 1 I. j m i o o s :• >1 im p .i in m m n. : • (nicardipine) : ii \ 1 lnn .......................................... it. |... . •. \i>> • . c i s w o . n i i s *¡ , ups. : • .1.. • -.1 n . l o o r , Is i « P r e s e n t a t i o n , b a s i c N ' H S i o m m s J p r o d u c t l i c e n c e n u i t i h r r v i V K I ’ I M t . psuU ■ ........ nis. iisliivnt :->,v •. Iii.n i.l. mi '" i n e I I'l > ' 1 1*1 Iv . ’ ’s*. Js'./.n ii.. ! SO.Iu; l I’s r-s>11.11 t . .iin 1m in . .... 1• a • ; I ‘ tu .: .ti. 1: l. .HI I -H ill. I ..........I'l ... •:i. M \R l M M "ijssf. ■HIV I 's . I. S ! ’ll 11 III I. S ,.U . .lis I m ills i l . S \ n>. :....... I Hs : ’ks M !k l > ...... 5YNTEX DO ^ '• » o r t i o i / i t r m a a ; •JS? p h a r m a x ; An overall low incidence' o f side-effects was confirmed in 10,932 patients w i t h ^ ^ hypertension and angina.1 --'V*T-' I f W h a te v e r you g iv e your h a e m o p h ilia p a tie n t w ill help shape his future. You can now give him a high purity factor VIII derived from the p la s m a o f h e a lth y U K d on ors, screened by the National Blood Transfusion Service. One that undergoes a unique and h ig h ly e ffe c tiv e v ir u s inactivation process.'-2-3 Quite simply, 8 SM . The new high purity factor VIII from BPL. 8SIVL PURELY FOR QUALITY IM R IS LIFE 8 S M (H igh P urity Factor V III) P R E S C R IB IN G IN F O R M A T IO N Ind ica tio ns: Treatment of classical Haemophilia A. Do sa ge : Minor bleeds: 7-13 iu/Vg initially. Severe bleeds: initial dose 9-25 iu/Kg body weight For fuU instructions, including dosage for major surgery, se e Oata Sh e e t Adm inistration: Reconstitute Factor VIII in Water for Injection provided. Stow intravenous injection not exceeding 10ml per minute. Contra* ind ication s: Hypersensitivity to mouse protein. W a rnings etc: Contents should not be used if Factor V III vial does not oontain a vacuum or if the Factor VIII forms a gel or d o t The risk of transmitting viruses including those causing hepatitis and A ids cannot be entirely excluded. Side-effects: Specific hypersensitivity, occasional flushing, nausea. increased pulse and headache may occur. Precautions: M a y contain blood group antibodies. Patients with A, B or A B blood groups should be monitored for sig n s of intravascular haemolysis. Antibody development should be monitored after treatment. Patients should be vaccinated against hepatitis B before commencing treatment Sterilised Water for Injection must not be injected on its own or for any other purpose than reconstitution of 8 S M . B a s ic N H S cost: 48p/iu. Presentation: Nominal 500iu or 1000iu /vial supplied with 5ml or 10ml Water for Injection. P rod uct Licen ce n u m b e r PL 08601/0015 (see Oata Sheet). Sterilised Water for Injections Ph.Eur., P L 1502/0003 (Phoenix Pharmaceuticals Ltd.. Gloucester. U.K.). Fud prescribing information and Oata Sheets BPL A IS A UNIT OF THE CBLA SPECIAL HEALTH available from: BPL, Dagger Lane, Elstree, Herts W D 6 30X. Tel: 081 90 51 81 8. R e fere nces: 1. Piszkiewicz 0, et al. Inactivation and removai ol hum an' immunodeficiency virus in monoclonal purified anti­ hemophilic factor (human). T h r w n t a ù ^ e ^ r d f c 1989; 55: 627*634. 2. Data on file. 3. G riff® K ffle K r a M p ^ .c h a r a c t e fl sation of the Method M A H F p r p s p s 'le v in e p w to reduce the risk of v im s transmission, in Roberts H R (ed): Proceedings ot the sym posium on biotechnology and the promise of pure FVItl. Brussels, Baxter Healthcare Publications, 1989:69*85. AUTHORITY WITHIN THE NHS 1031 THE LANCET VOL 338: OCT 26, 1991 TABLE I V — DESCRIPTION OF 9 CASES OF SOFT TISSUE SARCOMAS Sex. Year of destht 1, Australia M ,46 <1980 2, Denmark M, 32 <1980 Cause of death Connective tissue lower limb (I CD 171) Connective tissue lower limb (ICD 171) Alive, Jan, 1984 M, 47 <1980 lll-deftned cancer 4, Denmaik M , 64 <1980 Prostate cancer 5, Denmark 6, New Zealand M, 35 Alive, Ja n ,1988 7, New Zealand M , 55 1980 + Connective tissue upper limb (ICD 171) M, 43 <1980 Connective tissue unspecified 8, UK (ICD 171) 9, Denmark M , 56 Alive, Ja n ,1984 3, Denmark M , 34 Years since first • iM iu iv y r .* « Longest held jO u Years of êX p u S U fe ê x p u s ü f e Fibrosarcoma of the hip Sprayer 16 16 Neurofibrosarcoma, lower limb Mesenchymal sarcoma (possible Itposarcoma, retroperitonewn) Haemangjopericytoma, bade Leiomyosarcoma, prostate Production, transportation/scorage 10 <1 Production unspecified Production transporcarion/storage Production, transportation/storage 14 21 17 <1. 8 2 Fibrous histiocytoma, lower limb Sprayer 12 12 Neurilemmoma Spindle cell neurilemmomai sarcoma Sprayer 14 12 Sprayer 18 <1 Leiomyosarcoma, larynx Non-ocposed 26 <1 1 additional incident ca se occurre d after the end of fo llo w -u p in N e w Zealand. * C a s e s 2 . 3 .4 . 5 .8 . a n d 9 p reviou sly reported.2’4-7 f Precise year o f death not provide d for reaso n s o f confidentiality. t H ist o io g y from c an ce r registration or medical records. H isto lo g y record not retrieved for c a se 1. workers, and similar to that of production workers (table III). The cases arose in seven countries. (Not included in table III are 3 cases in cohort members who were alive at the end of follow-up or whose certified underlying cause of death was not ICD 200 or 202.) Mortality from Hodgkin’s disease was below expectation. Other neoplasms More than two-fold increases in risk were noted among exposed workers for several less common neoplasms, most of which have not been previously associated with exposure to chlorophenoxy herbicides. 7 deaths from testicular cancer were recorded, with at least a two-fold increase in mortality for the combined group of exposed workers (SMR=220 [89-454) and for the production workers (5 deaths, SMR=278 [90-648]). 5 deaths occurred 5 or more years after first exposure, and risk was higher in workers probably exposed to TCDD (SMR=296) compared to those probably not exposed (SMR = 164). Thyroid cancer mortality was increased for the combined group of exposed workers (4 deaths, SMR=357 [97-914]), the excess applying both to sprayers and production workers, with deaths registered in three countries. 3 deaths from thyroid cancer occurred 10 or more years after first exposure, and risk was higher for workers probably exposed to TCDD (SMR=426) compared to those probably no- exposed (SMR=308). 3 deaths from neoplasms of other endocrine glands occurred m the UK with increased mortality for the combined group of exposed workers (SMR=454 [941328]), and separately in sprayers and production workers. Increased mortality from neoplasms of nose and nasal cavity (3 deaths, SMR = 283 [58-827]) was similarly observed only in the UK, with the highest risk in sprayers. The mortality of cases exposed through accidents was not increased either for all causes (33 deaths, SMR = 98 [67-137]) or for all neoplasms (13 deaths, SMR =120 [64-205]). Similarly, no increased risk was seen for chloracne cases for all cause mortality (13 deaths, SMR = 66 [35-113]) or for al neoplasms (5 deaths, SMR = 98 [32-228]). No deaths from soft-tissue sarcoma or nonHodgkin’s lymphoma were observed in these groups, but the expected numbers were very low. Results were virtually unchanged when analyses were repeated with exclusion of all workers with less than one year exposure. Analyses by time since first exposure and duration of exposure for workers probably exposed to TCDD did not show any trends. Analysis using Poisson regression for all cause mortality, all neoplasms, soft-tissue sarcoma, and non-Hodgkin’s lymphoma, did not reveal different partem of risk than that shown in the SMR analysis. Discussion The IARC register provides an opportunity to study, with a common protocol, the mortality experience of workers producing and spraying chlorophenoxy herbicides and/or chlorinated phenols in ten countries. This cohort study is the largest to have been done on these categories of workers. Nonetheless the attempt to associate risks with specific agents was only partly successful because there was often simultaneous exposure to several different chlorophenoxy herbicides or chlorophenols (table I) and to other pesticides, raw materials, intermediates, and processing chemicals. The risk specifically related to chlorophenoxy herbicides is best evaluated by looking at sprayers, who are exposed mainly to these compounds and, in smaller amounts, to other herbicides, and only to negligible amounts of chlorophenol impurities. Workers producing chlorophenoxy herbicides may also have been exposed to chlorophenols during the production process. It was not possible to identify a large group of workers exposed solely to chlorophenols. The most toxic dioxin (TCDD) can be formed during production of 2,4,5-T or 2,4,5-TCP so the identification of factories which did not produce 2,4,5-T or produced only very small amounts and of sprayers not using 2,4,5-T allowed a population to be distinguished in which exposure to TCDD was unlikely (with the caveat that even occasional exposures to high concentrations of TCDD may lead to accumulation of high tissue burdens18). A non-significant increased risk was observed for soft tissue sarcoma, the excess being significant for sprayers in an analysis by time since first exposure. All 4 cases (in four countries) occurred 10-19 years after first exposure, a time shorter than that observed in Sweden10or the USA.16The increased risk was not confined to workers probably exposed i7 m B ersatolofiiea, l *>95?) 5 ^ - T h i r t y - o n e c a s e s o f ehloracr.e were found among workers engaged i n th e production o f 2 , ^ , 5 - t r i e h l o r o p h e n o l and i n th e <©r.version ©f the l a t t e r i n t o 2 , A , 5 - t r i c h l o r o p h c n o x y a c e ti c a c i d and i t s e s t e r s . Animal experi.eer.ts,. c a r r i e d out by p a i n t i n g r a b b i t s ' e a r s , have shown th e e s u s e Di ehloracr.e t o be r.ot t r i c h l s r o p h e n e l i t s e l f , but t o x i c b y-p r od uc ts formed i n the a l k a l i n e h y d r o l y s i s o f 1 ,2 ,l * ,5 - t « t r a c h l o r o b c r .s e n e i n t o 2 , ^ , 5 - t r i c h l o r o p h e n o l . Compounds that may a r i s e i n t h i s p r o c e s s were s y n t h e s i s e d , and t r i - and te tr a c h l o r o c i b c r .z o f u r a n and t e t r a c h l o r o d i ber.rodioxin were found t o be h i g h l y a c t i v e . Furthermore, 2 , 3 » 6 i 7 - t e t r a c h i o r o d i b e n s o d i o x i n was i s o l a t e d as a by­ product formed i n the manufacture o f t r i c h l o r o c h e a o l , and the p o s s i b i l i t y o f i t s formation from sodium t r i ch lorophen oxide was e s t a b l i s h e d . C h lo r in at ed compounds, used ns i n d u s t r i a l m a t e r i a l s or formed a s by­ p r od u ct s, occupy an important p o s i t i o n among t h e chemical and p h y s i c a l i n t o x i c a n t s capable o f producing acr.c and f o l l i c u l i t i s . ■ * * * The f i r s t c o z e s caused by t h e s e compounds were ©boerved a t t h e b e g i n n i n g o f the c e n tu r y with the i n t r o d u c t i o n o f th e e l e c t r o l y t i c c h l o r i n e p r o c e s s . The view put forwdrd, and l a t e r c o r r e c t e d , by Kcrxhoincr, a c c o r d i n g to which the d i s c a o o i o caused by fr e e c h l o r i n e , hau l e d to the c o n f u s i n g but common d e s i g n a t i o n "c h lo r a c n c " . . S i n c e the i n t r o d u c t i o n o f c h l o r i n a t e d n a p h t h a l e n e s , uacd i n v a r i o u s branches o f i n d u s t r y on account o f t h e i r u s e f u l p r e p e r t i e o ( r e s i s t a n c e naphthalene d i s e a s e " ! , wlvich og.iin i s u n s a t i s f a c t o r y i n rainy r e o p e c t a . k 0173 1 Chlcracne hoc r e c e n t l y been observed i n the »sr.af acture o f pentjjchloroyhcnol. I t w i l l l a t e r be d i s c u s s e d s h o r t l y whether pentachlorophcr.ol i t s e l f i s to be regarded a s the i n t o x i c a n t proper i n th e s e c a s e s . * # l>* .. The c a s e s wheae c t i c l o g y i s aov d i s c u s s e d were found among v^rkars ir. a chemical p la n t i n Hamburg,. who were engaged i n the r-snufacture o f • 2'it»« 5-t ric hl- 'vo ph cnol and i n i t s c o n v e r s i o n i n t o the h e r b i c i d a l ?!*• » 5 - t r i c ’hlr>r©4:htfr>oxyaeetic a c i d and i t s e s t e r s . Out o f a t o t a l o f p? p a t i e n t s , 9 cho-cd s e v e r e , moderate, and 8 s l i g h t symptoms. The symptoms developed i n the summer and f a l l o f In th e c a s e o f Bore h i g h l y exposed workers, f a c i a l d e r m a t i t i s accompanied by erythema ar.d s w e l l i n g appeared f i r s t , but withdrew l a t e r to g i v e way to a c r . e i f s r symptoms on the f a c e , then on o t h e r p a r t s o f the body as w e l l . Ir. most c c s e s , however, the h i s t o r y s t a r t e d n o t with a c u t e d e r m a t i t i s but with comedones and then p u s t u l e s , a f f e c t i n g the z y g c m a t i e - t e n p o r a l r e g i o n . The d e r m a t o l o r i c a l symptoms found on f i r s t examination c o n s i s t e d o f numerous comedones, r e t e n t i o n c y s t s , ra ng in g from the s i z e o f a pinhead to t h a t o f a l e n t i l , f o l l i c l e s f i l l e d with h y p e r k e r a t o t i c m a t e r i a l , inflamed p a p u l e s , p u s t u l e s , and l a r g e r f u r u n c l e s . The f a c e , e x t e r n a l car, nec k, ar.d the nape were i n v a r i a b l y a f f e c t e d , s e v e r e c a s e s a l s o e x h i b i t i n g symptoms on the c h e s t , back, abdomen, e xtens or s i c e s o f arms and t h i g h s , and on the g e n i t a l s . The e f f l o r e s c e n c e was g e n e r a l l y s o dense t h o t p r a c t i c a l l y no f o l l i c l e remained u n a f f e c t e d . Vhcreas f a c i a l symptoms were mainly c h a r a c t e r i s e d by comedones and r e t e n t i o n c y s t s , secondary i n f e c t e d e f f l o r e s c e n c e ( f u r u n c l e s and p u s t u l e s ) was frequent on the nape and the trunk ( s e e }*igr. 1 and 2 ) . In a d d i t i o n t o d e r m a t o l o g i c a l symptoms,, s e v e r a l p a t i e n t s deve lop ed c h r on ic b l e p h a r i t i s and c o n j u n c t i v i t i s . Host p a t i e n t s complained o f l o s s o f a p p e t i t e , d e b i l i t y , and weakness i n the l e g s , in o t h e r words, o f syiepto.T.G i n d i c a t i n g g e n e r a l i n t o x i c a t i o n . rig. n T ig . 2 Ho chan;* i n the l i v e r , k i d n e y s , c e n t r a l nervous s y s te m , end i n the hemopoietic system was f i r s t , found on thorough c l i n i c a l examin.sticr.. Son* p a t i e n t s had ar. a n c e i d a t y o f t h e g a s t r i c k u i s e . Owing •©* g c r e i s t e n t c o s p l a i r . t a , new ¿ a t o m i s t i c and n e u r o l o g i c a l e x a m in a t io n s were c a r r ie d out on s e v e r a l p a t i e n t s a few weeks l a t e r , r e v e a l i n g • i Y c c t e d l i v e r i n th ree e a s e s . D e t a i l e d c l i n i c a l d i a g n o s e s w i l l n o t hf>e vcr be d i s c u s c e d h e r e . The course o f the d i s e a s e was e x c e e d i n g l y lo n g and p e r s i s t e n t . Alth ea c o n t a c t with the i n t o x i c a n t s had been d i s c o n t i n u e d , r e l a p s e d dermato­ l o g i c a l sysptems appeared even 15 • 2C e o n t h s l a t e r , d e s p i t e i n t e n s i v e i n t e r n a l ar.d e x t e r n a l t h e r a p y . 1't jolorv An¿sal experiments were c a r r i e d out w it h a view t o c l a r i f y i n g th e e t i o l o g y o f ehloraene by t h e . u s t o f r a b b i t s ' e a r s , on which Hofmann ar.d Neumann , Braur. , Landes , and o t h e r s had su cceeded i n i n d u c i n g symptoms by u s i n g c h l o r i n a t e d n a p h t h a l e n e s , th e symptoms r e s e t t l i n g those o f ehloraene i n man. In each c a s e the i n s i d e o f one car was painted d a i l y with c p o l y g l y c o l s o l u t i o n o f the su bs ta n ce t o be t e s t e d f e r i t s c h l c r a c n e - i n c u c i n g a c t i v i t y , w h i l s t the oth er e a r , s e r v i n g aa a c o n t r o l , was t r e a t e d with the s o l v e n t a l o n e . In e a s e s o f p o s i t i v e t e s t , f l a t s u r f a c e inflammation f i r s t de ve lo pe d i n 2 t o A weeks, fo ll ow ed a few days l a t e r by the appearance o f f o l l i c u l a r s w e l l i n g , h y p e r k e r a t o s i s , and s n a i l c y s t s ( s e e f i g . 2 ) • H i s t o l o g i c a l exa.nir.stion showed a c a n t h o t i c e x t e n s i o n o f the e p i d e m i c , edema, and l o o s e , inf lamed c e l l i n f i l t r a t i o n i n the c u t i s . The f o l l i c l e s were d is te n d e d and f i l l e d w it h k e r a t o t i c i s a t e r i a l . Larger e y t t s were formed i n l a t e r s t a g e s ( s e c T i g . * 0 . fis- 3 P a b b i t ' s t a r t r e a t e d with a 0.15S solution o f tctrachlcrodibcnsodtoxin _ H isto lo g ica l picture of the r a b b i t ' s t a r shown i n F i g . J K \ k having been used with s o r t than 100 s u b s t a n c e s i n the pnst two y e a r s , the r a b b i t - e a r t e s t e n a b l e s the c h lo r u c n c - i n d u e i n g A c t i v i t y o f a oub*iancc to be a s c e r t a i n e d with hig h p r o b a b i l i t y . Th* f i r s t r e s u l t s were r e p o r t e d by one o f us*^ a t t h e 22? d Congress o:* ’ Cermar. U e r x a t e l o r . i s i s i n V ie n n a. * I t was f i r s t shown t h a t , c ont r ar y . t o - p r e v i o u s a s s u m p t i o n s , 2 , ’«, 5 - t r i c h l o r o p h c r . o l war no t t o be e n r e i d e r e s a s ; t h e e h l c r a c n c - i n d u c i n g f a c t o r . T hi s «merged ir o n '¿hi o b s e r r s t i e n tlfcat the e xp ect ed symptoms wire not produced os t h e r a b b i t s ' t a r s with a '¡jl* s o l u t i o n o f pure 2,*», 5 - t r i c h l o r o p h c n o l i n p o l y g l y e a l , b - t they were produced by th e t e c h n i c a l p r o d u c t . S i n e * the s t a r t i n g m a t e r i a l , 1 . 2 , ^ , 5 - t e i r c t h l c r o b c n a e r . e , was i n a c t i v e bn the r a b b i t s ’ e a r s , i t war t o be assumed t h a t the i n t o x i c a n t was among th e b y - p r o d u c t s formed ir. the o l k a l i n e h y d r o l y s i s o f 1 , 2 , A , 5 - t e t r * c h l o r o b c n s e r . e i n t o 2 ,^ ,5-triehlcraphcnol. a Ol! U + N. Oil ------- a ^ C »5-teira- chlorobenaer.e li^iJ-trichlcrc- Sir.ce the d i s t i l l a t i o n r e s i d u e could not e t f i r s t be s e p a r a t e d , s number o f such s y n t h e t i c compounds were s e l e c t e d f o r t e s t i n g , which were l i k e l y to be formed i n the h y d r o l y s i s o f t e tr ach lc ro b cr .a e n e a t 1cC C, th e s e compounds b e i n g the c h l o r i n e d e r i v a t i v e s o f diphenyl e t h e r or.d o f diber. 2ofuran (d ip h e n y l c n e o x i d e ) . Whilst the c h l o r i n e d e r i v a t i v e s o f diphenyl e t h e r and u n s u b s t i t u t e d and monochlorir.atcd dib cr.sofuran were i n a c t i v e i n t h e animal e xpe ri m en ts , t r i c h l o r c - and t c t r a c h l o r o d i b e n a o f u r a n r e s u l t e d i n the e xp e c t e d symptoms, even when they were s p p l i e d i n O.Cjr«** s o l u t i o n s . In a d d i t i o n to the above symptoms, both compounds e x h i b i t e d s t r o n g h e p a t o t o x i c p r o p e r t i e s . The o r a l a d m i n i s t r a t i o n o f a c i n g l e dose o f 0 . 5 to 1 r.g/kg l e d to s e v e r e h e p a t i c c o n d i t i o n s i n r a b b i t s . Jîowover, c h l o r i n a t e d dibcr .zo fur ans c oul d not be d e t e c t e d as a by- prcduct l a th e p r o d u c t io n . The c l i n i c a l examination o f a la b o r a t o r y a s s i s t a n t who de ve lo pe d a s e v e r e c a s e o f c h l o r a c n e A ft e r c o n t a c t with t e t r a c h l o r o d i b e n s c a i o x i n i n d i c a t e d the p o s s i b l e c a u s a t i v e f u n c t io n o f c h l o r i n a t e d d i b c n i o d i c s i r . a (d ip h e n y l c n e d i o x i d e s ) . Fu rther expérimenta w it h r a b b i t s ’ c a r s showed tetrachlorodibcnr.odioxins, e s p e c ia lly 2 ,3 ,6 ,7 - t e t r a c h lo r a d ib c n s o d io x in , t o bo very h i r h l y »»ctive. Three or four p a i n t i n g w i t h 0 , 0 1 - O.CC55* s o l u t i o n s , a p p l i e d a t i n t e r v a l s o f J to days , were found t o Vo s u f f i c i e n t to produce s e v e r e in in u v c a t l o n and f o l l i c u l a r h y p e r k e r a t o s i s . A s i n g l e doso o f 0.C5 - 0 . 1 mg/kg (p er o s ) r e s u l t e d i n s e v e r e h e p a t i c c o n d i t i o n s , and, in c o s t c a s e s , i n death w it h in 5 to 20 dayn. Autopsy r e v e a l e d d i s t e n d e d n e c r o t i c t i s s u e s and engorgement o f the l i v e r . 47156 2 : was shewn t h a t 2 , 3 : d » 7 -t c tr a c h I o r e tl ib e n ; i. o d io x in can be fcre.cs from •♦ it i - o m o l e c u l e s o f »odium tr ie l - l o r c n h c n o x i d c with th e e l i m i n a t i o n o f tv s e o l c e u l e s o f 7>*aCl. 2-to::c o v e r ; 2 , 3»6 »7- t c t r a c h l credit or, sod 3 waj i s o l a t e d a s a by- product formed in the a l k a l i n e h y d r o l y s i s ®T t r i r a eh lore bens er.e i n t o t r i c h l o r o p h e n o i . T h is o b s e r v a t i o n l e a d s t o the c o n c l u s i o n th at t c t r a c k l o r o d i b e r . s o d i o x i n i s r e s p o n s i b l e f o r the or. fcascs o f c h lo r a c a e i f not e n t i r e l y , c e r t a i n l y t o o c o n s i d e r a b l e ex T i sheuld be added t h a t n e i t h e r pure Z . ^ J - t r i c h l o r o p h c r . o l r.cr pure per.tachlercphenol c oul d ind uce the e xpe ct ed symptom» on r a b b i t s ' e a r s . I t i s t h e r e f o r e p r ob ab le t h a t thr r e p o r t e d 1 c a s e s o f e h l o r a c n c , c s i e n s i b l y » r i s i n g a f t e r c o n t a c t with pentac'nlorophcnel, were caused •net by t h i s compound, but l i k e w i s e by t o x i c .by - pr odu c ts , r e l a t e d to th ose examined in the p r e s e n t work, e s p e c i a l l y s i n c e pentachloropher.cl i s prepared from h e x* c h lo r ob e n s tn e by oJ.kalinc h y d r o l y s i s , » n s l o g c u s l y to the p r e p a r a ti o n o f t r i c h l o r o p h e n o l . ‘eremccs 1 K . t t ’.x u n j I f . J . JUmrr; Jr.J. >|„). Su»g 70, I I * . 1951. 2 IT.; Ck)«»*i..e. fa iiia r. ..v l,rf;^ UMt. 195V i C x m m r r . ;/_• 21.1. Arbcil> » > « luin /rL fii* » c l.u ii J. 74. 1955. i t l l t < t k t i m r r , X*_- M in c h . m r .|. 'S’tclir. JC. 273. 119?; Yc/io n d l. V I I . V««;». D rim a l. C*». I l r c U » 1901. 157. S //. 7 7 ,„ «nil TT. / On««««,: 7.11. Arbcium ru.’ii'* A t l«r.i*.CJiui j ^ It';. 1957. i I* « ./.., K .: D in a . H 0 % Ji91, l? 3 l. • S i A u /j, A . //..* V « n r. X a i II. D u r k . D rn fiilu iik ^tii* K * » ; r t 0 7V.cn v .m 75. hi» 77. J. 1974. 7 ' 1 ' i j . L.: XU.». f , : K i . t . 315 u..d *97. 19».; 7, .14, J9*3; 7«, !;1 , 1919. — Tf’i u t r : Zbl. C cvtrl.ci.*ji< » c i , ]00, 19)1. 7. S c h u l s , K. H. , L e c tu r e d e l i v e r e d * t the 23rd Congress o f Ceraar. D e r m a t o l o g i s t s , Vienna, Hay 23 - 27» 195& | j P - o o ) OCCUPATIONAL- A C N E '(’Chloracne, i s o - c a l l e d ) • B y K l m m i g ..& ¡Schulz .•Derraato.log'ica.;l.T5, 5 ^ 0 , 1957 c . /.• Among .Translated f rom G e r m a n ‘iby iJ.; ..Barandy the.' 'different •chemical'land, p h y s i c a l toxicants whj caus.e; skin., acne., d n d follicultls.i 'to/a.'pathogenic extent, i chipr.inate.d.‘products .'and byproductS..:ha've. ;be'.en playing .an .. • ■ Important. -role. "' ‘ .'.'•.•.The', first- s u c h ; '■ cases.' pf- i l l n e s s e s 7,. i n d u c e d - b y • . . c h l o r i n a t e d - m a t e r i a l s > . were.o b s e r v e d /ar.o.undi the end. of ■ .. ; . the -century, in ^.connection :■with,-.the"-newly ^introduced- process. . of. -obtaining c h l o r i n e through eiec-trolysi?./ Th e 'o p i n i o n ■ ;. whi;cii ^Herxh e i m e r expressed,-'-but 'lateh'.''changed, :was that-. ' ...■free,-;chl;ord1n e :,was; the cause,'of "l'lln'es's.es;,->and. l e d - t o the ' ..v . • : . ,• . ' ' . . . t •. ' ■ . . • / wide spread:’ ,mi'sus e ■of the'word ''•chl-orache:'''.in! German ‘ ■ • ’ ,' j > * •.' i. . 1 . . . *. • • ,••••’.* ' i * * . / 1• . ; ’V ,V ... l i t e r a t u r e 1■ ' ¿inceuthe--Introduction o f ;.chlorinated:'naphthalene, • ' -V - ; =‘:'-v ^ \ ; ’ •which,.'due.i to its. advantageous-.-|?echi?i'c.ai .¡properties- .(like • '- '•" a c i d resistance,-'.fire-water .repell'ency-i-good i s o l a t i o n ' ■ capacity,-’etc.-); a p p e a r e d In "different''Indus trial'applica-:- • ..'.Vi -.; ; , tIonsj." t h e / o c c u r r e n c e (.TeIe.ki,;Braun, ' . G r i m m e r , e t a l ) .’. thes.e',-illnesses■w i t h ' ■, ■ ■ .. of ch-loracne/.'lalso-lias.increased. the •': .Wauer.&.'-Teiekl identified.. q u i t e .I n a p p r o p r i a t e word "Dernadiseas More ' ¡ c o n t e m p o r a r y are-' the ;:o b s e r v a t l o n s : of i n t o x i c a t i o n s . f r o m - p e n t a c h l o r o p h e n o l p r o d u c tion',,".' wher;e''pentachlorophenol . . ; In contac-t;'with' the c.aused;;ch’lbrache-.: A l t h o u g h for *. these-'c a s e s ,' the pentachloropehh.ol'.itself- c a n b e - r e s p o n s i b l e , ,. skin, . / we.-will, h a v e .to- c a r r y on '. t ■ ■ f u r t h e r -i n v e s t i g a t i o n s = f . , : - • . • ' I ■'.*■ ::—/ wrxoxxrrd_ri. O A — K -i J L 4 ’ . I v . ; ; ' ; ! 7 3 2 5 S i 171S8 -2 - .'Thé'.actual-.pbservatlons-tol'.whid.h.: wé 'by. experiments could •' •.achieve ’ --were .'performed on wo’rkçrg ;of yo'ne ..-of•/the chemical. ' • fact pries,.-Ifl' Hamburg, engaged; in. thé .•production 'of ' •' 2 , h j 5-'*rCCP: and ' .ics'endproduct-. !th e kérb-ic ldô' :2 i4,5 -1rich! or o -• : ' ■' - .--V':’-V ,\ ■ . ,;y ' ..'.'phénoxyacetic 'acid"and its \eâ ter'sy Vt.-A; :t.o/tais'.of.3 1 p e r s o n s ■: became/.sick/ ;from. which ’9 .showed;>ide'spréadJ‘ heavy- deforma: tiôns'j-':T4;-persons.* .general*:Qpn^i'Çion.Sidqt-er^ôrated,and 8 . '; •• v 'iv*-'y-., ..persons,'showed only minor.;changesw.'".' .-.' y-.-: '. ■ Thé. clinical-. appearances; developed .'in: summer and Vautumn- of . ‘On one worker/'..obvdou'sly-;.heavily; exposed,-' ; symptoms-'appeared , :flrst as'a:dermatitis.-on .:the. face, ■ •'•' accompànied:by, erythema (redness} , -'and, swelling’of the fape,/after}which-conditions/on ;;the/fac.e ,'acne. (like deforma-. ' ■ ■. tions) 'developed. • Still later., '.other' typés--pf '.pustules; formed, r In.■most, cases/ the symptoms; appeared Vas‘-blackheads .'in • :the beginning^, while in the-:lattef:;.stk^eJ:.bolls developed." ;'■'on ■the cheekbone, region, without.’.acute.-dermatitis .-As- .-far-.as 'the first ;observations'yof,'these skin ' deformations,‘are çoneerned,.-they..’'co'uld.. be.¡composed of ■ 'Innumerable./blackheads, and/pr- retention-'.systems wit h size. ..varying-'from./pinheads/to lentil;;- of •fplliQular ■ ' .'-bond h y p e r k e r a t o s i s , of inflamed; boils'i-vpr/'.Qf 'f u r u n c l e s .. In;, ali.-c a s e s / -the inf e c t e d .parts; wé r e ; t h e -face, earlobes,,•; . .••• ' ‘ •/• . , ■ • .- ■ • ;i' .. ; ; .' . -,; -, ' ■ . . •. necks while '.in heavier cases,’ the symptoms ..'spread on •-, the. chest,-.-back, .abdomen, -sides/ .Upper/'ieg and on' genitals., ; :'in.’.general'-, ,:the a l l o c a t i o n s .¡of .thèse ^eruptions were'.unusually 'thick, to such 'an ’extent: that-'hardly a * ;-3 S5 i s - ;* . ' 7 3 :2 5 7 • 17159 a.' follicle, ''remained undeformed."-• While.;’m o s t b l a c k h e a d s V . \ * ,arid retentlop •systems have.;-:l?een;:.qba erv.eidf;bri.,-.the face,. ■ .' '' .types, o.f /secondarily infected-, eruption's/-('f.uihmcles) were . 1 , * *i. '* . ; . •'* '1'1* ■ *,'**^.*•1* • quite •frequent', op the neck '.and'pn^.the'vtrxan^.l'of the bo 4 y v ' Several-.patieri.ts.'.-- besideis'ithese*-skin',Reformations developed- chronic' eyelid .c.onJunetiyiti?'.:'.the 'other; c o m p l a i n t s ^ -. Generally, \ of ■the.'patients.'were.-loss of appetite;,-;•w e a k n e s s in t h e .l.ejgs ¿-yahR/other;’s y m p t o m s whichindicated.-aR-¡overall intoxication»'.;. 'y-’S' v; r' ■-The ^further, clinical^.examirta'ti'ohS; .reported d a m a g e -• / . of. t'he/liver',. d a m a g e of c e n t r a l .-nervous •.system a n d - d a m a g e ' " of, thp; blpod-rec.overy system, .alsp^, suffered.¡'hypoacidity S e v e r a l 'patients' (less.'acid): i n •their’.'stomach ■■■ ■■ Juice. ;' A,-week or so l a t e r , ' due' to „ a g g r a v a t e d cases, in'te.rnar-'ahd n e u r o l o g i c a l several/patients. examihation^-.; were..'resumed on. This- time-,; 'indipatl'ans--.proved l i v e r ■ damage, 1'i'n;'three-cases . • We. ,'wlll;.¡not;.describe her e .details 1 of .this c l i n i c a l r e p o r t . : • : the.. ■ ./ .. . : . : Th.e- duration of the ¡illness; .proved ;to.;be long and endurii' Although .'there was not any. contac.trwith.'the-.toxic-sub-, stances-,'-'despite .intensive;'lnterriai'.'ahd external therapy, even. 1 5 -:$Q months after the ;beginning-,,';•marks 'qf skin deformations:kept appearing.. ."’I \ //Investigations '.of 'th£ ,causer (ethiology) .'; Animal' e x p e r i m e n t s flnd-.the'.toxic a g e n t - i-, :: h a v e .been, 'conducted in o rder .'to c a u s i n g :the'.'illne.ss. ■ As test - i / ;7« s a ; objects, lVl60 -4- I the ¡rabbit/s ear.-was found ’’thé¡-Ihostï/aui’-tabie.; on which« .. t 1 . V , V V J| '•.*.*)<•* . ’.*'* !' • i* ••' ' *. ; Hoffman;, ¡Neumann,.-Braun,. •L a n d e s , ' . e b a ' l h a d -already ."worked; with;, chlorinated naphthalene’ ,: paying/induced ... .'appearances'; si-mliar to that/ of.'hvHnap :¿h.io’ racne. ;The • • ,• • * i *■ * . * • . ' • ‘ • ............. • ' • *•* ' ’■ i • * .•internal'.surface'•of one ear.-was/dài'ly-i'treated by the. ■ • ■• I*. ..■•••*•• : • '•.substance '.'suspected as -the:'cause.;,of4chloràcne. The • #• ; substance.: was dissolved in ;'pbiygi'yc,olv//The.’.-other; ear :'V ■• • .. las- control--was- treated only-/with:'the.-'sdlyen-t. (polyglycol). .. .V,;', lri\:ppsitiy-e!' ::cases; thé/ tests, i*e's.ulted":first (within ' . "2-4 -weeks ), in-‘flat -spread- inf lamination -and'.¿ays later; ’swollen follicles^:.hyperkeratosis ^ d . smailV.-cys'ts,'' ; ; H i S tolçgical findings■haye-/been-:.-Acanthus, /like wfdenfng :pf.i.the àpidemisy■adëma.ta'-ahd^c'ios.éiy developed, cell infiltrations in the .cuticle-, . ‘'-the..:enlarged follicles. - were filled 1 with' keratoid m a t e r i a l i r V p l a t e r phases .. . thèse'.-developed ,themselves'..into--eyèh''.:iargèr'::cysts . . /'As--the .a.lniost two years •long ¡research," carried on - with .more -than 1 0 0 substances .with-’the 'rabbit ear' test ■ •■•i , . ■ indicated/'one can safely- m ake stat.ènie’nfs .about' the ' '• ' -, . ' v . v :: . • chloracne-causlng■effect of/certain'Materials-. ; "' -The-first'results preSenfedhby :u'sj'Vhad been reported; ■at. the 2Î3rd-German Dermatological.-Congress-‘in Wien (Schulz-). . ■ The •rep'ort .first pointed o u t '•that -it'i's'.hot.-the .2^ 4,5--' ■ 'trichlorophenol which -is the', cause /aa/tyas.' originally •:.• .believed-/,’.because- treatment -with-.'ptire-...2 ,.■4 /-5,frfcrlchTor..ophenol . 73 25 9 171JB1 -5- r •- •(5# poiysiycqi-- solution) did •not;..Show '.ahy.'.observable • appearance's, 'op..rabbit *3 ear,’.'.but ¡.treatment-.-With ' ■■ * t.-./ -t. . ' ■ ' technical 'product': did cause/chldracre , Because the ; .■ • .s tarting; product, 1 ,2 ,4, Srtetrachipr'obenzene' spread •on'.the' rabbit 's ear has been without-e iffOct; we- h a d ’to assume that/-the. .toxicant'we'./aie1. 'searching\f or- must. be. one ,'qf-th ,byproduct^, generated b y :alkaline:•hydrolysis! ¡from ,:1 ',2 -,4> 5 -• :• 1• -■,/-., ■•■■‘• • ■.1‘ ’ ! '• ■■.‘I'.'v’;' . • ' .... •'te.trachlp.rpbenzene t o -forro^^4,5-;triehiqr.qphe.nol. ' /t.•.Because -.it:;wasn't possibl'e- -tolisolate; th e •byproducts frorn.the'.'residue,'. we looked- for,’.cpmpQurids,-.-within- reason, ■" / =•; - ■ | V 1' :V '/••'; \y\yy.'-. V.: '■ '• that •'cduid/’forni''.from the 'Saponi'fIcat'lpn.-ofi ‘tetrachloro- • benzene: .at ■,i80°C..' At first,1' t h e r e w a s .made..'available . to us- some ^chlorinated products-.Of;-diphenyl, e t h e r a n d "dibenze^uran. .'• • .■ '!' - ■; -■ ■ '. .'While t h e ;.'c h l o r i n a t e d 'derivatiohs.-ofI'dlphenyl ether, ■■ • ?. nonsubSt.ituted arid m o n o c h l o r i n a t e d / ' d i b e n z o f u r a n I n the ' '» • *» ,*. * • . ,, .* *• ■• ’* • , ■ • animal, t e s t - p r o v e d ineffective,' ith'e. trichl'qro :a n d . tetrachlotodibenzofuran in;-a boncenfrafee•p-f 'O..05£' already-.induced-described deformation's.'. Both omp'ounds have- strong liver, p o i s o n i n g ' c a p a c i t y . • of .these ' One dose of. . 0 :5 - to. 'i.O'.' m g . per.kg b o d y W e i g h t talpen. O r a l l y by- the-' r a b b i t d / r e s u l t e d - i n s e r l o u s :/liver ^ i n j . u r i e s B u t - so far, 732S 0 17162 no-one.c o u l d ,detect chlorihated'ldifceriz-pfurane in the . /- .byproducts .' } •" •• The ‘C l i n i c a l ;.\ - '-V; : observation: of one.'-worker, w h o ' a f t e r the; exposure-: to; tetrachlorodibenzodib^ine 'became.. ■ ;• • • '.•: • - * - • ; * : • . '• ' s e r i o u s l y dll. of ■;chloracne-,V^ointedv‘i 'to, !‘,chlorinated . . - • :• dlbehhpdl'qxlne '(diphenylehe.dipiid-ej; ;a^;::art! i m p o r t a n t • '• -causing ^agent.. • •■ v1 .As further': studies Vindicated; :v . . ‘ chlorodibenzodioxine, » ■ tetra- ' • chlorinated dibenzodioxlne; 'especially.:2 y 3 ,6 -,7 -tetra- • ' •;V : . • ; * V • ' •; . infe.c.ted;thev r a b b i t •'? ;ear with' an- unusually strong vigor Three -to,’four- times . - 0.0055? solution-' Within- 3-4 'days.-- . . • • ■’ ; •■v 1' v :v'. were' sufficient.,to cause 3 e;rious ;;swe.iiings/'als.o abnormalities.' ■ brush ing.s w i t h . p . O l ■ of fbll-i.cles, ‘accompanied- by ..hyperk-pro title.' deformations. -■ . One. oraliy-’.admlhistered dose! {'of- P.s0*>*:li0..i;.;mg/kg' body •. . • weight’.resulted'in heav-y liver-.injuries :■ j -’Most of • 'the . animals.-'treated.': as above .expired-,; within8 - 2 0 .da y s :after . '• ' i . . • .*• , • . ' f . , • , . 1 ,. • • i ' i •, .’, . ’ .. . t . .treatment. ; Autopsy found, extensive;-nd'cr.c?si,-s _and fatness of the- liver.;. '/ ' •: • ". Meanwhilej.lt was chdmicali-y, Proven.-that 2> 3 j 6/7- ' :.- -i . .. •■' v. ' • 1 " tet.rachi-orodibenzodloxlne-.'lt.seliif.qrms'-.-from', two m o l e c u l e s Na-triChlorophenate, ' '. ''.-. V splitting' dff' twp--,moiecules NaCl. -■. . . •••■ Furthermore,- we, succeeded.in isolating ;2,3,6, 7-te.tra'chlorodibenzodldxine from 'the byproducts /-.-.produced ■ by. the technical saponification:of-;.,hetrachiorobenzene to ■ trlchlorpphenol-J. .On the ground-'-of .•'thi'S'-ilnding,. we. are - ; able to ".conclude-.that this .t'etrachidr'odlbenzodl.oxlne is ; 73 26 1 lV l63 i' t : -7- , ■■ . responsible ,- if.-not entlrely;j at-least •essentially, for. the .observed -illnesses' due to chloracne. . V * , • i •In. conclusion, be reminded that .’application of pure'-2 ,4;5-trichlorpphenpl and p.entachlprophenbl on .rabbit-.' s- ears 'did not' induce' any •described ¡symptoms whatsoever.' -.¡Therefore, it .is highly probable that " the; published chloracne cases caused- by "pentachlorophenol (Header i ;B a b e r ) .--actually iwere not'-cause’ d--by "the 'compound itself)/.but likewise by tp^cic byproducts-„- ' These byproducts were in. .the submitted substance ■(penta.) because the manufactur• • .* ' i *• ing process'of. pentachlorophenol .is =similar to the process of. irichiorophehol, chlorobenzene.. . an alkaline hydrolysis ■of hexa, . ■ SUMMARY ,1 • ' ■Amongst .workers who are employed;'in the preparation of- 2,4,5^trichlprophenol and its 'transformation to 2 ,.4,5 -' . trichlorophenpxyacetic acid or Its* i .esters, -31 cases-of■ ' •. ' , _ . i •* " . . . sp-called; chloracne were seen. * • It'.‘could -be 'shown . experimentally 'by brushing -into'a rabbit’-'s--.ear, that it 1 ' , i . ' , _ -..' ’ i Is not itrlchlorpphenol i t s e l f bub a ' t o x i c , • product ■ formed b y t h e ' a l k a l i n e h y d r o l y s i s ' o f 1 , 2 , 4 , 5 , -tetrachloro'oenzene to 2 , 4 , 5 -brichl'orophenol w h i c h is- the ..cause- o f the chloracne. From the' .synthesised combinations,-which'-might come in questior • • t , 1 1*• 3 -.and'4 'times c h l o r i n a t e d dibenzofuran. and- a lso t e t r a c h l o r o b e n z o d l o x i n e p r o v e d v e r y active. 2-,'3 , 6 ,7 -tetrachloro.dibenzo- d i o x i n e was .isolated out of the b y p r o d u c t s . a n d the p o s s i b i l i t y of 1t s 'f o r m a t i o n from N a - t r i c h l o r o p h c n a t e is proved. ■ 73 26 2 1716 4 C ' r~ T(J:I. E. Getzensas^rT e c hnical S u b c o m m i t t e e NACA Her b i c i d e THE DOW C o m mittee CH EM IC A L M ID L A N D COM PANY M IC H IG A N MAIN LABORATORY REPORT SHEET ' DATE 5 M a r c h 1 9 to ch arg e. M A IN L A B . N U M B E R . YO UR NUMBER i n v e s t i g a t i o n of method:-- ^or ;he d e t e r m i n a t i o n of 2 . 4 - P in the DESCRIPTION present cT c h l o r o p h e n o l s and/or' dth'er'~Tmpurities A N A L T S E S O R TEST The problem, as p r e s e n t e d to this laboratory, was to d e v e l o p a ¡method.or m e t h o d s of a n a l y s e s for c o m m e r c i a l 2 ,4-P and 2,^, 5 - T formu jlalior.s that will d e t e r m i n e the 2 , 4 - D a n d / o r 2,4., 5-T. content ; It ¡was desired to have a m e t h o d or methods, p r e f e r a b l y one w h i c h r e q uires skill and e q u i p m e n t that are not too involved, that will d e termine o nly the r e s p e c t i v e p h e n o x y a c e t i c aci d in the event of possible a d u l t e r a t i o n , c o n t a m i n a t i o n , the use of a c h l o r i n a t e d s o l ­ vent as part of the f o r m u l a t i o n or p o s s i b l y the p r e s e n c e of o t h e r acid:-;. i The f o l l o w i n g report is b a s e d on the work done by this l a b o r a ­ t o r y , at y o u r . r e q u e s t . It is o u r hope it will h e l p towards s o l v i n g some of the p r o b l e m s m e n t i o n e d a bove ;. / T h r o u g h c o - o p e r a t i v e a c t i o n w i t h o ther m e m b e r s of. the c o m m i t t e e perhaps, a set. of m e t h o d s c a n b e worked out that will meet the needs of the. Industry'. T his report is not ar. e x h a u s t i v e study of the p r o b l e m but it is o u r ideas and., a p p r o a c h based on the a n a l y t i c a l e x p e r i e n c e we have ha d w i t h 2 ,4-0 anc 2,4,5-T formulations; One..problem, . as we see it at present, is the determination: Of the 2 ,4-1) o r 2,4,5-T, e s p e c i a l l y 2 , 4 - p in the p r e s e n c e of u n r e a c t e d c h l o r o p h e n c l s : O u r anal y t i c a l w o r k w i t h competitors' f o r m u l a t i o n s has turned up a few that c o n t a i n an e x c e s s i v e q u a n t i t y of c h l o r o pher.ols that have a p p a r e n t l y been c a l c u l a t e d as part of the total 2 . 4 - D content. The AOAC methods, 5 :ip3 and p.13^ (JAOAC, V o l ' V I I I , 1955) n o w b e i n g used, will d e t e r m i n e the total o r g a n i c acid c o n t e n t in.the case of a m i n e f o r m u l a t i o n s or the total c h l o r i n e c o n t e n t in the case of e s t e r formul a t i o n s . T h e s e totals will be c a l c u l a t e d as 2 . 4 - D cr 2 , 4 , 5 - T r e s p ectively; Th e AOAC m e t h o d s are e n t i r e l y s u i l ^ able when a good g r a d e of 2 , 4 - D or 2 , 4 , 5 - T a c i d s are u s e d to mak e the formulations. However, whe n a crude grade of acid is use d AOAC m e t h o d 5-155 falls dow n in that it shows a h i g h e r value for »Y UCMED DS 00009969 17.165 - 2 - _ 5 March thfe«v2,4-D-or 2,4,5-T content than- is actually present.' .The: re for-' thia is, that in a crude a c i d .some unreacted phehoQ.,3 2 ,:4 -f chlorophenol in the case of'2,4 t B-,. has' not. been remo v e d ;and th compound is.acidic" enough to titrate with a base and-contains high: chlorine content. . I Amine Salt.Formulations .; The.-AOAC"taethod for 2,4-D and- its s a l t s M s gi ven--below: fc information purposes. \■ 5.133.v- 2,4-BICHLOROPHENOXYACETIC. ACID" (2', 4 - D ) ' ' ( ^ W - O F F I C I A L (a) .'In preparations of free acid with-no::insoluble carrier.-«-Weigh 1 g sample into 250 ml.erlenmeyer,'’dlssol in 7 5 ml'neutral alcohol, and tltr:. with 0.1 N NaOHyHusir. 1 ml phenolphthalein, 2 .1 2 (d).; (1 ml- 1 # a l e . -thymol-, phthalein soln may be substituted, -provided this lndiaator has been used to stdze the: alkali.). .1 ml 0.1 N NaOH" = 0 .0 2 2 1 g 2 ,4--dichlorophenoxyacetlc acid. • V (b) JIn herbicides containing free acid'and lnfeolubl carrier.---Weigh sample equiv. to 1 g of the: acid into:-v 250;ml .beaker, add 25 ml normal-.NaOH'and 50 ml.-HsO/: warnr1 and- stlr:1 5 min. to dissolve, acid, and .adjust to r o o m p . temp,,-.Filter thru paper into- 250 ml separator and-wash h any lnsol.lmatter,',collecting washings .in separator.’'* Neutralize contents'of separator with lO# H 2S0 « j and 10 ' m l v'excess, and ext. with two. 75 ml-portions ether.i*.Corn-;' bine 2 ether exts.in separator,."wash f r e e 'from HaSO-^ -v with three -10 ml portions H2O/ and filter thru cotton':': pledget (previously, satd with ether) into 400 ml beaker.. •. Rinse separator with' ether, and filter rinslngs-cthru, the cottoh Into beaker. To contents of beaker add 25 ml::, H 20;-and fevi boiling, c h i p s , evap.-on steam bath until -ca 25 thl'i’ether-remains,:and then remove balance of/ether • ■ at room tempv in air current. To resldual aq. soln.: a d d '100 ml-neutral alcohol and titr . with 0.1 N NaOH*'/ as in ( a $ . ; , ‘ < (c*) Vln1herbicides containing salts of 2 ,4-dlchlorophenoxyacetlc acid.--Weigh .'sampleequiv. to ca .l g of / the free acid'and dissolve', in:-50 m l ■HaO. if lneol... carrier is present, filter thru paper and wash reaiduAt.:. Transfer clear soln to 250 ml separator, and proceedae In (b), beginning 'Neutralize contents of separator. Proposed Method for Amine Salt.' Formulations Perhaps; t h e :slmplefet method of analyzing for 2 , 4 - D acid in the presence 6 f 2,4-dlchlorophenol is:, to use the above AOACmethod a n d determine'.the end point with a different Indicator, or preferably'.by the -use of an electrometric titration.': The '" ' *• DS 00009970 -.17166 ) 5 March - 3 - 19 accorapar.lng curves (chart) show the effect cf the prese n c e of 2 , 4 -dichlorophenol w hen t i trating 2 , 4 - D c-. n t a i n i n g 2 , 4 - dichlcroiihIt can be seen the 2 ,4-D g ives a sharp break from about pH 7 ■to pH 10 w i t h a m i d - p o i n t at pH §.5The Indicators n o w used, p h e n o l p h t h a l e l n (about p H 9) or t h y m o l p h t h a i e m (about p H 10), catch this break very nicely. As the 2 ,'4-dichlorophencl content : increased the break becomes less sharp. W i t h 1 0 % of 2 , 4 - dichloro phenol a dded there is one b r e a k for the 2 , 4 - D at pH 6 to pH 7 and t h e -2 .^ - d i c h l o r c p h e n o l continues to titrate and then g ives ancthe: break at about pH 10-. 5W hat is proposed, is to titr a t e to an end point cf p H 7 p o t e n t i o m e t r i c a l l y , or use a suitable indicator, such as me t h y l red and c a l c u l a t e the pe r cent 2 , 4 - D fro m this titration'. This end point m a y give s l i g h t l y l ower values f o r 2,4-7 or. a cids c o n ­ taining no d i c h l c r o p h e n o l and s l i ghtly h i g h e r values for acids c o n t a i n i n g dichlcrophenol-. If the t i t r a t i o n were c o n t i n u e d fro m p H 7 to p H 1G one could tell w h e t h e r there was an y 2 ,4 - d i c h l o r o p h e n o l present by the nature of the break. If the break was sharp c h l o r c p h e n o l s could be a s s u m e d to be ab s e n t and the r e g u l a r end point could be used for the c a l c u l a t i o n of per cent 2,4-D. Ir. the case of a large d i f f e r e n c e in t i t r a t i o n betw e e n p H 7 and pH 10. tie pH 7 end p oint could be used w i t h the r e a l i z a t i o n that some a c c u r a c y is f o r f e i t e d for the b e n e f i t of scr e e n i n g out the c h l o r o p h e n o l s . An i n s p e c t i o n of the table g i v e n b e l o w an d the a c c o m p a n y i n g curve will i l l u s t r a t e the above points; Table Sa m p l e 2,.4-D I % 2 , 4 - D % 2,4-] % 2 ,4-D (Theory) pH at T h e o r e t i c a l end point 99-4 8, 5 9 9 -C 99'.‘7 at pH 7 at pH I Do w T e c h n i c a l ir 2.5% 2 , 4 - D i c h l o r o pher.ol a d d e d 96. ? , 7-5 96.5 100.4 h i 5.-2% 2 , 4 - D i c h l o r o phenol a d d e d 94.2 6.7 G4.5 101:9 IV 10..2% 2 , 4 - D i c h l o r o phenol added 89.3 7.0 89. 3 103:4 TI E s t e r F o r m u l a t i o n s D o e 3 the u n r e a c t e d 2 , 4 - D 0 r 2,4,5- T w hich A q u e s t i o n arises. is o ften p r e s e n t in e s t e r f o r m u l a t i o n s court towa r d s the acid e q u i v a l e n t of the ester? We at Do w have b e e n m a k i n g a separate free acid a n alyses, w hen necessary, and c o r r e c t i n g the total acid DS 00009971 17167 -■ if 5 M a rc h 195r equivalent for the free acid found. It appears that some companic are. c a l c u l a t i n g all the 2.4-D cr 2.4-,5-T present in their figures for pounds of acid equivalent pe r g a l l o n as i n d icated b y the anal> ses of their formulations.- The p r e s e n t AC AC m e t h o d - f o r ester, f o r m u lations a p p a r e n t l y justifies this.. Hpwever, the d e t e r m i n a ­ tion of free acid is a simple m a t t e r with most formulations. Propose! Me t h o d for F r e e Acid Content 1. Principle Th e free aci d present in e s t e r f o r m u lations is d e t e r m i n e d by. adding a sample of the f o r m u l a t i o n to alcohol and t i t r a t i n g the a c i d i t y with standard s c c i e m h y d r o x i d e to pH 7, 2. R e a g e n t s (a) S o d i u m hydroxide, (t) Alcohol, 95^-. 1.1 N standard Formula solution. 30 or F o r m u l a 2B, 3* Apparatus (a) pH meter. B e c k m a n L a b o r a t o r y M o d e l G, or its equivalent with a glass e l ectrode an d calomel ref e r e n c e electrode.. *»'. procedure W e i g h a 10'. 0 g ram sample of the e s t e r f o r m u l a t i o n int o a 250ml'. be a k e r and add 100 ml-, of alcohol. T i t r a t e the free acid poter.ticmetricaliy with 0.1 N sodium h y d r o x i d e to pH 75- C a l c u l a t i o n s (a ) 0._1 _H _NaOH _x_ ;0 ■ > .00 % free 2 ,^-D or •(b) ml. 0.1 JC NaC H x 0. 0 2 5 0 x 100 1 '' % free 2 ;*,5-T Discussion Chloropher.ols have als o been found by this l a b o r a t o r y in some e s t e r f o r m u l a t i o n s now :,r. the market. These formulations analysed in the o r c e r of 2 to 3% c h l o r o p h e n c l s on an e x t r a c t e d aci d basis by b o t h chemi c a l arid infra red m e t h o d s . This w ould raise the acid e q u i v a l e n t ar.aly-is of t h e 'f o r m u l a t i o n s a b o u t 1 to 1 .5# on the usual 3 -3^ or ^.C- lbs. acid oq.. p e r g a l l o n formulation.- ment An e x t r a c t i o n method is p r e s e n t e d w hich could be use d to supple the AOAC m e t h r d when the p r e s e n c e of c h l c r o p h e n o l s is suspecte DS 00009972 17168 C D 5. K a r o h :1956 5. T h i s pr o c e d u r e is based on-the e x t r a c t i o n and iso l a t i o n of the acid a f t e r the ester has been s a p o n i f i e d f o l lowed by the acird-base titration. The same comme n t s a p p l y to this tit r a t i o n as t o ‘the tit r a t i o n in part I. It is r e c o m m e n d e d to the com m i t t e e that ;the f o l l o w i n g m e t h o d should be inve s t i g a t e d f u r t h e r as it appe a r s to wor k f a i r l y well'on .m a n y f o r m u l a t i o n s but one cannot be sure that 'it would work equa l l y well on ail f o r m u l a t i o n s . ' Th e main d i f f i c u l t y a r i s e s In .trying to b reak the e m u l s i o n s formed by wett i n g age n t s -whose c o m ­ p o s i t i o n s are u n k n o w n to the analyst. Perhaps t h r o u g h ' c o - o p e r a t i v e effort this p r o b l e m can be overcome. Proposed Extraction Method for 2 , 4 - d in E s t e r F o r m u l a t i o n s 1. P r i nciple The 2 , 4 - D e 3ter p r e s e n t is sapon i f i e d with alc o h o l i c K O H solution. A f t e r e v a p o r a t i n g off the a l c o h o l 1 the solut i o n is a c i d i ­ fied and the 2 , 4 - D is e x t r a c t e d wit h m e t h y l e n e c h l oride w h i c h is e v a p o r a t e d off and the a c i d is t i t r a t e d wit h 0.1 N NaOH. 2. R e a g e n t s (a) S o d i u m hydro x i d e . (b) M e t h y l e n e (c) chloride, S u l f u r i c acid, ((d). Me thy i orange '(e)'.Methanol, Standard 0.1 N soluti-on. p r e f e r a b l y redistilled. reag e n t g r a d e , 1-4 dilution. indicator. ACS g r a d e or o t h e r s u i t a b l e alcohol. ((f) M e t h a n o l - K O H solution. D i s s o l v e 12-14 g rams of K O H in w a t e r an d a f t e r ..the s o l u t i o n has cooled'^to-room'tempe'rature d i l u t e to 100 ml. wit h m e t hanol. T h i s s o l u t i o n is s t a n d a r d i z e d 'a g a i n s t O . l N ' H C l u s i n g p h e n o l p h t h a l e l n indicator. 5. P r o cedure .'(a) W e i g h accurately, into a 125-ml. sotfhlet e x t r a c t i o n f lask a p p r o x i m a t e l y 2.5 g r a m s of sample. A d d a s u f f i c i e n t a m o u n t of m e t h a n o l - K O H s o l u t i o n to c o m p l e t e l y s a p o n i f y "the sample. (b) Add 25 ml. of m e t h a n o l an d 20 ml. of w a t e r and a few b o i l i n g chips to the solution. C o n n e c t the f lask to a w a t e r c o o l e d c o n d e n s e r an d r e f l u x on a hot p late for 1 .5 hours. '(c) R e m o v e the f l a s k f r o m the c o n d e n s e r a f t e r w a s h i n g d o w n with water a n d then cool. DS 00009973 17169 3 r 0 5 March .195 a (.i) T r a n s f e r the- s o l u t i o n to 400-ni. beaker, w a s h i n g out the e x t r a c t i o n flask with methanol. .Flac,.- the bea k e r on a steam bathand e v a p o r a t e off the methanol. .(e) Ccoi the b e a k e r and wash the w a t e r solution into a 3C 0 ml. p e a r - s h a p e d s e p a r a t o r y funnel. Make acid tc methyl crange wit h 1: H 2S 0 4 . Asa 50 ml. of r e d i s t i l l e d met h y l e n e chloride and. shake ... thoroughly. A l l o w the layers to separate. D r a w of f the met h y l e n e chloride layer, and w a s h It w i t h 25 ml. porti o n s "cf- d i s t i l l e d H 2O to remove the m i n e r a l acid. Extract the w a t e r layer twic.e more w f 50 ml. p o r tions of m e t h y l e n e chloride as above. Comb i n e the washe; m e t h y l e n e chlor i d e layers in a 400-mld beaker. : Add 25 -ml- ofi.watei and a f e w . b o i l i n g chips and e v a p o r a t e " o f f the m e t h y l e n e c h l o r i d e a steam bath. •• .■■■ ■ ci {f ) 'Cool t h e - w a t e r m i x t u r e th-_ .c-x^racted acid. (g)'Ti t r a t e w i t h and add ICO ml. 0.1 N N a O H .taking readings at pH 7 an d p H 10. 0 . 1 ' N N a O H *. 0.0221 x 100 ~ The m e t h a n o l ‘to -dissolve ~ fol l o w i n g .table r r — * 0 ^ = *.2 '4"D s h o w s sthe. results o b t a i n e d by this method. Table II fc 2 , 4 - p to pH 7 Sample l 2 ,4-p to pH 10 i . De w f o rr.u 1 a t i o n . 2,4-n =. by s p a c il ic 0tion ana j.y:;is . ( saper if i vat lor.) . 24.5 24.4 • 25-0 2. D-..W L\*rmu I-> t ion wit h 5 v 2 4-dichicrophenoi ada-sd. 2,4-P = 2 j. 9^ ( '-a leu la ted ) 24.1 24.1 30.8 30.8 Zl.21 25.3 A fter the aci d has been e x t r a c t e d and d ried the i m p u r i t i e s p r e ­ sent can alsc. ho d e t e r m i n e d by an infra-red o p e c t r o g r a p h i c anaivei: if the e q u i p m e n t is avallai i o . Ill The D e t e r m i n a t i o n of 2 , 4 - P i c h l o r o p h e n o l in F o r m u l a t i o n of 2,4-D The m e t h o d p r e s e n t e d b e l o w w o r k s v e r y wel l with, a mine salt; formulations. W i t h e s t e r f o r m u l a t i o n s some 2 , 4 - d i c h l o r o p h e n o l is indicated ever, on samp l e s that are k n o w n to c o n t a i n none.' T hus a value of up to 0.5 - 0.6;* does not a p p e a r tc be s i g n i f i c a n t in the cate of esters. The r e a s o n for the hig h values is not k n o w n as yet. Each c o n s t i t u e n t of an e s t e r f o r m u l a t i o n was d e t e r m i n e d sepa r a t e l y without s h o w i n g the p r e s e n c e of 2 ,4 - d i c h l o r o p h e n o l but the f o r m u l a t i o n m a d e f r o m t hese m a t e r i a l s showed an aBJ2arent value cf Q,z%. DS 00 0 0 9 9 7 4 K-V, t; r ••v v- .. .v <* 0 ■ 0 ■kk:'* .....-v ._-._!L _____ _____ _______ 5 .Marsh 195« Proposed Method £:■ Scope v This method is applicable to the determination of 2 f 4~dichloro.phenol in" the presence of the oils,'amines/ esters, and wetting agents used in the various formulations of 2 ,4-D acid. •.+' x * Principle -t - * The 2,4-dl'chlorophenol is 6team-distilled frdm an aqueous acid .mixture and the distillate i3 collected in a receiver containing .ar aqueous base. T h e amount bf'ipdine that will react with the 2,4-d: i-chlorophenol, producing 2 ,4-dichloro-6-iodophenol, is determined. :r 4' i - UH «. 3. Apparatus' *< /a) A standard steam-distillation-apparatus filled with a 500 ml. distillation,fTask. * . .. (b) Erlenmeyer,-flask, .500‘ml. '«/. s -- " \ 'U-. Reagents " ^ .... (a) Sulfuric .acid,'approximately 2 N solution. Pour 56 ml., of concentrated'H2 SO4 {97$) into about 800 ml.,of/water and dilute the solution to 1 1 1 te^*. -. . . * v* ,• •• T **•,v~ k • U y ■ -V +■' ■*/ -. w s T i* - >r^'- (b) Sodium carbonate* approximately 1 N s o l u t i o n . Dissolve 58 grams of anhydrous sodium carbonate in about 400 ml. of water and dilute-the solution to 500.ml, ' 1' ' ^ j 1• ^ " •sf:. 'V-J >r .Sw -RroaedureX \ ■ i .•-w,« •' - 4.’'**» “ 1--V rVrf>V./1" .:;*t ;a^ place -.ili to :3 gfarns^of saraple weighed to the .nearest" mi 1 1 1 . t. gram., in the*-5p0rml.,distillation-flask." Add 100 ml-»''of 2 N aijlfurl -itdid ,ladid attfteh the Tl*asic7to the-distillation apparatus. 1 .*>•.'a •.- rV.*k>-- / f ■TEJf-V ■*»« •-j i‘ \4. . V * 1' y ■v1 * i - r . ' / *r -• I (b) Place’:5*0 ml\ o f .1 ^ .sodium carbonate in .the 5 0 0 - m l . • ~ Erlenmey^r X l a 3 k apd use*, .the fl^sk as. ttyecJ?*ceiver on the distilla•jtion tlon apparatus. /aooa^attie. . ' •* •' . • .« ■* ’V'v Mr ;•*■ . .. < C^3 f i 5W' -* d-* -. >vin» 1. •••- . n 1. — ^ - -T; :v^'’ » ’ ’ .: DS 00009975 . ^ 1 7 l7 i V-' :: . V / • W uijgj-.*•;_ virJL-' ‘; .i*r- • •*• * , «»* • . ’I • ; -'-'Säftafgh-igöOv • ........ . - -**1 -;:‘L r'J \ ing thç distillate 'hhdàïet*.; the' tdiutfion^Efcand for.*'5. minuté^/ then, acidify the solution with, io m l ' o f £ N sulfuric acid*-.' * ¿’r. v ■ * - ■ *\ W.,-.-» , ». . ' . _ r-;, ■* . . ' ~ ‘ * > _i“ '" A: ■<- :-," .-# k (e) .Titrate the'-exces3 iodfifte' w i t h •0 .1 N- soditân thiosulfàtç/ using -stàrçh indicator solution. >*» '' j \ ... v v ^ . ; . ■v : ■ ' (f) Perform a blank titration >ae^ïdllows:'. ^jllace 5*0 $&1-. « ¿ f Q  N aodium carbonate and 15Q:'mi.. of-water in. the Érlenmey^;-flask.’ ; 7 Pipette 25.0 ml. af -.O.J, N iodine intd^tfie flask arid let -thé” solü- > v tion Starjd f.or.5 minutqs.- Theri acidify the iolupiqn wifch'iiLO of 2 N sulfuric acid-and., titrate .th^. iodine with*OM. N v sodiûm -thio­ sulfate , •using starch indicator’‘solution* -:. •. +■. . 'w * • V » ; r- . 6 .'Calculation . ~ >:•• 'i .■*■ . V *> , X ■ (.a) -'mX-. *6 .1 N sodiuft thlpefclfate'.‘tblank titration) >iV sodium thiosulfate (sample, titration) - m}. 0 . 1 )i iodine. ufc.e$ to react with the' 2 ,^-dlciUortjphenpl-. . . • •<••••• ‘.jjL-f ’ - ( *> S. Ù ^ M ? C 0 '*iz 7.- Notes ■y. : : ÎV*--' vi ' (a).. Thé. reaction beiweétì 2,4-dichÎorophèhûl .¿rid'-i'odinìi •lt.-aét''3^ Yellows': ■ * -V- Siv-.;' * ' v *■ * ,•\ *•*■"■* .i S êtvT' ■ ^7 ’.J '■f OH C ) " ‘ OH u : Cl ^«V. •XI.. . . -< . J v.'hi ■> •> r 2 . ■¥ . '*4 r» ■■ aa ■>*- .. ... •• A ^ ■■.. ~ ■■ v.a, r ...... ; cric 1 .»- -V „? *“ . *<.1 ’’ Ône mole 'Qf ftiàdijne La eaulvaléht tô l.inole^pf ?j4-dldhldr0phfhol ■• * i \ 4 *i - . .>^ :% ^ - ( b ) ;Tiite 'anal ytlcal procedure 1 * T nat, specific, for 2 ^rd^phlorii*' ^phenol. Many other, jphenfcls* vfîlJ, readt^eimiltfrly. /' ■’ V - W .* 4 ■;.* £ ’ * • ^ ' ' r * ' *V‘ ^ '*• '.■» I • rn 1 ■ ’ ’ ’I y **' »; (c):The simple .used for the- determination:- ¿hou^d.not-contàin ; over .0 , 1 5 jframs of '2 e4-dichlorcrphenol,;.-;.i . . ••». t j * ■' ■' 1.'■ . ‘ . •: " v r-,s* v fl*. ' ' /■ ■ •■ • ••' ■. >rv>»-.r . V. » .*> ^ • '8 . EitewCture flei'erence . . "V. ■ $' ■ ' L Jt . 1 \:.p- Kohn, Sus smarm, -Mohatoh. ( 1-925 7 » . 7 .*r** ■ .. - T.* \■ '•^i IV Conclusions • ,* ' ’ - v" ,-4y . . fi ?>. 4; From the preceding w o r k ;it cajn’he ^aeen thrnt the preserioe'oï dichloro^hepols In amine typa^iorraulations ^can pe,, Peadily detéetêd or, DS 00009976 \v i 0 , o ' - 9 - ■ • ; Si March 1956 analyzed to eliminate any contribution it would make towards the 2,4-D content. However, in the case of ester formulations, a small quantity of dichlorophenols, possibly up to 1# in the initial acid, might go,Ui\detected or give results whose validity could be questioned. v I t ~ appears that any gross contamination would be readily detected. The above methods are entirely chemical and should be able, to b performed by any laboratory now checking weed killers by the AOAC methods. Those laboratories to which an infra red spectrometer would be available (such as state labs with access to university facilities) have another method of analysis. Using methods I or II, the 2,4-D acid and accompanying impurities could be isolated, and an infra red spectrum of the acid would show the amount and identity of the impurities present. An infra red spectrum could also be made on the formulation and compared with a standard to detect any deviation. Some users are already doing this. V Suggestions for Further Work 1. It is felt that the method for esters presented in part II should be tried in the laboratories of the other members of the technical subcommittee. Special attention should be given to any modifications necessary in order to make the method applicable to formulations containing the various wetting agents used. 2. The method presented for phenols in part III is apparently not the approach the subcommittee wishes to take but it is presented here for information purposes and for the consideration of the sub­ committee. Some work would have to be done to refine the procedure to give better results with ester formulations. 3« It is also suggested that the methods presented be tried on 2,4,5-T formulations with the hopes that they may be applied with little or no modification. 4. Some work is being done with the infra red spectrophotom in analyzing ester formulations directly both qualitatively and quantitatively. A recent article on the subject appeared in the Ontario Research News, Vol. VII No. 2, April-June 1955 published by the Research Division, Hydro-Electric Power.Commission of Ontario, Toronto, Ontario, Canada. It was "Infra Red Analysis of ••Herbicides“ by D. C. Cordingley. The Dow Chemical Company cannot assume any liability in . connection with the use of these methods. DS 00009977 17173 •i • M T U “>7 V rr^ rrr i ..."2 ru*aicmx>H&raEitc>txii 12 I ' .' •*. * • »;..i ''•*• t C ur v f t . l , ; Tco lm lb al' 2, ^-0 ;. ■ i :1 . . ..-2 .51 2 ,^-Olciilor ¿phenol Added ■ •• '• • , •t .• ..................t • *f • 1 * p- • f - i f —"j r^ii f -- — ■' .• ' * ■ •• •. i ^ iirH "!‘ ITT ,*5'.2^’,z V A-’Di -T )lc ip o r o p h « ito l ’ASded !: > -v V / A ; .. 1- . - • ' • •’ ■ i : ? •. • • •; • N !:^CH :peK-'ifn , •- ♦ • .. 'V* • ¿ X T. * -r DS 0 0 0 09978 r*■ ■t October 29, 1962 Mr. P. W. Jarvis Kr. H. P. Wilkerson Dov Patent RKt Kixsd Alkyl Haters of P.,h-D and 2,h,$-T V« are attaching eoplaa of K. S. Weiner's lettar of October $th and D. M. Warburton's letter of .September Uth on subject. Oversimplified, The Dor Chemical Cwnpany contends Diamond Allcall Company is infringing their patents which claim mixtures of various lamer alkyl esters o f 2,1»-B and ?,U,*>-T, in limited amounts, alone and in combination vlth a hydrocarbon oil, permit lover freesing point compoaltiaag. This subject has been under running discussion between our Patent Department and Cow'a Patent Department for alnoat s year now. At this point, Keasrs. Verburton and Vainer have recommended that ve take out a license under subject patent. I personally cannot agree with their recommendations end counter-Buggest we advise Dov our chemical know-how and, indeed, practice in this area predata the issuance of their patent and heoca we are exempted. I feel Dow ehoald also bs advised, in view of this and to pressrva present good relationship, ve are willing to accept a royaltyfree license position under this patent and by so doing acknowledge to outsiders we were operating under their license. Up conclusions are based on the following observational 1. Dov first ealled this patent to our attention the latter pert of 1961, immediately following the sale of Butyl-T Ester to the U. S. Anqr Che¡deal Procurement District. The Chemical Procure­ ment bid invitation and specification clearly fall within tha realm of the Dow patent. At this time a rather complete examination of thla situation with Newark personnal indicated we not only practiced this eheedatry prior to the date of Dow's patent, but Ray Ouldl and others at that plant were willing to give dispositions to this effect. In addition, one of our lab notebooks confirmed this, unfortunately not specifically by date. A complete examination of old Koiker records was lmpossibla due to the loss of moat of those records during the i960 Newark explosion. Further an examination of Cleveland contract and purchase records did not turn up conclusive evidence which could be used to definitely establish our predating Dow's patent. Despite all of this, the key people involved express confidence of the validity of our position regardless of the absence of evidence to sake an air tight case in court. f* Dev's actions are not those of a corporation who is conplstsly confident of their own position. They Initially asked for St royalties and they later modified this to l-l/2> royalties with a forgiveness clausa prior to November 1, 1961. , Coat'd — DS 000 mbi t 1^175 \ Mr« F. W. J a rv is y" , 2 October 29 1962 Doit Patent 3« Thera is no uniforaity of opinion as to how such of our present« so veil so historical production st Newark» falls within the scope of this patent« I am fearful acceptance of Low's current l-l/2$ royalty offering would literally leers us liable for this same royalty payment on the bulk of our total production at Newark« I will be happy to discuss this subject further at your indication» and I beliora It is safe to say both Messrs« Warburton and Weiner will be happy to further expound their views. K. F. Wilkerson HPWivk enc* eci Mr« B. M. Warburton - Concord Mr. H. S. Weiner R. A« Ouldi - Newark H. R. Bvarson - Concord Hr. R« G. Richards 05 0001 I U 5 «_ m r n o r . c . n . Ir..ll r r.-t ?... ^orr; ~ c. y-:\:': ••Jr r?-i October 5/ 1962 Fk Mr. M. F. Wilkerson ÿiJî'.J! C 7; Mr. H* S. Weiner Mixed Alkyl Esters of 2,1:—D and 2,li,5-T CCT 5 un ^ ___ ‘ _ ,.t „ 1. Ihis is in reply to your requea- for corn-rents on the subject :..c.uc oi September lljth from Dick Warburton. There is no question but that the production of mixed esters of 2, h-D and— l-p,£-T made against government order #BA 30-070-CKL-l635>, NY 2-612 within Bov patents. The subsequent negotiations with Dow were for uhe ; purpose of reducing any payments to them down to an absolute minimum (preferably zero) because of selling material that fell within their patent claims. The two arguments which were used in the discussions with Bow were: 2,h a. Bow had used a questionable technique in their enthusiasm for having the government specify material which fell within Bow's patents. b. Validity of Bow's patents may be voided if liti­ gation is pursued by Low. 5% Bow originally was pressing for a royalty of of sales together v_th -n annual minimum. At the end of the discussions, Dow became willing to accept a license fee of with no annual minimum. This is a very reasonable Y^e for a specialty license. 1*5% Although we have questioned the validity of Dow's patents, Dick Warburton has stated that we do not have adequate data to assure ourselves that we could break the patents. It would be fairly expensive to search cut addi­ tional information for use in trying to break the Dow patent, assuming that this information exists. v_ For many years our Newark plant has been producing some materials which might be questionably interpreted as falling within Dow's patents. If Dow vigorously pursued analysis of some of our field materials, they could make the situation uncomfortable for usj and they might use this approach if v:s antagonize them further in the particular area in question. Based on the information we now have on hand, I would recommend that we accept the royalty fee on the complete block of Dow patents and assume that the only products which we have produced and are producing that fall within these patents has been the one specific government order in question. 1*5% The agreement that Dow offers is cancelable at anytime at our desire; thus, at anytime we feel we have enough information to break the Dow patents we can cancel our agreement. Furthermore, the agreement which Dow offers, essentially overlooks any activity in the patent area prior to November 1, 1961. This means that even if Dow should decide at any future time that our normal production over the past many years infringes their patent, they still would not request royalty payments on any material produced prior tc DS 00011466 17177 Nr. K. F. Wilke rs on -2 - Cctcber 5, 1962 November 1, 1961, Her.:ever, if we did not accept their present proposal, Dow would not be subject to this time limitation. I am assuming that Dick Warburton will comment if he disagrees with the presentation in this memo. H/ S, Weiner HSWtnk cc: Mr. B. M. Warburton 1 DS 0 0 0 1 1 1 b 1 17178 THE August 31, DOW 1962 CHEM ICAL A B B O T T COMPANY R O A D M I D L A N D . B U I L D I N G S M I C H I G A N Mr. J. 0. King Diamond Alkali Company Union Commerce 3uilaing C l e v e l a n d .14, Ohio Dear Mr. King: Russ Ashworth has requested us to furnish you wit h a "complete" analysis of 2 , U-Dichloropnenoxyacstic Acid. Our current sales specification has the following reauirements: 2, Dichlorcphenoxyacetic acid minimum Bromine absorption (calculated as 2,4-dic h l o r o p h e n o l ), maximum Pre e z ing point, minimum f“' /-N/-* 0.53 135° c We are enclosing our analytical method number 21310 covering the determination of the above items. The Assay method shown is that recommended by the Association of Official Agricultural Chemists. The bromine absorption determines unsaturates 'which are reported as 2,4-Dichloropheno The freezing point determination of course is just another method of establishing a minimum purity. While not a part of the specification, the following impurities might be present in the amounts shewn. Inorganic chlorides, calculated as NaCL, could be present up to 0.15?$. The sodium salt of 2,4-D could be present up to 0.1?$. ’Water could be a maximum of 0.1?$. Diphenoxy compounds and trichlorcpnenoxyacetic acid if present will be found as traces. The items covered in this paragraph are not routinely determined on each lot and are not a part of the specification. We hope the above information will answer the questions which you have had. Very truly yours, W. J. McCoy Resale Products Section Agricultural Chemicals Sales eb DS 00025788 THE DOW CHEM ICAL COMPANY MIDLAND A N A L Y T IC A L M ICHIGAN M E T H O D M arch 26, 1958 M ethod No. 21310 2, 4-DICHLOROPHENOXYACETIC ACID A . Scope This m ethod is applicable to the qu ality testin g of 2, 4-D ichloroph en oxya c e tic A cid ( 2, 4-D) . P ro ced u res are given for d eterm in in g the a s sa y , brom in e absorption , and fr e e z in g point. B. A ssa y 1. P rin cip le The total acid ity is d eterm in ed by titration with standard sod iu m hyd roxide solu tion and is rep orted as 2, 4-d ich lorophenoxyacetic acid . 2. R eagents (a) A lcohol, 95% ethyl alcoh ol (2 B ), n eu tra lized to the phenolphthalein in d icator end-point. (b) Phenolphthalein in d icator, 1% solu tion in 95% ethyl a lco h o l. (c ) Sodium hydroxide 0.1 N standard so lu tio n . Dilute 8 .0 0 gram s o f 50% sodium hydroxide solu tion with r ec e n tly b oiled d is tille d w ater to one lite r , and sta n d a rd ize against b en zo ic acid of known purity. 3. P roced ure ( a) W eigh a one-gram sa m p le into a 250-m l. E rle n m e y e r fla sk . D isso lv e in 75 m l. of n eu tral alcoh ol and titra te with 0.1 N standard so d iu m hyd roxid e, u sin g one m l. of phenolphthalein in d ica to r. (b ) O ptionally, the titra tio n m ay be follow ed with a stan d ard pH m e te r such as the B eckm an M odel H-2. A pH reading of 9 is used as the end-point. 4. C alculation ( m l. o f 0.1 N NaOH) x 0. 0221 x 100 = % 2, 4 -d ich lo ro p h en o x y a cetic'a cid . gram s of sam p le DS 00025789 1*7180 M arch 26, 1958 - 2 - Method No. 21310 C. B rom in e A bsorption 5. P rin cip le The sa m p le is tr e a ted with an e x c e s s o f b rom in e from a standard b rom ate-b rom id e so lu tio n . The amount of brom in e absorbed is ca lcu la ted to d ichlorop henol. 6. R eagents (a) B ro m a te-b ro m id e, 0.1 N so lu tio n . D is s o lv e 2 .8 gram s of reagen t grade p o ta ssiu m brom ate and 12 gram s of p o ta ssiu m b rom id e in w ater and dilute to one lit e r . (b) Sodium th io su lfa te standard 0.1 N so lu tio n . D isso lv e 25 g ra m s of sodium th io su lfa te, Na 2 S 2 0 3 • 5H20 , and 0. 5 gram of sodium carbonate in one lite r of w a te r. Standardize again st 0.1 N p o ta ssiu m iodate, a cco rd in g to the proced ure given in K olthoff and Sandell ( s e e 12). (c ) Su lfuric acid, 1: 4 so lu tio n in w ater. (d) P o ta ssiu m iod id e, 5% so lu tio n in w a ter. (e ) Starch in d ica to r so lu tio n . M ix one gram of solu b le sta r c h and five m g. of m e r cu ric iodide with a little cold w ater. Add m ore w ater to make a fluid su sp en sio n , and pour this into 500 m l. of b o ilin g , d is tille d w a te r. B oil for s e v e r a l m in utes and then cool to room te m p er a tu r e . Keep in a g la s s stop p ered b o ttle. 7. P roced u re (a) W eigh a fiv e -g r a m sa m p le and tr a n sfe r it to a 500-m l. g la s s stop p ered fla sk containing 200 m l. of w a ter. Add e x a c tly ten m l. of 0.1 N standard b rom ate-b rom id e so lu tio n , 35 m l. of 1: 4 su lfu r ic acid and sto p p er im m ed ia te ly . Shake v ig o r o u s ly for 15 seco n d s and allow to stand fo r tsn m in u tes. Add 15 m l. of 5% p o ta ssiu m iodide so lu tio n and m ix w e ll. T itra te the lib era ted iod in e with standard 0.1 N sod iu m th io su lfa te so lu tio n , adding a few m l. of sta r c h in d ica to r so lu tio n near the end-point. (b) Run a blank in the sa m e way (w ithout any s a m p le ) . Subtract the sa m p le titra tio n volum e fro m the blank titra tio n volu m e to obtain the m e a su r e o f brom ine con su m ed by the sa m p le . 8. C alculation (n et m l. of 0.1 N reagen t) x 0.00815 '--------------------------- -----a ---------------- x 100 = % 2, 4-d ich lorop h en ol. gram s of sa m p le DS 00025790 M arch 26, 1958 - 3 - M ethod No. 21310 D. F r e e z in g Point 9. P rin cip le During the c r y sta lliz a tio n of a m a te r ia l fro m its liquid s ta te , a m a x i­ mum tem p eratu re is reached which is m aintained for a period of tim e . T his tem p eratu re is co n sid ered the fr e ex in g point and is an in d ication o f the purity of the m a te r ia l. 10. Apparatus (a) T h erm o m eter, partial im m e r sio n , calib rated in 0 .2 ° C, range including 135 aC. (b) A gitator, nichrom e w ire with a 10-m m . d ia m eter c o il at the lo w e r end to en com p ass the th erm o m eter. ( c) T est tubes, 20 x 150-m m . and 38 x 200-m m . , P y rex . Support the s m a lle r tube c o n c e n tr ic a lly in the la r g e r which s e r v e s as an a ir bath. P a s s the th erm om eter into the inn er tube through a one-hole cork sto p p er which is slo tted to p erm it m ovem ent of the w ire a gitator. 11. P roced ure ( a) Into the 20 x 150-m m . test tube, place su fficien t sa m p le that the m elt w ill co v er the th erm o m eter up to the im m e r sio n m ark. (b) A fter m eltin g the sa m p le, p lace the tube in the air bath. A gitate con tin u ou sly. A fter c r y sta lliz a tio n s ta r ts , r eco rd the m axim um tem p era tu re as the fr e ez in g point of the sa m p le . E . R eferen ce 12. L itera tu re R eferen ces Kolthoff, I. M ., and Sandell, E. B. , "Textbook of Q uantitative In o r­ gan ic A n a ly sis, " Third E dition, Chapter 39, The M acm illan C om pany (1952) . ******* The a n a lytical p roced u res given h e r ein have been adapted fro m lite r a tu r e s o u r c e s or developed upon the b a s is of ex p erim en ta l data which a r e b e lie v e d to be r e lia b le . In the hands o f a qu alified an alyst they are ex p ected to y ie ld r e s u lts of su fficie n t a ccu ra cy fo r th eir intended p u rp o se s. H ow ever, The Dow C hem ical Company m akes no rep re sen ta tio n or w arranty w h a tso ev er con cern in g the p roced u res or r e su lts to be obtained and a ssu m e s no lia b ility in connection with th eir u se . U s e r s are cautioned to co n firm the su ita b ility of the m ethods by appropriate t e s t s . Anyone w ish in g to rep rod uce o r publish the m a te r ia l in w hole or in part should req u est w ritten p e r m issio n from The Dow C hem ical 1 7 C om pany. DS 00025791 ■N vaca L*TR0PH­ CLT/sb P" THE DOW CHEM ICAL COMPANY POST O PPtCC November 22, 1966 Mr. C. L. Dunn Synthetics Department Hercules Incorporated 910 Market Street Wilmington, Delaware 19899 MIOLANO, / MICHIGAN SOX 312 4««41 / Dear Chuck: Enclosed is the draft of the proposed comments on behalf of the NAC ITFPHT, which we discussed by téléphoné November 22. Although we have until December 8 to submit comments I would like ours to be mailed by Friday, December 2, to avoid any slip-up. Therefore, I will need your suggestions and those of the others receiving this letter early in the week of November 28. As discussed, we will not hold up the l e j t t e r for any dis­ cussions with FDA .and hope that our comments will provide the opening for a conference with the proper parties in FDA if we sense the need for one. I would suggest the telephone for comments, and for your convenience my telephone number is (area code 517) 636-5014. / Sincerely, - V — Lypm., Cha-i-rman " Phenoxy Herbicide Tolerances Members ITFPHT Dr. L. L. Danielson Dr. W. L. Popham J. A. Noone abc Enclosure DS 00025741 17125 - DRAFT Hearing Clerk Room 5440 Department of Health, Education and Welfare 330 Independence Avenue Washington, D. C. 20201 Dear S i r : The National Agricultural Chemicals Association Industry Task Force on Phenoxy Herbicide Tolerances representing the basic manufacturers (Chipman Chemical Co., Inc., Diamond Alkali Co., The Dow Chemical Co., Hercules Inc., Monsanto Co., Thompson Chemicals Corp., and the Thompson-Hayward Chemical Co.) of 2,4-D (2,4-dichlorophenoxyacetic acid) herbicides; submits the following comments concerning the proposal published in the Federal Register of November 8 , 1966, pages 14359-14360, to establish tolerances of 2,4-D in or on certain grains by amending 21 CFR 121.142 and adding new sections under part 121 . _____ . 1. The industry manufacturers and markets 2,4-D products registered by the USDA for uses on the grains listed which are not covered by the salt or ester forms given in the proposal. 2. In §121.142 as proposed there are certain items which we do not understand, or believe to be typographical errors : . In paragraph (b) (2) We are not familiar with the usage of "n" in the nomenclature: diamine. n-oleyl- 1 ,3-propylene The "normal" configuration of oleyl is usually considered inherent. In paragraph (b)(3) the proposed list includes "isopropyl methyl octyl (isooctyl)," which would appear to lack necessary punctuation. We presume it should read "isopropyl, methyl, octyl (isooctyl),". DS 00025742 171ft -2In paragraph (b)(d) we do not recognize the name "polyethylene glycol butyl ether” as an ester moiety of 2,4-D now being marketed. However, propylene glycol butyl ether esters are registered and marketed. Clarification of this apparent discrepancy is needed. In paragraph (b)(3) "tetrahydropropyl" as an ester moiety is unknown to us. However, the tetrahydro- 'furfuryl ester is one which has been registered and marketed. Clarification of this apparent discrepancy is needed. 3. Many of the salt and ester forms of 2,4-D now manu­ factured, registered, and marketed for use on grain are not covered by the salt and ester forms given in the proposal. Furthermore, it is likely that future avail­ ability and manufacturing economics will dictate the desirability of using ester and salt moieties other than those listed in the proposal. In order to overcome these two deficiencies in the present proposal, and to avoid a hardship on the industry with respect to their particular needs for latitude in the selection of economic 2,4-D forms for manufacture, and the hardship which could be worked on the farmer due to the lack of suitable and economic 2,4-D forms, we propose that the salt and ester forms permitted by the order follow a more generic description as follows: DS 00025743 17187 y w -3- § 121.142 -----i'-U\ ______ (1 ) The inorganic salts, such as calcium, lithium, magnesium, potassium, and sodium. (2 ) Organic amine salts, such as alkyl, alkylene, or alkanol amine salts. (3) Organic esters, such as alkyl or alkoxyalkyl esters, or other esters as tetrahydrofurfuryl. The other, but much less preferred, alternative would be to amend the list of salts and ester forms according to comments received from individual companies for inclusion of the 2,4-D forms they manufacture and market. In view of the wide differences in the specific salts and esters listed in the proposal as published we can only assume that it was the intent of the proposal to provide for equal treatment of all of the 2,4-D forms now being used. We favor such an objective, but as pointed out the list falls short of including all of the 2,4-D forms now marketed and those that may be marketed in the future. We respectfully request that our proposals as set forth above be considered as means to accomplish the objective as we have interpreted it. Sincerely, G. E. Lynn, Chairman DS 00025744 17188 IJ> I • \ * 1 1 o r i ; tny V '* ' .^ ! CL COi:\’!>1*0SPIACI. 3/25/65 ji\O.V. JOHN CORT, JR. / E. L. CHANDLER CHLOROACNE - DOW MEETING cc: F. R. Kennedy - Mgr., Newark plant J. 0. King M. F. Wilkerson 2k, 2,k,$ On March Mike Kennedy and I met with two people from Hooker Chemical Co., two from Hercules, and with the Dow group to discuss the toxicological impurities associated with trichlorophenol and related materials. Dr. Rowe of Dow Chemical opened the meeting by stating that they had operated for 25 years without trouble; but, in the last year, they had 60 to 70 cases of chloroacne. Ten of these were moderate, and five to ten were extremely severe. Their approach was a qualitative one at first. They wanted to find the causative material, learn how to identify it, and try to avoid continual trouble with the unknown. They tested various materials from tar fractions and from, as they put it, "gunk", etc. They found that there are a number of suspect materials, probably 26 or 27; but the major "bad actor" that they identified and which seemed to consistently cause the problem was 2,3*7,8-Tetrachlorodibenzo p-Dioxin (symmetrical). C l - VI ox f o Cl This incidentally was previously listed as a suspect material by Cy Perkins of our company. A similar material is the unsymmetrical 1,3,7,8-TCDBD, also sometimes listed as 2,3,7,9-TCDBD. The Dow people used the white glove approach and found this contaminant on tool handles, benches, instruments, and other fomites. In test animals, they could consistently cause the symptoms to appear. Dr. Holder of Dow, one of their medical doctors, had excellent color slides of the various patients. The difficulty starts with multiple blackheads resulting in closed cystic structures which make the patient look like he needs to wash his face. The disease develops slowly, not appearing until six weeks to two months after mild exposure but appearing in five to seven days with very heavy exposure. One bench chemist has been under treatment for two years and his face is starting to show signs of clearing. Dr. Holder says that he believes this man's problems will be solved in another six months. Dr. Sadek, who does their micro­ scopic work in connection with their animal laboratory, showed photo micrographs of the cysts as they formed in the ears of rabbits. The cysts correlated with those found on the faces of the men. •1- ns 0 0 0 1 2 b I 5 171SS ■ Chloroacne - Dow Meeting (ELC) -2 March 25, 1965 Basically, there is a carotinoid deposit in the hair follicles and oil ducts in the face. These eventually go from the blackhead stage to form a closed, heavy core deposit. The chemical cannot be found in the facial tissues or in the cores, but the problem still persists after exposure* The best description of the acute stage is that the facial tissues resemble the exaggerated surfaoe texture of an orange, rather glazed and marbly with the enclosed hard core deposits. A secondary symptom, which does not correlate directly with the amount of facial dermatitis, is a fatigue reaction where the employee is completely listless, tired out, and nearly incapacitated. A complete biopsy of liver, kidney, etc., shows no degeneration of major organs. A complete clinical examination of the patients showed no measurable affect on heart, blood pressure, respiration rate, blood sugar, etc. The fatigued patients seemed to be helped by heavy doses of vitamins, perhaps related in some way to the carotene metabolism of the body (involving vitamin A, eto.) An oral dose of 17 micrograms immediately killed the test animals. The Dow people did not lower this dosage to obtain an LD^q but decided that, when they can detect this compound, it should not be in the product. They found that, after exposure to the material, washing within 15 minutes did not help a great deal, but did slow own the speed at which the symptoms appeared. Washing after one hour was of absolutely no help whatsoever in reducing total dermatitis or speed of appearance of the re£Ction. Moderate scrubbing with detergent does not remove this material. Extremely hard scrubbing can accomplish the task or the use of solvents, such as 1,1,1-trirhloroethene. t Dow has developed a new analytical method in which they have confidence in their sensitivity to 1 ppm. They can only state in levels below this that some may be present below the 1 ppm. They stated that they have not used micro-colorimetric methods, fnd the electron capture tests that they ran made only a very slight improvemert in sensitivity with this compound. Their analytical chemist stated that the electron cell saturates because of the presence of other materials in high concentration compared to the dioxin. This material has some strange properties. It has a fairly high vapor pressure but nevertheless is quite persistent as a contaminant. It can be separated from benzene by boiling if it is not carried down to dryness. The Dow people are extremely careful in all of their work with this compound. They use PVC throw-away gloves, and all samples are burned in a special furnace which operates at 800°F. These samples are sealed before going to the burner. They use bioassay methods on rabbits for qualitative checking only. The Dow people state that they intend to set a limit of zero with sensitivity of plus or minus 1 ppm on this material. They have analyzed materials from other companies, including our company, and have found amounts as high as 10 ppm in 2,h,5-T acid and 20 to ppm in phenates. ^0 They have made a single application to the ears of test rabbits and found that 20 p^m will not give folliculitis. Forty ppm does give a slight effect, and 100 ppm ir severe. They have made repeat applications of from 10 to 100 ppb, and 25 of there treatments do not cause a response; however, 1000 ppb (l ppm) gives a slight rerponse with nine applications and a severe reaction with 11 applications. They conclude, therefore, that 1 ppm with repeat exposure can create a real problem. 1719D Dc-.-'s people outlined a method for extracting and running samples on 2.!,-5-T; ,’,1;,5-TP; and phenols, it involves a chloroform extraction, followed by • Ch^L.roacne - Dow Meeting Karch 25, 1965 ■3- a caustic wash, and a reduction by boiling to one-tenth the volume before putting it in the chromatograph. They have given the gas-liquid chromatography method to us, along with analytical-grade dioxin material. Mike Kennedy has these materials and intends to pursue the laboratory work necessary to ascertain where and how much, if any, of this dioxin appears in our 2,Ii,5-T process, The purpose of this meeting was obviously designed to help us solve this problem before outsiders confuse the issue and cause us no end of grief. Dow is sending the test results on our material to us, incidentally; and this will further check our technique, etc. Sincerely, ¿O// E. L. Chandler ELCseen OS 0 0 0 I 2 b 1 1 171 S I ». UO T-i 3 .//- ¿ B - / CABLE ADORES« OOWCHEMCO RANCH SA LK S O P F IC I N EW Y O R K C IT Y RA N F R A N C IS C O P H IL A D E L P H IA LO S A N G ELES W A S H IN G T O N S A IN T L O U IS CLEV ELA N D H O U ST O N C H IC A G O SEA TTLE D E T R O IT BO STON T h e D o w C h e m ic a l C o m p a n y MIDLAND « MICHIGAN December 15, 1949 -a ci Dr. V. A. Drill Department of Pharmacology and Therapeutics Wayne University College o f ;Medicine 1512 St. Antoine Street Detroit 26 , Michigan . . ■e o> sO Nl vO NO h ro C3 Dear Dr. Drill: We are sending to you under separate cover, samples of 2,4-D (2,4-dichlorophenoxyacetic acid) and 2,4,5-T (2,4,5-trichlorophenoxyacetlc acid) for use in the toxicological studies on dogs. The sample of 2,4-D being sent is regular production material assaying 98 .5 jf and having a freezing point of 1 3 2 *8 *0 . m -»•— V . .The sample of 2,4,5-T being sent is also regular production . material assaying 100^ and having a freezing point of 148.8*C. Both of these materials are being supplied to you in the acid form. Both are fairly soluble in olive oil and both can easily ■ •be put in aqueous solution with caustic. I believe you will find that a slight excess of caustic is required to put these materials in ■ c solution and that onoe in solution, a large part of the excess alkali can be neutralized. Hence, for a 5.0# aqueous solution of the sodium salt of 2,4-D, the pH after solution 13 effected, can be adjusted down to 7.2 with HC1; with 2,4,5-T the final pH of a 1.0^ aqueous solution can probably be in the neighborhood of 10 . When 2,4-D or 2,4,5-T is used as an herbicide, the con­ centration usually ranges from O.l# to 0.2,4. The active material may be applied in any one of a number of forms depending upon the particular requirements of the Job. The most common forms are the sodium salt, alk&nol amine salts, and esters. Almost all the toxicological work so far reported deals with 2,4-D administered either as the free acid in oil or as the sodium salt in aqueous solution at a pH of 7.2. We have conducted a fair amount of toxicological work on the other forms of 2,4-D and also on 2,4,5-T in its various forms. We have observed that the form of the material makes little difference to warm blooded animals and that, acutely, there is not much difference between 2,4-D and 2,4,5-T. Paga 2 Dr. V. A. Drill December 15» 1949 The toxicity picture as we have it is given in the following tabulations! ' Animal Toxicity of 2,4-D when administered in Single Doses. Route Source Approx. LD^Q (g ./ k g .) O O Rat Rat Oral Oral Mouse Oral Mouse Guinea Pig Sub-Cut. Chicks Oral Oral Lit. Na Salt Dow- Incomplete Na Salt Acid Isopropyl esterB Lit. Na Salt Dow - Incomplete Acid Lit. Na Salt 0.666 Lit. 1.000 Na Salt Dow - Incomplete Na Salt Acid Lit. Na Salt Dow - Just started 0.70 0 .5 - 0 .6 0.5 - 0.7 0.375 -nI 07 >—* fo ca C7 0.3 - 0.5 0 .2Ô 0 0.5 - 0.7 0.5 - 0.7 0.38 - 0.76 Toxicity of 2,4-D when administered in Repeated Doses. Animal Route Source Notes Dogs Sub Cut or I.V. Lit. Na Salt 0.200 g.Ag./day-death in 2 da 0.100 g./kg./day death in 2-4 days 0.050 g./kg./day death in 3 days 0.025 g.As- / d a y marked affects Guinea Pigs Orally (/) Lit. Rats Orally in diet Lit. Dow Mice I.P. Lit. Na Salt 0.100 g . A s . / a a y 10 times in 12 day was tolerated 0 .1 £ tolerated 0 .1 j£ -caused very slight effects 0 .03% clear No marked hlatopatholftglcal findings No neoplastic growths Reproduction O.&. , . 17 ' tif,. Page 2 Dr. V. A. Drill Deoember 1 5 » 1949 Toxicity of 2,4-D when administered in Repeated Doses. - Cont'd. Source Notes Animal Route Chicks Orally Lit. O.O 28 g . A s * 3 times/week for 4 weeks - O.K. 0.280 g . A s * 3 t i m e s A e ® k for 4 weeks - growth depression Orally in Diet Dow 0.l£ for 1 week - O.K. 0.2jf for 1 week - O.K. except for slightly depressed growth rate. « Toxicity of 2#4,5-T When Administered in Single Posea Orally ÎO (This Information is from our data and is not complete - We are finishing it.) Animal CO c: Notes Rat LD 50 for the acid lies between 0 .5 -1 .0 g./kg LD 50 ?or the isopropyl ester lies between Mouse Guinea Pig LD 50 for the acid lies between 0 .2-0*7 g . A s LD50 for the acid lies between 0.2-1.0 g./kg for both the acid and Na salt Work Just begun 0 .5 Chick - 1 . 0 g.As* Neither 2#4-D nor 2,4,5-T are more than vary mild skin irritants even in concentrated form. In diluted form ready for use, they present no health hazard. Studies conducted upon guinea pigs by Hill and Carlisle on the inhalation of 2,4-dichlorophenoxy acetic acid dust, either wet or dry, but of unknown particle 3 l z e , indicate that the dust is not likely to cause systemic intoxication. This has been born out by our own e x ­ perience with men handling the dust. The dust, however, is capable of causing irritation of the nose if the concentration in the breathing zona becomes sufficiently high. The following references may be helpful If you wish to consult the literature for a more detailed description of procedures, etc.s .Y .» m, .« ‘ Dr. V. A. Drill Page 4 December 15# 1949 1. Toxicity of 2,4-Dichlorophenoxy Acetic Acid for Experimental Animals. Edwin V. Hill and Harold Carlisle (Camp Detrick* Frederick, MD.) J. Ind. Hyg. Toxicol. 29, 85-95 (1947) C.A. 41: 5217a (May 20, 1947) 2. Tolerance of Farm Animals to Feed Containing 2,4-Dichloro phenoxy acetic acid. J. V. Mitchell, R. E. Hodgson and C. F. Gaetjens (U.S. Dept, of Agr., Washington, D. C.) Animal Sci. 5, 226-32 (1946) C.A. 40 (17); 5198a (Sept. 10, 1946) 3. 2,4-D Toxicity. I. Toxicity Towards Certain Species of 4. Effects of 2,4-Dlchlorophenoxy Acetic Acid on Experimental Animals. Nancy L. R. Bucher (Harvard University) Proc. Soc. Exptl. Biol. Med. 6 3 , 204-5(1946) ,.C.A. 41: 808 (1947) DOW 7 5 1 2 9 V Pish. Jos. W. E. Harrisson and Edward W. Rees (La Wall and Harrisson, Research Consultants, Philadelphia, Pa.) Am. J. Pharm. 118, 422-5 (1946) C.A. 41 (2529) (1947) Data on the acute oral toxicity of both 2,4-D and 2,4,5-T for dogs is lacking. Therefore, it is suggested that the acute oral étudiés be started at your earliest opportunity so that information ’ « ill be available for choosing appropriate dosage levels for the 90 day feeding tests. In the single dose experiments we suggest that a notation be made regarding any symptoms exhibited at the various dosage levels, body weights for each day during 3 or 4 days immediately following administration and on alternate days during the rest of the 2 -week observation period. We do not feel that it is necessary to do any elaborate tissue studies on acutely dosed animals. We would, however, like to see animals that die and those that survive autopsled and the gross condition of the G.I. tract, liver, and kidneys noted. A few sections at critical dosage levels might also be desirable - at your discretion. 17196 Dr. V. A. Drill Page 5 December 1 5 , 19^9 The requisition for this work has been approved and I will see that an appropriate check is deposited as before. If there are any details which are not clear or If any problems arise, please contact us at once. DOW 7 5 1 2 0 8 In the 90 day feeding tests, we suggest that the material be administered with a part of the diet. Dosage levels cannot be decided upon until acute data is available. We would suggest that general ob­ servations, growth reoords, and perlodlo hematological examinations (initially, after 30 days, and after 90 days on the experiment) be con­ ducted during the experiment. At autopsy, gross and histopathologlcal studies on the liver, kidney, stomach, intestine, spleen, lung, heart, adrenal, testis or ovary, and p o s s i b ^ brain and vascular system are of importance. We believe that ne ga c1^^fliratngs at upper dosage levels make similar studies at lower dosage levels unnecessary. I regret that I did not have more time last week to spend with you. Nevertheless, I was very glad to get home early and avoid the snowstorm that settled on this area about 5*00 p.m. that evening. Please give my regards to Dr. Hays. Sincerely yours, THE DOW CHEMICAL COMPANY V. &. Rowe biochemical Research Department VKR/mg 171S7 9u 4 Before attainting to o.uestion the validity of the roo.uirc~.ent for restrict­ ing livestock from sprayed areas for seven days following application it is DOW 510645 necessary that we mako some reasonable assumption as to the amount of herbicide remaining on any edible forage in the treated area. In the special cr.se cf i right-of-way spraying this is an extremely difficult thing to do since much cf the material used is for the specific purpose of tree stump control ar.d as such does not actually come into contact with the livestocks normal forage. In a general review of the herbicidal literature the greatest application c rate found was 6.0 § per acre (B). This value, as a maximum, has also boor, cited in correspondence from The New York State Cooperative Extension Service at Ithica ( James E* Dewey to Paul C, Couldin, ‘April 8 , 1966 ) and as such scons to be a more than fair amount to assume is being sprayed on the actual foragebearing portions of the right-of-way. ¿¡¡(/a ere comoutes to 6 2 ,$mgm/so. ft. and based on the data of Grigsby and Farwell £ 19 ) t-o 890 mgm 2,li-D or 395 ngn 2,U,5-T oer nound of forage. Just why the 2,ii-D, sprayed at equivilant rates oer acre, shows uo an a greater concentration in the forage is unclear but is probably related to the grasses V.. greater absorption rate for this chemical. Grigsby and Farwells data on this point is also somewhat variable with some tests showing only half as much (oCmnc) 2 ,Ii-D remaining in the crops. Since right-of-way spraying uses a mix-cure of both 2,1;-D and 2,U,5-T, some assumption is necessary as to how the 6 ocur.ds cf stray per acre is split between the two chemicals. For the purooss of calculation ic will bo assumed here that this split is 2:1 2,lj-D to 2,!i,5**T, since this arrange­ ment will favor that compound (2,U-D) which shows up to the greatest externa in the forage. Actually, I believe the NYSiT&G literature on the subject indicatec a cr.idominar.ee of 2,h,5-T. 171S8 Based on the above assumption the amounts of chard.cal remaining Jr. ih forage arc- roughly 60Cmgm of 720 mgm/?. 2}h-'0/!r ar.d 120mgm/£ 2,1:,5-" for a total oonc.utrni: Although 2,li-D and 2,u,5-'T differ somewhat in thoir iouicclogl properties it is veil rocognizea that either may be consumed by live atocl at : of lOOngm/kgm^for extended periods without inducing any ill effects in the In order for an average ruminant (770 doseage ( which would cause him no harm ) he would likely amount of 1;8.5 ) to acquire this have to injest the rather -f of sprayed forage per day. Even were an animal actually to acquire the above coseage, cr.d '»hie ^assumes that not only does he actually consume 1:8.5 # of forage nor d-ey but t: all of it comes from the sprayed right-of-way, there is ar.nle evidence in the 9 f ’9 0 T S ' A O a animals (l^<2cl7)* literature to suggest that he could continue to do so for time -ericas greats: than 2 l/2 months (l5) before even slight evidences of damage were noticed. Obviously, long before this time period could ela-ise, the normal lose through evaporation, penetration in the soil and dilution by periodic raindal would act to reduce the concentration in the forage to the point that no car.~ whatever could possibly exist. Ihe above example should help to dispel any unfounded notions as to the toxicity of herbicides to grazing livestock and to put into proper persnecuive the obviously over-restrictive condition listed or. 2,1;-D labels. In essosir.j the forgoing remarks it should be borne in rind that the amount of herbicide chosen for the example (6-?/acre) is undoubtedly far- greater than the rare •.’hieh would probably be used for forageablc areas on the right-of-way. Ac verily mho rate of application of these chemicals is proportional to the amour.r of brash and undergrowth in the area and as such an application rate of p^’/ecre would indicate an almost comletely overgrown area with little if any available forage. (2) 171S9 In. addition to the above exannle, a perusal of the cxis cur.¿, sc_on ^— o literature discloses several points which argue against the necos? .¿y o* re­ stricting cattle from sprayed areas for seven days following application. 1. Because of the already mentioned dissipating affects of m o o_.cr.cnts on the concentration of herbicide remaining in the forage it is clear that tr.e greatest danger of livestock poisoning is of short duration- pernaps, **s only for the first week following the spraying treatment. 'While the above Q example has cite^evidence to show that even unusually hign concentrations c_ ^ O .herbicide are not harmful over extended time periods, there is also evidence to Ot * rf* indicate that livestock have enormous resi3 tar.ee to very high doseages for short term exposures. Dr. V. K. Rowe (17) for instance has run experiments which show that single doseages of $00 and 10CO mgm/kgm of Esteron Brush Killer (1:1 2,L-D: can be invested by livestock without having mortal effects, -ver. at the lower concentration this would mean that a grazing cow could accidentally drink over two gallons of the NYSS&G mixed spray without suffering any ill effects. Gbviously, the possibility of such an occurrence is extremely remote but the example does indicate that the resistance of the livestock *wC shor"w ex*“ posures is so great that even very sloppy handling of the spray materials should present no untoward danger to foraging animals. 2. Grigsby and Farvell (19) in a well documented-paper in 19$0 have roported a suco'esful experiment which should also Point out the cver-restrictivenoss of the directions on the 2,li-D label. In their tests cattle were fenced into small plots and forced to graze on land sprayed with 3«3 jl/acrc of both 2jli~D and 2,h,$-T for a period of two weeks. Despite the fact that the livestock were present when the snrays were anolied and had no alternative but to graze tho sprayed forage, they were ccr-^letely healthy at the end of the two '.:z z (3) 1 7200 period. The above reference is from the Quarterly Bulletin or the Michigan Agricultural Experiment Station and can certainly be considered tcbe unbiased. 3. Additional evidence for the low toxicity of herbicide! sprays e immediately following application can be gained from a paper by k.E. Coldsteir. and J.F. long (l6). These investigators actually sprayed 2,h-D and 2,L.,5>-? directly on livestock without causing any harmful effects. In another test cut forage was sprayed twice a day with the herbicides and then fed to the cattle without inducing any ill effects. The above exoeriment was continued for six straight weeks and still no illness was noted in the livestock. The above sit­ uation clearly represents a degree of herbicide accumulation which weald be un­ DOW 510648 likely to be obtained in a field situation even immediately following a spray­ r.d long term safeness ing treatment and argues convincingly for both the short a of 2,li-D and 2,1*,5-T. 00 AT- tvc.ilf.tle editions of Chenictl Abstracts for the yerr IvCo vo re­ searched under the headings ,:ilerbicides = in mi.T_’ .c,!, end "Jil;-: - Herbicides One reference t . s . s found (73241 H {¿.) in the Aug. iO“-* oo.) and this nas in the last issue availsble on Oct. 10, 1066. the Klingiean (b) et al paper has as yet beer, indexed. Ho reference to Similarly r.o reference as yet exists in the abstracts for the related paper by Yip ar.d ¿-.'ey (,cj -hi describes the analytical test method used by Klin gran. The paper by Klingnnn has been analysed fer incorporation into the c literature study and also has been commented on as it relc tes to the case £• hand, references (a) arc (cj are being sought. through the hern Li errry at BtSOISWOdf or residues In”. Cornell. (a) Cetsmin.-tion of 2 ,4-h t-.ssic.ues in /nine! Products. ana J.B. Boners. lbj 0.0. Cross; Eull. Environ. Contain Toxic? 1 1 ■('} 10-1-7 Hoc Residues in the Forage and in j.'rcn Cove Grr-tin-• 1nr.-_j- Treated r.-ith Zsters cf 0,4-D. sayton L. liir.grr.n, Chester 1. Gordon, George lip end H.P. Burchfield. •■•eegs Vol. 1-1, p!24- 167 1366. (c) Analysis of 1,4-1 Residues in ’’ .ill-: end Fora‘e . George lip or.d itonalc ¿2. L'ey,Jr. Weeds Vol. 14 pl£7- 1063. 172 0 2 *•**' - 48640 July 9 , 1 9 6 5 Albert M. Kligraan, M.D., Ph.D. Department of Dermatology Hospital of the University of Pennsylvania 3 6 th and Spruce Streets Philadelphia 4, Pennsylvania o Dear Dr. Kligraan: -Vi 252988 In regard to the skin response on rabbits, we nave attempted to quantitate this by applying C.i ml of test solution to one to two square Inches of the surface of the inner face of the rabbit ear. ' Vie find that when “he total dose does not ex­ ceed about 0 . 2 of a microgram of -.-he acnegen, no follicular prominence or epithelial hyperpi_:.l.a develops. When the total dose 13 about 0 . 5 bf a »urogram on this area, the response is marginal; 1 to 2 mioregrams almost always proc :es a response, and 4 to 8 alcrograma usually produce a severe response. We have net as yet been able to quantitate the dose required to cause 5 C/I- mortality from skin exposure, but we are sure it is well above the total dosages noted above. O vO PO DOW 1 I am sending you under separate cover a small amount of 2,3,7,8 -tetrachlorodibenzo-p-dioxin • This is the material which is a potent acnegen and is highly toxic. I have checked back on our figures and find that the. single dose oral DDcn rabbits is in the neighborhood of 1 0 0 ralcrograms/kilograra, and we had or.e animal die which had received a single dose of 16 micrograms/kilograra. It is safe to say, however, that doses of 0 . 5 to 1 . 0 mg/kg are always fatal, although deaths may be delayed for 10 to 2 0 days post treat­ ment. The typical clinical picture Is severe liver and kidney injury. In view of this information, it does not seem probable that the dosages shown Ln the accompanying suggested protocol for the human work would be likely to constitute any serious systemic hazard because the dose on a per kilogram basis would be far below that which produces any significant effect systeralcally ln the rabbit. I might add that the rabbit 1 far mere sensitive than the rat to this type of compound. Nevertheless, the seriousness of the consequences that might develop from testing with this type of compound require that we approach the matter in a highly conservative manner. It 17204 17203 A. M. Kllgman, M.D. 2 July 9, 1965 There is another item upon which comment should be made. I have indicated in the suggested protocol that a two week ob­ servation period should be used prior to starting the next series of experiments. This is because our experience with both animals and man indicates that there is an induction period. In a few instances, we believe an eruption in the human has developed four to six weeks post exposure. Also, we have had a few serious flare-ups which have developed within a matter of days, post exposure. I have compromised on a two-week observation period, but of course, any treated Individual should be watched for at least two months post test • DOW 1 2 5 2 9 8 9 Is with this thought In mind that I have developed the attached protocol. The number of persons per experiment is your decision; I would suggest two as a starter. When applications are repeated, I would like to have them made on consecutive days, if it is convenient to do so. Although the time required to conduct these experiments will require several months, I believe it is the safe way to proceed, using a few people at a time with careful observations on each. The observations are to be made at your discretion, but I would urge routine SGOT's and alkaline phosphatases as a minimum. You asked about materials in which this test substance is soluble. I have indicated it is quite soluble in chloro­ form and benzene and slightly soluble in alcohol. I be­ lieve that a solution in pC/ 5 0 alcohol and chloroform would be quite appropriate for your work. In rogai’d to covering the exposed area, I would suggest that when the treated area has dried that it be covered ilgatiy with a gauze simply to keep the material from being brushed away or having a person contaminate his hands or clothing Inadvertently. I hope I have answered your questions, but if you have hny others, please do not hesitate to contact me. -sincerely yours, V. K. Rowe Biochemical Research Laboratory 1701 Building VKR/Jd At t a c h . co Medical Department : Gordon, Holcer, Kramer J. E. Peterson L. bilverstein H. R. Hoyle V. K. Rowe (2) To6.¿5-66631 -7 172 " Quik Print INSTANT PRINTING & PHOTO COPYING 98 Prince Will>am Street, Saint John, N.B. E2L 283 (506) 634-8840 We can "Custom Print" Post-It™ Notes fiV JI ft ft A ft ... ask our sales rep. fordetails V%ftrmO O tr U rais<’<( a. q u a n d a ry aro u n d lli<’ m u n t r y re g a rd in g d is p o s a l. T w ou ld In* (lie lirsf. In ad m it that. we. reco n tm en datio n s m ade to me h,v statT as to w h a t we. m ig h t issue, p u h lid y , an d f have p e rs o n a lly tu rn e d them d o w n heeanse. (h e y «lo not a n s w e r the question p ro p e rly . AAV. a re . th e re fo re , h o ld in g a. n a tio n a l co n fe ren ce on th e of ~.D .t id e in w h ie h we are h a v in g people come in fro m v a rio u s segm ents C D » r in te re s t, i 11<•I u«I i u r. H .w i.n v . T do n ot see the d ilfe re n c c . I f th ere is one. do you w ant to te ll m e? A ir . I h r n w i T . A n im m in en t h a za rd «ve know is n ecessary fo r su s ­ p e n sio n . W h a t I am a s k in g is w h e th e r il is a lso su llie ie u t ? S e n a to r I l.u r r . lla v e von got that stra ig h t ? I >r. I ’ .w i . k v . I am m>| sure I u n d e rstan d the leg al d iffe re n ce . S e n a to r I I . x iit . !/•( me sec i f I can sla te it. We, are agreed that an im m in e n t h a za rd is req u ire d before von may su sp e n d . I f an im u iin e iil h a za rd is p re se n t. m il-I vm i suspend ? M r. I '.w i.n v . I lo n e to ad m it I w ould be m ore c o m fo rta b le i f I had a la w y e r s i ll i n g w ith me to a n sw e r that question because th e re m a y be a legal d is tin c tio n that I am l ot a w a re o f. S e n a to r Il.x ir r . T h e o n lv th in g the qiic.-linn raises is w h e th e r von a re re q u ire d b y the law in llie e x c n l an im m in en t h a z a rd is disclosed to snsp«Mid o r whet tie r you m e re ly m ay suspend i f th ere is an im ­ m inent h a z a rd d isclo sed . M r. I ’ .w i .k v . [ am not d e a r on that p o in t. Í w ill he honest w ith y o u . I am not c le a r on that p o in t. M r. I h r K x v r r . A n o th e r questio n y o u r statem ent, b rin g s to m ind is e x a c t ly w hat, the dili'o renro is belxveen an im m in en t h a za rd and just a p la in h a z a rd . AA'e ad ve rte d to the fact that C o n g re ss d id not define the d iffe re n ce . C a n yo u a rtic u la te the. d iffe re n c e as you see it an d ns yo u a p p ly it. in y o u r practice, in su sp e n sio n and c a n c e lla tio n ? D r . M v k k i . v . M a y I f r y an d a n s w e r to th a t as n e a r ly as I n ia v i p a ra p h ra se , th e one in th e d ic tio n a ry th a t I use,? I t seem s Unit, im m in e n t m eans so m e th in g th re a te n in g to h ap p e n im m e d ia te ly . {’0 G 8 6 6 1 MOO Now, \vp, li,ave, of course, fri ve» t In* top priority, t lie liijrli priority, ili additimi lo lite, somethin}; 111rea ten in;; lo lnippcil i niiiiolnt. I t sla Ion, "T lm Soorolnry in ay, w licn lie flmls flint suoli action Is noco.ssary to |irovont an Iniinlnont lim am i to Ilio im lilic, l>y n rilcr, susppnfi Ilio registration of an économie poison Im tnctlinloly.” I rpcnminonil tlia t tlils clarificatio n lie nfifirfi to t lie record, n esp cctfu lly suhmltted, Nun 11. rtAVI.KY, Director, Srirnrr. and Kdaralian. I ) r . R v i.im v . W e ll, let us look a t th is . A l A p r il 15 o r M a y 1. i f . fo r e xa m p le , fire , is p lan te d in (lie sprint W h e re w ou ld vou d ra w d ie lin e ? I ) r . l i i i m . v . W e ll. I jruess I w ill m il oo beyond llie w nrtl “ n o w .” Im m in en l h a z a r d m e a n s t h re a t e n in '; to hap p en im m c d iu le lv . M r. I ’ u K w r r . In the case, oT fond c ro p s , w ill it a lw a y s he the case d ia l ih e y w ill lie. eaten fi m o n th s a f t e r s p r tiy iiifr w ith 2 . 1 .5 -T ? D r . I ’ m .h i . v . N o t a lw a y s , th o u g h ,, ns I r e c a ll, (lie r is k o f food cro p s fo r w h ich there, a re re«ristered uses. 1 th in k th a t tn k in « ; in to acco u nt llie lim e o f the issu an ce o f can cel la I ion o rd e r an d the s p e c ific lis t o f final c ro p s, as f a r as T re c a ll th em , d ia l is the case. M r. I ’ u K w r r . D o cs is fo llo w th a t i f the evidence, w ere a b so lu te ly d e a r d ia l w h e n e v e r w e a p p lie d 2 .1 .5 - T to food cro p s a n il those food cro p s w ere eate n , we slood a 75 p ercent ch an ce o f a h ir d i d e fe ct o r, s a y , a 00 p e rc e n t ch a n ce o f a h ir th d e fe c t, (lin t the use on food cro p s w o u ld n o t c o n s titu te an im m in en t, h a z a rd to h e a lth and yo u w o u ld n o t he. a u th o rize d to fake, a c tio n ? D r . R .w r .r .y . I t h in k w c are. g cttin< ; h a c k to w h e re we co nclud ed th e he.nrin'rs la s t tim e . W c a re s p e c u la tin '; w ith o u t d a ta . I fin d it. v e r y d iffic u lt to d evelo p a p re c ise p e rce n tag e s ta n d a rd w ith o u t 17207 51 h a v in g sonic e o n rre lc d a ta in fro n t o f mo in o rd e r to m ake a jn d g m cn f. I>r. IlvKiii.y. M a y T g iv e yon a ta n g e n tia l a n s w e r and p o in t ag ain to a com m ent flin t D r . K a v lc y m ade w ith respect to o u r need fo r a u th o r ity to make. a te m p o ra ry cessation o f m ovem ent w hile, we d e te rm in e w h e th e r o r not an im m in e n t h a za rd w o u ld re s u lt? A n d if seems fo me fhe ease th at yon p ro vid e d w o u ld he. such a case. M r. l ’ n 'K w r r . Y o n w ou ld have a u th o rity to act? D r . I ’ v r.m .v . W e do not now have a u th o r ity in m y o p in io n — not c le a r a u th o r ity — to a c t in such a ease. O b v io u s ly , th ere w o u ld come a tim e i f we. were, su re o f the. h aza rd w hen such a u th o r ity co uld he e xe rc ise d . A n d we w o u ld do w ell to w a rn , i f we co u ld w a rn , o f im p e n d in g a c tio n . D r . R w i . r . v . I th in k w h a t we are d o in g is p o in tin g up the diflie u lty in m a k in g th is k in d o f a d e cisio n . M r. Mi c k w i t . F th in k it. c e r t a in ly does point, o ut th e d iffic u lty . T f im m in en t h a za rd is to he dc.lincd in te rm s o f m o n th s, o r less th an m o n ilis . and i f due process m a y ta k e as m uch as *2 o r •> y e a rs , then c le a r ly , i f im m in e n t h a za rd is so defined, you do n ot have, adequate a u th o r ity now to p ro tect the p u b lic h ea lth . D r. liv K iu .v . AYe h c lic v e we need a d d itio n a l a u t h o r it y . We. said that e a r lie r . M r. K u k w i t . The. D a y s memo w h ic h M r. W e ll fo rd re fe rre d to p re scrib e s c a n c e lla tio n in the. ease o f a reasonable doubt-'as to s a fe ty . Do yo n b elieve th ere is no reasonable doubt in the use oT 2,-1,fi- T on past m e la n d s ? D r . I 'w i .r .V . T h e w ord ” iv a s iiiia h le " here, o f co urse, is siih ie e l to in te rp re ta tio n . A n d o u r in te rp re ta tio n is that th ere is not snllicient. e vid en ce to h a te reasonable do iihl in reg ard to range and p asturelan d : that is r ie h t. .Mr. K ic k w i t . Is th ere not a reasoiiahle douhf ahont the d e g ra d ­ a b ilit y o f d io x in ? C an yo u say that it lias been proved beyond a reasoiiahle, douhf that d io x in is d e g ra d a b le ? D r . F’ v k k i .v . F>i \ K a v le y review ed the state o f o u r k n o w le d g e in the fo rm a l sta tem e n t. Aon w ill re ca ll that o u r k n o w le d g e at. the present tim e sta le d that p h o to ly sis o ccurred ra th e r q u ic k ly in s o lu ­ tion exposed fo s u n lig h t. O ne m ay ra tio n a liz e , hut. one does not. k n o w , th at the le a f s u rfa c e a llo w s p h o to lv sis to ta ke p lace . I n the so il s u r fa c e a p p a r c n llv d io x in is so hound that d e stru c tio n «Foes not la k e p la ce . N e ith e r does it m ove. A m i. th e re fo re , hound to fho s u r fa c e , tin* h a z a rd is not im m e d iate. T h i s is as f a r as o u r knowledge) goes. A n d we are. se e k in g , as you w e ll k n o w , to o b tain kn o w le d g e as q u ic k ly an d as th o ro u g h ly as we can in th is v e ry d illie u ll. a re a . .Air. K i c k w i t . T arn not su re 1 h eard you c o rre c tly so let me s u m ­ m a rize w hat I th in k yo u s a id . In s o lu tio n , w hen sub jected to a s u n la m p , d io x in w ill degrade ra th e r q u ic k ly , lm t when hound to s o il, w hen put. on s o il, even u n d e r a s u n la m p it w ill not deg rad e r a p id ly . D r . B v r n r .v . T h a t, is o u r in fo rm a tio n c u r r e n t ly ; y e s , s ir . M r. K i c k w i t . A n d as to g ra s s , w h en yo u p u t i t on g ra s s , we h a v e no d e te rm in a tio n as y e t? D r . B v r.rn / r. AA"c h ave no direct, d e te rm in a tio n ; n o , s ir . S 0 E S 6 G rP " M r. H n n w r r . in ease, cun we sa y it lia s been proved l«*y»n»r:i> i n r*». o x I s t M its* l o its tllrfrhMl Dr. I '. 1 i i v. Vi-i. That i~ <1itli-r<-111 iban the w ay von staled it¡mi a f. mi mu c ago. Mr. I'. 11 i, « n . Il h i I read "a lea oiiahlc iloiibl c \M - as I o sii fel v” as meaning when grouped with ill" a--nmplion that the hnrdeli of prool ¡>, on |he lua mi fact u n r . which yon have staled is till* case, that the maim fact nrer must prove licvnml a I'ciroimdilr doubt that there is saTely. lie must elim m ale that doubt. I f be does not elim i­ nate il. we have a reasonable d"tib|, and .-ann-lial ion should ensue. Dr. H a v i .k v . \ \ e. have, to come back to the slalcm enl 111:it we liavc Mot. found a basis for reasonable, doubt (bat (lie product as il is now registered and used is unsafe. M r. Jtir.ic w iT . W h ic h lea d s yo u to the c o n clu sio n that vm i h ave n o t lo im d a b asis fo r reasonable, doubt th at d io x in on p a s lu n T .m d is not d e g ra d a b le ? D r . B v i-m .v . W e ll, th a t DOlirJusion is hm | him * In w liir li I »mTiI be le<| lieeause. in the, p ro cess o f d e te rm in in g w h e th e r o r not d io x in s e x is t and in w in d , level th e y e x is t. Y o u re c a ll that on the T ib o f A p r i l , w h ic h e v e r it. w a s, w hen wo w ere h ere, we entered in to the reco rd first e o n firm d e x a m in a tio n o f c u rre n t, le v e ls oT d io x in s in li.l..r>-T w h ic h w e re on the. w h o le quite, lo w . T h o s e are a m a tte r o f re co rd . S o we h a v e to fa k e in to acco u n t first, w h a t a re (lie fa c ts. A n d w e m u st. I b e lie v e , d e te rm in e th e fa c ts w ith respect, to w h e th e r o r not. an d lo w h a t e x te n t d io x in is p re se n t. 172CB r,:j . 111 Mi.1 ,i . jMimitdiv« to no into it, any lu riu cr, bill I avoiiId like fo say tlnil if yon Iiatl no reasonable doubt 11s to dioxin’s degradability, wl»v n it you running these tests? I>r. Itvr.iu.Y. I would not go beyond Mu; furls. Wind, wo reported is Iliat in !Ui hours on tiro soil surface, avc found no evidence as to tlic degradability ¡n sunlight. .Mr. H ii kavit . And yon have no ca ¡donee as to tlie degradability of dioxin an g ra ss? I >r. Itvr.in.Y. 'I’ltal. is correct. .Mr. itii'i\wcr. And you have, no evidence as to the. dcgvadability of dioxin in cows, in cow tissue and in human tissue if humans should invest, produels which are the produce of those c.oavs? Mr. H a y i .k y . I would hesitate, to say that we have to hare reason­ able doubt about a product before we make a scientific im piiry in regard to (lie phenomenon involved. I would hesitate to say that. Mr. lluuovrr. I withdraw that. I tut l will not withdraw my conrlusioii that you have not proved In me beyond a reasonable doubt that I here is no bazard. Mr. Ha y i .k y . That is a judgment. Mr. Ihi'Kw iT. Applying; this same form of approach to -1). did mil the I >ii ii let ies Import - a v that 2. i I t wa- put ent iall v da ilife mi is { And is there any ditl'erenee between ti e term-; potentially dangcroii.s and reasonable dinilil a ; to sa fel v Mr. Mvkim. v . The fnllli.ll lr>o|d cm C lih -. 1 hrlii'Ar. a »I ii•-•-( nunte from tlie report whi> li rel’i-rred to is ic c e-ti-r.- of J. I M a m i al«o referred to lb te-a litters .->11•ji-»-fi-i| |o I 11. pi-r in n iie b no inerease of a bn urn la I Tel n s-s pi r lit ic r >■'ill i I. .Mr. It M l , ivrr. A ll' tlic.-e lin er n-ed in ptudm l- euivenllv mi the market { I )r. H y k iii .y . -T. In light of this evidence, and in light of tlie. possibility that there may be dioxin in J .l- I ) it Avould appear to me th a t the rec|uisife. reasonable doubt exists. l ) r . B v k k i .v . W e .ll. s i r , I hope and l (ru s t Huit. you \vm ask h h .^ qu estio n s when tlie ] I FAY w itn e ss is b efore yo u to m o rro w . Am i in the m eantim e, if. is o b vio u s. s i r , tlm t. we lu iv e not. (lie b a sis fo r re a so n ­ able (loiil)f, sttflicicn f tinion the c a n c e lla tio n o f reg iste red uses o f l i . I- D . M r. r .m is w r r . W liie li m enus Unit, yo u lu n e not. found :i reasonable (loulit. as lo t lie sa Tety o f _ M - D ill eurrent. uses. | ) r . K v r.in .v . Y e s . M r. I ’.K K W ir. Does (lie evid en ce I cited create a n y douhl w h a ts o ­ e ve r in y o u r m ind f D r. R v is u .v . S i r , I lu n e review e d I lie evidence most r a r e I w ily . T h e I Jep arl ment. lia s not found / siillicie n t b asis fo r e stab lish m e n t o f a reasonable d o n ili w a r r a n t in g the. ca n ce lla i ion o f ‘J .- l- D . A n d I c o n c u r in th at p o sitio n . .Mr. Hick wit . O u r lir s l w itn e s s th is m o rn in g . M r. W r l l f o r d . sucrg e slcd that actio n to lim it th e use o f 2 . 1.Ò-T w ould be in c o m |d e le w ith o u t s im ila r a c tio n on S i l v e x , w h ic h is clo se ly related lo '-?.l.a-T . M r. W e ll fo rd 's reasonin'.'' w as th a t both p e sticid e s lu n e g .l.ó - lr ic h lo ro p h e iio l as an in te rm e d ia te product am i that d io x in s are fo rm ed in p ro d u c in g th is in te rm e d ia te . I am in fo rm e d th a t D r. V e r r e t l's w o rk at F D A h as sh o w n S ilv e x to lie h ig h ly te ra to g e n ic to c h ic k s . Ilo w w ou ld yo u a n s w e r M r. M e llfo rd 's a rg u m e n t? D r . H v v .m .r. A g a in , r e fe r r in g to 11 F A Y the q u estio n , flu* p r e ­ lim in a r e in fo rm a tio n that we lo n e w h ich is lim ite d . I b e lie v e , to a s in g le eonlpjefe a ssa i' w ith -oon* c o n h n ir.il mu ' i f that a ssa y an d verb al re p o rts o f o th e r e x a m in a tio n - on :’.I..'i T. that c u rre n t m a n u ­ fa c tu re is assum ed I n c o n ta m h -- Ilian ) ppm of let rncldorndih'ctiv.opara d io x in . f I n o . ' t a d to tic c .r r / 'i.’ 1 in m i a u - w r r hecau-c the e vid e n ce upon w h- h ■' ■ . d I....:- . .11. I .C i :!•. I o\ (•> v. a • it I re fe r. I sa id ‘J . l.ó - T . I am Soria . I ii. ioi < i■. i \ ■Mr. Hn m u i . Hot lie .n o h tin- n idem e is s m a ll, von re g a rd ¡1 ns proo I ).o i . m>1 a Ira -on.al ile doni it f D r . I ’« v iu i.v . Heyond a iva -n n a b le dn iih l that w h a t, s i f t M r. Hu ixWi r. A s to I lie sa let v o f S ilv e x . I ) r . H v r.m .v . I have -a id th ere is su llicie n l evidence, in in v o p in io n at- p resent a v a ila b le to e sta b lish a reasonab le doubt, o f the s a fe ty o f (he. reg iste red uses o f S ilv e x . M r . B in c w r r . I n o tice th at S ilv e x is one o f the IS p e stic id e s t h a t von liste d to be checked fo r d io x in co n ten t. D r . l! y i:i ;f ,v . Tf. is. ind eed, ft- is one o f the Ir ig r o u p in w h ic h in m y o p in io n m ost p ro b a b ly t e tr a d io x in w ill he p resent. A n d , th e re ­ fo re . we are se e k in g to determ ine, w h e th e r o r not in fact it is p rese n t. M r. R ic k w i t . A n d w hen do yo n expeet the re su lts o f the. te sts on th is and (lie o ilie r 17 p ro d u c ts ? D r . R vv .iu .y . 1 v e ry nnieh hope that, w ith in .1 m o nths, we w il l h ave com p leted at. least th e lirs l,g o - iiv o n n d on a ll o f the IS . M r. R u t v w it . W I iv " m o n th s? D r . H vi-.ui.v. 'W h y ? M r. H ic k w i t . I a s k th is qu estio n fro m ign oran ce. - r. /!> r.m.v. I i m d c r s l u m l . It is s i (111>I \‘ :i m ailer of (lu* rare and sophist ii*:i I inn of the method. I In- time rc(|iiim l lit g<4. I in- jolt done. Mc have Ittiill, Dr. Hayley has j)(iinlc<( oui, ;m isf tl.-i ( if in l;il)ry--l s:i y huill. I fli;i that to eipiipped ;m isolai inn l:ili(ir:ilory. M V have the seienl isls. MV ¡wo, in I’.-Mi. romlv I" proceed. Tlio. lime. therefore, would l»o I lie. lime re<|uired lo do llio analyses :md verify them. Mr. liri'Kw rr. Thanl,- von vrrv imicli. S o n iilo r H a r t . ( ¡n ille m o n . (h a n k y o u . Il, h as lioon an in te re s tin g and iu fo ru u d ivo m o rn in g . ( 'o n g ra lu la l ions a g a in fo r tlio. e ffo rt that, y o u . I him s u re , p u t in to d e velo p in '!; and then p e rs u a d in g d e p artn ie n la l aeceplanre. o f (h e suggested am e n d m e n ls. I hope im p ro v e ­ ment in llia t. ltasie. la w soon w ill l»e w ritte n . 1 ) r . I ’ . w i . k v . T h a n k y o u , M r . ( 'h a irin a u . S e n a to r H art. MV. a d jo u rn , lo resum e to m o rro w a t 11 a .m . in th e -m o rn in g in th e h e a rin g room o f th e (.’o m in ittco on Com m erce, 5110. (M ’ h o re u p o n , a t 12 40 p .m .. th e h e a rin g recessed to reco nvene at 11 a .m . on T h u r s d a y , J u n e I S . !!)7 o .) ¿ 0 £ 8 ( o 04 EFFECTS OF 2,4,5-T AM) RELATED HERBICIDES ON MAN AND THE ENVIRONMENT -1----TH U RSDAY, JU N E 18, 1070 U.S. Sknatk, COMMITTK ON Ct»l MKIM!K, SuiK'OiUMITri'.K ON Enkiic.y, NaTUR.U, Rksouim-kr, ANO Till’. JOnVIIIONMKNT, W ashington, D.C. 'I'I k ! sn b co m m illc e m r.l, p u rsu an t. fo a d jo u rn m e n t, a t _11 : ¡55 a .in . in n iiiin r.110, Xe.w So o alc. Ollico. i ’m ild in g , H o n . P h i l i p A . H a r t ( c h a irm a n <>f (In- sn b co m n iit le e ) p re s id in g . I ’ re.-enl : S e n a to r J l a r l . S o iia in r I I m : t . T I io «•oniinilloo w ill lie. in o rd e r. I.i l mío a lie in p t in ap o lo g ize lo I lie. w itn e sses w lio lia v c lioon incmm ■.i -ii i o n - I In llii- ; n i i ti ill o d e la y . A H ire lin g w as c a lle d y e s lc rdav n i I !-.■ ■ I »■■[loior.il ¡o l ae.' ii'.- fu r in a .in . a n il I fe ll co m p elled In | , n : ■ ( i l l . . I n ; li wo o "iild in u ia L'o 111i 11lt*-5 a lililí* m o le re s p o n sib ly :ii : . i - ¡ a • l .i- \ a - i 'o iil ' I o i - ru n n i i c / c i ci \ b ody c b e 's b u sin e ss. | M' • - I "ila v i- I ' m <1i • ilign i-bed science a d v i s o r lo I lie. I’l .■ .I• • '. I >r. I mi I '.i■ •'l” o. statement or dr. i.r.i: a . d .iRridge . science advisor to the ri:r.rim ::t and director , oitice of science and TECH­ NOLOGY : ACCOMPANIED BY DR. EDWARD J. BURGER, JR., TECHNICAL ASSISTANT h r . h r I '.i iim m .. M r. ( T ia ir m a n , I have. asl,-ed m y asso ciate , D r . C n i-yer. o f m y ollico, lo a cco m p a n y me. l i e is an .M .l). w h o has been fo llo w in g the m a ile r s re la te d fo h e a lth an d the o th e r e lle c ls o f pc.-1 io ide.'. M r. C h a irm a n . I have, te stifie d before, th is com m ittee, on A p r i l 15 on the ‘2 .1 .5 - T s u b je c t, an d I am not sure, th e re is v e r y m uch to add lo w hai I said a t th a t- tim e , h u t there, are, a fe w p o in ts T w o u ld libo lo re v ie w and e m p h a size . I re» iewed I lien so m e th in g about th e h is to r y an d d e ve lo p m e n t and value o f I he use o f th is h e rb ic id e an d I used th a t re v ie w as a te xt from w h ich to d r a w w h a t T co n sid e re d to he. some, im p o rla u l g cn cra li/ a lio n s about p e sticid e s, and Ille se are some o f (h e m a ile r s I w ou ld libo lo repeat. Eel. me begin b y p o in tin g o u t th a t 2 ,1 ,5 - T is a pesi ir id a i c h e m ic a l w h ich has been in tro d u c e d in lc n lio n a lly in to m a n ’s s u rro u n d in g s because, o f I he benefits p resu m ed (o fo llo w , it s p u rp o se w as lo se rve as an a d ju n c t to o th e r m eans o f weed and b ru sh c o n tro l in lan d a m i ( 57) 5!) w a te rw a y :m1 cel ion o f w om en o f e h ild lie a r in g age. T h u s the D e p artm e n t o i \ : •r ii ■ 1111 ore suspended the rc g i-l rat ion o f lu p in ! fo rim d a t ¡n il* o i the " 1■ 1!;iIh w fo r uses aro un d the home and o f ¡ill fo rm u la tio n s fo r use on lake . ponds an d d itch lu n iks. In a d d itio n , re sist rat ions Mere c :in c i,| | i ,d fo r uses o f n n n ru |iiid fo rm u la i ions a ro u n d the hom e am i o f a ll fo rm u la l ions fo r use on food 'Top-- intended fo r p u b lic ■■no-mopl ion. H I Ibe total amomil- of •J.l.a T ii ia| in t liis count r v fo r ¡ill p u r ­ poses it w as c s tim a lc d Ib at these rest r id in n s a p p lie d to about 20 percent--;tbe. 2lc to nll'ord the incrcMsed cost, o f develop­ ment nnd furl her development of vnlunhle new products m a y be discournped or provenled. lienee I suggested licit new w a y s of distrib ulinp I lie costs of (his work mny have to be found. Kxpendit ures of public funds ¡iiid f¡ovrrnm rnt participation in this resenndi m a y lie desiruble. I em p h a size d lic it ¡it a n v p o in t in lim e , we find it d illic u lt to per. co m p le te in fo rn c il ion about the I rue h a za rd s o f m iiv p e slic id e o r ¡m y o ilie r (diem ieul su b sliin ce . T h a t is, reseu” eh in th is nrc.u ( ms in m iiv o th e r) I ims no finite, end p o in ts. Il m ny In k c lonp e x p e rim e n ts w ith m11 k in d s o f leve ls nnd ¡ill k in d s o f o iro in .isln n ce s to im ik e n n v such a sse rtio n nnd one run n e v e r be sure. w ind, new reseurcli re s u lts w ill tu rn o u t. A s one p e rfo rm s m ore rescai-cli to in v e s tip n lc v u rio u s h yp o th e se s, one in e v it a b ly raises a d d ilm n a l i|iie stio n s— ns w ell ¡is u n sw e rs. I t fo llo w s fro m th is I I im I n n v re g u la to ry system fo r p i'stic id e s m ust be nlile. to neeomm odnfe new ¡ind unexpected in fo rn c itio n . I p o in te d o u t tlu it o u r p rese n t arran g e m e n t fo r re g u la tio n is not s n llic ie n tly fle xib le to reflect n ew in fo rn c il ion ms it encniM les fro m re se llre h . A p n in , these p o in ts w ere c Icmi I v illu s l r.-ilcd h v the ense o f 2.1.5-T. W in d I sa id in A p r il w us (h u t there, does not e x is t n. n ie c lc m ism w h e re b y the ( ¡o vcriim en t. m a y exercise, p rm h s it nnd u n e rp iiv n e iilly e ll’e c tiv e re stra in t. te m p o ra rily on the. re ce ip t o f new , u nexp ected in ­ fo rm a tio n nnd p o ssib ly p r e lim in a r y re s u lts an d w h ile a w a it in g m ore d e fin itiv e , co n clu sio n s. Til m a n y w a y s the F e d e ra l G o v e rn m e n t d id act, w ith d is p a tc h in flic case o f 2 . l ,r>-T. A f t e r th e O cto b e r lit) announcem ent, about, r e s t r ic ­ tio n s im posed on 2 ,t..ri- T a d d itio n a l research stu d ie s w ore Iiopun in a n u m b e r o f apencies. T h e s e stu d ie s w ere in itia te d both b v th e G o v e rn m e n t an d b y in d u s tr y . T h e aitn in e v e ry case w as to c o n firm S 0 G 8 6 6 rM 9Sl 17211 58 (¡0 m ohili/.ed on I lie s|>nr o f Mi<’. m om ent fo r - J .l.fi- T h ave been a cco m ­ p lish e d on ;t m ore s y s te m a lic b asis ¡m il x v illu m t the s p irit, o f !i c r is is n ecessary to u rge them on { F u r t h e r . -T. N o n -. 1 m id o ttie rs h ave o illin e d tin ' resenreli xvnrk on ‘2 ,1 ,5 - T nnd I lim e term ed it re h d ivo .lv s o p liis lic n lc d . V e t 1 w ill hitvo to n d m it tied th ere Inis hern utmost, no w o rk done, to e lu c id a te the in e ln h o lir h a n d lin g o f th is h o rh irid e ill fin* :tn i inn I o rg a n is m . T h e re is lit t le knoxvn in liio e lie n iie :d te rm s o f the m ech an ism o f its a c tio n s an d (h e re is e s s e n tia lly no k n o w led ge, o f a n y possible, in te ra c tio n s betw een th is ch e m ical an d o th e r m a te ria ls . In s im ila r fash io n we a rc p o o rly in fo rm e d about, the c h a ra c te r­ is tic s o f the dose-response re la tio n s h ip fo r v e ry lo w dose. le v e ls. T h i s , o f co u rse , is the s itu a tio n w h ic h we la ce in re a l lif e in the ease o f a v a r ie t y o f e n v iro n m e n ta l a g e n ts —in c lu d in g p e stic id e resid u es. I lc r o th e prob lem is a s ta tis t ic a l one. In o rd e r to d e riv e m e a n in g fu l a n s w e rs w ith a n y u se fu l level o f confidence, v e ry la rg e co lo n ie s o f e x ­ p e rim e n ta l a n im a ls must be tested, o fte n o x e r a. lo n g p e rio d o f tim e . I suggest, these co n im e id s to illu s tra te , that, there, a m v a rio u s le v e ls o f s o p h istic a l ion in rese arch . Tn the rea lm o f p e stic id e s the level o f o u r rese arch a r liv if .ir s m a y not. h ave kept, up w ith the stall* o f that, art n o r w ith a co rre sp o n d in g Ir x c l o f »(iiesl ¡o ilin g to w h ich p o lic y m a k e rs and the p u b lic an*, now se e k in g an sw e rs. T h e v e ry e xcellen t report on re - e a i■ -!i needs co m p iled hv an a d v i­ s o ry task force to the S a lin iia ' l u a il u l i- o f F .n x ilo iim c n la 1 H e a lth S c ie n c e s out lined llie -e research are as \ c r v w ell and v r r v e x p lic it ly . T h i s r e p o r t . I a m i n f o r m e d , is ju.-T lia x e been rare, e v e n ts— it is x-o.ry ra re to (m d m easurab le resid u es o f “2 ,!.u - ’ l'. on food— th e re fo re ono 60£866f V. 01 , | j , | j,ni | i : m : I n k n o w t o n m u c h a b o u t , l In*. t o x i c o l o g y o f I In- I m i 'i . i ■ |. |c . N m v w e a r e m o r e , p u r l ir .n l:ir. I l e d I h a t. w c s h o u l d h o m o r e , r x p l i o . i t a b o u t . a s s u m p t i o n s s u - h a s Ih o - o . I f (.h ey a r c v a l i d t h e y w i l l s t a n d o n t h e i r o w n m e r it .. I f t h e y are. mil. v a l i d w o s h o u l d e h . i n »re t h o r n . I a m h a p p y l o s a v t h a t , m y o ff ic e is e x a m i n i n g q u e s t i o n s s u c h n s t h e s e a t t h e p r e s e n t t i m e . T h a n k you. S e n a to r H a rt. S e n a t o r 11 act . T h a n k y o u . Y o u su g g est. th e p o s s ib ility ! t h a t t h e d o v e r n m e n t m a y h a v e to assu m e, a g r e a t e r r o l e in a n y t e s t i n g a r e a b u t s p e c i f ic a lly in t h e m a i l e r o f p esticid es. J )r. D irJh u n u i:. Y es. . . . S e n a t o r J I a u t . Y ou i n d i c a t e , t h a t , o t h e r w i s e t h e h i l l to i n d u s t r y m i g h t h e h i g h e r t h a n w e m i g h t d e s i r e , w h i c h I s u p p o s e , is a n o t h e r w a v o f s a y i n g a n i n d u s t r y c o u l d n o t a f f o r d it. J l o w s h o u l d w o read th a t? D r . D n lh im r.F .. W h a t J m e a n t t o s a v is i f i n d u s t r y is r e q u i r e d to c a r r y o n y e a rs o f v e ry e x p e n s iv e re se a rc h b e fo re a n y n e w product, c a n lie m a n u f a c t u r e d , o b v i o u s l y i n d u s t r y w i l l n o l o n g e r h e i n t e r e s t e d in m a n u f a c t u r i n g n e w p r o d u c t s becau se, t h e y c o u l d n o t r e c o v e r fh o l o s s . ' T i m s the. c o m m u n i t y , ( h e s o c i e t y w o u l d he. r o b b e d o f m a n y fu tu re, v e r y v a lu a b le c h e m ic a ls w h ic h so c ie ty m ig h t, lind e x tr e m e l y i m p o r t a n t f o r h e a l t h a m i o t h e r r e a s o n s . T o im p o s e . Ibe, b u r d e n o n a p a r t i c u l a r c o m p a n y t h a t he. I o r e i t c a n m a r k e t , a p r o d u c t , i t m u s t u n d e rta k e m illio n s a n d m illio n s o f d o lla rs m o re w o rth o f research t h a n ¡1 h a s in ( lie p a s t w o u l d s i m p l y s l o p t h e d e v e l o p m e n t o f n e w p ro d u c ts . T h e re fo re , it se e m s to m e o n ly fa ir, sin ce w e w a n t to p ro te c t N O ' i d y a s a w h o l e h u t a l s o t o e n c o u r a g e , b e .n e li ls t o s o c i e t y , t h a t S 'l.T - i y a s a w h o le , o u g h t l o p a r t i c i p a t e , i n t h e c o s t o f d e t e r m i n i n g v ' - ii i l l " d a m a g e s m n v h o n s w e l l a s w h a t I h e b e n e f i t s m a y he. S ' " i i o r l i v e r . T h a t t h e n w o u l d h e y o u r basic, a n s w e r t o ( h e 11*■i• <>r a r g u m e n t t h a t r e s e a r c h is j u s t a n o t h e r e l e m e n t o f t h e (■" ' ’•! ('■ ■ -on. I U . I 'i I I i . Vc . 11 •. • | | i. I : 11 t h e i i ' i t i i f t h e p r o d u c t s h o u l d h e a r t h a t c o s t a l o n g v. it h hi !,■ r i o i Jr. D r I h :tf" ,i . D v re-llv . I a m n o t s a y i n g th a t, t h e m a m i f a e I s h o u l d n ol a l - o l.i-a r ‘ , . l a c l i a l r o - f ^ . J I,* s h o u l d m a k e s u r e l l . a l l h " p r o d u c t tl c i t h e i-: ¡ i,g f o m a c l cl is n o t d a n g e r o u s l y p o i o i i o i i ~. d o e s n o t h a v e " I n m u - n d v e r - e h u m a n h e a l t h e f f e c t s . I i id i i f r y l i o i d d h e r e q u i r e d t o u n d e r t a k e a r e a s o n a b l e set. o f e x p e r i ­ m e n t - . a n d t h e y a l w a y s d o . i n a 1-'-u r e t h a t t h i s p r o d u c t h a s a r e l a ­ t i v e l y g o o d s a f e l y f a c t o r . Dili it m a y l a | , c v e a r s t o l i n d mil; l o w le'-cl a n d e a s i l y h i d d e n d a n g e r s w h i c h s n i n c l i i n r s m n v h e c o m e o b v i ­ o u s o n l y w h e n m a s s i r e . is u n d e r t a k e n . T o h e l p a v o i d th e s e , d a n g e r s T t h i n k som e. I 'V d e r n l p a r t i c i p a t i o n in I h e r e s e a r c h p r o g r a m w o u l d he d esirab le . S e n a t o r I r.w rr. D o y o u k n o w w h e t h e r t h e a d m in i s / r a t i o n i n / e i i d s t o e m b a r k o n b r o a d n e w r e s e a r c h p r o g r a m s in t h i s a r e a ? D r . D i d ’icuioi--.. T h e r e are, s e v e r a l a g e n c i e s w h i c h are. d e v e l o p i n ' » ’ p l a n s , p u r s u i n g r e s e a r c h i n t h i s a r e a , a n d T b e li e v e , a n a d v i s o r y c o m m i t t e e o f (he. D e p a r t m e n t , o f I I E W h e a d e d b y D r . E i n i l M r a l c l:i' t ■■ :» I nrrr 0 0 -2 0 2 — 70------r, Od ■>H CM r- G2 i s M i n k in ; ; s o m e p r o p o s a l s t o J I T C W a b o u t s u b s t a n t i a l l y e x t e n d i n ' ; i l s r e s e a r c h a n d t e s t i n g a c t i v i t i e s in t h i s lie ld o f p e s t ic i d e s , a n d ab o u t, d e v e lo p in '; e x te n s iv o fa c ilitie s, la rg o a n im a l c o lo n ie s a n d la r g e sc a le te s tin g e q u ip m e n t a n d p e rs o n n e l, to c a r r y o u t e x te n d e d te s ts in t h i s field . T h e se a re re c o m m e n d a tio n s th a t a rc b e in g fo rm u la te d a n d aro b e i n g p r o p o s e d t o I l i O W k I d o not. k n o w w h a t t h e s t a t u s o f t h e m i s a t th e. m o m e n t . S e n a t o r J l . u r r . It. is l i k e l y y o u w o u l d n o t h a v e t h e f i g u r e w i t h y o u , b u t. let. m e a s k t h e q u e s t io n . P e r h a p s it. c o u l d b o p r o v i d e d f o r t h e r e c o r d a n d I h a v e n o id e a w h a t it w ill s h o w . P u t, w o u ld it be p o s s ib le t o i d e n t i f y t h o s e a c t i v i t i e s w h i c h are, n o t u n d e r t a k e n b y t h e D o p a r l i n o n t o f D e f e n s e t h a t . are. c o m p a r a b l e , t o the. l i n o i t e m r e s e a r c h a n d d v e l o p m c n t t h a t , is d o n e b y t h e D e p a r t m e n t o f D e f e n s e ? T h e t o t a l f i g u r e f o r r e s e a r c h b y th e. D e p a r t m e n t o f D e f e n s e , is i n t h e r a n g e o f $7 b illio n a y e a r . I lo w m u c h a r e w e s p e n d i n g in o t h e r re s e a rc h ? D r . P u l ’nmm::. T h e t o t a l F e d e r a l b u d g e t , f o r r e s e a r c h a n d d e v e l o p ­ m e n t in t h i s c u r r e n t , y e a r is c l o s e t o £ 1 7 b i l l i o n . S e n a t o r 11 a i m ’.. I n c l u d i n g t h e P O P ? D r . P u' I ’. i .-iu o k . I n c l u d i n g t h e P O P . I f y o u l a k e out. s o m e w h a t o v e r $ 7 b i l l i o n o f P O P f u n d s , i t is $!> b i l l i o n t o $ 1 0 b i l l i o n in a l l o t h e r b r a n c h e s o f the. ( ¡ o v e r n m c n l . S e n a t o r I I . \ i : r . W r w i l l let o t h e r s j u d g e w h e t h e r t h e a l l o c a t i o n o f t h e r e s o u r c e s is o r is n o t p r u d e n t . I t h i n k it is g o o d t o h a v e i t i n th e record. Y e s t e r d a y w e r e c e i v e d te-1 ¡ n i n n y f r o m t h e D e p a r t m e n t , o f A g r i ­ c u l t u r e . W h e n w e t h i n k a b o u t c h a n g e s in the. s v s l e m o f p e s t i c i d e r e s e a r c h a n d c o n t r o l w e h a v e t o t h i n k a b o u t , c h a n g e s in t h e ba sic , l a w o f p e s t i c i d e , r e g u l a t i o n s . I n c l u d e d in I lie ( e . - l i m o n y y e s t e r d a y f r o m th e D e p a rtm e n t o f A g r ic u ltu r e w ere a n u m b e r o f su g g e s tio n s a n d c h a n g e s t h a t t h e y r e c o m m e n d h e m a d e , i n the. b a s i c a c t . A r c y o n f a m i l i a r w ith I hose s u g g e s tio n s ? P r . I ) i ; I *»i: 11w:i P r . J t n r g e r t o l d m e a b o u t , t h e m t h i s m o r n i n g a n d I h a v e a r o p y o f t h e m h e r e , a n d we. h a v e d i s c u s s e d t h e m . T h e s e a r c in l i n e w i t h s o m e o f t h e s u g g e s t i o n s w e h a v e h a d w i t h A g r i c u l t u r e a n d o t h e r a g e n c i e s ; n a m e l y , (hat. t h e r e is n o t s u f fic ie n t f l e x i b i l i t y in t h e p r e s e n t , s t a t u t e t o lal;e. a s u i t a b l e a c t i o n in a l l e a s e s w h e r e n e w in f o r m a l io n b e c o m e s a v a il a b le . S o m e t i m e s n e w in f o r m a l i o n l i k e t h e I ’i o n e t i c s s l n d v is v e r y s u g ­ g e s t i v e bill, c a n n o t , b e s a i d t o b e f i n a l l y i - o n c l i r d v c b e c a u s e , o f tins sm a ll n u m b e r o f a n im a ls a n d sm all n u m b e r o f r ir r n m s la n r o s i n ­ v o l v e d a n d I h e s e p a r a I i o n o f a n i m p u r i t y m a v not. h e l a t u m c a r e , o f . It w i l l f r c q n e n l l y h a p p e n t h a t y o n w i l l g e t p r e l i m i n a r y s u g ­ g e s t i v e . r e s u l t s n o t su f fic ie n t, t o a b o l i s h the. use. o f a c h e m i c a l b u t siil li c ic n t. t o la k e . som e, p r u d e n t , a c t i o n u n t i l m o r e , f i n a l r e s u l t s h a v e been o b ta in e d . T t h i n k t h e A g r i c u l t u r e , s u g g e s t i o n s d o move, i n t h i s d i r e c t i o n to g iv e , f o r e x a m p le , w h a t th e y call p r e l i m i n a r y s u s p e n s io n a u t h o r i t y . S o i f a d a n g e r s i g n i s r a i s e d y o u ta k e , p r u d e n t , t e m p o r a r y a c t i o n a n d c o n tin u e f u r th e r research . I f th e f u r th e r research co n firm s th a t s a f e t y is t h e r e a f t e r a ll y o u c a n rem ove, t h e s u s p e n s io n . I f f u r t h e r r e s e a r c h p r o v e s t h e d a n g e r , t h e n p e r m a n e n t s u s p e n s i o n c a n bo ach ie v ed . 0TER661 V O'5 I i • v ill D r . D u D R im m . I t h i n k I h a v e n o v e ry ex p ert, c o m m e n t e x c e p t to n o te th e e x p e rie n c e w ith i n m y o w n fa m ily t h a t la b e ls o n p a c k a g e s 1721 CO S t- lK ilo r J I.MtT. I d i d n o t q u a r r e l y e s t e r d a y w i t h lice ] rl : : n i . l " f A g r i c u l t u r e ' s int.ei p r r l a I i o n o f t h e basic. a r i . ( t v c r n i p h t I h a \ - i i i ' l . a s ' V e a l w a y s d o , t o ju s t-iT y w h a t w e d i d , n a m e l y , th o s e . o f u - "h<> w r o te . t.lio. l a w . I a m n o t c o n v i n c e d t l i n t t h a t s t a t u t e ^ p r o h i b i t s i h e D e p a r t m e n t o f A g r i c u l t u r e , w h e n , :is y o u s a y , t h e s i g n a l g o e s u p fro m s u s p e n d in g th e m a r k e tin g o f th e p ro d u c t— I am n o t su re th a t C o n g r e s s s h o u l d bo h e l d to h a v e s a i d that, w e e x c l u d e d t h e p o s s i b i l i t y o f a te m p o r a r y su sp e n sio n . J u s t as I w as n o t y esterd ay ^ T am n o t su re y o u a r c n o t e q u ip p e d , a n d d id n o t p la n to d e b a te w h a t lim its th e re a rc u n d e r th e e x is tin g law . ] ) r . D u T ’im in r.. N o , I a m n o t a n e x p e r t o n t h e q u e s t i o n o f in te rp re ta tio n o f th e la w , b u t it h a s s im p ly been ta k e n f o r g ra n te d , m a y b e n o t p r o p e r l y a n d m a y b e u n d e r a n i n t e r p r e t a t i o n th a t, s h o u ld lie f u r t h e r d e v e l o p e d , b u t i t h a s b e e n t a k e n T or g r a n t e d t h a t p r e ­ lim in a ry o r te m p o r a r y su sp e n sio n w as n o t p ro v id e d f o r , e x p lic itly a t le a s t, in th o s t a t u t e . I f ( l ie l a w w e r e i n t e r p r e t e d t o a l l o w t h i s , i t w o u l d b e fi n e . S e n a t o r I T aiit. I c a n n o t i m a g i n e t h e r e w o u l d b e a n y d i d e v e n t c r ite r ia f o r a te m p o r a r y s u s p e n sio n th a n a su s p e n sio n . I still h a v e t h e f e e l i n g t h a t t h e s u s p e n s i o n is n o t f o r a t h o u s a n d y e a r s . I f y o u s u s p e n d a n d t h e n d is c o v e r th a t y o u r a l a r m s w e r e g r o u n d l e s s , su rely ' you c a n u n su s p e n d . T h a t w o u ld a rg u e th a t y o u c a n te m p o ra r ily suspend. D r . D t r U u m m . T f t h a t is t h e c a s e I t h i n k t h a t , is fin e . I t a p p a r e n t l y n e e d s t o b e made* m o r e e x p l i c i t t o t h e p e o p le , w h o are, d o i n g t h e s u s ­ p e n s i o n b e c a u s e t h e y d o n o t f e e l t h a t I b e y h a v e t.liis a u t h o r i t y . S e n a t o r I Ta u t . C l e a r l y t h e y d o n o t . A re, y o u y e t i n a p o s i t i o n t o a d v i s e w h e t h e r y o u w o u l d s u p p o r t o r recom m end s u p p o r t o f th e su g g e s tio n s f o r la w c h a n g e s m a d e y estcrd o v I-,- A g r i c u l t u r e ? D r . D i • i m i i u k . I t h i n k i t is f a i r t o s a y t h a t w e w o u l d b e l i e v e t' • • „ „ a r e p r o p e r m o v e s . A g a i n , a s I s a y , w e a r e n o t e x p e r t s i n r l . - .. ■ t v i;-|.| t h e l e g a l f i e ld . W h a t , w e t r i e d t o d o is t o f i n d I h - ............ ■ u i d t e c h n o l o g y t h a t is a p p l i c a b l e , a n d w o l e a v e it. t o I lie ( , ,|i —i ■ ‘• ’id t h e l e g a l a u t h o r i t i e s t.o d e t e r m i n e w h a t s p e c i f i c r e g n h i l i.ii, a n d ■f a 11111• :irr> r e ' i u i r e d . I'Ul ll i i u l : 11 a d d i l i n n a l l l - x i b i l i t d o e s p rin cip le, so u n d v e ry d e s i r a b l e I n u--. - i m p l v I — m - r e - e a r r h r e s u l t s , y o u k n o w , a n n e v e r t h e final a n s w e r m ile • I h e v a r e e x l r e m e l v c o n e h r- i re su lts o f e x tre m e d a n g e r. I t is a l m o s t n e v e r p o s s i b l e i n s a v I h il a l l t h e r e s e a r c h h a s b e e n d o ne, a n d if, p r o v e s t h a t t h e t h i n g is b u e v e r s a f e . S e n a t o r i r A i r r . C o n v e r s e l y , f o r e v e r a n s a fc. T h e r e w ere sev eral o th e r su g g e stio n s t h a t A g r ic u l tu r e m ad e. O n e r e g a r d e d th e in e ffe c tiv e n e ss o f h a n d l i n g p e s tic id e r e g u l a ti o n b y la b e lin g . T h e y w e re g o i n g to r e c o m m e n d re s trn c l u r i n g ^ t h e la w to r e q u i r e a g r a d i n g b y d e g r e e o f t h e h a z a r d s o i a p c s t .ir .i d c a n d t o e n s u r e t h a t e x t r e m e l y h a z a r d o u s p r o d u c t s w o u l d b e p e r m i t t e d t o be, h a n d l e d o n l y b y i n d i v i d u a l s o r i n s t i t u t i o n s l i c e n s e d t o d o so . D o v o n h a v e a n y c o m m en t on t h a t one? It n i t r i i nut are a d e q u a I n l y r e a d a n d t h a t 1Ins l a b e l i n g p r o b l e m i s a d i i b r i d i (m e. S e n a t o r I I akt . A s A g r i c u l t u r e i n d i c a t e d , not, :i v e r y r e l i a b l e h a n d l e f o r p r o t e c t i o n a g a i n s t i n j u r y In h e a l t h o r e n v i r o n m e n t . W e l l , svo w o u l d h o p e , lim i, y o u w i l l lu m i y o u r d i s t i n g u i s h e d s c i o n filir. s u |) |) o r f . f o f lic r e c o m m e n d a l i o n s U n i t A g r i c u l t u r e h a s m a d e . A c o u p l e . o f o i l i e r q u e s t i o n s , a n d 111 is? o n e s l o Ilio, d i l f e r e n t a c t i o n s f i m i l u n e I icon ( a k o n w i t h r e s p e c t l o p e s t i c i d e s o r h e r b i c i d e s b y d i f ­ fe re n t d e p a rtm e n ts o f th e G o v ern m en t. A g rirn ll u ro su sp en d ed I th in k y o u said a b o u t 20 p e rc e n t o f th e u s e o f L M .fi-T . J ) r . J > u B i ; i i m -,k . T d i d n o t i n t e n d l o i m p l y t h a t w a s a l l A g r i c u l t u r e . I s a i d (lie, t o t a l s u s p e n s i o n m u m m i e d t o 2 0 p e r c e n t , o f the. t o t a l u s e . S e n a t o r J l . w r r . I t is m y u n d e r s t a n d i n g t h a t , t h e D e p a r t m e n t o f D e f e n s e , l i a s s u s p e n d e d il e n t i r e l y I o n i s e , i n V i e t n a m . D r . D p l ’i u n c n . T h a t is c o r r e c t . S e n a t o r ll.w rr. A n d lite D e p a r t m e n t o f I n t e r i o r v e r y r e c e n t l y s u s p e n d e d i t f o r u s e o n p u b l i r l a n d s : l a n d s in i l s o w n e r s h i p . I> r. D i f l l i u n c i '. . Y e s . S e n a t o r l l u r r . D o w d o w e e x p l a i n ( lie d i lie ren t, r e a c t i o n s f r o m t h e s c i e r a i d e p a r t m e n t s w i t h r ' " p r r l l o Mie s a m e p r o d u c t ? D r . .! » r J ’.imioi-.. I d o n o i k n o w Mia/ 1 c a n f u l l y e x p l a i n i t , I m t f l i c s i t Mat i o n i n m i l i t a r y o p e r a t i o n s is imi n e c e s s a r i l y the. s i t u a t i o n i n n o r m a l p e a c e f u l o p e r a t i o n s in I b i s c o n n i r v . In m i l i t a r y o p e r a t io n s , b y n e c e s s ily . l l n - e e lte m ie a ls a r e d i s t r i b u t e d b y a i r e r a l l . a n d i t is not. a l w a y s e a s y Iti c o n i m l w h e r e I b e y g o h o w f a r a w a y t h e y b l o w o r c \ e u I'ual tin- a i r . r a l i is h i l l i n g I he. r i g h t t a r g e l . T h e r e f o r e I Iliin k so m e w h ;i 1 m o re p ru d e iie e m a y be rrf|tiire d . W h e n y o n a r e d o i n g if in a n o r m a l n a y . in a g r i e n l l o r a l p r a c t i c e o r l a n d m a n a g e m e n t , y o u r a i l b e u n i r l i m o re ea r e f i l l a n d llialco s u r e , f l u i i l l i e m a t e r i a l d o e s n o t g e t o n fo o d c r o p s o r in y o u r w a d e r s , w h i c h w i l l e o n f a m i n a t o Ilio w a f e r s , o r g e l o n g e a r i n g l a n d s o n w h i c h a n i ­ m a l s w i l l he, g e a r i n g a n d t h e r e f o r e g e t i n t o m i lk ’ o r m e a t . I m r l m i a t c l y 2 , l . o - T d e g r a d e s q u i l e r a p i d l y . I f i s n o t like. D D T . Tf y o u s p r a y a p a stu re , w i t h 'J .l.ò -T . e s s e n tia l ly all t r a c e s o f i t a r e g o n e a f t e r a b o u t Mirre, m o n i Its' e x p o s u r e , t o w i n d , r a i n , a n d s n n . T h e r e f o r e c a l i l e c a n q u i l e s a f e l y graze, o n g r a z i n g l a n d t r e a t e d w i l l i 2 . 1 .o - T a f t e r f b i s p e r i o d . A l s o , i f it. g e t s o n l o u d i t is l i k e l y l o d e g r a d e p r e f f y r a p i d l y , f i l m i g l i i t is d e s i r a b l e l o b a v e n o t o l e r a n c e f o r f o o d , l i n i w h e r e , i t is u s e d i n a r e a s w h e r e Micro is n o h i m i a t i p o p u l a t i o n a n d w h e r e M icro is n o d a n g e r f i t e o n l a i n i n a l i n g f o o d o r w a t e r . Mien a c o n t r o l l e d liso c a n be. e x t r e m e l y v a l u a b l e , a n d s i n e c . n o d a n g e r s w o u l d b e r e s u l t . i n g T l l i i n k i t is p e r f e c t l y p r o p e r t o b a v e c o n t r o l l e d u s e i n I b i s c o u n t r y . S e n a t o r D . u r r . I V l i a t d o y o u s a y , t h e n , t o I n t e r i o r ’s p r o h i b i t io n f o r u se tm it s l a n d s ? D r . D t;I)i:m c .r„ I g u e s s I a in n o t f a m i l i a r w i t h h o w e x t e n s i v e t h a t u s e is. S e n a t o r IT.-wrr. I a m f o l d t h a t I n t e r i o r ’s a c t i o n w a s t a k e n o n l y yesterd ay . D r . D i ' I f n m o K . I se e . I a m n o t. f a m i l i a r w i t h th e . b a c k g r o u n d f o r th a t a c tio n o r th e e x te n t o f it; o r m aybe, th e y fo u n d th a t o th e r m a - ITe866 l tc r i.'ils c o u l d I >t! u s e d <111 | h i! 11i i: l a n d s . lia/i.ardotis Ilian we snspeet llii'il they may he n sliiiid 1••r ire no Inlerior lands. S e n a l o r ll.MST. Y o u r e m i n d e d m e n f a (pic;.I in n I k i c k e d m y s e l f y c s i c r i l n y f o r n o t J i a v i i u r s - k e d tin - 1 ) o p a r l m e n t . o f A g r i c u l l u r o w iI ness e s, l ’o r h a p s y o u c a n h e l p . Y o u m e n t i o n e d P U T . A s I r e c a l l (lie. t e s l i m o n y y e s t e r d a y , u n d e r the, F J F I t A A c t . a s c i e n c e a d v i s o r y r o i m n i f l r c is e s l a b l i s l i e d w h e n ( h e r e i s n. e a n e e j l a l ’u iii p e o e n l i i r e a i m e d at- a p r o d u c t . T h e y e x p l a i n e d M i n t in ( tie e a s e o f P O T t h a t s o m e s i x m o n t h s h a v e p a s s e d s i n c e the. e a i i e c l l a l h m p r o c e d u r e w a s i n i t i a t e d a n d n o e o m m i l l e e s h a v e b e e n f o e i i i e d : l i e n e e (lie, |i a s s a o ; e o f t i m e , l i a s b e e n e x t e n d e d a t l a s t b y ( h i s a m o u n t i l n r i n « ; w i n c h , u n d e r t h e e a i i e c l l a l io n p r o c e d u r e s , m a r k r / i n g o f t h e p r o d u c t g o e s o il. W h y t h e f i - m o n l h r i c ­ h ly ? P r . P i r .i .in m :. T c a n n o t e x p l a i n t h a t . T d o n o t k n o w w h y l l i e r n s h o u l d h e a l o n g l a g hot w e e n th e s e , t w o e v e n t s . 'I'lie. n n l v t i l i n g T c a n t h i n k ' o f is sin c e , t h e S e c r e t a r y ' s p e s t i c i d e a d v i s o r y c o m m i s s i o n l i a s b o r n e o n l i m i o n s l y at. w o r k ' o n t b e p e s t i c i d e p r o b l e m , e s p e c i a l l y w i t h a t t e n t i o n ( o D D T , t h e y w e r e d e p e n d i n ' ; o n it. t o e x a m i n e I b i s p a r ­ tic u la r pro b lem . S e n a t o r i r . u r r . T re p eat., I s h o u l d h a v e a s k e d t h e m y e s t e r d a y a n d J d i d n o t . J ’u t i f t h e y r e a d s o s t r i c t l y I h e s t a t u t e w i t h r e s p e c t , t o su s p e n sio n , T w o u ld a s s u m e t h e s a m e strict, r e a d i n g w o u ld te ll (h e m th a t th ey c a n n o t s u b s titu te th e M r a k C o m m iss io n f o r tb e ex p lic it s t a t u t o r y r e . r j n i r e m e n t t h a t M ic ro b e a s c i e n c e b o a r d e s t a b l i s h e d f o r each o f th ese p ro d u c ts . n m l ¡iini'il ,■ vH 04 I >r. D i r l ’ c m c i :. I w o u l d a y roc. I t h i n k m a y b e ( lie l a w d o e s n o t so t a t i m e a t w liic li t l i o .s c i e n c e a d v i s o r y c o m m i s s i o n s l i a l l lie e s t a b l i s h e d . .S - n a to r J I art. N o ; it d o e s n o t. I t w a s a s s u m e d t h a t i t w o u ld bo e s ta b lis h e d a t le a s t w ith a ll d e l i b e r a t e s p e e d , a n d G m o n t h s se e m s to be u n d u e d elay . J ) r . D u I ’ r id c u . Y e s , I a g r e e . W i t h y o u r p e r m i s s i o n , I w o u l d l i k e f o a s k t h e D e p a r t m e n t oC A g r i c u l t u r e t o p r o v i d e a n e x p l a n a t i o n o f th is a p p a r e n t d elay . (T h e in fo rm a tio n fo llo w s:) D ep a rt m e n t of Agriculture, O f f i c e ok t h e S ec r et a r y , Dr. I,ek A. Dunr.inoE, Washington, J). C. July 7, 7370. E xeat t i re Heard ary, Connell on Environmental Quality, Executive Office of the ¡’resilient, Wash lily Ion, D.C. D ea r D il DuI.Rinan: Jn reference to the quest Jmi raised at the Hart Committee hearing aa to wliy it lias taken so Inm: to establish an ad.Yi.sory enmtniltee on D1)T, we submit the following explanation: (a) After the nniionneeineiit. of cniiccll.-ilmp, the companies involved did not request an advisory coinmillec or piiblie hearing for the four uses of DDT to 1«> cancelled milil Ihe laller pari, of the lilt-day period provided for appeals liy Ihe Federal liiseelieide, Fungicide, and Uodelilieide Act. th) .Meetings and diFeiissimis were held with rcpresenlntive.s of the National Academy of Sciences on mal.eiip of Ihe commit Ice. (c) Previously we had ashed for lists of names of persons to serve on ad­ visory eommittees for oilier cancelled products, nml they were already In the process of compiling them. (r. D u T ln iric T :. T f y o u a r e t a l k i n g a b o u t s c i e n t i f i c i n f o r m a t i o n , T ■ . . •1 ' " U> ¡uuiii fi J m> ili;il jn> will !i;iii' :■n ■f Imni y I i' 1> ' i n-1'. I In should have, :i p:iI<•111. *ir :i pi"l''l imi l■11' hi- m •' :■• -.'-a ■r }, ip r o d u c t so Ihal, lit1. r;m itimvit tin-, very large r u s t s to dcvr'"p it. Whereas, if lie. instantly published nil the in formal ion about 11*■y-' to himIni this product so Mint ntliers would insliinlly si art making it. wit limit Ilie expense of development, this would obviously he ;m mi l:iir Kind of competition. Our whole system is bused upon the fuel, that inventors of new pit«-esses and products have, probation to regain their investment and recover their costs. Therefore I think the publication anti the dis­ tribution of information with regard to the manufacture of products and materials is a proper trade secret. On the other hand, when it is clear that human health is at sf.ako I would assumo there should be mechanisms by which Government agencies in proper authority could he told something about the com­ position of the product, so that they would he able to dotermino whether or not there might he materials in the product which ought to be investigated for their harm. I do not know exact ly what the law is on this, but it would seem sensible. Senator H art. Your suggestion is that when a question of health is raised with respect to a product, data and information on the product, should be made available to the appropriate Government agency for its determination as to a question of health and safety? Dr. PuBmnor.. Yes, sir. Senator H art . That excludes, of necessity, the judgment and (lie comment of perhaps very gifted men and women of science, in ar­ riving at the determination of whether public hcnllh is or is not. in jeopardy. This is not. to suggest, that the appropriate agency lacks qualified and competent people hut surely they do not have a mo­ nopoly on that. I- Micro some way, notwithstanding the obligation to protect, trade se.'i11■' and encourage invention and discovery, we can do a better job <■( |"'nnilting the outsider, whether it is the head of (he cliemi'' *'.y di ¡i.ii i ni'-nl at. Cal Tceh or someplace else, being brought, in and liavin:- an >i|i|i>>rlunity to sharpen (lie judgment oi everybody? Dr. f)i-f'.ini.r:i:. Well, I think that the various advisory mechanisms available tn tin- various Government agencies ought, in general to accomplish t hat (ibjei-live. A science advisory group can he called in (o consult no a pai l ii nlar problem, on (be possible dangers of tlio particular rliemi.-als t hat happen to lm in a particular commercial product. I am sure Hull-they could tap the rest, of the scientific community t.o find out. whether ehemiral A or chemical B is of a nature that it would likely he harmful. Tliev do not have t.o reveal (he whole conposition of the product in order to say this product happens to con­ tain a certain amount of compound A, is there any evidence or any chance or any reason to believe that this compound A is harm­ ful. I think the knowledge of the scientific community could be ob­ tained. Senator ITatit. Should 1m obtained? Dr. D u B ridce. And should be, of course. TERATOLOGY STUDIES WITH CHLOuODIHENZO-P-DIOXINS • DOW- -412185 967. K,' D iane C ou rtn ey P rim ate and P e s t i c i d e s E f f e c t s L a b o r a t o r y E n v ir o n m e n ta l P r o t e c t i o n Agency R esearch T r i a n g l e P ark, North C a r o l in a 27711 P l e a s e sen d p r o o f t o : K* D ian e C ou rtn ey, PhD E n v ir o n m e n ta l P r o t e c t i o n Agency ..... N a t i o n a l E n v iro n m en ta l R esearch C e n te r . P r im a te f, P e s t i c i d e s E f f e c t s L a b o ra to r y R e s e a r c h T r i a n g l e P ark, t.’C 27711 ‘ .... _________- ............ - .......— ........................... . P r e s e n t e d in p a r t a t.-th e American Chemical S o c i e t y m e e t in g , W ash in gton , D .C ., S e p t . 1971. ’ ' 17218 ABSTRACT I C o u rtn ey , K.D. (1973). DOW 412186 T e r a t o l o g y s t u d i e s w it h . c h l o r o d ib c n z o - p - d io > : in compounds: T o x i c o l . A ppl. Pharm acol. 0 0 , 0 0 0 - 0 0 0 . The o r a l a d m i n i s t r a t i o n o f 100 or 200' p g / k g / d a y o f a m ix t u r e o f 40% 2 , 7 d i c h l o r o - and 60% 2 , 3 , 7 ' tr ic h lo r o d ib e n z o -p -d io x in or doses o f 5 or 20 n g / k g / d a y o f o c t a c h l o r o d i b c n z o - p - d i o x i n t o p r e g n a n t ÇD-1 m ic e from day 7 - 1 6 o f g e s t a t i o n d id n o t a f f e c t f e t a l v i a b i l i t y o r g r o s s m orp h ology. The o r a l or s u b c u t a n e o u s a d m i n i s t r a t i o n o f 100 to 1000 p g / k g / d a y o f 1 , 2 , 3 , 4 te tr a c h lo r o d ib e n z o -p -d io x in to p r e g n a n t CD-I m ic e from day 7-16 o f g e s t a t i o n was n o t t e r a t o g e n i c . In c o n t r a s t , th e o r a l or s u b c u t a n e o u s ' a d m i n i s t r a t i o n o f 25 t o 200 p g /k g /d a y o f 2 , 3 , 7 , 8 t e t r a c h l o r o d i b e n z o - p - d i o x i n produced a h ig h i n c i d e n c e o f f e t a l m o r t a l i t y , c l e f t p a l a t e and h y d r o n e p h r o s i s . 172 jA ’.' M*x7V**'^M**#,***,*H"*‘l*'**,t»*f**,**Vi:- V V 'rT ^\‘< * ' * ., » t’ •. • «*• * L i u.i * I ' * • 2 and p a t h o l o g i c a l e f f e c t s has been p r e s e n t e d by Kimbrough ( 1 9 7 2 ) . «A * 9 P o s s i b l e mechanisms o f a c t i o n or a c t i o n s o f TCDD w ere s u g g e s t e d To d a t e , it DOW a t a symposium on D i o x i n s (NIEHS C o n fe r e n c e , 1 9 7 3 ) . is •n o t known how many o f t h i s c l a s s o f compounds s h a r e t h e e x t r e m e l y 412187 t o x i c and t e r a t o g e n i c p r o p e r t i e s o f TCDD. T h us, t h i s s t u d y was und ertak en to e v a l u a t e t h e t e r a t o g e n i c p o t e n t i a l i n m ic e o f o t h e r members o f t h e c l a s s o f c h l o r i n a t e d d i b e n z o - p - d i o x i n compounds. MATERIALS AND METHODS Female CD-I m ic e and p r e g n a n t 'C D - I m ic e w i t h known i n s e m i n a t i o n d a t e s w ere p r o c u r e d from C h a r le s R iv e r L a b o r a t o r i e s , W ilm in g to n , M assach u setts. pregnancy. D e t e c t i o n o f a v a g i n a l p lu g i n d i c a t e d day 1 o f The m ic e , from a procurem ent b red a t t h e same t i m e , w e r e randomly s e l e c t e d and - a s s i g n e d t o c o n t r o l or e x p e r i m e n t a l g r o u p s . The v a r i o u s c h l o r i n a t e d d i b e n z o - p - d i o x i n s w ere p r e p a r e d and s u p p l i e d by Dr. A. Pohland o f t h e Food and Drug A d m i n i s t r a t i o n Yang,' 1 9 7 2 ) . ■ ( P o h la n d and • Compounds w ere a d m i n i s t e r e d o r a l l y o r s u b c u t a n e o u s l y . O ra l a d m i n i s t r a t i o n was by means o f g a s t r i c i n t u b a t i o n u s i n g a volu m e o f 0 . 1 m l/m o u s c /d a y . a d m in istr a tio n . The f o l l o w i n g s o l u t i o n s w ere u s e d f o r o r a l D ib c n z o -p -d .L o x in was d i s s o l v e d o c t n c h l o r o d i b e n z o - p - d i o x i n was d i s s o l v e d in c o r n o i l . The i n 15Z a n i s o l e i n c o m o i l . 17219- bU 3 The rem ain in g compounds were d i s s o l v e d in 57. a n i s ó l e in corn o i l . Compounds a d m in is t e r e d su b c u L a n e o u sly were d i s s o l v e d i n D.MSO . I DOW <*' ' employing; 0. 1/ îuguiîO/<îny« In o r d e r t o s e l e c t d o s e l e v e l s f o r t h e t e r a t o l o g y s t u d i e s , i n t u b a t i o n d a i l y t o f e m a le CD-I m ic e f o r 14 d a y s . They w ere o b s e r v e d f o r an a d d i t i o n a l 7 d a y s . For t h e t e r a t o l o g y s t u d i e s , compounds w e r e a d m i n i s t e r e d from th e 7 th through t h e 1 6 t h day o f g e s t a t i o n - . T h e s e m ic e \>:ere s a c r i f i c e d on day 18 e x c e p t t h o s e r e c e i v i n g o c t a c h l o r o d i o x i n and . t h e i r r e s p e c t i v e c o n tro ls. They w e r e s a c r i f i c e d on day 17 o f g e s t a t i o n . sa c r ific e , f e t u s e s w ere w e ig h e d , exam ined and s t o r e d i n B o u i n ' s s o lu t io n u n t i l n e c r o p c ie d . i n c o m p il in g d a t a . Upon The f o l l o w i n g c o n v e n t i o n s w ere o b s e r v e d I f a fet'u s was e i t h e r dead o r r e s o r b e d ,. i t was r e g a rd ed as a dead f e t u s . p h y sic a l a b n o r m a litie s. Only l i v e f e t u s e s w e r e exam ined f o r A f e t u s was c l a s s i f i e d abnorm al i f i t w a s. a l i v e and had a t l e a s t one t y p e o f anom aly ( r e g a r d l e s s o f t y p e ) . A f e t u s was s a i d t o h a v e abnormal- k i d n e y s i f k i d n e y s was a f f e c t e d . a t l e a s t , one o f i t s Tn c a l c u l a t i n g t h e r a t i o s o f l i v e r t o body w e i g h t i n t h e m o th e r , m a te r n a l body w e i g h t was d e f i n e d a s t h e * d i f f e r e n c e b etw een t h e w e i g h t o f t h e m other bn t h e day i t was k i l l e d and th e g r a v id u t e r u s w e i g h t . M a te r n a l w e i g h t g a i n was d e f i n e d a s th e d i f f e r e n c e in the c o r r e c t e d m a t e r n a l w e i g h t on t h e day i t was 17219 412188 tl-e v a r i o u s c h l o r i n a t e d d i o x i n s were a d m i n i s t e r e d by g a s t r i c ku 3 ; . ' The remaining compounds were dissolved in 57, anisolc in corn oil. Compounds administered subcutaneously were dissolved in DMSO % ** employing'0.l/mouse/day. # ,. DOW 412189 In order to select dose levels for the teratology studies, tie various chlorinated dioxins were administered b y gastric intubation daily to female CD-I mice for 14 days. They were- observed for an additional 7 days. For the teratology studies, compounds were administered from the 7th through the 16th day of gestation^ These mice were sacrificed on- day IS except those receiving octachlorodioxin and their respective controls. They were sacrificed on day 17 of gestation. Upon sacrifice, fetuses were weighed, examined and stored in Bouin's solution until necropsied. The following conventions were observed in compiling data. If a fet'us was either dead or rcsorbed, it was * • regarded as a dead fetus. Only live fetuses were examined for physical abnormalities. A fetus was classified abnormal if it was alive and had at least one type of anomaly (regardless of type). A fetus was said to have abnormal- kidneys if at least one of its kidneys was affected. In calculating the ratios of liver to body weight in the mother, maternal body weight was defined as the difference between the weight of the mother bn the day it was killed and the gravid uterus weight. ' Maternal weight gain was defined as the difference in the corrected maternal weight on the day it was 17220 ■ . • 1• /, killed and its weight on day 6 of pregnancy. for each litter, then across litters. Averages were calculated Statistical analyses were performed using the student’s "t" test. ' .RESULTS AND DISCUSSION - - The .results from treating female CD-I nice with various doses of .the different dibenzo-p-dioxins are presented in Table 1. Adminis­ tration of the compounds for 14 days at the doses indicated produced no lethal dose values. The dosages for the dibenzo-p-dioxin, dichlorodibenzo-p-dioxin, and octachlorodibenzo-p-dioxin are expressed as milligrams per kilogram of body weight per day while the others .are expressed as nicrograns per kilogram of 'body weight per dayi . The change in body weight’reflects the difference in body weight on the first day of the study to the last day which was seven days after the last dose. The only unusual value is from those mice which received 50 mg/kg of dibenzo-p-dioxin. Further study is needed to determine if this increase of. almost seven grams is real or not. Limitations of the supply of these compounds precluded further — exploration of dose studies at this time. * In general, none of the’.. ”dibcnzo-p-dioxins studied were as toxic as. TCDD, the 2,3,7,8’ " > tctrachl.orodibcnzo-p-dioxin isomer, and some of the compounds could be considered relatively non-toxic. 17221 DOW 4121.90 • ■ .a. 5 Toxicologic results of administering che various dibcn;:o-pdioxins to pregnant CO-1 i;iicc arc presented in Table ?.. The. diluent control solutions of 5% anisóle in corn oil, DMSO or 15% anisóle in corn oil did not adversely affect fetal aortalicy or fetal weight. administered orally at doses of 100 and 200 aicrograms/kg/day had ‘ no.advcrse effects on the fetal and maternal parameters. The fetal weights of these two groups are higher than those of their respective controls. They are also higher than values which might be antici­ pated for a gestational day 18 mouse fetus. . It is assumed that 'these nice were very near tern since one member of the experimental groups-littered (omitted froa these data), and thus, these mice might be considered almost day 19 mice instead of day 18. The * , maternal weight gains of the experimental groups were slightly higher than the values of the control-groups, but these differences T7ere not statistically significant. This slight increase in maternal weight gain was also seen in mice treated with the 1,2,3,4 tetrachlorodibenzo-p-dioxin isomer administered orally at doses ranging from 100 to 1000 micrograms/kg/day. Whether or not’. this' increased weight gain is a true increase in weight or a manifestation .of edema needs to be explored since studies with- ~ TCDD produced marked maternal edema. In contrast, the subcutaneous administration of the 1,2,3,4 tctrachloro- isomer produced a slight decrease in maternal weight' gain compared to controls. "•niinei'.s.'wu.'!tr.u.'ar'.xm.'-.T.rr r.v— .. r"7?;.<ítí The TW.'.’.ftrif.C d o w 412191 The mixture of the dichloro- and trichlorodibcnzo-p-dioxin 6 difference in chase values war. not s t a t i s t i c a l l y s ig n if ¡c ant. In marked contrast, TCDD adversely affected fetal weight and. . kg/day. Mo n mortality, and maternal weight gain at a dose of 100 micrograms/ Dose levels of ?.00 and 400 yg/kg/day produced generalized edema in the mothers, and vaginal bleeding after the sixth dose ‘with some mice aborting shortly thereafter. The increase in the ratio of liver to body weight seen in the mice receiving the lower doses either orally or subcutaneously is primarily due to an increase in the liver weight. The dose of ■50 yg/kg/day produced a decrease in maternal weight gain, and at the tvo highest doses the obvious edema made it difficult to interpret maternal weight changes. The subcutaneous administration 4 of TCDD produced more fetal mortality at lower doses than oral •administration. * This suggests that the bioavailability of a subcutaneous dose is greater than that of an orally administered dose. Treatment of ptegnant mice with octachlorodibenzo-p-dioxin at 5 ing/kg/day had no adverse'effects on fetal or maternal parameters. At a dose of 20 mg/kg/day, there was a slight reduction of fetal • < . weight which was not statistically significant. Also, the reduction .. .....— in maternal weight gain was not statistically significant due to a 17223 7 v e r y l a r g e stan d ard deviat. io:i. / Tlio i n c r e a s e i n th e r a t i o o f l i v e r t o body w e ig h t was p r i m a r i l y duo t o a lo a n in. body w e i g h t . F etal Mortality was not a f f e c t e d a t c i t h e r d o s e . All of the live fetuses were examined for malformations. o These o results arc shown in Table 3. The mixture of dichloro- and trichlorodibenzo-p-dioxin produced .a'slight increase in the number of abnormal fetuses. Hto At the lower CD CD dose this was partly due to an increase in kidney malformations which were a mild form of hydronephrosis. Since most of these fetuses (9/10) were from one litter, and kidney malformations were not' observed at the higher dose, it is very doubtful that this malformation was produced by the compound under study. At both dose levels there was an increase in the incidence of clubfoot. This may reflect uterine crowding, since these fetuses weighed slightly heavier and the litters were slightly larger than'the controls. However, this does not negate a possible compound effect.- ■ The 1,2,3,4 tetrachloro- isomer did not increase the incidence of malformation at any dose level by either oral or subcutaneous administration. Since this strain of mouse has a tendency to 4J-spl^y --- clubfoot, the SK incidence of this anomaly observed at the 1000 ... ----------microgram/kg/day done level needs further substantiation before • * • being accepted as a compound effect. •a»v..v*s«*>*^**r v». "T»W *r>\**-*rt 8 In contrast TCDO produced many abnormal fetuses at all doses studied ana by both routes of ad::iin.i serntion.- The majority of the. malformations were cleft painter, and hydroncpbrotic kidneys, both unilateral and bilateral. A few other anomalies such as hydrocephalus TCDD administered subcutaneously produced a greater teratogenic response at a lower dose than adminis­ tration by the oral route. Administration of the isomer by the subcutaneous route at the lowest dose produced about 87% abnormal fetuses per litter. This made it difficult to demonstrate a .dose related response since this is close to being a maximum response. At the higher dose with both routes of administration many fetuses were observed with marked edema and petechiae. The oral administration of 5 or 20 mg/kg/day of octachlorodibenzo- * ' p-dioxin to pregnant CD-I mice did not affect fetal development morphologically. The only malformation detected in this group of fetuses was a single cleft palate at the low dose. • • ' CONCLUSIONS • TCDD, the 2,3,7,8 tetrachlorodibcnzo-p-dioxin member of thirs♦ « . . . class of compounds was the most fctotoxic and teratogenic compound studied. The related compounds were relatively non-toxic and were not teratogenic at the doses studied. . .............. .. .•« i - J«.* Cl xt" ___ DOW 412194 and open eye. were occasionally seen. 9 T!æ oral admin istirai; ion of 100 eu* 200 i:ii.crommï;/k /deiy of a mixture of 402 2,7 dlchloro- arid CO/! .2,3,7 triclilorod ¡bc-nzn-p-d u»:in to pregnant CD—1 mice from day 7 through 16 of gestation did not affect fetal viability or gross morphology. DOW Tlic oral administration of 100 to 1000 microgrnns/kg/dny or the subcutaneous administration of 5C0-or 1000 niicrogrnms/kg/day- 412195 of 1,2,3, t\ tctrachlorodibcnao-p-dioxin to pregnant CD-I mice did not affect fetal viability or gross m o r p h o l o g y . The oral administration of 5 or 20 milligrams/kg/day of octachlorodibenzo-p-dioxin to pregnant CD-I mice did not affect fetal viability or gross morphology. ' The oral administration of 25 to 200 nicrograms/kg/day of ‘2,3,7,8 tctrachlorodibenzo-p-dioxih, TCDD, to pregnant CD-I mice produced a high incidence of fetal mortality and malformations. The malformations were almost exclusively cleft palate and hydronephrosis. Maternal toxicity was evident at the higher dose levels with marked edema, vaginal bleeding and abortion. ■ACKNOWLEDGEMENTS: I gratefully acknowledge the technical assistance -- ------ of Mrs. J. Putnam and Mrs. M. Ebron. I also thank Dr. A. Poiiland of the Food and Drug Administration for the generous supply of dioxin compounds. ' ' ‘ 172 1 •r* * ■ 10 • Tabic 1. Oral Administration of Dioxins to Female CD-I Mice For 14 Days No. Dead/ Doses Change body Wt. (gms) 6 6 6 . 1 mg/kg 10 50 0 0 1/14 +0.6 -0.3 +6.8 6 6 0.5 mg/kg 1.0 0 1/8 -0.1 +1.5 6 ■ 6 6 10 yg/kg 50 ■ 100 '.■1/9 •0 . 1/13 +1. 2 +0.8 +1.-6 6 6 6 6 5 yg/kg 10 '50 100 0 0 0 0 0 ■ -0.2 ' +0.8 -0.9 2,3,?, 8-Tetrachlcrodibcnzo-p-dioxin 10 . 10 yg/kg 0 '+0.1 Octachlorodibenzo-p-dioxin . 6 6 6 0.5 mg/kg 0.75 1.0 1/110 0 Dibenzo-p-dioxin t' 2,7-Dichlorodibenzo-p-dioxin Combination of: 40/? 2-,7-Dichlorodibenzo-p-dioxir. 607 2,3,7-Trichlorodibcnzo-p-dioxin • ?, 3,4-Te trachlorod ib enz o-p-d iox in . ■ +0.1 +0.7 -0.4 '«g w n r ; **! 1 7 c i* .i 412196 Dose/ Day DOW No. of Mice Compound DOW 412197 I i T o x i c o l o g i c E v a l ú e t i o n o f C h l o r in a t e d D i b e n z o - p - d i o x l n Compounds i n P re g n a n t CD-I Mice (Conpounds A d m in is t e r e d Cron Day 7 to 16 o f C e s t a t i o n ) j i « X SD X SD M aternal L iv e r /D o d y W eight x 100 TT SD 0 . 1 m l/m ouse 15 6 1 .02 0.1 6 3 .5 1.9 3 7 .S 0.59 2 / 3 m ix t u r e 3 ! i i j j oral oral 100 pg . 200 Pg . 6 5 3 5 1 .3 6 1 .25 0.13*** 0 .1 9 * * 4 .6 4.4 1 .1 0 1.5 9 3 .0 7.3 0 .6 4 0.45 oral oral oral oral 100 250 500 1000 4 10 20 5 10 1.C9 1.1 0 1.C3 . 1 .0 3 0 .09 0 .1 2 0 .08 0 .09 4.8 4 .8 4 .5 3.7 0 .5 1 * 1.44 1.5 6 1 .31 7.3 7.7 7.8 s. 3 0 -4 7 0.3 7 0 .43 . 0.5 3 su b e su b e 500 Pg 1000 Pg 5 6 7 2 1 .24 1 .31 0 .0 7 0 .07 3.4 2 .3 0 .S 2 0 .57 7.6 8.1 ‘ 0 .4 0 0.44 su b e . 0 .1 n i /n ou se 6 14 1 .19 0 .1 7 3 .1 1.9 6 7.5 0 .54 oral oral oral oral oral 25 . 50 100 200 400' Vg pg Pg Pg Pg 7 7 6 6 5 6 13 14 87 97 1 .13 1 .01 0 .95 d d 0 .1 3 ’ 0.1 3 0.1 2 3.4 ' 3.4 2 .1 d d 2.2 0 1 .07 3 .57 3.6 0 .0 3 * * 0 .4 4 * * * 1.C0 su be sube su be su be 25 Pg 50 Pg 100 Pg 200 .Pg 5 6 6 6 36 56 72 76 • 1.25 1 .2 0 d d 0 .07 0.15 3 .0 2 .3 d d 0 .8 6 1 .1 7 ' 9.7 9 .0 ü d 0 .4 2 * * * 1 .09* oral 0 . 1 n l/m o u s e 5 8 0 .61 0 .05 O.ff 1.47 • 6.2 0 .22 oral oral 5 mg 20 mg 6 6 14 . 12 ■ 0.6 0 0 .53 0 .05 0.05 0 .3 -0 .1 1 .4 0 2 .31 i i 1 1 1 DMS0b ' ■ ( 2 ,3 ,7 ,8 -tc tr a c h lo r o ■ * | 'i 1 | 1 1 1 1t • ’ 11 15% a n i s ó l e : c o m o i l c 1 p i p ctach loro 1 t a b \~ \ i M atern al Weight ^Caín (g) oral ■ . \ D o s e / k g /d a y F etal Weight (g n s) j 1 ,2 ,3 ,4 -te tr a c h lo r o i Route No. o f . L itters 5% a n i s o l o s c o r n o i l i , r D ib e n z e -p -d io x in ■ Compound ’ tan Av. 7. F etal M o r ta lity / L itter 1722 v«**».? rir } Í 4 1 ¿ .L ^ Table 2. Toxicologic Evaluation of Chlorinated Dibonza-p-dioxin Compounds in Pregnant CD-I Mice (Compounds Administered from Day 7 to 16 of Gestation) £ r, p < « h' r t D ib cn zc-p -d lo x ln • Ccr-.pcur.d F etal W eight (g n s) M atern al Weight ;Cain (g) Ma t c rr.al L i v e r /F.ody Weight x 100 X SD X SD *V SD C*2 r- Ê . ► 52 a n i s ó l e : c o m o i l .oral 0 . 1 m l/m ouse 15 6 1.0 2 0.1 6 3 .5 1 .93 7 .S 0 .59 t« K i» ?» ** 2 /3 n ix tu r e 3 ‘ oral oral 100 pg . 200 Pg 6 5 3 5 1 .36 1 .25 0.13*** 0 .1 9 * * 4 .6 4 .4 1 .1 0 1.5 9 3 .0 /.J 0 . £4 0.4-5 1 ,2 ,3 ,4 -te tr a c h lo r o oral oral oral oral 100 250 500 1000 4 4 5 5 10 20 5 10 1 .0 9 1 .1 0 1 .0 3 1 .03 0 .09 0 .12 0 .08 0 .09 4.8 4 .8 4 .5 3 .7 0.51* 1 .4 4 1 .56 1 .31 7.8 7.7 7.8 3 .3 0 .47 0.3 7 0.4 3 V 0 .58 1 1 1 t suoc. su b e ' 5 0 0 Pg 1000 Pg 5 6 7 2 1.24 1 .31 0.07 0.07 3.4 2 .3 0 .8 2 0 .5 7 7.6 8 .1 0 .4 0 ‘ 0 .44 ■ su b e . 0 .1 n l/n o u se •6 14 1.1 9 0 .1 7 3 .1 1 .9 6 . 7.5 0 .9 4 25 . 50 100 200 400 Pg pg pg pg Pg 7 7 6 6 5 G 13 14 87 97 1 .13 1.0 1 0 .95 d d 0 .1 3 ’ 0 .13 0.1 2 3.4 3.4 2 .1 d d 2 .2 0 1 .07 3 .57 3 .6 9.4 7.8 ■ d d 0 .6 3 * * 0 .4 4 * * * • 1 .00 | oral oral oral oral oral ! J i ! su be su b e su b e sube 25 50 100 200 Pg pg pg Pg 5 6 6 6 36 56 72 76 1 .25 1 .2 0 0 .07 0.1 5 3 .0 2 .3 0.6 6 1 .1 7 ' 9.7 9 .0 0 .4 2 * * * 1.0 9 * 15Z a n i s ó l e : c o m o i l c; i ¡ o cta ch lo ro c ! oral 0 . 1 n l/m o u s e 5 8 0 .61 0 .05 5 rtg 20 a?g 6 6 . 12 14 0 .6 0 0 .53 0 .06 0 .05 •i ; » D>íS0b t 2 , 3 , 7 , 8 - t e tra c h lo r o • r ¡ ¡ t» r \ *{1 \ \ i D o s e / k g /d a y R oete No. o f . L itters Av. 7. F etal M o rta lity / L itter oral oral * pg pg . pg . pg . • • • d d a r.ixturo = 407. 2,7 dichlorodibcnzo-p-dioxin and 60« 2,3,7 trichlcrodibcr.zo-p-diexin •b D!i30 =» dír.cthylsulíoxide .\- sacrificed day 17 of gestation: all others sacrificed day 18. \ • . . 4. .. r» nr,, ^ ai • a '*.v _ o d ' u d d O.ff 0.3 -0 .1 1 .47 6 .2 0 .22 1 .4 0 2 .31 6.6 7.2 0 .22 0.G0* *- ' t f DOW 4121.99 o CT) T c b lc 3 . ’ T e r a t o g e n i c E v a l u a t i o n o f C h l o r in a t e d D ib en zo-p-■ dioxin Compounds i n CD-I Mice D íb c n z c -p -d io x in . 'Compound Routc D ó s e / k g /d a y * No. o f • L itters Av. No. U ve • F etuses/ U tter 5Z a n i s o l e r c o r n o i l oral 0 . 1 ml/rcouse 15 11 .0 0 .8 2 / 3 r . i: : t u t e a ■ oral oral 100 UB 200 UB 6 5 12 .3 .12.8 3.2 3.8 oral oral oral oral 100 vg' 250 ug 500 vg 1000 ug 4 4 5. ‘ 5 1 1 .8 . 11.5.1 1 .6 Ü .S sube su be 500 ug 1000 UB 5 6 11 .6 . 12.2 su be 0 - 1 m l/m ouse V oral oral oral o r a l' oral 25 50 100 200 400 7 7 6 6 5 • 1 I ¡ * 1 15% c n i s o l e : c o m o i l c sube su be su be su be 25 UB 50 ub 100 UB 200 ug 5 6 6 6 oral 0 . 1 irl/m ouse 5 11 .2 o cta c h lo r o -0 oral oral 5 mg 20 tng 6 6 1 1.2 11 .6 ! 1 ,2 ,3 ,A tetra ch lo ro i i 1* DMSO3 : 2 , 3 , 7 , 8 . te tra c h lo r o » f * a 'b c d ! i ub ug us UB US . 11 .3 . • 1 0 .9 •1 1 .0 9.7 1.5 0.4 ’ 7.7 5 .3 3 .5 3 .3 • ' Av. Ko. Abnormal F etuses/ L itter 04 rZ A notta licn /'i'o ta l rCtUSCS 1 C left T alate Kidr.oy C lu b f o o t . 0 1 4 0 0 10d 1 9 22 0 .8 0 .5 0 .2 1 .0 2 0 0 0 0 1 0 0 2 3 0 0 5.4 1 .0 0 1 0 4 2 3 0.2 0 0 1 4 .6 8.1 8 .3 1.5 0.4 3 19 66 100 ICO 34 72 71 ICO 50 3 7 13 14 50 6 .7 5 .0 3 .5 ' ‘3 . 1 . 82 79 85 100 53 53 95 33 0 0 0 0 0 .2 0 1 0 0 0 0 0 m ix tu r e ** 4CZ 2 , 7 c i c h l o r o d i b c r . z o - p - d i o x i n and COZ 2 , 3 , 7 t r i c h l o r o d i b c n z o - p - d i o x i n • D>’iSO «* d i r . c t h y l s u l f o x i d e s a c r i f i c e d day 17 o f g e s t a t i o n : a l l o t h e r s s a c r i f i c e d day 18 9 /1 0 i r o n one l i t t e r ' 11 17 0 13 / 13 REFERENCES 1. ¿ H e ib e r g , J . , W a lle n , >î., P.vodkin, R. , and Appclbaun, I . , 2. C ourtney, K.D. and Moore, J . A . , " T e r a t o l o g y S t u d i e s w it h p - d i o x i n " , T o x i c o l , and A p p lie d P h a m a c o l . 20,1 3 9 6 - 4 0 3 , 1971. Higginbotham, G .R ., Huang, A.', F i r e s t o n e , D . , V e r r e t t , H . J . , R c s s , J . , and C am pbell, A .D . , "C hem ical and T o x i c o l o g i c a l E v a l u a t i o n s o f I s o l a t e d and S y n t h e t i c C hloro D e r i v a t i v e s o f D i b e n z o - p - d i o x i n " , N a tu r e 22, 7 0 2 - 7 0 3 , 1 9 6 8 . 4 . ' Kimbrough, R.D. , " T o x i c i t y o f C h l o r i n a t e d Hydrocarbons and R e la t e d Compounds", A rch. P a th . 9 4 ,. 1 2 5 - 1 3 1 , 1 9 7 2 . 5. N eu fc cr t,,D . and D i l l n a n , " I . , " E m b ryotoxic E f f e c t s i n Mice T r e a t e d w i t h 2 , 4 , 5 - T r i c h l o r n p h e n o x y A c e t i c A c id and 2 , 3 , 7 , 3 - T e t r a c h l o r o d i b e n a o p - d i o x i n " , Naunyn-Schm Archi. P h ar m ac ol. 2 7 2 , 2 4 3 - 2 6 4 , 1972-■ 6. P oh lan d , A .E . and Y ang, G . C . , " P r e p a r a t i o n and C h a r a c t e r i z a t i o n o f C h lo r in a te d D i b c n z o - p - d i o x i n s " , J . Ag. Fd. Chem. 2(3, 1 0 9 3 - 1 0 9 9 , 1972'. 7. '. : • . P o la n d , A., S m ith , D . , M e ctcr , G . , and F o s s i c k , P . , "A H e a lt h S u r v e y o f Workers i n a 2 , 4 - D P la n t and a 2 , 4 , 5 - T P l a n t " , A rch. E n v ir o n . H e a lth ¿ 2 , 3 1 6 - 3 2 7 , 1 9 7 1 . 412200 2 , 4 ,5 - T r i c h l o r o p h c n o x y . A c e t i c A cid and 2 , 3 , 7 , 3 - T e t r a c l i l o r o d i b e n z o - 3. DOW I n d u s t r i a l l y Acquired. P o r p h y r ia ” , A rch. D e r m a to l. JS9, 7 9 3 - 7 9 7 , 1 9 6 4 . U 8. • S parscliu, - C,L* , Dumi, F,L=, and Rovo,. V .K ., "Scudy o f clic T c r a C o g e n ie ily o f 2 , 3 , 7 , 8 - T o t r n e l i l n r o d i b o a z o - p - d i o s i n in clic R at" , / Fd. Cosmee. T o x i c o l . j>, /.0 5 -4 1 2 , 1971. I Ifì ZZì t A\nn i t ' *rw\Nv/-n> '«■•••liuovt'ai jiv rijicé ii« » ryrr*r.v.r rrr.* .v — ....... . 17232 SUSPENSION OF 2 A 5 - T , SILVEX FOR USES ON: RIGHTS-OF-WAY FORESTRY' PASTURES NQI SUSPENDED FOR USE ON: RANGELAND RICE SILVEX ALSO SUSPENDED FOR: AQUATIC USES TURF AND LAWN USE OTHER CANCELLED 2 A 5 - T FOOD CROP USES EXCEPT RICE Original Articles Journal of Occupational Medicine The Mortality Experience of Workers Exposed to Tetrachiorodibenzodioxin in a Trichloropheno! Process Accident DOW049918 January 1980 Vot.22 No. 1 Judith A. Zack, M .P.H , and Raymond R. Suskind, M .O. A standardized m ortality analysis was conducted on workers exposed to tetrachiorodibenzodioxin in a trichlorophenol process accident at the Monsanto Company plant in Nitro, West Virginia. One hundred and twenty-one workers who developed chloracne resulting from this acci­ dent on March 8,1949. were selected for study. Follow-up o f this group was 100% complete. The standardized mor­ tality ratio for all causes o f death was shown to be 0.69, with 32 deaths observed and 46.41 expected. For the categories o f malignant neoplasms and circulatory diseases, the standardized m ortality ratios were 1.00 and 0.68, respectively. Because o f the small size o f the cohort and the relatively small number o f deaths observed, the results of this study cannot be considered conclusive. However, it is important that no apparent excess in total m ortality or in deaths from malignant neoplasms or diseases of the circulatory system was observed in a group of workers with a high peak exposure to tetrachiorodiben­ zodioxin who were followed over a period o f nearly 30 years. The results o f this study w ill be incorporated with those o f a larger study which w ill include plant workers ex­ posed in the course of 2.4,5-trichlorophenoxyacetic acid production during the period 1948 to 1969. A wide variety of acute and sub-acute health effects has been reported in workers involved in the manufacture of 2.4.5-trichlorophenoxyacetic acid (2.4,5-T) from 2,4.5-trichlorophenol (TCP). The most consistent clinical finding is chloracne. a skin disease characterized by comFrom the Dto^rtmcm oi Med »ein« and Environmental Health. Momamo Company. ¿00 N Lindbeffh Blvd. St loud, MO 63166 (Mi Zack. EptdemtoiotriU. and the Institute oi Environmental Health. Kettermf Laboratory, the Umvcmty oi CiiKinruo Medical Center. Cincinnati. OH 4S267 (Or. Suskmd. Deectort edones, cysts, pustules, and abscesses. Hepatic dysfunc­ tion, peripheral neuritis, disorders of fat metabolism, and porphyria cutanea tarda are other frequently reported findings in these workers.' Chloracne has been shown to be essentially due to 2.3.7,8-tetrachiorodibenzodioxin (TCDD),1 a byproduct in the synthesis of 2.4,5-T. The sub­ ject of this paper is the chronic health effects of exposure to TCDD, as reflected in the mortality experience of a * cohort of Monsanto Company workers who developed symptoms of chloracne following a trichlorophenol pro­ cess accident at the Nitro, West Virginia, plant in 1949. Production of trichlorophenol began in the fall of 1948 at the Nitro plant In this process, the reactants 1,2,4,5-tetrachlorobenzene. sodium hydroxide, and methanol were all added to the autoclave. Heat was ap­ plied and, when the pressure reached the desired point the autoclave was vented. On March 8,1949, about six months after production start-up, a violent reaction and decom­ position occurred when temperature and pressure within the autoclave became excessive. The relief valve opened and the fumes and tarry residues from the deepmposed contents of the autoclave were discharged into the at­ mosphere and into the interior of the building. Employees who worked in the area of TCP production or were involved in the clean-up began to develop symp­ toms immediately following exposure to the material which was discharged from the autoclave. Symptoms in­ cluded eye and respiratory tract irritation, headache, diz­ ziness and nausea, and a severe irritant reaction of the ex­ posed skia After these initial symptoms subsided, the chloracne and other symptoms became evident Ashe and Suskind1"* examined a total of 12 more severely affected workers on three occasions during the period of 1949 to 1953. Another 26 persons with chloracne. apparently not related to the accident were also examined in 1953. The Journal o< Occupational Medidne/Vot. 22. No. 1/January 1980 11 17234 ! 12 accidental industrial intoxication. In 1976, a TCP process accident in Meda, Italy, resulted in the contamination of a large and densely populated area.* A preliminary mortality study has been conducted in two o f the 11 towns affected. The overall m ortality rate did not differ from that expected, but increases in deaths from liver cirrhosis and leukemia were suggested. The chronic toxidty of TCD O exposure to animals has - been more extensively studied. TCD O toxicity has been thoroughly reviewed.* Chronic toxicity to TCD O is manifested by liver necrosis, thymic atrophy, and deple­ tion of the lymphoid organs. Two studies indicate that chronic administration of low levels of TCD D to rats is associated with an increased incidence of neoplasia. In one study, the oral administration of TCDO produced an increase in hepatocellular carcinom as and squamous cell carcinom as of the lung, hard palatefnasai turbinates, or -tongue" in another study, TCD D fed to rats produced tumors in 3896 of the test anim als." Neoplastic nodules and cholangiocartinom as of the liver were observed. The study reported here w ill examine the m ortality ex­ perience of a cohort of 121 em ployees involved in the 1949 trichlorophenol process accident with special em­ phasis on cardiovascular disease and on neoplasms, par­ ticularly of the stomach, liver, lung, and skin. Population and Methods in this study, the development of chioracne. a hallmark of TCD D exposure, was used to identify employees, for study. The study population consists of ail persons with chioracne w hich could be attributed to the 1949 TCP p ro cess accident One hundred and twenty-two employees who developed chioracne following this incident were identified from plant safety records dating to the time at the accident and from workmen’s compensation and plant m edical records. O ne hundred and twenty-one white m ales were included in this study — one female who was living as of the endpoint of the study was not in­ cluded in this mortality analysis. It is assumed that all of the skin disorders recorded in the plant records represent true cases of chioracne and not other types of occupa­ tional or nonoccupaticnai dermatitis. An analysis of the chioracne cases and exposures not associated with this accident but rather with the normal TCP/2.4.5-T produc­ tion processes w ill be the subject of a future paper. The data were analyzed by the modified life-table method using the updated Moroon program.1* In this method of analysis, the age-, race-, time- and causespecific m ortality rates for a standz/d ^JzLr-'tn (in *Ss case, the population of the United States) are applied to the person-years lived classified by age. race, and tim e A standardized m ortality ratio was calculated as the ratio of the observed deaths to the expected deaths for 22 selected causes of death. The statistical significance of differences between observed and expected numbers was based on the Poisson distribution and statistical signifi­ cance was determined at the 5 9 i level of significance. For the purpose of analysis, each member of the study cohort was assumed to have entered the study on M arch 8.1949, the date of the accident. The vital status of each member was determined using standard follow-up tech­ niques and ascertained as of Decem ber 31.1978. For each person found to be deceased, a death certificate was ob- Mortaiity Experience of Workers Exposed toTatrachtorodibenzodkwn/Zack and Suskind 17235 ■ e i6 6 W M o d . clinical symptoms, in order atrelative frequency,* included acneform lesions; severe pains in muscles of upper and low er'extrem ities, shoulders and thorax on exertion; fatigue; nervousness and irritability; decrease in libido; dyspnea; vertigo and intolerance to cold. O n examination, x all of the cases had chioracne. Several were severely hyperpigmented. especially on the face. O f the six workers ex­ amined in 1949 and 1950, four had liver enlargement and one had sensory loss in one foot Liver impairment as in­ dicated by hepatomegaly, tenderness and soreness in the right upper quadrant and epigastrium and a delayed pro­ thrombin time, was observed.1 * * In 1953, four of the six workers examined in 1949 and 1950 were re-examined and six additional workers involved in the accident were also exam ined The findings in this later examination indicated a general regression of both the cutaneous and noncutaneous symptoms w hich had been present earlier. A ll of the workers showed a marked improvement in their skin lesions — there were residua of - the acne and a few active lesions. In a few cases, workers continued to com plain of aches and pains of the lower ex­ tremities and back* nervousness, excessive fatigue, and dyspnea. No clinical explanation for these com plaints could be made based on the results of the physical ex­ amination.* The findings c f the examinations by Ashe and Suskind are consistent with those which have been reported in other industrial episodes which occurred subsequently.1 The acute health effects of TCD O exposure are described in the literature.7 but little is known of the chronic effects. Severe! reports describe the occurrence of cancer and other deaths in workers exposed to TCDO which, suggests an association between exposure and the subsequent development of a variety of neoplasms.**' These reports, however, are generally of sm all groups of workers with relatively short periods of follow-up and are considered to be-preiiminary in nature, in a 25-year follow-up study, 17 deaths were observed among a cohort of 75 Cerm an workers who had been involved in a 1953 TCP process accident* O f the 17 deaths observed (11-25 expected depending on the choice of a control populationl six were from cancer (four or fewer expected), five from car­ diovascular disease (as expected), two horn suicide (fewer than one expected ! one from liver cirrhosis, one from a urogenital tract disease, and two from external causes. O f the six cancer deaths, three w ere from stom ach cancer in the age group 6069. a number significantly higher than expected. Two other cancer deaths were from o a tce ll carcinom a of the lung and one was from adenocar­ cinoma of the colon. A sim ilar accident occurred in the Netherlands in 1963 in a factory producing 2.4.5-T.* Eight deaths have- been observed among 93 exposed workers. Five or six of these deaths w ere from cardiovascular disease. The proportion of deaths due to myocardial infarction was noted to be high. Jirasek et al* '* and Pazderova" followed 55 of the 78 Czechoslovakian workers who were affected by chloric n e resulting from occupational exposure to 2.4.5-T and pentachlorophenoi. In this study, five deaths were ob­ served. These included two deaths from bronchiogenic carcinom a (less than one expected! one from cardiovas­ cular disease, one from liver cirrhosis, and one from an Tabla 1 . — Observed and Expected Deaths Among 1 2 1 M ales Exposed to Tetnchlorodlbenzodloxin in a Trichlorophtnol Process A ccid ent ICO He. (Eighth Revision) Cause All causes o1 deatn All malignant neoplasms Buccal cavity and pharynx Digestive organs and peritoneum Stomach Liver All other digestive organs Respiratory system Lung Alt other respiratory organs Skin Genitourinary organs Lymphatic and hematopoietic tissue Other sues Diseases of the nervous system and sense organs Diseases of the circulatory system Arienuscferotjc heap disease, including coronary heart diseaso All other disease of (he circulatory system Diseases of the respiratory system Diseases at the digestive system All other diseases External causes ot death 140-209 140-149 ¡50-159 151 155-158 — 160-163 162.163 — 172.173 185-169 200-209. — 320-389 390-458 410-413 — 480-519 520-577 — 800-998 Observed Expected SMR 32 9 0 0 ■ 0 0 0 5 5 0 . 1 0 3 0 0. 17 13 46.41 2.59 0.50 0.18 1.91 3.02 2.85 0.17 0.15 1.18 0.88 0.94 0.38 25.01 17.74 Í.6 9 * 1.00 f t t t ' t 1.68 •1.75 t f t t t t 0.68 0.73 4 1 0 2 3 7.27 2.78 2.26 3.18 3.78 t t t t t 9.04 0.30 •p < 0 .0 5 IL e ss than 5 observed deaths tained. The underlying cause of death was coded to the 8th Revision of the International Classification of Diseases. Adapted” by an experienced nosologist Results All of the 121 members of the study cohort were traced. Eighty-nine were verified living and 32 were verified deceased by death certificate. The results of the standardized mortality analysis of the 121-member study cohort are shown in Table 1. The standardized mortality ratio for all deaths is shown to be 0.69. with 32 observed deaths and 46.41 expected. This i; the only statistically significant difference shown in this table. There were nine deaths from malignant neoplasms with 9.04 expected. There were no deaths from stomach or liver cancer. There were five lung cancer deaths versus 3.02 expected and one skin cancer death with 0.15 ex­ pected. The malignant tumor was a fibrous histiocytoma presumably of dermal origin, which is rare. There were three deaths from neoplasms of lymphatic and hematopoietic tissue with 0.88 expected. There were 17 observed deaths from circulatory diseases with 25.01 expected. The standardized mortality ratio for circulatory diseases was low at 0.68. Case summaries for the cancer deaths are given in Table 2. . Discussion Because the study cohort was small and only 32 deaths were observed, the results cannot be considered con­ clusive. Nevertheless, the analysis of the mortality ex­ perience of these workers indicated no apparent excess of total mortality or of deaths due to malignant neoplasms or circulatory diseases. The TCDD-exposed workers in the present study repre­ sent the largest group ever investigated after long-term follow-up. The criteria for inclusion (presence of the workers at the 1949 accident and the subsequent occur­ rence of chloracne) limit the group to those with a signifi­ cant exposure at that time. The latency period of 29 years Tabl* 2 . — Cancer Oeaths Among a Cohort of 121 M ales Exposed to Tetnchlorodlbenzodloxin in a rrichtorophenoj Process Accident. Y ia ro t Birth Year at Hire Year at Outh Outh Certificate Statement ot Cause at Oath Smoking History* 1909 1910 1911 1922 1915 1920 1943 1927 1939 1945 1939 1948 1962 1970 1964 1973 1970 1978 Cigarettes Cigarettes Cigarettes Nonsmoker Cigarettes Cigarettes 1919 1907 1910 1943 1943 1939 1973 1971 1978 Lung cancer (162.1) Pulmonary carcinoma (162.1) Sroncniogemc carcinoma (162.1) Bronchiogenic carcinoma (162.1) Lung cancer (162.1) Malignant fibrous histiocytoma ot sort tissue origin (173.9) Hodgkin s disease (201.0) Lympnatic leukemia (204.9) Acute myetogeiMus leukemia (205.0) Cigarettes Pipe Cigarettes ’ Smoxing nistory was obtained ay interviaws with former co-workers of the decedents Journal of Occupational Medicine/Vof. 22, No. 1/January 1980 - 13 17238 F u iu re R isk In the industrial countries we have grown rich during the age of hierarchical business corporations, in which each executive arranges what the man below him w ill do with his hands, ail the way down to the man turning a screw on the assembly line. Now, two rather fundamental things have happened. First we have begun to realize that workers in rich countries don't like working in such places. Secondly, the rich countries are moving out of the postmanufacturing age. but they still have great hierarchical cor­ porations in w hich executives sit behind their desks trying to arrange what the man below w ill do with his imagination. This no longer works. New forms of business organization w ill have to be found, probably changing big corporations into confedera­ tions of entrepreneurs. The firms and countries that w ill go bust in these circum stances are those that try to replace hierarchical corporations by even more ossified forms of hierarchy — say, by deciding that you mustn't have a boss trying to arrange what f r e e " men do with their imaginations, but can have a trade union committee doing so in­ stead. - from -UiMKd S uus Cxn Keep Craw«v, - And leed - It .1 W niws* fay Nom ao « K iw . mSnwMomm. luiv 197» 14 Mortality Experience of Workers Exposed to Tatracfttarodibenzodioxin/Zack and Suskind 17237 DOW 049921 6. Suskind RR: Chloracne and associated health problems in the ' manufacture of 2.4,5-T. Report to the loirn Conference. Nadonai In-stitute of Environmental Health Sciences. International Agency for Research on Cancer, Lyon, Franc» lanuary 1 1 ,197ft. 7. Young AL. Caicafro |A . Thaikan CE. at ak The toxicology, tovironmental fa t» and human risk associated with herbicide orange and its associated dioxin. U.S. Air Force Occupational and En­ vironmental Health Laboratory. Report OEHL TR-78-92. Brooks Air Force ftas» Texas. 1978. ft. International Agency for Research on Cancan Long-term hazards Th* «udion « ill to th«nfc M r* J m t Y u ** Mr. Raiirip Hcp iat and M r* of polychlorinated dibentodkjxms and polychlorinated dibmv PforiJ« Kartmfor tta r u m u ik i tho data cadacttoa. zofuram . IARC Internal Technical Report No. 7SAX31, Lyon. 197ft. 9. lirasek L Kalensky I. and Kubec K: Acne chlorine and porphyria cutanea tarda during the manufacture of herbicides. Cask Dermatol References 4*306-317. 1973. 1. International A ftn cy for Research on Cancer IARC M anotraphi 10. lirasek L Kalensky I. Kubec K. at a t Acne chlorine, porphyria an tit« {valuation of th• Carcinojentc Risk at Chemicals to Man. VoL cutanea tarda, and other manifestations of general poisoning during 15. Sons* Fumigant» th* Herbiddas 2.4-0 and 2.4,5-T. Chlorinated the manufacture of herbicides. II. Cesk Dermatol 4914V 157. 1974. □ibcnzodioxjns and Miscellaneous Industrial Chenucais. Lyon; IA RC 11. Pazderova I, Lukas E. Nemcova M. et ak Chronic poisoning by 1977. chlorinated hydrocarbons formed in the production of sodium 2. K'««m«g | and Schulz KH: Occupational acna (so-called 2.4,5-tnchiorophenaxyicetat» Free Left 2*332-339,1974. chforacne) duo to the cNom ated aromatic cyclic exon. Den - IX Koebe R |. Keyes DC. Beyer |E . et ak Results of a two year m m h tie a 1lSc540-54* 1957 chronic tonicity and onc ogen»city stutfv of 2J7.S-teoachlorodibnnz» 3. Ashe W f and Stokind RR: Repotts on cM oncne.case» Monsanto p-diamn in n o . Toxicol Appf Pharmacol 4*279-303,1978. Chemical Company. Nitro. West Virginia. Reports of the Kettering IX Van M iller IP. Laikh II. and Allen lit Increased incidence of Laboratory. December 1949 and Aphl 1950. neoplasms in rats exposed to low levels of 2J7.5-tetrichlorodiberao4. Suskind RR: A clinical and anvironmentai survey. Monsanto p-dtaon. Chemospfiere *337-544,1977. Chemical Company. Nitro. West Virginia. RapoR of the Kettering 14. Monson RR: Analysis of relative survival and proportional mor- . Laboratory, |u iy 1953. takty. Comput Biomed Res 7:32S-33X 1974. 5. Suskind RR: Chloracne and associated problems Report to the 15. Elgth Revision. Imemetianai Classification of Disease» Adapted Conference of the National Institute of Environmental Health fo r Use in the United States. U.S. Department of Health Education Sciences an Chlorinated Oibenxodioaina and Dibenzofumn» Aprd 3. and W eifar» Public Health Service. PHS Publication N a 1691 1973. Washington: U J . Government Printing O ffice 1977. is longer than that of any previous study, and the follow­ up is complete. Therefore, although the cohort is sm all, it represents the best opportunity so far to study the long­ term effects of TCD D on mortality. By augmenting these data with the results of com parable mortality studies, the long-term effects of TCD D m ay be more definitely evaluated. 9 t 1x-• \ i f Ralph R. Cook, M .D., M .P.H .; Jean C . Townsend, M .S.; M . G erald Ott, M .S.; and Lawrence G . Silverstein, M.S. This study describes the m o rta lity experience o f a cohort o f 67 males in vo lve d in a 7964 chloracne incident. Presum ably as a result o f skin ab sorption o f the process contam inant, Z 3 J.8 -te tra c h lo ro d ib e n zo -p -d io xin (T C D D o r dioxin), 49 o f these tric h lo ro p h e n o l p ro d uc tion workers developed the skin condition. W ith in the lim ita tio n s posed by cohort size and length o f fo llo w -u p , TC D D does n o t appear to have adversely affected m o rta lity experience. O verall, fo u r deaths occurred and 7.8 were expected. O f these, one death was due to cardiovascular disease (3.8 expected) and three deaths were a ttrib u te d to cancer ( 7.6 expected). N one o f the findings w ere statistically sig­ n ific a n t at a = 0.05. Further fo llo w -u p is contem plated. Chlorodioxins are found as trace contaminants of various commercial chlorinated phenols and as minute byproducts of routine combustion.' The most toxic of the 75 possible isomers is 2,3,7,8,-tetrachlorodibenzo-pdioxin, known also by the less specific rubrics TCDD or dioxin.' At sufficient dose, TCDD produces the dermatologic condition chloracne.1 This was the most prominent clinical sequela of the Seveso, Italy, accident* and is usually considered the sine qua non of excessive dioxin exposure. Among industrial populations exhibiting chloracne, researchers have also found porphyria cutanea tarda, hepatotoxicity, and a variety of ill-defined neurological abnormalities.1 Investigations of human effects with long latency only f r o m D o w C h e m ic a l U S A . M id l a n d . M l 4 6 6 4 0 ( D r C o o k . D ir e c to r . U S A r e a E p id e m io lo g y . Ms T o w n se n d . E p id e m io lo g is t . M ic h ig a n D iv is io n , M r O tt. S io s t a t is t ic ia n . U S A r e a E p id e m io lo g y , a n d M r S ilv e rs t e in , R e s e a r c h M a n a g e r . U S A r e a In d u s t r ia l H y g ie n e ) M r O t t is c u r r e n t ly at th e U n iv e r s it y o ! M ic h ig a n . S c h o o l o ( P u b lic H e a lth . D e p t o f E p i d e m i o l o g y 530 recently have been initiated. Because of allegations by Vietnam veterans of delayed health problems from exposure to dioxin in Agent Orange,4 U.S. Air Force personnel who worked with this defoliant are being studied 7 Health, Education and Welfare (HEW) agencies are setting up a dioxin exposure registry for U.S. industrial workers,* and research teams from several universities are evaluating those exposed during a 1949 chemical plant explosion in Nitro, West Virginia.7 In this mortality study, vital status was traced for 61 employees of the Dow Chemical Company who were exposed to 1CDC in 1964. The objectives were to determine whether overall mortality through 1978 was greater than expected and whether, among the deceased, unique patterns of exposure or mortality were obvious. M ethods and M aterials The possibility of exposures to TCDD was manifested in early 1964 when employees from a trichlorophenol manufacturing area began reporting to the industrial medical department with skin conditiens which were subsequently diagnosed as chloracne. Intense evaluations by industrial hygiene and toxicology personnel dem­ onstrated that the condition probably resulted from skin absorption of the process contaminant 2.3,7,8-tetrachlorodibenzo-p-dioxin. As a result of changes in both plant operations and personal hygiene, potential for exposure had decreased by June 1964. To facilitate epidemiologic research, the industrial hygienist assigned to the process area categorized all job classifications into high and low potential exposure. This was based on conditions existing prior to control changes. The high-exposure group included (1) production employees who worked in the area of highest TCDD con­ tamination, (2) employees engaged in sampling opera- fl« p rln t« d front J o u r n a l of O c c u p a llo n a l M «dl e in « A u g u s t , 1960. V o lu m « 22, N o . 9 p p. 53 0 *5 3 2 J O M 1980 17238 DOW097720* Mortality Experience of Employees Exposed to 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) . .t t Table 1. — Age Distribution ot 61 Employees Potentially Exposed to TCOD During 1964 by Job Category and by Oate First Employed In Process Area. Exposure Group and Age Distribution Group 1. (High potential exposure) Total 20 - 24 25 - 34 35 - 44 45 - 54 55 - 64 Group 2. (Low potential exposure) Total 20 - 24 25 - 34 35 - 44 45 - 54 55 - 64 Total First Employed In Process A ru Prior to July to June 1964 December 1964 39 3 13 10 8 5 34 2 12 8 7 5 5 1 22 4 6 9 3 0 16 0 5 9 2 0 6 4 1 0 1 0 tions, and (3) maintenance personnel assigned to produc­ tion equipment The low-exposure group included pro­ duction personnel who worked away from areas of highest contamination and maintenance employees not directly involved with production equipment. The ex­ posure groups were further subdivided into those who worked in the process area sometime between November 1963 and June 1964, and those who first worked in the area from July through December 1964. Sixty-one employees were identified from department monthly census lists and from a list of maintenance employees known to have worked in the building during 1964. The age distribution of these employees, by ex­ posure group and by date first employed in the area, is shown in Table 1. Vital status of all 61 men was deter­ mined through December 31, 1978. Following methods previously described, expected numbers of deaths were computed from cause-specific and age-specific mortality rates for the U S. white male population.* Results Acne-like lesions were observed among 49 of the total cohort of 61. The severity ranged from questionable O.e., a few comedones on the face which the employee thought predated his work in the process area) to severe (cysts and comedones over face, scalp, ears, neck and back). Subdivision of the population by date of exposure appeared to be more important than job classification in discriminating between persons with and without chloracne. Among those employed prior to July 1964, an acnegenic response was observed in 30 of 34 persons in the high-potential-exposure group and in 14 of 16 in the low-potential-exposure group. Only five positive responses were observed among the 11 men first em­ ployed after June 1964; four of these five were in the highpotential-exposure group. The vital and employment status of these 61 employees as of December 31,1978, is shown in Table 2. Overall, four deaths were observed, compared with 7.8 expected. Of the observed deaths, one was due to car­ diovascular disease, versus 3.8 expected; and three were due to malignant neoplasms, versus 1.6 expected. None of these findings was statistically significant at a = 0.05. ( 1 2 1 0 Environmental and health parameters of the deceased are described below. Case 1. — The subject worked 35 years with the com­ pany, beginning in 1928. During his first 17 years of employment he was a loader and truck driver. Alter a five-year absence, 14 of his remaining 18 years with the company were spent in the trichlorophenol area. During 1964, he worked on a job involving potentially high ex­ posure to TCDD. Although a few comedones were ob­ served on his face and back, his recurrent acne was described in 1964 as not typical of chloracne. He had a positive smoking history: a pack per day for an unknown number of years. In 1972, three years after his retirement at age 60, he died of adenocarcinoma, primary site unknown. No autopsy was performed. Case 2. — The subject worked in construction and maintenance for 24 years. In 1964 he was assigned to trichlorophenol production, working in an area of low potential TCDD exposure. During this period, he was seen for a rash of the right ear and face. No definitive diagnosis of chloracne was made. Records indicate he was a cigarette smoker, averaging a pack per day for 35 years. He died of a fibrosarcoma in 1975 at age 53. Autopsy was performed. Case 3. — The subject worked 31 years with the com­ pany, beginning in 1942. During 24 of these years, he worked in the trichlorophenol process area. Although in 1964 he was in the low-exposure category, he developed chloracne. He smoked a pack of cigarettes per day for 20 years. His death, in 1976 at age 56, was attributed to a Tabla 2. — Vital and Employment Statua Through December 31, 1978, of 61 Employees Potentially Exposed to TCDD During 1964. Vital and Ns. of Employe*« Employment Statui Total Still working Retired Deceased Left company Deceased Alive 61 40 11 4 ' 0 6 531 172 38 glioma with metastases. No autopsy was performed. Case 4. — The subject began working with the com­ pany in 1946 at the age of 41. He spent 20 years in the trichlorophenol area. In 1964 he was in the high-exposure group and, during this period, he developed mild chloracne on the face. He smoked for 30 years but quanti­ ty is not recorded. He died in 1976. seven years after his retirement, of hypertensive heart disease at the age of 71. No autopsy was performed. Discussion This cohort was relatively small and therefore provides results of low statistical power; nevertheless, the findings are of clinical significance. Overall mortality was about 50% of that expected, below the "healthy worker effect" postulated for a population with this length of follow-up.10Much of the decrease was due to a deficit in cardiovascular deaths. While cancer mortality was slight­ ly elevated (3 deaths observed versus 1.6 expected), each of the malignancies was a different type and none was ap­ parently primary in the liver, a site of concern.4 In the absence of a sentinel tumor such as those found in asbestos (mesothelioma) or vinyl chloride (angiosarcoma), one could postulate that 2,3,7,8-tetrachlorodibenzo-pdioxin depresses human immunological respopse, thereby increasing the risk to all malignancies; however, in the animal study that would tend to support this hypothesis, the dose required also produced a variety of systemic tox­ ic effects." In the cohort studied here, only one of the cancer deaths occurred in an individual with documented chloracne, and no deaths occurred as a result of other diseases related to depressed immunologic capacity. These findings, and the lack of a dose-response based on exposures defined by an industrial hygienist, suggest that the cancer mortality experienced by this cohort was a chance occurrence. The latency period for this cohort, at least in respect to the peak exposures experienced in 1964, exceeded 14 years. This latency period would seem sufficient to allow the identification of a potent human carcinogen, especial­ ly one producing unique tumors. In addition, many of the employees had worked in the trichlorophenol areas prior to 1964 and, thus, the effective latency for any potential exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin extended beyond the years of study. All of this suggests that 2,3,7,8-TCDD is not a potent human carcinogen. Further research on this and other cohorts will have to be con­ ducted to determine whether it is a weak carcinogen in humans. Conclusion This analysis of the mortality experience of 61 males in­ dicates that, within the limitations posed by cohort size and length of follow-up, 2,3,7,8-tetrachlorodibenzo-pdioxiri even at levels sufficient to produce chloracne, does not increase overall mortality (4 deaths observed vs. 7.8 expected). Further, it does not appear to increase risk of cardiovascular death. While overall cancer deaths were slightly above expected (3 observed vs. 1.6 expected), no single type of tumor was predominant and therefore dioxin cannot be considered a potent humarl carcinogen with organ or tissue specificity. Continued surveillance of this group's mortality experience should provide additional information pertaining to the chemical's potential as a weak carcinogen for humans. T h e a u th o rs w ish to tha nk M s . M a x in e C o in fo r e d itin g the m a n u sc r ip t A ll c o rre sp o n d e n c e re g ard in g this re p o rt s h o u ld in c lu d e the refe ren ce n u m b e r B-6OOO27-0O. References 1. Smith Rl: Dioxins have been present since the advent of fire, says Dow. Science 2011166-1167. 1978. 2. Blair EH (Ed ): Chlorodioxins — Origins and Fate, Advances in Chemistry Series 120. Washington. D.C.: American Chemical Society, 1973. 3. Oliver RM: Toxic effects of 2.3,7,8-tetrachlorodibenzo-1.4-dioxin in laboratory workers. Br I Ind Med 3Z49-S3, 1975. 4. Bisanti L. Bonetti F, Caramaschi F, et al: Experience of the Accident of Seveso. Proceedings of the 6th European Toxicology Society Con­ ference. Sept 4-7, 1978. Budapest Akademiai Kiado. 1979 5. Poland AP. Smith D, Melter C. and Possick P: A health survey cf workers in a 2.4-D and 2,4.5-T plant Arch Environ Health 22:316-327. 1971. 6. Wade N: Viets and vets fear herbicide health effects Science 204:817. 1979. 7. Cunby P: Plenty of fuel for Agent Orange dispute. IAMA 242:593-597, 1979. 8 Anonymous: HEW sets up dioxin exposure registry. Chem Enf News 57:16,1979. 9 Ott MG. Townsend 1C. Fishbeck WA, and Langner RR: Mortalif Health 33:3-10, 1978. 10. McMichael A|: Standardized mortality ratios and the "healthy worker effect": Scratching beneath the surface. I Occup Med 18:165-168. 1976. 11. Kociba Rl. Keyes DC. Beyer |E, et al. Results of a two-year chronic toxicity and oncogenicity study of 2.3,7,8-tetrachlorodibeiizo-p-dioxm in rats. Toxicol Appl Pharmacol 46:279-303, 1978. 532 17 v f\ ■ »' ASPLUNDH c^SST'lM O O 979 A S P L U N D H TR E E EXPER T CO. P. 0. BOX 268. D A N V IL L E . XY 40422 • AREA CODE 502 > TELEPHO NE 361-8811 G A S T O N ROSE V ice PRESIDENT September 25, 1978 Federal Register Section Technical Service Division (WH-569) Office of Pesticide Programs, EPA Room 401 East Tower 401 M. Street, SW Washington, D.C. 20460 Attn: 0PP 30000/26 Gentlemen: I represent the Asplundh Tree Expert Company in the state of Kentucky and have been Vice President for three years. I have been using 2,4,5,-T in Kentucky for the past 26 years to con­ trol brush on right-a-ways for the various utilities in the state. I started using it as a sprayman on a crew. It has been the most effective method of controlling brush along the right-a-ways, and I have seen no ill effects to wildlife or any other livestock. If 2,4,5-T is not to be re-registered, we will turn to hand clearing or mowing, which would cost us approximately five times as much. Neither of these methods would be nearly as effective as 2,4,5-T. Needless to say, I am very much in favor of 2,4,5-T being re-registered. Sincerely, Gascon Rose Vice President :kh cc Wendell Ford Walter Huddleston Carol Hubbard William Natcher Romano Mazzoli Gene Snyder Dr. Tim Lee Carter John Breckinridge Carl Perkins 17241 9 oO LETTERS RECEIVED -% 17242 ASPLUNDH ASPLU NO H TREE EXPERT CO. B L A IR M IL L ROAD. W ILLO W G R O V E. PA. 1 90 90 • A R E A C O O E 215 • T E L E P H O N E : 7 8 4 -4 2 0 0 01002 8 CSGTGMOCI 1034 West Street, Amherst, MA October 13, 1978 Federal Register Section Technical Service Division (WH-569) Office of Pesticide Programs, EPA Room 401 East Tower 401 M. Street, SW Washington, D.C. 20460 ATTN: 0PP 30000/26 Gentlemen: As a Division Manager ar.d Vice President of ASPLUNDH TREE EXPERT COMPANY, I wish to acquaint you of my concern regarding the study by the Environ­ mental Protective Agency on the re-registration of the Herbicide .245T. I, as an employee and user of 245T, have worked closely with this material since 1949. I have had the responsibility of applying this material and assisting people in making decisions about its use. As an applicator who has used 245T to treat undesirable woody growth on Utility Rights of Way over a period of 28 years covering many thousands of acres of brush, I feel that you should be aware that during this period I have not received a claim from an employee or ex-employee of any health problem or am I aware of any that existed. I am sure that you are aware of the many discrepancies that exist in the newspaper, radio and television reports with unsubstantiated claims of health hazards. 245T, when properly used in the control of unwanted vegetation on utility company's Rights of Way, offer a substantial savings to the maintenance budgets. The alternative measures of control would multiply maintenance costs and thereby be directly reflected in utility rates. At this point in time, I an not aware of other chemicals or mechanical control measures that offer the benefits achieved by the use of 243T. 17243 Page 2 As an active member of the International Society of Aboriculture, Western Mass. Shade Tree Association, Massachusetts Tree Wardens and Foresters Association and the Maine Arborist Association, I sincerely request chat you give serious consideration to the positive aspects of the use of the herbicide and use your influence to keep 2A5T as a tool for Right of Way brush control. Respectfully yours, Joffre G. Schnarr Vice President pc; Ken. Paul Tsongas Ken. Edward Brooke Hc*n. Silvio Conte Hon. Edward Boland Hon. Joseph Early Hon. Robert Drinan Hon. Edward Markey Hon. Thomas O'Neill Hon. John Moakley Hon. Gerry Studds 17244 CRSGTGMOO Federal Register Section Technical Service Division October 13, 1978 UTI h* <1 ÎO 00 Cfr-s \CT( Yes AES Copy Date Bruce Walqren x X 8-18 -9Q4-Z43-2622 Gerald Farrens X X 8-18 Georqia ROW Construction 404-27B-6905 James H. Hicks X X 8-18 4 N. G. Gilbert Corp. 404-294-5490 Bob Bowen X X 8-18 5 Davey Tree Expert Co. 216-673-9511 Dick Abbot X X 8-18 5 Nelson Tree Service Inc. 513-294-1313 Paul Russell X X 8-18 7 Townsend Tree 614-593-6037 Dent C. Dailey X X 8-21 8 Noxious Veqetation Control 614-486-8994 Sally Watson X X 8-18 9 Karl Kuemmerlinq Assoc. 614-471-4144 Franklin N. Brown X X 8-18 10 Funk Bros. Tree Service 419-325-2113 Kenneth H. Funk X X 8-21 II Noxious Veqetation Control 814-623-6351 Walter Grobert X X 8-23 12 Bartlett Tree Expert Co. 614-453-0653 Burl B. Shreve 13 U t ilit ie s Forestry Service 814-765-7115 S. J. Wayrynovic, James Davis X X 8-18 14 Bartlett Tree Expert Co. 615-247-2154 Herb Merri11 X X 8-18 15 Glume System Tree Experts 713-782-9450 H. L. Graves, Gen. Mgr. 16 Trees, Inc. 713-692-6371 Thomas Gunning 17 Davey Tree Expert Co. 214-593-3122 Merle Talbot X X 8-25 18 The Daltons of Indiana, Inc. 219-267-2460 Lex Dal ton X X 8-18 19 N. G. Gilbert Corp. 317-284-4461 John Elsesser X X 8-24 20 Townsend Tree Service 317-282-1234 Donald F. Townsend X X 8-21 21 A s p i n il f ill f i n i s h f n n f r n l f n 317-482-2041 Fernand Perras X Shannon Tree Co. Walter Shannon, V.P. X 8-18 8-21 22 717-296-6351 X X 1! CONTRACT0I1 1 Walqren Tree Experts, Inc. 203-249-5266 2 Farrens Tree Surneons 3 Rhone Name-Ti tie of Person No Out (spnt previnn ly) web x 8-23 X X Do n 919-4770485 Craiq M. Black X X 8-22 Uavey Tree Expert Co. 704-596-8066 Gene Efird 8-22 Stackhouse, Inc. qiq-735-]704 James R. Fdmnndsnn X X IT U S DO N _ J L _ 2,4, J-T DO MJ SPIJHY X W ( IK 1 21 31 Nelson Tree Service 1L -*3 14 U ...H __Too 1a iQiistr-UcT.iQJ] C(L_ X X See 1lavey n oi r r ce--- — u-ci —Hottu utt a X NOT USIN< _ L i 5-T X 8-21 8-21 web 9-1 Se ¡Mail i Off ce cb 919-273-6927 w. d. Pooie X 2 G2 L I 8-23 8-24 8-22 r ¡1 CONTRACTOR UTi l 11Y OpRAC1 uno Rhone flanio-Ti Lie of Person 45 Asplundh Tree Expert Co. 617-032-5721 Patrick V. Smith 46 B a r t le t t Tree Fxoert Co. 606-324-9414 Flmer W. Reynolds Mo Out yes Yes AES Copy Da to X X 0-23 X X 8-22 or P : Stun is 47 Ilenkels & McCov. Inc. 215-646-0000 John J . Burns X X 8-25 4ft Southern U t i l i t y Const. 205-871-0410 Melvin J. Uornberaer X X 8-22 49 Nelson Tree Service. Inc. 419-433-6471 Herb .Dotson, Mqr. X X 0-22 - 50 Ilenkels A McCov. Inc. 301-650-5522 Joseph B. Dugan X X 8-24 51 A g ricu ltu ra l Services, inc.______________ 612-330-5001 Ted Meidnnfeller 5? Davev Tree Exnert Co. 003-543-3029 Ray Bannister X X 8-22 53 Asolundh Tree Expert Co. 414-931-1610 Robert Wakefnrd X X 8-24 54 CUSCO . 703-362-9210 Mr. Bob Sayre X X 8-24 55 love A A ssociates, Inc. 004-372-4941 Wi 11 i ain Kp p I X X 8-25 . 56 l'Jes_Lv.ar-n Cnrp.._________________________ _ 004-023-2257 John (.lack) Onegy (sent previously) X X 8-23 57 Chem-Spray 310-425-0671 R. A. Rains X X 8r24 _5Q. In d u stria l Heed Control •?lfl..?37-7755 .1 0 ..¿a leeds. Inc. 012-440-5677 John Uaronich 60 ’arker Layrie Tree Service 615-037-6565 John P. Lavne (sent previously) 61 ■IcKibhon A McKibben 717-323-0205 B i l l McKibben 6? Jiem-Trol. Inc. 913-342-3006 Bob Tolman 63 iadison Snravino Service 405-237-0294 Weslev Madison X ___s _ _ J h H _ 61 lute Tree Service 712-792-9009 1 . J. Onto X. M i ). I. Brown Tree Fxoert Co. 615-037-6565 John P ("Parker*! lavne (sent prpvio 66 015-725-7269 Chuck Kaseno Nelson Tree Service v/cb & J . 0. Brooks cb Richard X DO I IT US 2,4, i-T (sent prev ) r( ^ X 8-24 X X 9-1 X X 8-25 X cb ~ ¡sljU x_ ___ Hi 8-24 X 8-24, 0-24.. r a 67 _6 8 U 1 1U î T y O CONTRACTOR l i TRAL I ui\S l’iione Name-Titie of Person No Out Chem-Aq 318-9(11-0349 Russel Mier cb Nelson Tree Service (Main office) 313-7P7-7W7 Vir cb Yes AES Copy Date — • 1 — «» I’G Q i'T G M O C _ ____ ___ \ l.i 1! ZJ\ o ASPLUNDII REGIONAL MANAGERS Name-Title of Person 1 ATE (Conn.) ..#47 B ill Neidiq, V.P. 2 J30 Fri Rpganr V.P ATE (N.Y.) Mo Out Yes isent previn K 1V/ ) AES Copy DaLe X 7-?S X X 8-3 X 3 ATE (Georgia) 052 Conrad Bostock. V.P. X X 8-3 4 ATE (Texas) m Richard A. Bates. V.P. X X 8-3 5 ATE (Virqinia) #42 Dan Cole. V.P. X X 8-4 6 ATE (Maryland) #35 Bob Co llier X X 8-4 7 ATE (Mass.) #45 X X 8-3 8 ATE (California) #75 9 ATE (Maryland) #38 10 ATE (Florida) #54 11 ATE (Connecticut) #46. 12 ATE (Pennsylvania) #22 13 ATE (Pennsylvania) #34 14 ATE (Minnesota) #65 15 ATE (North Ca;olina) #50 16 ATE (Ohio) #61 17 ATE (Oklahoma) os. r^ to Phone 10 ATE (D .C.) 19 Ed Cumminos. V.P. Jack Curtin X DO N)T US : 2,4, i-T 8-4 Charles Dalton, V.P. X X 8-4 Rick Dannenmiller X X 8-3 • X 8-7 Harold Duncan (Car #614) B ill Eqqers, J r . X X 8-3 Jerry Erickson, V.P. X X 8-4 Paul Erickson X X 8-4 Norman HoDe. V.P. X 8-7 M0WI IG X X 8-21 Howard Kidder. V.P. X X 8-4 #40 Werner (Dutch) Lanqe X X 8-3 ATE (New York) #32 Fred Mehre X X 8-8 20 ATE (Tennessee) #57 Ray Muse, V.P. 8-t4 _2L flTF ( 111 i nn i <;1 #66 ATE (Kentucky) #59 Farl Reynold«:, V.P. Gaston Rose, V.P. g £ Q £ T f i M O < 1 __JL_ X X X X Dudley W. Jordan. V.P. --! 8-4 8-3 à •-i * /' Phone ASPLUNDII REGIONAL MANAGERS flame-Ti tie of Person No Out Yes AES Copy Date X X 8-9 23 ATE (Massachusetts) m Joffre Schnarr, V.P. 24 ATE (California) m Mel #55 Dallas Schiver, V.P. X X 8-3 X X 8-3 X X 8-3 2b ATE (Florida) 26 ATE (Louisiana) #58 Ray Spencer, V.P. 27 ATE (Indiana) #60 Bob Spudis, V.P. 2M ATE (Texas) X Sease, V.P. #69 Dick Troxell X NOT 1SING CIIEMI :al 8-3 NÖT1 surer 8-4 HERB CI DE 29 ATE (New Jersey) #27 Milton Walsh, V.P. X X 8-3 30 ATE (Florida) #56 Sam Sandlin X X 8-18 31 ATE (Pennsylvania) #23 Merle Weity, V.P. X X 8-4 32 ATE (Texas) #71 Dwight Watkins X X 8-8 33 ATE (Utah) #73 Lloyd Eqemo X X 8-3 #72 Donald Kuhn X X 8-9 35 ATE (Michigan) #64 0. Dan Stewart X X 8-8 36 ATE (Alabama) 205-633-9037 (off. Roqer Ferry X X 8-9 34 ATE (Washington) sj o_ 9 SGGT6 M O O ( f * d p r ! .n'fnnturr. of Memt-pr) i-'-.'JSithV CONGRESS ■* . . . r . r > d _ S r.S S if J N OXI O.• March 13, 1978 M r . .—Eiraas...o f..G e o rg ia --------- ; introduced the following b ill ; which was referred to the Committee o n ..... <5—^! ;y>.v .To abolish the Environmental Protaction Agency **-fi ‘ - .V-;. \. ;;E: .VK ¿ y - - ;'.A2 j Be it enacted by che'Senate and House of Representatives a of che United Scaces of >America in Congress assembled,-.-.Section 1. ;•V;f: A ■’^abolished. The Environmental ‘Protect ion ¡Agency is hereby All- functions\ \ activities"powers, and. ¡ducies of- .Xhe Environmental •Protection Agency are' terminated and shall ,not . ' -.be trahsferred- to •any- agency o t .instrumentality of the United States';.'. Notwithstanding vany other provision of law, all regu- : iacionsi.. orders, % rules,, determinations, contracts,' certificates, jj’ .-r-iicenses,’ and privileges issued , made, granted, or allowed co -a. V • •’i'*' x-:v *• % • ‘xi „•.V-.-:'," •*•• • ‘ • -, / / J /S S /W 17252 D O W 9 1 3 5 2 S IN THE HOUSE OF REPRESENTATIVES 2 1 become effective by the Environmental Protection Agency on or 2 before the date of the enactment of this Act shall cease to have 3 effect. A Sec. 2. The Director of the Office of Management and Budget shall cake such action as he deems necessary, in accordance with 6 applicable .laws and regulations, 7 affairs of the Environmental Protection Agency, including matters 8 affecting personnel, 9 and records of the Environmental Protection Agency. 10 Sec. 3. ('? T 5 to conclude the outstanding contracts, assets, liablicies, property, Unexpended.balances of appropriations, authorize- 11 . Cions, allocations, or ocher funds related to the Environmental 12' • Protection Agency shall be available for use by the Director of 13 the Office of Management and Budget until the end of che fifth 14 fiscal year after the fiscal year in which this Act is enacted. 15 „Such use shall be for che purposes for which the appropriations, 16 authorizations, allocations, or ocher funds were originally made 17 available, but only co the extent required to conclude che affairs IS of che Environmental Protection Agency pursuanc to Section 2. 19 After che period specified in the preceding sentence, any unex- 20 pended balances remaining shall be returned to 21 of che Treasury. Che general fund ; // 1 / j 17253 / *'> 9 cO>K ) June 23, 19/8 O C CD \ I JO Mr. Tom Price KIRBY FOREST IH0USTRIE5 P. 0. 2ox 577 ~ Si-1 slice, Texas 77657 Oear Tom: _• ' ; •' in compliance with.your request, please find listed below the s ta tis tic a l information of Campbell Air Service, Inc, for the past 12 years or scoco/;: . as regards to the use of 2,4,5-T for Rights-of-Kay Srusn Control a'id T o : r y Pi \\a Release: .... , Rights-of-li>y Crash Control 1) 2) 3} Average work days ’per crew per year Average flig h t hours per crew per day Average hours per day each crew member is in direct contact with chemical, including mixing and leading.. - 71 ? .51 4 Forestry Pine Release 1)■ Average work days per crew per year. 2) Average flig h t hours per crew per day 3) Average- hours per day each crew member is in direct contact with chemical.including mixing and loading 41 2.25 4 Please note that one crew working both rights-of-way and forestry would av?rage 112 clays per year and In our experience the maximum would not exceed 120 Jays or 4 months. 17254 rage 2 June 28, 1973 For your further information Campbell Air Service, Inc, has not experienced any In ju rie s, nor i l l effects, to any employee, as a result of chemical usaage 1n our operations. Every precaution is taken to prevent spillage and leakage by maintaining a s t r ic t schedule of Inspections and maintenance. The ciieMical 1s transferred from it s original container to closed mixed tanks by means of suction pump and nose, where i t 1s mixed with water and subsequently delivered to saddle tanks on the helicopter, also by means of pump and hose. Also, I would liko to add that I personally have been using and in direct contact with this chemical for the past 25 years, and have experienced no i l l effects, whatsoever. I have 2 children and each of them have children, and there are no i l l effects to any, as a result of my experiences with the chemical I conclude, that after seeing first-hand the tremendous accomplishments thru the use of tnis chemical, that to question Its use is utterly ridiculous. Yours very tru ly , . CAMPBELL AIR SERVICE, INC. W. B. Rowe, S r ., President WGRSR:jw 17255 ¿2SCTGM OO Mr. Tom Price KIR8Y FOREST INDUSTRIES C A M P B E L L AIR S E R V I C E , INC. P . □ . B O X 8 7 2 • V IV IA N , LO U IS IA N A 7 1 0 8 2 P H O N E A/C 318 - 3 7 5 - 3 2 0 7 , 4 2 5 -8 2 1 8 rC uO «' C B»». ». ■ C *. O AMO * » ■» * C Q • IC S .«ITC S. OCT*C" »▼ I t e * CO»T «CIU«H » " I » t CO«» 17256 TO t e s o t « E a s te r n S h o r e N a t u r a l G as C o m p a n y P . O. BO X 6 1 5 D O V E R . D E L A W A R E 196 01 1978 OOW913524 Aug us t 2 3 , Aspl undh E n v i r o n m e n t a l S e r v i c e s M r . Jim S k e 1ton B e n e fits L e t t e r Coordinator BI a i r Mi l l Road W i l l o w G r o v e , PA. 19090 Dear M r . S k e 1 t o n : We do not use Z,k,5~T RPAR. S incerely yo u rs, EASTERN SHORE NATURAL GAS COMPANY Wayne M o r r i s P r o j e c t Designer WM/kd 17257 i ssseiGMoa ol> LETTERS RECEIVED 172S8 September 15, 1978 DOW913523 Mr. Dennis Holewinski, Manager ASPLUNDH Environmental Services Blair Mill Road Willow Grove, Pennsylvania 19090 Re: 2, 4, 5 - T (RPAR) I Dear Sir: i This letter has been prepared in accordance with your letter of August 4, 1978, regarding re-registration by EPA of 2, 4, 5 - T formulations. i c ! 1 i ARCO Pipe Line Company has not used this material extensively in weed control on our pipeline rights-of-way, however it has been used on our pipeline station properties very effectively in control of broadleaf vegetation over the last few years. Alternatives to the use of 2, 4, 5 - T formulations on our station properties would include the less effective use of diesel oil. If 2, 4, 5 - T should not be re-registered, the economic consequences would amount to the lower cost of diesel oil but result in the greater cost of labor in killing the weed roots which the diesel would not do. Sincerely.^ G. E. Clapp ■d' GEC:vrr AflCO Pipe Line Company A p p ro v a l □ H a n d lin g □ C o m m e n ta In fo rm a tio n To: □ u F ile □ N o te A R e tu rn □ A s R eq u esteo n LJ C o n t a c t Me □ yr Mr. Dennis Holewinski We have not sent copies or this letter to EPD or State Representatives or Senators. You may do so if you believ that our comments are anpropriate. u 1-1 S ig n a tu re A 1— l D a te : Fro m : G. £. C/aoo J3 0 ' .-»QÄ-A 17259 9-L5-7S • ‘ •, ... ■'i i . . . • •: , . . .s . : • • ' , .•••■.. , ■ ■, ; . M •' V ' . / ■ • ^ ; 1 . • • .. _ . •t • r • *v . *. .‘ *1’'' »■* . • ■ : « . - ' I't-r ; • . •. '■ • • •••• . . " A . j :^ ■ . ". i» « . . : . » v .~ r: • '' •' ‘ - .*• -.• « .‘ • -/ •• ■ ■i s , • : . j j ■: \ 1 * . 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'.• 0BZ LI •V ; " ' : ' - : : ■/ vij*;'’•'.*! •iv¿ A i »: H : / T > «. • - V > .•.'' . t . j-i v is* p * ( ; ;*-i \‘s :•■ ’i. . •*} : ., ' . r .. w? ^‘ •-T. ,;X' ►‘ T J ! -4 ' ••.:?/ v Vv'VV\__ i'- ;>• 'vw^.. • F'jr .V . y - ‘-’V • »«'V • ,. •,* J . /i f *».*»>•• .a í "j'.i, '!.••• ••••»--.i•.■/• ■. iV • .':- i '• ?j ; +. ' ,.V ' ri -<-\•’ «*.'£^ <*î •/ ♦. ^ J- i' /1f i ■ 't. )?i •rÀ y- ..«•;* ..... . ^ •»:v,i-1^ • ^ • ' .'i:-A ;-« v:’-¡ • v-/- •!■ .. ■ :,V:¡Ü"'¡: '■ ■ ^ x ; : 7 • ■ x x v . : v ■. !•". ¡ '.v * '* iV.r -sivvi-«■->»■*:.-1»;1 • •w • ' V i ' ■■ ■' '» » -.- lî', . j - ■■■'. ^-y . /i/... '■■•’ ■ •’ i.- :X - s ■-; ;'i -VX nò.;;, ¡,.;r. , ^ ■ i „v, („’•>!•• • •. ..> *'/ \ i i 7 .■ •-V■■ ^ : "»XWX.. ïrv^'^ iï^rï. v.lUr^ ' i*' ’ •, 1¿ •' > •' . . ^‘ ^V : 1 ' V • >■'; y., » :*' '..„ ^ v:v í.-:^ix:-• i *.•• ^ ;« .it'1 .-ï’'.•••^; v*3 W x .v j' •- /-; • .* ^>* * • .• . V l!v í‘ 0‘1ÿ 7 í' * c 1’-^ •“ r «*k '• .. ’• ■’ ;■ ... ..!• ' V->,-'-V, ï r irr' • r . i f r S* •. »• ■.;•»; J ’-..'».■. r 4 ■',■■;■■.-• vít-'-vv y \ ' ' V •;.<.* . ' «■ í1 -«: - ' 4 1 *»• i • . »*• '■'l '• \ . * * - v;.-7 :; ' - ■■ .¡■.■- .• ’• •>• .'I I A \Q O -^ ^ ■•ç-i v : ^ - -, .■ ... '• " •;i/.■ .•>:•'■ •.. -J '. ’ ' *í a ' v ü 1- r |M,( :rS Yes AFS Copy Date X X 7-28 No e>peril nce D0 NCT US 2.,4 5-T 7-28 X X 8-2 X X 7-28 X X 7-28 17261 n Pipeline or Contractor l Buckeve Pipe Line 2 ARCQ Pipe Line_________________________ 215-678-8005 !__ Christman, R/W__________________________ X 3 C o n so lid a te d Gas Supply 304-623-3611 -_R jn e t Environmental____________________ X 4 I. a nre 1 Pipe Lin e 717-737-8611 1. E. Johnson 5 Columbia Gas T ra n sm issio n ' 304-346-0951 6 T ra n s c o C o m p a n ie s I n c . _____________ 201-862-8600 Jim Houston 7 . ARCQ. J i p o lin e 316-331-1300 Gen. Clat.p, Fnv. Eng. 8 Ar-nrn 713-923-3300 H. 1. Mayes X OWN 0 R0 IS 7-28 9 AVror Gas O.ompanv____________ 918-743-9148 Donald F. Baker X NO Cl EMIC IS 8-2 10 Mnhama-Tonn. N a tu ra l Gas Co._________ 205-383-3631 J. W. Solomon 11 A1gnnrpiin Gas Transmission Co. 617-254-4050 Wm. Lawson 12 AVtied Matprials Cnrp.__________________ 405-842-4403 Truman Peek X 13 American Natural Gas Service Co. 313-965-8300 Vince Lajiness, Env. X H Ainom Pi De line Co. 312-856-5.111 Wm. Domax X 15 Apnllo Gas Co. & Carneqie N at'l. Gas 412-462-7121 B. F. Morton X 16 Arkansas Louisiana Gas Co. 318-425-1271 J. A. Irvin 17 Cambell Air Service 318-425-8218 Jim Eakin 10 American Petrofino Pipe Line Co. 915-263-7661 Wayne Bartlett X 19 Ami no i 1 U.S.A. Inc. 713-686-9261 Harold Nissen X C Q •____________________ P io n L in e C o. n i! & Phone Name-Title of Person 215-967-3131 Mo F. Rornaker. Rea. Mar. B. 01 lic e ; Ena. . 7-28 cb ^ ^ M C X X 7-28 X X 8-2 D0 NIIT US 2,4, i-T DÛ II jT U S 2,4, i-T 7-28 8-4 ROW )n Fa 'inland s 8-7 DO N)T US 8-2 2,4, î -T X X 8-2 (sent pre1 .) x X 8-2 NO C IEMIC US Amoro Gas Co. 713-948-2501 Mr. Castil le, Envir. 21 Anadarko Production Co. 713-526-5421 Richard Gains, or Clyde Anthen ____ . H. R. Ledeker X 8-3 8-7 D0 F!)T Uil *Ox 1 A * \ »-T 20 2_2_ Apro Pipe 1 ine. Inc.____________________ 316-442-3620 Out N0 flfIFMK / US t)5e L'3 ÏÏC T Weed) Conl . 8-2 8-4 Q- 7 // 1‘ ipeline or Contractor 23 Arapahn Pipeline Co. Name-Title of Person Mo Mr. A. G. Sprawka 303-842-2081 Out Yes AES Copy Date 8-4 X _24_ ArhiirHff Pippl iü£ £.0 • 918-560-6357 . Charles Hoffman V 25 501-783-3101 Lewis Belcher X DÔÜC T USI 2 4 r -T No Sf ray 1rog. Use [ rust* Hog 501-521-5400 James Walker X Use [ rush Hogs 8-2 Arkansas-Oklahoma Gas Corp.____________ 2f> Arkansas-Western Ras Co. 1 Phone 8-3 8-2 27 Ashland Pipeline Co._____________________ 606-329-3333 Clarence'A. Clark X Use [ rush Hogs 8-2 28 Rarlger Pipeline Co. ■■312-439-0270 Merle Helqland X 8-2 29 Belle Four.rheJIipeljne.C q.._____________ 307-756-3292 Lvle Sessions, Supt. X Mech< nica D0~W n i s i 2,4 5-T 8-4 Ralph Eaton X NO C EMIC IS 8-2 _30_ pighpart frudp Oil Cnrp .________________ .918-582-7211 31 piarli 1akp PipelineCo._________________ 32 Rlark M p s a Pipeline- Ine._______________ 602-774-5076 crystal n il _ai. Company.... 3.16-3.31 -13QQ . John R. Sebastian J. G. Montfort X 318-222-7791 ßur-ro - Pipel ine—Corp_______________ :______ .505-398-6308 X C. A. Norvell X .J5_ Butte pippl inp Co 915-684-5511 Jim Waddell X _3ß_ 918-333-4111. Georae Todd X 913-434-4832 Joe Hicks X 806-669-2581 R. A. Keaqy X Calnpv Pine Line Co. 714-877-2414 J. R. Scruoas. Maint. Sunt. Carolina Pipeline Company 803-708-3220 Skin Maclnnis, P .L , Supt. 40fi-252-9326 Mr. Bratlie X ,_42_ Central Florida Pipe Line Co. 813-248-2148 R. P. Rruhck X . JLÌ Chamnlin Petroleum Co. 4O5-233-7600 Rnhert. Crews .M. Chandeleur Pipe Line Co. 502-587-7531 LI U 1 * 1. • AL ASL Cahot Cnrpnrat.inn 8-2 X X 00 N( T US 2,4,! -T 0-2 RÔ" 01 e kn iws ab jut 8-2 2,4,« -T 00 Nl iT US 2,4,! -T 8-2 Up t( 1 Ind vidua 1 8-4 Forei lan DO NtiT US 8-2 HERB CIDE > DO N cb X X 0-2 S J1 L Cenex Pinpline Mr. Incjles _____ ¿ T ^ jC in A A O i 1 * ROW n cr jplanc Mai tain no :OWs No Exoeric■nee Not 7ami iar w i '! r. A. 8-2 0-2 8-7 f "n II ; PEL' 's ^ r ^ TOR Out AES Copy Pipeline or Contractor Phone 45 Charter Gathering Co. 713-923-3404 Aubrey Williamson, Frank Smith X “ use Chem Sprai/" 8-7 46 Chase Pipeline Co. ■316r321-6380 Andv Hendricks X Z A ^ >-T 8-4 X 8-4 Name-Title of Person Mo Yes DO NIT US 47 Chevron Pipeline Co. 801-359-7761 Jerry Brower, Sr. 46 Chevenne Pipeline Co. 307-634-2064 C. E. Siemers X 49 Chir.aD Pipeline Co. 312-885-5411 Mr. Ed. Scott X 50 Cities Service Gas Co.___________________ 405-236-0601 Mr. Turney X DO NIT US HERB CIDE ROWS on Past ire & Farms DO N)T US 2 ,4 , >-T DO NIT US 2,4, i-T 51 C ities Service Pipeline Co.____________ Mr. Ansal Neal X Mowi ig an 1 Hand Cutt inq 918-586-3750 Enq. X 52 Citrone11-Nobile Gathering, Inc. 205-433-6167 Don Smith 53 Clajon.GaS-CiL_____________________________ 915-336-3379 Chas. Moody cb 54 Clear Creek, Inc,_________________________ 316-263-8145 Dalton Alspaw cb _55.. Coastal States Gas Producing__________ 713r627-3700 J. C. Baker X ._5£_ -Them—Spray__________________________ ______ 713-486-1891 Steve Crosby iZ _ Collins Pipeline Co, 713^757-2131 J. L. Solomon 404-261-1470 F. .1. C o llin s. Mqr. ROW cb 303-473-2300 W. I . Blount cb 412-228-3200 Geo. Walz _aa_ Colonial p ip e lin e r n ___________________ _5i_ Colorado Interstate Gas Co. iü _ •si 61 l\D CO 6? Columbia Gas Transmission DaLe X 8-7 8-7 8-7 8-7 8-8 8-7 X Own |n ROIs DO NIT US 2,4, i-T X No Mlinte lance 8-7 X 8-9 8-7 No S irayi ig ___ Jtow_ js/ye ir DO NIT US X 1 A >-T Commonwealth Natural Gas Corp. 804-644-2931 R. J. Godfrey Continental Pipeline Co. 713-956-1130 Don Butter 61 Cosden Pipe 1ine Co. 915-263-7051 D. M. Bardwel1 64 Crown-Rancho Pipeline Corp, 713-224-8550 J. D. Winzeried ___ x_ M C 1EMHI1L5— . 66 Cullman-Jefferson Counties Gas. 205-734-1911 F. W. England -6C_ UelUJbrCli£r.okee.Coiinties Gas (list. 205-845-3731 Wm. ■A . Wri nht ___ a..Jto_l|EMIX JLQEi...__ 8ji7 In n''' 1 M- i, » O f! .......... RTR£ T .8-7 cb I i r t i im i / l U i'I i I!* -i. _iiZ Great, lakes Gas Transmission Phone ..aa _Gre.at Ye H oms tone Corp.________________ 910»749=1660 Name-Titlo of Person _ .... Räder _. . Mo Out rtcb 00 F JT U5 E X CHEF fCAL NO BRUSH X .CONTROL USE NO 1 X CHEMICALS 0-0 8-10 8-0 X USE C3NTR7CT0R Suppl y 0n‘ y X Labor T^eker 0-8 8-8 cb No HE 1BIC1 DES 8-8 On RC Ns Don1" Knot about 2,4 5-T 0-8 Use 0-0 Conio actor Knov Don't Abou 8-9 2,4 , £-T Use Erush Hogs Some Torde n 10- ; 8-9 __ 8-9 _£ L2 __ __ X X 0-9 X No MijluLêj ance _ B.-9 ... .lr p jq ^ T R A A O f 1 - ■ dmH-LJM *-' ",UN — II 89 90 91 92 Phone Pipeline or Contractor Name-Title of Person Out X Use Rri çh Ilf ns 918-585-2631 . Mr. F ile r or W. R. Keathly Hess Pipeline Co. 601-425-1(196 B illv Green The A. S. Helbiq Co. 216-376-8116 Robt. Helbiq, Sr. rh Gulf Enorqy & Development Corp. 512-828-0501 M. B. Parks rh 93__ Gulf Refininq Co. 713-226-3448 B ill Traylor rh 94__ Houston Pipeline Co. 713-654-6161 Robt. Newell X 95 Hioh Plains Natural Gas. Co.___________ 806.323-6464 Paul Wilson 96 lliiskv Pipeline Co. .307-587-4711 Mr. Spear 96 Hydrocarbon Transportât ion Inc. ■402-348-5371 (see reqional offices) Mack Mickelberg, Eng. 98 “ "(Minneapolis) 612-884-2204 99 " "(Midland. TX) 915-682-7964 I00_ " "(Liberal. KS) 316-624-1911 I0]__ " "(Great Bend, KS) 316-792-2161 "(Des-Moines. IN) 515-243-6139 103 Standard Oil (Ohio) lf)/l Standard Oil (Texas) _ 517,898.7971 Mr. Henman 214-757-7110 Jim Goodwin Inland Gas Co.. Inc. 606-324-7171 106 Interstate Storaqe & Pipeline Coro. 609-267-9100 03 a \ I07_ 316-267-0361 yhaw!: Pipeline Corp . 316-262-1408 I0£L I'.-meh Pipeline fn. 402-462-2441 IQiL Knnc ac - Mehra^l-a Nat 11 Ga<; Cn l lii_ Kentnrky West Virginia Gas Co.________ 606-886-2311 105 Yes X X N o rush 1 8-9 X X x iL£E B. E. Ashford James A. Stricland James Asburv 0?.Qf! T 0 AAOfl 8-9 8-9 DO 10T >E 2,4 ,5-T DO 10T USE X 2,4 ,5-T DO MOT 5E 2,4 5-T NO JRUSli X . PRO NO 3rusl X —Car iXfxL Mr. Sampson - Date IIke Mnwi n y---------Onl. Pas ure F arm -and__ X T. Moore Philip Jenkins AES Copy Mo Santé Fe (Gulf Cnetral) Pipeline !QZ_ -3 to 1 lUK -r> — __ cb-. ROt on __ __ pi al-ao —x V 8-9 9-10 9-9 9-9 9-10 -9.-1Q9-10 î __L1Û C MAP' ihi nfT nr, 1 n 1 tt A .......................... ................................ ................ ,........... ...................... t’ lui L1JJI 1 1 \ 7 ^ u r t " / u i r^; | (JK • • - ................. - - - ' /^s a Pipeline or Contractor ill Kaw Pipeline Co. (See Texaco) 713-666-8000 R. W. Olbrich cb 11? Kenai Pipeline Co. (see Chevron) 415-094-0773 Chas. Stevenson cb Phone Name-Title of Person — — — '^2 to 03 Cft — i Ta^CTCMOn No Out Yes AES Copy Date T I CK L E D A T E _________ 0 3 1 0 - 0 2 6 0 -7 4 4 0 (7 4 4 ) June 2D, 197S DOW9Î3514 c. Office of Pesticide Program Technical Service Division Errvlrcrnentil Protection Agency 401 li Street, «S,U. Washington, D. C. 204¿fl Gentlemen: • The Pennsylvania. Department of Transportation has usei 2,4,5-T for may years without serious problems. 2,4,5-T hasproven to bs an economical and effective control far undesirable trees and shrubs growing along the Department's 45,000 alias of highways. Applications of 2,4,5-T include foliage brush spraying and damnrt basal application. Without 2,4,5-T, the Department would be forced to use other herbicides which have not had as widespread and varied use as 2,4,5-T. Substitute herbicides, in ever;’ case, would cost the Department core ooney to achieve the sane results as 2,4,5-T. Sincerely, i nsideration. P l e a s e ensure that any further correspondence on this i s s ue Lears the identifying notation O P P -3 Q O O O / 2 6 1 >ank you for your interest in the Office of P e s t i ci d e Programs' activities. |C 988 Federal Register Section Information Branch Technical Services Division (U'H S6Q) Office of P es t i c id e s Programs, ’£PA STATE OF MAINE 9d^' DEPARTMENT OF TRANSPORTATION S T A T E O F F IC E R O G ER L BUILDING AU G U STA . M A IN E May 25, 1978 MALLAR DOW913511 Commissioner Douglas Castle, Administrator for Pesticide Programs US Environmental Protection Agency Washington, D.C. 2046Q fii Dear S i r : It is my understanding that an RPAR will be held in the near y future involving the continued registration of 2,4,5-T. I also understand that arguments are being presented for and irii against the suspension of the use of 2,4,5-T during the RPAR y period. I wish to be placed cn record an opposing any suspension of i the RPAR period end request that your actions on this product be linitod to an RPAR review. Thank you for your consideration. Very truly yours, Department of Transportation Roger L. Mallar, Commissioner By: Martin C. Rissel Engineer of Maint. & Operations HCR/lov oc: 04333 T. Stone 172C8 5TAT€ O F MAINE D€PARTM€NT OF TRANSPORTATION TRANSPORTATION BUILDING AUGUSTA.MAIN€ 9j 0 04333 OOW913510 R O G E R L. m A U a R August 3: 1978 Mr. Jim Skelton Asplundh Environmental Services Blair Hill Road Willow Grove, PA 19090 Dear Sir: As requested in your telephone call, I have attached copies of the Maine Department of Transportation letters to EPA regarding the RPAR on 2 4 5-T. Theodore M. Stone Landscape Architect Bureau of Highways TMS:mc attachm ents 17269 IOWA DEPARTM ENT OF TRAN SPO R TATIO N O H M UUUU S Z •? ft H * l 9 7 * 9 d j. 600 Federal Register Section Technical Service Division (WH-569) Office of Pesticide Prograns, SPA Room 401 Bast Teuer 401 M« Street« SH DOW913509 August 3, 1978 The Highway Division of the Iowa Department of Transportation as a positive program governing right of vay maintenance which recognizes the benefits accruing to the public in beautification« compliance with state law regarding control of noxious weeds, and revintion of vegetative growths which would adversely effect rainage, sight distance and snowfall« AS Chief Engineer with administrative responsibility over 10,000 miles of state highways requiring a maintenance budget'of $41 million, judicious expendi­ ture of funds for right of way preservation is necessary« brush control program formerly utilized 2, 4« 5-T principally to control volunteer growth after cutting brush« However, when it was indicated that 2, 4, 5-T might be removed from the list of re­ gistered herbicides, we elected to discontinue the purchase and use of that chemical« For the past six years Tordoa 10-K pellets, Hyvar X-L or Krenite has been utilized for brush control« The substitute chemicals are affective and acceptable« Under present circumstances no reason appears to exist for revising present maintenance practices, even if 2, 4, 5-T is re-registered. Vary truly yours, FHQickw bcci / Dennis Holewinski.Mgr. R. H, Given Asplundh Environmental Chief Engineer Services Blair Mill Road Willow Grove, PA 19090 9 JIJ Federal Register Section Technical Services Division (WH 569) Code No. 30000/76 Office of Pesticide Programs Environmental Protection Programs Environmental Protection Admin. Room 401 East Tower 401 M St. S.W. Washington, D.C. 20460 De'.ar Sirs: DOW913508 4738 wildrye Boise, Idaho 83705 August 7, 1978 . . My first experience with the use of 2,4,5-t P was in Llie years between 1952-58 when I was working for the Federal Govern­ ment with responsibilities which included range-land improvement. We were able to increase carrying capacity as much as 400% with the use of the 2,4-D, 2,4,5-T sprays, usually applied by airplane. The Conservation Cost-Share Program of the government paid for about 50% of the cost of this woody plant control. Prior to this, our only method was by mechanical beating, etc. at a much greater cost while obtaining a much poorer quality job. Many thousands of acres were improved' in this manner and I have remained in the area since and have not observed any detrimental effects whatsoever, nor have I even heard the hint of any. At the present time I am responsible for right-of-way vegetation control. My estimate is that should we lose our use of 2,4,5-T for woody plant control, the cost would increase dramatically, about 1,000%. This would cause a very serious cost situation and could very well bring about unsafe conditions and deaths as a result.' We have struggled very hard tc held devn costs ar.d my is that the unfounded rumors, started probably by some uninformed or hysteria! persons, will not deprive us of this valuable material that we have worked with so very successfully over so many years. Gentlemen, please allow common sense and sound scientific reasoning, rather than fear prevail on this 2,4,5-T, RPAR issue. to Very truly yours, J. E. RINARD 17271 w_....j.. . Humber of acres in ycur systen .. «.•-r y*i"!i ua^ii ui i uic mW incc . ^ 2 .Number of mi 1es in yo u r systern )i , . States in which you have riqht-of-way areas O';!*-'/, £ \ Percentage of your total ih?3 right-of-way acreage that is under some form of vegetation management proqram7 ■^ / .V - v ~Oj_& rr,/ '-r.• n- ro Number of right-of-way acres that were treated during 1977 A MECHANICAL METHODS USED FOR VEGETATION MANAGEMENT v Approximate percentage of total ROW acreage that is'treated by mechanical methods b. ^ ¿ 1 ) ,c Percentage of these mechanically treated areas that were treated by the % of a ll mechanically following methods: treated acreage treated with each method below approximate cost per acre R oller chopping Brush raking • Sheardozing ¿OSGTGMOn a. ; ? / J - q -f. Brush hog 7" Mowing Other methods MANUAL METHODS USED FOR VEGETATION MANAGEMENT a. ‘ Approximate percentage of total ROW acreage that is treated by manual methods b. Percentage of these manually treated areas that were treated by. the . . ' - , % of a ll manually treated acreage treated' with each, method below ' approximate cost . per acre Chain saw cutting ___________ :___________________ _____________________ Trimming U jcl following methods? Girdling /L -■a—-' c/ Other methods 1—£—•fw 0 I A*/ . , »-■//'i ^ A J L CL--. CHEMICAL METHODS USED FOR VEGETATION MANAGEMENT a. Approximate percentage of total ROW acreage that is treated with brush r A n t i* n l rh o m i r a l e / / \r\ ‘*0 . a! a* '/ - -------------- Vii *• ..*» ; ■■ ■ **i, .>‘ .-li V“ ' A « JL s ■L\ 1018 0OW913424 June 1, 1978 Federal Register Section Technical Services Division (WH-569) Office of Pesticide Programs, EPA Room A01 East Tower Washington,DC RE: 2,4,5,T - Notice of Rebuttable Presumption _____ 43FR17116, et. seq., April 21, 1978 Dear Sir: The Detroit Edison Company has reviewed EFA's rebuttal presumption against registration of 2,4,5,T. The Detroit Edison Company conccnds that the studies referred to in the April 21st Federal Register Notice do themselves sustain the burden of proof that under commonly recognized practices of use, the anticipated exposure of 2,4,5,T, as it is now formulated, to applicators, users and local populations is not likely to result in any significant acute adverse or chronic effects. Detroit Edison contends that the EPA's determination is in error. Furthermore, Edison contends that 2,4,5,T is an economic and uniquely effective tool in controlling the growth of high growing tree species since it does not impact the growth of low growing trees, shrubs, herbs, and grasses. The Detroit Edison Company knows of no other herbicide which controls tall growing species while preserving a well-balanced monocotylcdonous environment. The banning of 2,4,5,T would have significant adverse impacts on both the coses of controlling tall growing species and on che «eschtics of rights-of-way controlled in some other manner. The studies referred to in the April 21st rebuttal sustain the burden-of-proof that under commonly recognised practice? of anticipated exposure of l',4,5,T, as it is now formulated, to appli­ cators, uses and local populations is not likely to result in any significant acute adverse of chronic impacts. I refer to the bulk of the studies in the presumption rebuttal. These studies demonstrate that 2,4,5,T which contains less than .1 ppm of TCDD (as required by current U.S. Specifications) when applied or dosed to laboratory animals at rates comparable to the dosage 3nd exposure of humans is not likely to result in any significant adverse effects. The data presented (pg. 17119 F.R.) indicate that 2,4,5,T is not - -17273 OOW913425 Federal Register Section June 1, 1978 Page Two persistent and is readily metabolized by mammals. The data presented (pg. 17120 F.R.) indicate that there is no major problem of bioaccumulation of 2,4,5,T since it is neither strongly lipophilic nor hydrophilic. The EPA has errored in its conclusion chat 2,4,5,t exceeds certain criteria for r.isks. The error lies in the use of inappropriate data as "effect" levels. Test animals are exposed to more 2,4,5 .T/TCDD than would be expected as a normal exposure. Also, assumptions are made regarding application practices which are contrary to commonly recognized practices of use. The State of Michigan requires that applicators of any herbicide or pesticide be fully clothed. V.'e know of no application of 2,4,5,T done by persons having bare arms, hands, or legs. Examples of the use of in­ appropriate data are: 1. Third Summary of Scientific Evidence Relating to Rebuttable Presumption - Part 1(a) under oncogenic effects (pg. 17124 F.R.) In this study, The test organisms (mice) were fed higher levels than usual to assume for human consumption, since 2,4,5,T is not used on consumable crops. 2. In the same section, Part B (pg. 17125 F.R.) the test organisms (mice) were exposed to higher levels of TCDD (3X) chan the current formulations of 2,4,5,T contain. Therefore, the use of this study is unrealistic in looking at oncogenic effcccs. 3. In the same sections, Part 2 (pg . 17126 F.F..) acute r.vt a ! it ie • to control organisns (rat.-.) -ere higher than test organism:, exposed to several concentrations of TCDD. Therefore, the test is not valid since the source of concrol mortality and subsequent test oncogenic responses may be due to pre-test history of the test organisms, or to poor holding techniques. 4. In the same section, Part 3 "Exposure Analysis", the hypothetical exposure analyses sec up a lisc of criteria which "a priori result in a rebuttable presumption. The use of a woman's weighc as the standard increases the potential exposure on a dose per weight basis. The exposed person is assumed Co have bare arms, hands, head, and sometimes legs. In addition, the aforementioned inappropriate data are used as "effect" levels. Lastly, che basis of the margin of saiecv is not explained and appears to be only a subjective appraisal of quantitative information. 17274 In light of the facts tha.t 2,4,-5,T docs not appear to result in any significant adverse effects and chac the banning of 2,A,5,T v:ould have significant adverse economic and aesthtic■consequences , The Detroit Edison Company contends thaC the benefits from the use of 2,4,5,T far out-weights the risks associated with use and a pre­ sumption against registration (and use) should not be established. Sincerely, Dennis A. Leonard Environmental Affairs bcc: J. J. Gessner A. Heidrich, Jr. J. E. Knight P. J. Eisele D O W 913426 Federal P.:■lister Section J une 1, 19 7S Page Three 1019 Part of the A lleghany Pow er Syetem C a b in Hill. G reanab urg. Pa. 15601 (412) 837-3000 June 2, 1978 Environmental Protection Agency Office of Pesticide Program Technical Service Division WH-569 401 M Street, S.W. Washington, DC 20000 2.4.5-T Herbicide Review Dear Sirs: In response to your "Environmental News Release" of April 12, 1978, I will state the benefits of the present registered uses of 2,4,5-T by outlining the field problems that would result if the use of this herbicide was eliminated. Without the availability and use of 2,4,5-T as the backbone herbicide of the brush control program on the West Penn Power Company System, the effectiveness of herbicide solutions would be reduced. The hydraulic ground foliage method of applying herbicides containing 2,4,5-T in a water carrier will result in 957. or better kill of tall-growing tree species. Basal bark methods utilizing oil products as a carrier for 2,4,5-T can result in similar results where low brush density allows these methods to be used. Without the ability to use 2,4,5-T, the effectiveness of these methods would be ’reduced 30X to 507., resulting in unsatisfactory brush control. The use of alternative chemicals presently available would result in higher rates per acre and a greater use of more persistent materials. This course of action could easily increase off right-of-way damage along the edges of rights-of-way and would force the unnecessary introduction of a larger amount of herbicides into the environment. The cancellation of 2,4,5-T for use on rights-of-way will result in higher maintenance costs to obtain a lesser degree of control. The results obtained through the use of alternative herbicides could dictate returning to hand clearing. As a consequence, our present total annual vegetation control budget of $3.5 million would increase to $6.5 million if we were to hand clear those areas scheduled for spraying. This increase in expenditure would be compounded due to returning every six years to clear the brush. An example cf typical charges following initial clearing is as follows: DOW913421 West Penn Power Company Environmental Protection Agency Page 2 June 2, 1978 1973 1975 1979 1985 1991 1993 r r Herbicide Treated Hand Cleared With Equipment Clea red $100 80 --80 Cleared $260 $1,200 - - $ 400 400+ 400+ -- Over the above 20-year portion of the line, the annual cost per year with herbicides is the total cost of $260 divided by 20 years = $13/year. Without herbicides, the total cost of $1,200 divided by 20 years = $60/year. The differential of $47 when applied to the total acres underneath our transmission and distribution system would approximate an annua 1 increase in expenditures of $4 million. Assuming this amount of money was available, it would be highly questionable whether enough men and equipment would be available to perform this type of work. In addition, with each clearing the wildlife population and habitat will be adversely affected. It is interesting to note that workman's compensation races for brush cutters and tree trimmers are approximately three times greater chan the rates for herbicide spraymen, indicating a higher risk in using saws than in using herbicides. Utility right-of-way brush control depends largely on the use of 2,4,5-Trichlorophenoxyacetic acid alone or in combination with other herbicides. Therefore, the necessity for the continuation of the registered uses of 2,4,5-T is important to the safe, economical, and uninterrupted transmission and distribution of eleccrical energy. In working in the herbicide field as a research forester, in railroad vegetation control, and in my present capacity for a total oi 15 years, I have not become aware of any toxic effects to man or animals attributable to 2;4,5-T when used according co the label. As a practical observation, I have noticed the red-taiied hawk population increases around herbicide treated utility right-of-way. The increase in population and increasing number of nests on our structures indicate a high small animal population is present to support the increase in the hawk population. It is my sincere hope that facts such as chose mentioned above, magnified by similar conditions in 3,600 U. S. eleccric utilities, present the Environmental Protection Agency with a true picture of the potential economic and environmental repercussions which could result from cancelling the registration of 2,4,5-T. -Vér^ truly yours.- ■L Peter E. Spangler System Forester T) 22tG T 6A A O a WEST PENN POWER COMPANT CC: % S v :- •c^» • r .. ^ -•- A ¡nr s 3# ^ . Hr. Douglas Cos t i e , A d m in istrator, EPA Hr. Edwin L. Johnson, Deputy A ss is ta n t A dm in istrator fo r P e s tic id e Programs, EPA Dr. Rupert C o u lter, OSDA Sen. Richard S . Scbwelkar Sen. H. John H einz, XIX Rep. Joseph S . Ansae roan Sep. John H. Dent Sep. Joseph H. Gcydos Rap. WillLam F. Goodling Rep. W illiam S . Moorhead Rep. A ustin J . Murphy Rep. John P. Murtha Rap. Gary A. Myers Rep. E. G. Shuster Rep. Douglas Walgren — - j y W '- F . “ S' .1 ( —.’S'-'< \L*3 e O fe -: 53 ? it® Owfc&7 BCC: Charles Beckwith, Dow Chemical Paul H. Johnston, Asplundh 5 cr* » J " D eo ALO i2«JM ix o T Z e -W i^ A h c .»i‘ £.7'7 DOW913423 Environmental. P ro te ctio n Agency Page 3 June 2 , 1978 1706 May 31, 1978 TO: PROPONENTS OF PHENOXY HERBICIDES June 7, 1978 - 9:00 a.m Ramada O'Hare 6600 Mannheim Rd. Des Plains, Illinois Tel. (312) 827-5131 2,4,5-T is a useful and necessary tool for the following: 1. 2. 3. 4. Right-of-way brush control Rangeland brush control Forestry Weed control in rice In order to better coordinate the activities of these interests, it was thought desirable to assemble a group of individuals that could mobilize the necessary effort to respond to the RPAR. Reasons for the meeting: 1. 2. 3. 4. 5. Establish lines of communications among the key groups present. Determine capabilities of each organization in regards to making key political and user contacts. How to achieve maximum effect with the news media on forth­ coming benefit statements from user groups. Review of RPAR process and the necessary jobs that need to be done. Review of legal actions in various states regarding 2,4,5-T. Come prepared to participate by reporting what work your organization has underway and difficulties encountered to date. We will see you June 7. sj. H. Davidson Agricultural Products Department nc 17279 0Ow 914314 MEETING TIME AND PLACE: • GROUP MEETING TO COORDINATE EFFORTS ON RPAR FOR 2,4,5-T M N 0 0 1 665 SUBJECT: -J. V THE DOW CHEMICAL July 5, 1978 D. D. McCollister L. L. Smith M. L. Leng kJ COMPANY M ID L A N D . M IC H IG A N 48640 O J. H. Davidson M. J. Traynor, 2020 J. A. Gray, 2030 $ POLICY QUESTIONS ON THE ORGANIZATION OF THE 2,4,5-T RPAR REBUTTAL I am organizing the assembly of the RPAR document and have a couple of questions which must be answered by Friday noon, July 7th in order to schedule our personnel needs. 1) Do you wish to include in the RPAR submission copies of the documents referenced in the RPAR position 'document when they are also referred to in our paper? We could instead give the bibliographic reference and cite the Position document reference number. o to lA -S> ,3 2) Do you wish to submit copies of references not directly cited in our papers? We can prepare a list of additional references which EPA would then be able to request and which we would likely be free to discuss if appropriate topics came up. We will need to know the overall organization of the document by the end of next week (July 14th), in order to answer such questions as: a) Should the references for each section immediately fellow that section, or should all references be compiled at the end? The former arrangement will allow us to compile whole volumes as the collections are completed. We can number pages using the section designation. b) Since the sections will vary in size, I do not believe we should tie our volume numbers and our section numbers too tightly together as some sections may require two volumes I suggest using Roman numerals for the volumes and capital letters for the sections. We can number our references D.r.l, D.r.2., etc. Attached is the proposed compilation schedule. Please reserve the morning of August 2nd to help us verify the accuracy of the 10 complete copies. Alice H. Morgan Government Registration Health & Environmental Research At tachment ebg 17280 ..........*:.......... / * /' , ./ r . /C lOuÜ DOW 798866 EVALUATION OF THE MUTAGENIC POTENTIAL OF 2,4,5-T AND TCDD IN RESPONSE TO A RPAR ON 2,4,5-T By B. A. Schwetz, D.V.M., Ph.D. Research Manager and K. S. R a o , D . V . M . , Ph.D. Research Specialist Toxicology Research Laboratory Health and Environmental Research Do w Chemical U.S.A. Midland, M i c higan 48640 17281 Rodenticide Act (FIFRA), the basic environmental standard CO for major regulatory determinations is "unreasonable Op oo 05 adverse effects on the environment". The term is defined in Section 2 (bb) of the act to mean "any unreasonable risk social, and environmental costs and benefits of the use of any pesticide". The Environmental Protection Agency1s registration guidelines establish the data requirements for registration of a pesticide. Sections 162.84-1 to 162.84-5 of these guidelines establish the requirements for testing to establish the safety of compounds for mutagenic effects in order to register a compound. In making the determination that a rebuttable presumption has arisen, the registration regulations require the agency to take into account the type of effect, the statistical significance of the findings, and whether the tests were conducted in accordance with the material requirements for valid tests as recognized by experts in the field. Section 162.3 (y) of the registration regulations defines the term "mutagenic" as "the property of a substance or mixture of substances to induce changes in the genetic complement of either somatic or germinal tissue in subsequent generations". An important aspect of this definition is that the EPA considers the demonstration 17282 humans. potential of a test substance since it is well recognized that it is unlikely that a single test system' is capable of assessing all potential types of genetic change with sufficient sensitivity and, in addition, incorporate the toxicological concerns relevant to mammalian physiology and metabolism, as well. Many new test systems have evolved in recent years or are in the process of being developed presently, especially in the area of in vitro short-term tests to evaluate muta­ genic and carcinogenic potential. Nearly all of these tests suffer from lack of validation between laboratories and across different classes of chemicals. Until a satis­ factory degree of reliability has been demonstrated for these tests, it does not seem appropriate to use the results of such tests for making critical regulatory decisions. For example, in regard to the microbial tests in particular, consideration must be given to the fact that it is impossible to simulate the route of exposure encountered by man in these tests, liver microsomes are not an accurate reflection of 17283 8868 Multi-test evidence is necessary for assessing the mutagenic substances through disposal of the material or its metabolites, and the influence of dose level upon response is not inter­ pretable. Therefore, the usefulness of these test systems even for the process of defining the needs for further testing has significant limitations. CD toxicity (1). They concluded that there were insufficient data on the mutagenic potential of 2,4,5-T and TCDD, and that further testing was needed. Mutagenicity was not a trigger for the RPAR. The results of the laboratory tests to assess the mutagenic potential of 2,4,5-T and TCDD are summarized in Tables 1 and 2, respectively. Our review of the literature revealed considerable additional information to that included in the RPAR Position Document 1. TESTS IN NON-MAMMALIAN SYSTEMS Negative results were reported by Anderson et al. (2) in spot tests with salmonella; ten different phenoxyalkanoic acids and five commercial formulations containing these compounds did not increase the frequency of back mutations. A group of 110 different herbicides was evaluated for their ability to induce point mutations in one or more of four different microbial systems using histidine-requiring mutants of Salmonella typhimurium. The amount of 2,4,5-T used in the test plates was not indicated. 17285 2,4,5-T was found to be "doubtfully mutagenic only after activation". In the absence of enzyme activation, 2,4,5-T was not mutagenic in any of the five strains of organisms (TA-100, TA-1535, TA-98, TA-1537, or TA-1538). In the presence of enzyme activation, there was no increase in the number of revertants in the frameshift strains (TA-98, TA-1537, or TA-1538); the increase in the number of revertants in the base substitution strains (TA-100 or TA-1535) was less than two-fold. This increase of less than a two-fold magnitude was referred to by the authors as a doubtful mutagenic effect? increases less than two-fold are generally not considered to represent a positive response in this test. Seibert and Lemperle (4) tested 32 herbicides for their ability to induce mitotic gene conversion in a diploid strain of the yeast, Saccharomyces cerevisiae. The culture medium contained 1000 ppm 2,4,5-T; no evidence of mutagenic activity was found for 2,4,5-T. Shirasu and co-workers (5) conducted tests with the REC-assay procedure using H17 REC+ and M45 REC~ strains of Bacillus subtilis. The "dose" of 2,4,5-T was 20 yg/plate; no evidence of mutagenicity was found. v. ■172SS not described in sufficient depth to critically review the procedures used. Another study in Saccharomyces cerevisiae RAD18 has recently been reported by Zetterberg (7). 2,4,5-T was found to be mutagenic at an acidic pH but not in solutions with neutral pH. 2,4,5-T concentra­ tions in the range of 0.02-0.06 mg/ml were evaluated over a range of pH values. The authors concluded that while 2,4,5-T caused mutations in acidic conditions, it was unlikely that mutations would be induced at neutral pH, such as would be found in gametes. Cells would apparently not take up the dissociated form of 2,4,5-T. Numerous mutagenicity studies have been conducted in the fruitfly, Drosophila melanogaster. In a study by Davring and Sunner (8) chromosomal defects in oocytes and nurse cells of Drosophila females were reported at very low concentrations of a commercial formulation of 2,4,5-T butoxyethyl ester. The significance of these observations 172&7 Several sex-linked recessive lethal studies have been reported in Drosophila. In a study reported by Mujumdar and co­ workers (10), Drosophila were given 2,4,5-T at concentra­ tions of 250 or 1000 ppm in their diet. A slight increase in sex-linked recessive lethals was found at the high concentration, 1000 ppm. In contrast to these positive findings, Vogel and Chandler (11) found no effect on the incidence of sex-linked recessive lethals in Drosophila given 2,4,5-T at concentrations of approximately 1000 and 2000 ppm in their diet. As already indicated above, Magnusson (9) found an increase in the incidence of direct recessive lethals in Drosophila given 1000 ppm 2,4,5-T in their diet. This was not accompanied by cytogenetic changes in the insects. * 172S8 There was no evidence of mutagenicity at 100 ppm of 2,4,5-T. TESTS IN MAMMALIAN SYSTEMS In addition to the above tests in non-mammalian systems, numerous tests have also been conducted in mammalian systems. Dominant lethal tests were performed in mice by Buselmaier (13) by injecting 100 mg 2,4,5-T/kg intraperitoneally. The males were subsequently mated during six weeks after treatment with untreated females in order to assess all stages of spermatogenesis. There was no indication of an increased pre- or postimplantation loss. Buselmaier (13) also tested for point mutations in the host-mediated assay using Salmonella typhimurium and Serratia marcescens. 2,4,5-T caused no effect at a dose level of 500 mg/kg. Thus, 2,4,5-T was found to be negative in both the dominant lethal test and the host-mediated assay. 172Ö9 S74 is based on forward mutations in the inserted DNA. host-mediated assay by Styles (15), serum from rats treated with 2,4,5-T was used with his mutants of Salmonella typhimurium. No increase in the number of mutants was observed. The results of several cytogenetic studies appear in the 2,4,5-T literature. In a study by Yefimenko (16) rats were administered 2,4,5-T at dose levels of 0.001-1 mg/kg. Chromatid aberrations and chromosome adhesions were reported after a dose of only 0.01 mg/kg of the butylester of 2,4,5-T to male rats. This interpretation is based on the information contained in an English abstract and a translation of the original article from the Russian literature. In a study translated from the Japanese literature (Fujita, 17), the effect of 2,4,5-T on cultured human lymphocytes is reported. The concentrations of 2,4,5-T ranged from 0.025-25 yg/ml. Chromosome and chromatid aberrations were reported, but as mentioned in the RPAR position document 1, it is not possible to distinguish whether this was a toxic effect or a potential genetic effect of 2,4,5-T. 17290 were observed which may have been related to toxic effects rather than mutagenic changes. The judgment of the authors in their classification of aberrations has been challenged (Ramel, 19) and leaves the value of the data reported in this paper highly questionable. Another in vivo cytogenetics study was reported by Davring and Hultgren (20) in which mice were dosed with a commercial 2,4,5-T ester formulation. Chromosomal aberrations were observed in the mouse bone marrow cells in this study but close examination of the data reveals that the effects may well be caused by the solvent and/or emulsifier used in the herbicide preparation and not by the 2,4,5-T itself. The same preparation was used in Davring's experiments in Drosophila (8). In addition to these published reports on studies of the mutagenic potential of 2,4,5-T, several additional pieces of unpublished data are included. An abstract published by Babbitt and co-workers (21) is attached regarding studies of the effects of 2,4,5-T on two human cell lines - spleen fibroblasts and lymphocytes. No data were included in the published abstract. 17231 UJ cn in the overall assessment of mutagenic potential. In the <1 case of 2,4,5-T, a study was conducted at the Dow Chemical Company in which Sprague-Dawley rats were maintained on diets providing dose levels of 2,4,5-T of 3, 10, and 30 mg/kg/day for three successive generations (22). Effects were not seen in this reproduction study which were suggestive of mutagenic effects of 2,4,5-T. If 2,4,5-T were a potent 0 mutagen which caused changes which were transmissable to subsequent generations, a reproduction study would reveal the effects of a potent mutagen. The results of this repro­ duction study, considered together with the rest of the data from all of the mutagenesis studies, indicate that 2,4,5-T is not a potent mutagen. At most, 2,4,5-T might be considered to have weak mutagenic potential. The results of the mutagenicity studies on TCDD are summarized in Table 2. Hussain and co-workers (23) reported that TCDD was mutagenic by causing intercalation in bacterial systems. An increased frequency of mutations was found in E . coli Sd-4. No effects were seen in Salmonella typhimurium TA-1530, but increased mutation frequencies were seen in strain TA-1532, a 17232 on the effect of TCDD in the Salmonella tester strains developed by Ames (24) . No evidence of mutagenic effects was observed in these tests. Two different mammalian tests have indicated a lack of mutagenic potential for TCDD. Khera and Ruddick (25) reported the results of a dominant lethal study in Wistar rats that were dosed with 4 or 8 yg TCDD/kg/day for 7 consecutive days. The male rats were caged with untreated virgin females for 5 days during 7 sequential mating trials after dosage with TCDD. The dose levels administered were clearly toxic, since 11 of 20 and 2 of 20 male rats died after receiving 8 or 4 yg/kg/day, respectively. were observed. No dominant lethal effects An in vivo cytogenetics study in rats has been reported by Green and Moreland (26). In their study, rats were given 10 yg TCDD/kg orally five times in one week; additional groups of rats were given 5, 10, 15 or 20 yg TCDD/kg as a single dose intraperitoneally. Examination of the bone marrow of these rats revealed no increase in the incidence of chromosomal aberrations relative to control rats. Another unpublished study by Green is mentioned in a 17233 CC TCDD/kg twice weekly for 1J weess. " «u x m . i c u ■:-- ... . of chromosome breaks occurred at dose levels of 2 and 4 yg/kg in male rats and at 4 yg/kg in female rats compared to the frequency of chromosome breaks at the lowest dose level. The results of this latter study are not available for review and inclusion in this response. The results of the mutagenesis tests on TCDD indicate that under some test conditions, this chemical may be mutagenic in microbes. In whole animal mammalian tests, TCDD has not been found to be mutagenic in the reports of studies that have been available for review. The recent data of Sidney Green's representing rats which were dosed on a subchronic basis with TCDD will need to be examined before a more definitive answer can be given regarding the mutagenic potential of TCDD in mammalian systems. Based upon the definition by EPA of the term "mutagenic" (the property of a substance or mixture of substances to induce changes in the genetic complement of either somatic or germinal tissue in subsequent generations), the results of studies of the mutagenic potential of 2,4,5-T do not indicate that this herbicide represents a mutagenic hazard. 17234 CO GO Heritable mutagenic changes induced by 2,4,5-T have not been demonstrated. CONCLUSION In conclusion, numerous studies have been conducted to evaluate the mutagenic potential of 2,4,5-T and TCDD in nonmammalian and mammalian test systems. None of the studies in microbial organisms indicate a significant mutagenic effect,.for 2,4,5-T. One study in yeast indicated mutagenic changes at acidic pH's but not at a neutral pH as found in mammalian tissues. Positive and negative results were seen in studies in Drosophila. Tests in whole-animal mammalian systems have either indicated negative results (dominant lethal test, host-mediated assay and micronucleus test), or uninterpretable results (cytogenetic studies). Thus, 2,4,5-T is definitely not a potent mutagen and might be classified, at most, as a weak mutagen in some test systems. O Additional data from one laboratory w hich have not been published are reported to indicate a positive cytogenetic change in rats dosed subchronically with TCDD. The final evaluation of the mutagenic potential of TCDD should take uix<=o<= u a u a xxxL.vj a o ^ u u m . wixcrxx uxxcsy u c u u u ic a v a n a u i c • ^ ^ ^ ^ M 4« ^ ^ M> ■ *■ !^ t *• «>%4a 9 *1% M 4« •w W M A VM ^ ^ a 1 «a W 1 . 1. . . (1972) Evaluation of herbicides for possible mutagenic properties. 3) J. Agr. Food Chem. 20_, 649-656 . Ercegovich, C. D. and Rashid, K. A. (30 August 1977) Mutagenesis induced in mutant strains of Salmonella typhimurium by pesticides. 174th American Chemical Society National Meeting, Division of Pesticide Chemistry. 4) Siebert, D. and Lemperle, E. of herbicides: (1974) Genetic effects induction of mitotic gene conversion in Saccharomyces cerevisiae. Mutation Research 2_2, 111-120 5) Shirasu, Y., Moriya, M., Kato, Furuhashi, A., and Kada, T. (1976) 6) Mutagenicity screening of pesticides in the microbial system. Mutation Research 40_, 19-30. Fahrig, R. Comparative mutagenicity studies (1974) with pesticides. IARC (International Agency for Research on Cancer) Scientific Publications 10, 161-181. 17297 Hereditas 68_, 115-122. 9) Magnusson, J., Ramel, C., and Eriksson, A. (1977) Mutagenic effects of chlorinated phenoxy acids on Drosophila melanogaster. Hereditas £5, 121-123. 10) Majumdar, S. K. and Golia, J. K. (1974) Mutation test of 2,4,5-trichlorophenoxyacetic acid on Drosophila melanogaster. Can. J. Genet. Cytol. 16_, 465-466. 11) Vogel, E. and Chandler, J.L.R. (1974) Mutagenicity testing of cyclamate and some pesticides in Drosophila melanogaster. Experientia 3£, 621-623. 12) Rasmuson, B. and Svahlin, H. (1978) Mutagenicity tests of 2,4-dichlorphenoxyacetic acid and 2,4,5-trichlorophenoxy acetic acid in genetically stable and unstable strains of Drosophila melanogaster. Ecol. Bull. 2_7, 190-192. 172ÏÏ8 3 14) Jenssen, D. and Renberg, L. (1976) Distribution and 98884 Zbl. 91, 311-325. cytogenetic test of 2,4-D and 2,4,5-T phenoxyacetic acids in mouse blood tissues. 15) Styles, J. A. (1973) Chem. Biol. Interact. 14_, 291-299. Cytotoxic effects of various pesticides in vivo and _in vitro. Mutation Research 21, 50-51 (abstract). 16) Yefimenko, L. P. (1974) Materials for assessing the gonadotropic and mutagenic action of the herbicide 2.4.5- T butyl ester. Gig. Tr. Prof. Zabol. 1£, 24-27. (Pesticide Abstracts 1_, abstract #74-2885) . 17) Fujita, K., Fujita, H., and Funazaki, Z. (1975) Chromospheric abnormalities brought about by the use of 2.4.5- T. 18) J. Jap. Assoc. Rural Med. 2A_, 77-79. Majumdar, S. K. and Hall, R. C. (1973) Cytogenetic effects of 2,4,5-T on in vivo bone marrow cells of Mongolian gerbils. Journal of Heredity 64, 213-216. 17239 a commercial 2,4,5-T ester product. 21) Hereditas £5^ 123-134. 8885 of iji vivo bone marrow cells of Mus musculus induced with Babbitt, B., Risch, S., Choffnes, E., Kalis, J., Zupanic, M., Boody, G., Benson, D., Spier, S., Kleese, R., and Wickstrom, J. chromosomes. 22) (1972) Effects of 2,4,5-T on human Genetics 7^1, s3 (abstract). Smith, F. A., Schwetz, B. A., Murray, F. J., Crawford, A. A., John, J. A., Koçiba, R. J., and Humiston, C. G. (1978) Three-generation reproduction study of rats ingesting 2,4,5trichlorophenoxyacetic acid in the diet. R&D Report - Dow Chemical Co., U.S.A., Midland, Michigan. 23) Hussain, S., Ehrenberg, L., Lofroth, G., and Gejvall, T. (1972) Mutagenic effects of TCDD on bacterial systems. AMBIO 1, 32-33. 24) Ames, B. N. (1974) Communication from Dr. B. N. Ames to Dr. P. C. Kearney. 17300 Khera, K. S. and Ruddick, J. A. perinatal effects and the dominant lethal test in Wistar rats. 26) 27) Polychlorodibenzo- Chem. Ser. 120, 70-84. 798886 p-dioxins: (1973) DOW 25) Green, S. and Moreland, F. S. (1975) of several dioxins in the rat. Toxic Appl. Pharmac. 33_, 161. Moore, J. A. p-dioxin. (1978) Cytogenetic evaluation Toxicity of 2,3,7,8-tetrachlorodibenzo- Chlorinated Phenoxy Acids and Their Dioxins. Ecol. Bull. 27, 134-144. \ Iu TABLE 1 Summary - Laboratory Tests For Mutagenicity of 2,4,5-T Test System Reference Number RPAR Reference Number Dose(s) Tested Results Ames Test Not stated - 110 Herbicides were tested 2 Not listed Ames Test A. 9 pg/plate + Doubtfully mutagenic after activation 3 148 Comments Saccharomyces cerevlslae D. --------— <-------------- 4 1000 ppm - 32 Herbicides were tested 4 Not listed Bacillus 6ubclll6 20 pg/plate - 166 Pesticides were tested 5 Not listed 31 Pesticides were tested, very little description of methods 6 Not listed *> E. coll (5-MT resistance) Î E. coll (Gal RS strain) CO o Serratia marcescens (a 21 and a 742 strains) - ? ^ LO E. coll (strep, resistance) 7 _ Saccharomyces cerevlslae 7 - In Vitro Cytogenetics (human lymphocytes) ? Saccharomyces cerevlslae HAD 18 Û.02-0.06 mg/ml J + Mutations only at pH < A.5; o.II r -If i nr <; ip^ ' 1 i *1 v ;i r ntMiCml Drosophila melanogaster (in vivo cytogenetics) 1000 ppm in diet Drosophila melanogaster (direct recessive lethal) 1000 ppm in diet Drosophila melanogaster (somatic mutations) Host-Mediated Assay and Dominant Lethal (mice) 100 mg/kg IP Micronucleus test (mouse) 100 mg/kg Host-Mediated Assay (salmonella typhimurium) In Vivo Cytogenetics (rats) H* «si CO 25-200 ppm In diet ? 0 .001-1 mg/kg In Vitro Cytogenetics (human lymphocytes) 10~7 -10_AM) (0.025-25 pg/ml) In Vivo Cytogenetics (gerbils) 10-100 mg/kg/day CD U3 In Vivo Cytogenetics (mice) Not seated + + + 50Z Decrease in fertility at 250 ppm chromosome effects seen; unsubstan­ tiated in other tests 8 172 Slight increase in sex-linked recessive lethals at 1000 ppm 10 178 No effect on sex-linked recessive lethals 11 Not listed Same sample used by Davring and Sunner (1971) 9 Not listed - 9 Not listed 12 Not listed Tested In genetically stable and unstable strains - - 13 Not listed - - 1« Not listed - Used serum from rats dosed with 2,4,5-T (abstract) 15 Not listed + Abstract and translation only 16 151 +? Not possible to tell If effect was mutagenic or toxic 17 169 70 & ig/kg Questionable classification of aberrations 18 169 + Effect may have been due to solvent or emulsifier 20 171 Poseí >3 7•seed Test Svscea r isuLcs .bes Tese Not s t a t e d 110 H e r b i c i d e s w e r e t e s t e d A ae s T e s t 1. 9 „g. p l a t e Oo u b cf u LL v c u c j ^ n u accivaclon Saoc'narosYces c e r e v i s t a e D, 3JCÜ.1-J» SUOCiLid E. c o l i v2-MT r e s i s t a n c e ) . C3Í i ^j>il S 1-3 LOUO pen 32 H e r b i c i d e s w e r e t e s c e d Not listed 20 place Ibo P e s t i c i d e s were t a s t e d Not listed a'CTj • " ) j e r r acid r a rc o s c e n s la _ l a.u a 7-2 s e r e i n s ) l» c rep . ho c l i s t %:d after 31 P e s t i c i d e s w e r e t e s t e d . .•«:£■■.• l i t t l e d e s c r i p t i o n a f - i e t. . . u is resi s t anee? Saccrarcrfoes c-areMitae in . i c r a •.vcocenecie s \ \:-jzan l•—?nocyces > aa c : : u r : r . v : ¿ a c e r o v l . ^ t a e HAJ 13 0.01-0.Cr rc/di 130 rr~ Dr;so oni.a telano-Mst-jr (ettect in acienesLj; D ro sjo rila re la n o sa ?ta r 1 >cx*Lir..sed r e c e s s i v e l e t h a l ) D ro sa o h ila r.e ia r.o c js :e r je:c-L ;n . J. - 1,. r ----xViyj TAHl.K ■* 1 'fUt-. ^^ ,t.■. '< N iX Ce/\ i (M. ■, Summary - Laboratory Tests For MuLagenicity of 2,4,5-T Positive Mutagen Dose(s) Tested Test System 2.4.5- T: Results Employed Comment s Yes 110 Herbicides were tested Non-Mammalian Mutagenic Tests > . Ames Test Not stated *- A, 1■' ' ■' ' i ' w £lU^a , A\., U a-.^ -c. /,A , r ^-Uju ju,1 J. -.aí •.y.U ßi,j^X | ' 7 f. 2 ¿\t 1 ‘ 1 : Davring and llultgren, 1977 Hereditas^ 85, 123-134 798891 J. Agr. Food Ge i1. 20, 649 Ames Test ^ f , '■ ín ’ -TTJjTHA^x^ yd ffrvprv**' fy OOW 7 9 8 8 9 2 " ^ n r ? 1.s h _^y nyy>-0 • p m * 9 * ' 'Z i -bP V T*?*' w^nrtfV^T f f f l f * * 1" Hippmpr>'^o 'jin ^^vtx WO-nO'o 8i ava ^ 9QZ-S1. ¡ría/ ^| LhP) ^ »vw x -o rtlQ 7>tf yr^ry tyf-mA^ros wi^00^ ■1 5 1 |W “7/ X a ’' f p p " ? f ^ f T f 17 èy j-lo ro ixÿiï^itBiyVQ" (^-rpjv} ^ n j v ^ ^ Qy^-Q / o-rvvv ^ TrtfrvT? fT T (- jtoW % y jíi» U 'Q Q ¡ '-^ ] ^ ^^ ^v\ (^_c YinTl^mvv0v3iRA fc» ^ '^ ? ( ^ S P i f c r q T 7^ ' * * " ? ) 2 ( ^ r ^ q r lh L T ° Y ~ ° I ? V ) C ^ r f ffy ) ^ P -a ^ r v r i/j j y .ç ) * fiü UM T t'^TTT^^VTrV«/^' ^VT^^vVT^ ORP7T^ ^ ' p r v < T*rnr‘n ítfn rp J i £ J yyn-rrv >-*-07? fffV. y ri V- ' ^ z f X V 1 iw 2 yy*) ■J D r^ yw 'T^V TTT^/' c —^ Yty"*y ^^000| é«=e 6 (^ p-vvOTT^Trvt^" Ç trvyOTJjryjrVtA/ n ^tíí^vj^va/ Drynv4^xOV 7*^* p ^rg y mnr»TrvrV3y V73^ m 5 vV>^V s (~ UOVY 7 9 8 8 9 3 c (Vf s 17309 TABLED ? Summary - Laboratory Teats For Mutagenicity of TCDD _________ Test System_________ l)ose(r;) Tested TCDD: Ames Test In Vivo Cytogenetic (rats) In Vivo Cytogenetics (rats) j/c-aJL O ____________ Kelerencu up to A.G pg/plate + Ho Not stated - Yes - A memo to USDA Hussain, S. e£ ail^ 1972 Ambio. 32-33 Ames, B. N., 1974 (unpubl islied) i tn Mammalian Mutagenic Tests Dominant Lethal (rats) to Resul ts Non-Mammalian Mutagenic Tests Ames Test and E. Coll TCDD; Positive Mutagen Employed ______________ Comments_________ ■ I 0, A, Ö pg/kg No Highest dose level lerLal to some of the males 0, 5, 10, 15, 20 pg/kg No Abstract - m i y üreen, S., 1975 Toxicol. Appl. Pharmacol. 33. 161 t<0 Abstract and translation only Yeflutenko, L. P., 1974 Gig. Tr. Prof. Z.ihol. IB,' ^ 0.001 - 1 mg/kg + fJiuA ^ pAMiL«ttallLer^ Klieru, K. S. and Ruddick, . . A., 1973 Advances in Chemistry 120 70-84. ^6886^ MOO