fd Cotrnel. Toxicol. Vol. 5, pp. 293-308. Perjiinon Press 1967. Printed in Great Britain BIBRA Annual Scientific Meeting * Scientific Evidencesind Common Sense as a Basis for Food-Packaging Regulations J. P. Frawley Hercules Incorporated, Wilmington, Delaware 19379, USA I ara honoured by your invitation to meet with you tonight and to discuss with you some of the problems associated with assuring the safety of food-packaging materials. However, I am equally humbled by my own inadequacies to discuss our subject matter as expertly as it deserves. Unfortunately for all of us, there is no individual who can be considered an expert on all aspects of food packaging. Although essentially all of the individual components used in food packaging originate in a chemical plant, the technology for formulating and converting these materials into useful containers varies with every substrate, whether it is plastics, paper or metal. Moreover, the marketing relationship between producer, formubtor, con­ verter and the food industry is notably different for each segment of this complex industry. Consequently, it is a formidable task to become an expert for even one aspect. Each of you here this evening possesses expert knowledge in one or more aspects which I wish I had. It is unfortunate that telepathic communication has not reached my level of intellectual development, so I could benefit from your experience. In fact, the only thought waves reaching me suggest that many of you should be delivering this lecture rather than I. Therefore, tfyou will consider me to be a substitute speaker, you may be alittle more tolerant towards my remarks. When was the last time you sat down in the solitude of your study and attempted to write out a geometrical proof that the shortest distance between two points is a straight line? Most or us would have a difficult time doing it today because, as you recall, it is not sus­ ceptible to proof. It must be accepted. Indeed, some of the most difficult things in life to prove are the obvious ones. A number of months ago, I sat down to try to prove something which was obvious to me—that there are some uses of food-packaging materials which cannot involve any hazard to health of the consumer of food. I had no preconceived idea of the end point I would reach, but it seemed like it would be fun. Sometimes now I wish I had resisted the temptation and invested my time in some other form of recreation. My main exercise was to try to determine a level of use of any food-packaging component which could be considered safe regardless of its degree of toxicity. Many of you know the conclusion I reached; namely, that any component of a food container or coating which is 'Editor's note: This paper was delivered to the Fifth Annual Scientific Meeting oT the British Industrial Biological Research Association (JtIBRA), held in London on 25 January 1967. The Annual Scientific Meeting, instituted in J 962, pro* ides an opportunity for members and guests of the Association to receive an address from an eminent toxicologist on atopic related to BIDRA's field of interest. Previous speakers have been Professor H. C. Hodge, Dr. A. J. Lehman’, Professor L. J, Goldwatcr and Dr. J. M. Barnes. 293 RSV 0012026 c 294 ( J. P. FKAWLEV present at 0 2% or less is safe beyond any reasonable doubt, and consequently, should not be subject to government regulations. When I first advanced this proposal, it was presented within the framework of existing legislation in my country, as a mechanism for correcting some of our mistakes. Tonight, I shall cast my remarks in a different vein, since your country has not yet committed itself to a regulatory procedure on packaging materials. I do not pretend to be able to propose the best regulatory procedure for Great Britain. There are too many aspects of your business and government operations which 1 do not understand. However, I can review some of the evolutionary history of our regulatory procedure and suggest some ways to avoid the mistakes we have made. According to the title of my lecture, I am scheduled to talk about scientific evidence and common sense. For no particularly good reason, I am going to reverse this order and address myself to the common-sense aspects of food-packaging regulations first. It has always seemed axiomatic to me that in all matters of environmental health, the degree of hazard should define the degree of control. The amount of attention devoted to each problem should be in relation to the hazard. To distribute our limited efforts on any other basis is a form of gambling with public health. Unfortunately, in this decade of doubt, the scientific community has little conlrol over the area of its explorations. For the most part, the decision is made by national governments as to which area of environmental health should receive concerted attention and a! least in the United States, these decisions are not always made on the basis of relative hazard to health. This certainly has been the case for food-packaging materials and it appears that many countries are prepared to follow in our footsteps. In order to give a certain degree of perspective (which I believe is the foundation of com­ mon sense) in this matter, let us reflect on a few of the sources of environmental exposure to chemicals. Obviously the overwhelming majority of the chemicals to which we arc exposed are the natural ones which constitute our diet. Wc tend to overlook these and seem to be content in assuring society that synthetic chemicals will not cause more disease than wc already have. Reluctantly, I shall dismiss any further comments on these natural products except to note that it is refreshing to have Dr. L. Golberg and the BIBRA staff occasionally remind us of our prejudice. If we restrict ourselves to a consideration of synthetic chemicals contributed to ottr environment, certain obvious sources come to mind: drugs, pesticides, food additives, air pollutants, water pollutants, cosmetics, occupational exposures, household chemicals and food-packaging. As I have already suggested, logically, the amount of lime and attention devoted to each of these areas should be in relation to the hazard to health. Sometimes the hazard lo health is difficult to evaluate until a significant amount of lime and money has been invested. However, after the degree of hazard has been defined, we have the responsi­ bility of accepting the facts and of adjusting our cITort accordingly. In recent years, in the United States, wc have invested more industry, government and university time and money on food-packaging materials than on any environmental health problem other than pesticides and drugs. At the same time we have constructed a complex and restrictive maze of government controls which is too involved to be understood by the regulated industries. After 8 yr of effort wc have now clearly demonstrated that the return on our investment has been negligible and that the health hazard is slight in comparison with other sources of chemical exposure. Consequently, I believe wc have a responsibility to the public of restoring a more equitable balance to our programme. By on equitable balance, I do not mean that wc should ignore all aspects of food packaging, but find some RSV 001202? FOOD-J’ACK AGING CONTROL 295 common-sense approach to allow us to concern ourselves with potential hazards and not with predictably safe practices. . . It is to this assignment that I applied myself last summer—to try to develop a scientific ■ basis for a start, and only a start, towards a common-sense approach to food-packaging regulation. However, before proceeding with the scientific evidence I have collected and the conclusions I have drawn, I have made two statements which require documentation. First, that the return on our investment has been negligible and second, that our regulatory scheme has been too complex to serve its intended purpose. Following enactment of our law, the major task facing the industry was evaluation of -current industry practices. Many of you are familiar with some of the larger research -programmes undertaken by different segments of the industry, for example, the petroleum • wax studies by the American Petroleum Institute, the can enamel studies by the can pro: ducers and the rosin product studies by Hercules. Many other programmes which, received .less publicity were conducted on regenerated cellulose, polyethylene and other polymers, -paper coatings and wet strength resins, to mention only a few. The net result of this invest;-ment of millions of pounds has been that more than 90% of the prior industry practices -have been confirmed as safe, through a combination of low toxicity and low migration, and - have been endorsed by our Food and Drug Administration (FDA), by inclusion on our - permissive list. This general endorsement of the vast majority of industry practices testifies : to the fact that most uses of packaging materials are inherently safe. V However, before sufficient facts were accumulated to confirm the low degree of hazard associated with packaging materials, we had committed ourselves to an “omnibus*’ perrmissive list, containing every conceivable chemical which might even remotely come in r contact with food. Wc now have 94 separate food-packaging regulations or lists dealing with different uses of packaging chemicals, from 967 ingredients* for adhesives to S ingre-dients for zinc-silicon dioxide matrix coatings. These regulations contain over 43,000 words, : about 10,000 words more than the regulations for all intentional food additives. In 1966 ; alone, the 8th yr of the law's existence, over 200 new uses of packaging chemicals were ; approved and published in our Federal Register. Even a superficial examination of these : regulations reveals tbat'thc vast majority of these words are devoted to the enumeration of ; thousands of chemicals for one or more specific uses under which most cannot migrate to ; food at an unsafe level,‘regardless of their degree of toxicity. Unless you work with these ; regulations on a daily basis, are familiar with the multiple cross-references and have -■.sufficient technical training to* understand what chemicals are covered by some of the vague r generic terms, it is almost impossible to determine the approved uses of a given chemical, vWe have created a complcx jnaze of regulations, too lengthy and involved to be understood : by most of the regulated industry,"with the unanticipated result of a growing apathy towards ; correct interpretation. _ ........ . ' This type of “omnibus* permissive list came about in the United States at the insistence : of some segments of industry, coupled with a change in interpretation of our laws by the 7"FDA—a change which revoked the long-established principle of de minimis nan curat lex • .(the law does not concern itself with trifles) by claiming that the law docs not recognize any :;ievel of a chemical as insignificant. This denial of the existence of a toxicologically-insignij ficant level or biological zero fs“analogous to a denial of the existence of night, on the rgrounds that you cannot prove the absence of light. In all countries outside the United *.*967 does not count the numerous reaction products cleared for one or more of these chemicals. If these .- - are counted, tlie number exceeds 3800. RSV 0012028 296 3. P. FJIAWLEY States, the term toxicological insignificance has real meaning and significance. I believe it is a sound scientific principle which must be preserved and eventually I hope will be restored in my country. It is this principle which 1 believe is the very' crux of intelligent commonsense regulation of food-packaging materials. Let us take stock. Experience has taught us that most uses of food-packaging materials are safe beyond any reasonable doubt. Experience has also taught, at least iu the United States, that an “omnibus” permissive list not only diverts the energies of our corporations, government and universities into predictably, unprofitable research, but can lead to some, if not general disregard for the law. This leaves us with the epnclusion that some mechanism should be found for subjecting to a permissive list only those uses of packaging materials which pose a potential hazard to health; that is, constructing a “non de minimis list” or “relevant" list. Here is where I invite each and everyone of you to sit down and define those uses which can be assumed to be safe. As I stated earlier this exercise sounds like fun, but it is just plain hard work. I am not certain that my solution is the best, but I assure you it is the result of many hours of reflection and analysis. In its briefest form, I believe that-any chemical suitable for use in food-packaging is safe for man at a level of 0*1 ppm in the total diet. Extrapolating this dietary concentration to a practical and meaningful guiddinefor regulatory purposes, use of a chemical in a container at a level of 0*2 % or less will contribute less than 01 ppm to man’s diet. On the surface, this may not appear to propose a major improvement, but application of this guideline would permit deletion of 75% of the citations in the United States regula­ tions and I nin certain would permit more efficient use of manpower, in establishing permissive lists in other countries. I do not ask that you accept this conclusion on faith. So, as briefly as possible, 1 should like to review the scientific basis for this conclusion. First of all, what level of a compound, which is suitable for use in food packaging, but of unknown toxicity, can be assumed to be safe in the human diet? 1 know or no better approach to answering this question than to examine our toxicological experience and tabulate the experimentally determined S3fc level for all the compounds which have bceo studied. Because 90-day toxicity studies are generally considered inadequate for calculation of safe levels and because only a small number of these are published, I decided to review as many 2-yr chronic toxicity studies as I could find and to tabulate the "no-eflect” level confirmed for each. I can make no claim that 1 have found every 2-yr chronic toxicity study which has been conducted. I can only claim that I have tabulated the “no-cffcct” levels from every chronic study which I could find, without any selection or rejection except irradiated foods. In total, I was able to locate 2-yr chronic toxicity studies on 220 different substances (see Appendix), and although this may seem like a modest number, it represents between 4 and 7 million pounds in toxicological research. Last September I had been able to locate only 143 such studies, but with the co-operation of many of my colleagues in the field of toxicology, I-estimate that I now have collected about 90% of all such studies which have been conducted. Table 1 presents the distribution of “no-cfl'cct” levels for all of the 220 compounds. It is apparent from Table 1 that a small percentage of compounds will be extremely toxic—having a “no-eflect" level in experimental animals below } ppm, but that the majority wilt exhibit no toxic cflcct even at 100 ppm. Only 19 of the 220 compounds demonstrated RSV 0012029 FOOD-PACKAGING CONTROL 297 Table 1. Distribution of “net-effect" levels in 2-yr chronic studies •■No-effect” level (ppn>) All compounds (220) <1 <10 <100 <1000 <10.000 5 19 40 101 131 any toxic effect below 10 ppm. We might conclude that the odds of detecting a toxic effect at 10 ppm from any “unknown” compound are approximately 1 in 10. Let us now look at Table 1 a little more closely and examine the nature of these 19 compounds which had a “no-effect” level at 10 ppm or less. Table 2 shows the same in­ formation as Tabic 1, except two additional columns have been added which subdivide these 220 compounds into two categories: (1) a “heavy metals and pesticides” category and (2) an “all other compounds” category. I believe this breakdown is worthy of careful examination. The most apparent conclusion is that all 19 of the compounds, which were toxic below 10 ppm, were pesticides and heavy metal compounds. Equally significant is the fact that 39 of the 40 compounds, which had “no-effect” levels below 100 ppm in experi­ mental animals, were also pesticides or heavy metal compounds. The ouly compound in the “all other compounds” category which was toxic below 100 ppm was acrylamide. Table 2. Distribution of effect" levels in 2-yr chronic studies “NoefTcct” level (ppm) All compounds (220) Heavy metals and pesticides (88) Others (132) <1 <10 <100 <1000 <10.000 5 19 40 101 151 5 19 39 72 16 0 0 1 29 <5 It is obvious that the degree of toxicity of pesticides and heavy metals (which were used as pesticides at one time) is quite different from that of other commercial chemicals. Tills should represent no surprise because pesticides are synthesized, screened and selected for their toxicity to one or more forms of life before becoming commercial products. This contrast is more clearly shown by Fig. 1 which depicts the distribution of “no-effcct” levels for the two categories of chemicals. It is obvious that the average toxicity of a pesticide is about 100 times as great as the average for other chemicals. RSV 0012030 teo?too A S* pajao(as 3Auq I uoijtpps uj *iadcd 'Xpnitu 'pooj Xq uouoBJjxaoj aiqijdaasns puB s[q\tauit3d isoui aqj s< qaiq* ojiujsqns aqj pajoajas i 'sajcjjsqns jo sadXj |pj qju\ pip aip oi uidd [-0 utq> s^3l amqtijuoa pinoA\ qjiipw uoijipp« jo isaoj aqj auiuuajap oi jopjo ni 'ajojajaqj, •suojjrjnSaJ jo uojjvaqduioa Xjtjsnf oj juanryns jou aja saauajajjtp asaqj jo isonz jnq *asn papuajui sji pus ojyjjsqns SuiSopcd-pooj qa«a joj sj3A3[ jo sauas ajoq.sv u qsjjqBjsa pjnoa 3AV Maqjouu joj ueqj jaiuXjod auo joj juajajjtp aq yui j£ -sapjoq joj ueqi suipj joj juaiajjip aq n!'^ U *ai«JJsqns jo adXj qaca joj juajajjip si aug SuipiAip siqj ‘Xjpajqnopajq auij SuiptAip stqi pug oj si uiaiqojd mo ‘jaip aq) oj uidd i-o ojnqujuoa :ou jjtm sasu auios jeqj ‘snoiAqo Xucnba si ji 'junior ■asiAuoqjo ubaojcI ssapm •uidd [-o jo ssaaxa ui jaAaj b jb pooj oj SutjejUjui jo Xjii.tqBduo aqj ssassod oj paumssv aq jsiuu jauisjuoa pooj b jo juauodutoa jofuin Xub jeqj auo-tma oj snoiAqo sc ji *ip* jo jsiy •joairca sasn qarqAv pus ‘ubcu jo jaip aqj oj uidd l-Q ucqj ajoui ajnqTJjuoa Xbui sasn qorq.A sn qaj jjia\ qacipw sanqaptnS auios dopAap oj jdoiaue puu—pooj oj uoijBjStm—uisjqojd jno jo jaadsB jaqjo aqj Xgatjq japisuoa aui ja[ mo^ *uaaq aABq [ sduqjad pue 'aAijBAjasuoa Xirjessaaautm aaaq 3A®q | J«qi anftiB Xbui auios 'spunoduioa ZZl °q) J° apcoi jsoui aqj jo a^Bjui Xap/Sq/aiu aqj q)C00(/l uuqj ssa[ saptAOjd jatp uBumq aqi ut [3A3[ tudd [-o aqj jcqj A\oqs suoije{na[ea jeuoiiippe asaqj ‘paujquio^ *ubui snsjaA s5op puB sjbj jo jqSt3A\ Xpoq jo 3q jad uorjduinsaoa pooj jaSjiq aqj uoijcjapisuoa ojut aqBj jou pip { 'jsAoojojq ’uidd Q£ jb sjuuiiue oj ajss 3J3a\ rb jeqj papiqauoa aq uua ji 'uidd 00£ jo ooi *0€ *01 sduoj3 uuuis ojoj papuipqns cub sjaAaf ,tj33jja-ou„ asaqj jj *apnjiuSBui jo sjapjo ui Xjuo qeap avucj j uotiB[no]U3 3AoqB aqj ui jcqj jno jujod pjnoqs j 'XoBJnosB joj ’pjezuq qj[Kaq Xub oj aqqnd aqj pasodxa 3Acq jou pjnoM pu« sosbo aqj jo %00I ui pa.uoa uaaq aABq pjuoa\ oav *sa;pnjs Xjiapco; jnoqjiA\ [3Aa[ jBqj oj dn asn Jpqj pauiuijad puu uidd |-o ajus l[B ojbav Xaqj j«qj patunsse o.w pcq jnq 'pooj ui spA3[ joqtJtq qonui lu.posn aju s[BuajBui asaqj jo Xubj^ ‘jaqSiq jo uidd j-q jo uotjuujaaanoa Xaejaip b jb jaip s,ubui joj ojbs ojb s(Baiuiaqa jBpcaijsad-uou aqj jo 'spAa^ Mjaaya-ou„ pautuuajap X([cjuaui;jad>:a asaqj oj Xjajus jo uiSjbui P[Oj-Q0I icuoijuaAuoa aqj Xjdde sav ji a-ioj^ *s{*3;iuatp isqio nawli ^UBjq puv 'sjcjaui XAcaq puv cappiifad aiouap seuc pspeqs *spunoduraa QZZ uo uipnts wuoiqa ijC-j ut sjaASj ^jaajja-ou,. jo uoiinqiijstp Suiaxoijs iuuSoistj{ "I ‘Oij HffU 000*001 OOO'OI 000 *|»M| |9fl||«-OU 00> i/OtaiQ 01 p 1 rj% f* ^s*^ >’• - M "S h&U ss3] jo uidd oi js Xjpixoj Xub qqi.qxa giM jaquinu {[cues Xjaiiugui ub jBqi pun uidd oof Aiojaq [3Aa[ „jaaya-ou„ « aABq iji/a punoduioa (Biajaumioa (ooi jo mo \ uuqj JdA\aj) (buoisboso Xjoa b X[UO jBqj pajuarpui SBq aauajjadxa 'uoijcjapisuos jno uiojj sapcaijsad pue s^cjaui XABaq apnpxa om ji 'ajojajaqj. A3TLWVTU -<£ *f 8SZ c ( FOOD-PACKAGING CONTROL 299 an additive which is very readily extracted from its substrate, namely, rosin size. Tins combination of substrate and additive, I believe, represents the most extreme case of migration and values determined from rosin sized paper should represent a maximum for any component of any packaging media. Indeed, such data would be excessive for most uses of packaging components. In our initial efforts to study the migration of rosin size from paper, we used typical simulated solvents: various aqueous solutions, hexane, maize (or corn) oil, etc. This was wasted effort because, in water and oil, the extraction was a direct function of lime and temperature and did not plateau until essentially 100% of the rosin size was extracted and the integrity of the paper sheet was destroyed. Nevertheless a century and a half of experience has shown paper to be a satisfactory packaging material. Although these studies clearly demonstrated that rosin sized paper would be an appropriate choice for developing maximum migration data, they contributed nothing to the evaluation of safety of rosin size which was our principal motive at that time. As a consequence of this failure of the simulated solvents test to help define the. amount actually migrating to food, we prepared radioactive samples of rosin size, incorporated them into typical commercial paper and paperboard at known levels, packaged a wide variety of food in contact with these paper samples at typical package ratios, stored them at typical storage temperatures for typical storage times and determined the rosin size content of each food by counting the radioactivity. The study was far more extensive than I shall describe, because wc used several types of paper (greaseproof, waxed, unwaxed, etc.), containing three different levels of rosin size, 24 different types of food (water, ice-cream, oysters, apricots, green beans, dry breakfast Table 3. Maximum migration o[ rosin size* from uncooted paper under typical storage conditions Food Milk products Water Ice-cream Vegetables Green beans Green beans Lettuce Potatoes Meats Grouod beef Chicken Beefsteak Sausage Fruits Aprieots Apples Grain products Puffed rice Wheaties Flour Doughnuts Others Sugar Butter Temperature <*F) Time (days) Migration (ppm) 34 10 14 28 5-9 0-3 34 72 34 72 7 14 7 28 1*3 41 2-4 0-2 34 34 34 34 5 3 7 3 8-7 7-2 49 . 1240 72 72 28 28 Od 1-2 72 M 72 72 14 28 28 3 3-8 7-0 02 04 72 94 28 14 0-2 328 *4% in paper. RSV 0012032 * i I I c ( 300 J. 1*. FRAWLCY food, sugar, doughnuts, ground beef, butler, bacon, sausage, to name just a few) and anal, ysed each sample at several different storage intervals and temperatures. For our purposes I have selected only the uncoatcd and unwaxed paper and only the maximum migration levels obtained for the 18 commodities packaged in these uncoated papers under typical commercial storage conditions. Admittedly this gives unrealistically high values for rosin size which are not typical of industry practice, but for our present purposes, the worst case must be presented. Table 4. Calculation a/ maximum migration of resin size* to __ total diet * Commodity group Milk products Vegetables Meats Fruits Grain produets Sugar Butler, oils Percentage or diet 31 20 It 13 10 5 • 3 Contribution Average to total migration diet (ppm) (ppm) 31 1-0 2*0 0-4 38-2 6-9 05 0-1 35 0-4 0-2 0-0 328 09 Total... 9 7 *4% in paper. Table 3 shows the maximum migration value for 18 food commodities at various typical Storage times and temperatures when exposed to paper containing an average of'4% rosin size. It is obvious from some of these values that high levels of migration can occur with some foods, whereas other foods contain much less rosin size. The data in Table 3 can be quickly considered since the individual values are of no great significance, but the com­ posite of these values can be helpful. Table 4 shows the average consumption of these various commodity groups in the USt, the average migration to that commodity group and a calculation of the maximum level of rosin size in the average total diet, if 100% of the diet were packaged in uncoated paper containing 4% iosin size. Undoubtedly there art some differences in dietary habits between our countries, but 1 doubt that they would significantly alter the calculation. As 1 mentioned previously, three different sizing levels were used in these studies. Table 5 shows the final dietary calculations for the same foods, under the same conditions for paper containing 2 or 1% rosin size. The extrapolation is remarkably good. The last column shows the migration in ppm expressed on the basis of a unit of 1 % rosin-size in the paper or container. For each per cent addition to the container, man’s diet would couiain a maximum of 2 ppm of the additive, if the entire diet was in contact with that container. One further calculation is necessary in order to arrive at a realistic determination of the Table 5. Maximum Migration of rosin site to diet Level of sisus in paper (%> 4 2 1 Migration (ppm) ppm 97 4*4 1-9 24 22 1-9 fU-S. Department of Agriculture Dietary Evaluation of Food Used in Households in U.S., 1961. RSV 0012033 FOOD-PACKAGING CONTROL 301 level of addition which will contribute no more than 0-1 ppm to the diet. Obviously. 100% of man's diet is not in contact with paper, or any other single type of food container. There are five major types of food container substrates, glass, metal, paper, plastics and regenerated cellulose. In addition, there is a significant portion of food which is not packaged or is packaged io bulk so that most of the individual units are never in contact with the container. It is impossible to get reliable figures revealing the percentage of the food-pack* aging market shared by each type. However, it is conservative to assume that no mom than 25 % of man's diet is in contact with any given type of food package or packaging additive. _ Table 6 shows this final calculation of the maximum migration to the diet whiph would result from, the use of a component at a level of 1 % in the container (as directly measured from the rosin size experiments) and the maximum migration from a level in the container of 0*2 %. Undoubtedly, this calculation is an exaggeration for most uses of packaging com* ponents wliich possess greater insolubility or which are used in substrates more resistant to penetration than paper. Nevertheless, it permits the conservative conclusion that any compon­ ent of an article contacting food which is present in the article itself or its coating at a level of 0*2%or less by weight will contribuieto the dietalevel which can be ofnopossiblepublic health significance. Consequently, such trivial uses should not be included on lists of components permitted in food packaging. Tabic 6. Calculation of maximum contribution to the diet Maximum total diet migration ... 2 ppm/cach % Maximum diet in contact ... 25% Concrt in Maximum concn package in diet (/O (PPm) 1-0 0-5 _______ 02£J As most of you know, I submitted this conclusion to the profession and to the industry in the United States last September. It was worded differently, by describing a level of 0*2 % as GRA$* because of the particular structure of our law. It has received overwhelming and gratifying support and only a few questions have been raised. Our own Food and Drug Administration has authorized roe to tell you that they arc giving it serious consideration, but could not reach a decision prior to this meeting. At this point, I can only say that after 6 months, I am even more convinced that the conclusion is sound and conservative; and, that it offers a common-sense approach to a reduction in the extensive waste of time and money of both industry and government on problems which can' be of no possible public health significance. From a regulatory point of view, 1 believe it offers one mechanism of avoiding preparation and constant modification of an omnibus permissive list which experience has shown becomes so unwieldy and com­ plicated as to invite disregard. I do sot believe that type of situation is in the best interest of the consumer, industry or government. Now 1 have intentionally reserved for my closing remarks a discussion of the few questions and mental reservations about this proposal which have been raised by groups throughout the world. Perhaps, some of these points will answer some of the questions you would like to raise. 'Generally recognized as safe. RSV 0012034 c SOZ ( • J. P. FRAWLEY The most frequent comment is a concern that despite our toxicological experience to date we cannot assume that the next compound will not be toxic at 0.1 ppm. The same basic concern has been expressed in another way, by expressing doubt that toxicity data from 2-yr chronic studies represent a valid cross-section of chemicals, since some of the more toxic ones are rejected by short-term toxicity tests. It is, of course, possible that some chemical .may be synthesized at some time in the future which would be toxic at 0*1 ppm in the diet. However, it is almost impossible for such a compound to become an intentional component of a food container. For a compound to be toxic for man at 0*1 ppm presumes that it will be as "toxic or more toxic than any commercial pesticide. For it to be used as a component of a food container presumes that it must be manufacturedT packaged, distributed, and in other ways handled several times before contacting the food. It is inconceivable that a compound as toxic as this could pass through so many hands, in an industry not accustomed to handling highly toxic substances, without revealing its toxicity through injury to personnel. Once recognized, safe handling of such a compound would require such extreme industrial hygiene precautions as to be incompatible with converting operations and food-packaging practices. It seems to me that in order to produce an unsafe food'package, due to incorporation of a toxic ingredient ala level of 0-2% or less, it would require a deliberate or intentional act on the part of a manu­ facturer to poison the public, without at the same time poisoning his own workers. No amount of legislation or regulation can protect against such insanity. It has been suggested by a few of my colleagues that the extreme toxicity of such materials as aflatoxin rules out an assumption that any chemical is safe at even one part in a thousand million unless it has been tested. I believe that such an assumption is valid, if we limit our discussion to certain uses or industries. Again, I believe common sense tells us that it is inconceivable that anyone could manufacture millions of pounds of aflatoxin, or any substance of extreme toxicity and distribute it for use as a stabilizer in plastics or wetstrength resins for paper without finding out that it was too toxic for that industry. No company can afford to lose customers that way. Accidental contamination with aflatoxin or other extremely toxic substances is another matter, but this is outside the considerations of a permissive list. Whether a permissive list contains 200 or 20,000 substances, accidental contamination is no more or less likely. Quality control, inspection, and personal attention to details in manufacture are all necessary ingredients to the prevention of contamination of any product. A few individuals have questioned the validity of my estimate that no more than 25% of the diet will be in contact with the same packaging substrate or chemical. In rare circum­ stances, of course, some individuals may cat canoed foods almost exclusively and some may eat fresh or uopaekaged food almost exclusively. These variations in dietary habits, along with other intraspecies differences have been taken into consideration as part of the basic concept of our 100-fold margin of safety. Moreover, as mentioned above, the conservative calculations used above provide a 1000-fold margin of safety. The principal objection to this proposal in the United States has been administrative. Adoption of this proposal would obviate the need for many of our packaging regulations and would suggest a complete rewriting of Subpart F. For example, the "general adhesives*' and “defoamer in paper manufacture*' regulations would be replaced by a statement of good manufacturing practice that adhesives should not contact the food (as is already provided despite the fact that thousands of chemicals arc enumerated) and that defoamers may be used only prior to and during sheet-forming process (as is also already provided). RSV 0012035 303 FOOD-PACKAGING CONTROL I think the time necessary to accomplish this task would be time well spent and would be rapidly recovered in reduced administrative costs. Let roc close with this concept. Your country and mine have a limited number of com­ petent specialists in the field of environmental health. There are many problems facing our society which are competing for their time and attention, as well as for financial support. Included are community air and water pollution, industrial exposures, household chemicals, pesticides, drugs, cosmetics, food additives, confined environments of space cabins and submarines and food-packaging. Having some professional responsibility in all of these segments, I am convinced that food packaging constitutes the least hazard to health of all of these. Yet in recent years it has commanded more time and attention than any other area other than drugs and pesticides. It is~our moral and professional responsibility to invest our time and money in research which is likely to provide the greatest protection to health. I suggest that my proposal is a start toward restoration of a proper balance. APPENDIX No-cffect levels established by 2-jt feeding studies Compound No-effect level (ppm) Acrylamide1 40 Altlrin* <0-3* 1000 Alkyl ketene dimer* AHethrin* 4000* Amiben (2,5-Dichloro-3-aminobenzorc 10,000* acid)1 300 Ammonium sulphamate* <500f Antimony chloride1 30* Arsonic acid* 2300 7-Ascorbyl palmitate* Barium chloride1 2000f 10* Benzene hcxachloride, technical (BHQ? JO* o-Benzcne hcxachloride (o-BHQ* <10* ^-Benzene hcxschloride (5-BMQT 50* y-Benzcne hcxschloride (y-BHO* <800* d-Bcruene hcxcchloride (d-BHC)’ 3000 Benzoic acid1* 7500 Biiuva11 Butoxypolyprcpylene glycol (mol wt $00y 640 3000 Butylatcd hydroxyanisole (BHA)1* 2000 Butylated hydroxy toluene (BHT)M,tt Butyl 3,4-dihydro-2,2-dimethyl-4-oxo-l, 2tf-pyTan-6-carboxylate (indalone)14 40,000 30.000 13-Butylene glycol1* 2-(p-/rr/.Cutylphcnoxy) isopropyl 2'-chtoroethyl sulphite (Ammite)1* 100* 2000 lw-Butylphenvl salicylate1 Cadmium chloride* <10f Calcium disodium etliylenediamino3003 tctraacctatc1*1* Capian* 1000* Compound No-effect level (ppm) Cubsrsonc (p-Ureidobexuencarsonrc acid)1* 1000 Carboxymsthylccllutose (CMC)1* 10,000 Carotene” 1000 Catechol11 1250r Chlorbcnside (p-Chiorobenzy! p-chloroplisnyl sulphide)* 20* Chlorbcnside, sulphone derivative* 20* Ch Iordans* 2-5* bisOvChlorphcno:;>)mcthane' 300 ^Chlorophcnyl p-chlorobcnzcnetulphonate* 25* Chlorpropamide” 1230 Chlortetrasyclinc” 10.000 Citrus Red No. 2 (0.1.(1956) No. 12.156)” 500 Copper chromate* 500* Cub4“ 50* Cuprie chloride* soot Dalapon* 300* D & C Orange No. 5“ 10,000 D&C Orange No. 10** 10,000 D & C Red No. 9s* 300 D & C Red No. 10” 500 D & C Red No. 21” 10,000 17 & C Red No. 27” 10,000 DDD CTDE)1 10* DDT I* Dehydroacctic acid1 1000 Diiuinon4 0-73* Dichlone* <300* l,l-Oichloro-2,2-b«0>lphcnyT)cthane (Prrthanc)* 100* *Ptsticidc t Heavy metal t—Tumours at higher levels. RSV 0012036 304 Appendix (contd) Compound J. P. FRAWLEY No-dlcct level (ppm) 2,4-Dich!o:o-€-o>chloroanilino-i5000triazine (DyrcncV 2,4-Dichlorophenoxyethyl sulphate, 200* sodium wit1 • 4,4'-Dichloro-e-trichloromethyl20* bcnrhydrol (Kelthane)* 2500 Dicyandinmidc** 0-5* Dieldrm* 0,0-Diethyl OO-chloro-4-mcthyMoxo-2/.r-J-beuzo;>ynuw7-yl phosphorothioate (Co-Ral)1 2* Di(2-ethylhexyl) phthalate1 1300 Di-rt-hexyl uclatcM 5000 5000 Di-isobutyl adipate* DiUuryl thiodipropionic acid” 30.000 10.000 Dimethyl carbate1* 2,4-Diinetliyl-2-methylene-l,2,4100* thtadmoIiciine-5-lhione1 Dimethyl phthalate11 20,000 3,5-DiinethyJtctrahydro-l,3,5,2//thiadiazine-2-tliione (Mylons)” <10* O,O-Dinwthyl-0-(2,4,5-trichloropheoyI) phosphorothioate (RonncI)* 10* 600* 3,5-Dinittobenzamidc" 62* 3,5-Dinitro-o-toIuamide1 500* Diphenyl4*** 100* Diphenylamine4 3-(2-Diphenylyloxy>l,2-e poxy-propane1 2000 30,000 Distearyi thiodipropionic acid51 125* Diuron* Dodecyl benzene sodium sulphonale 2000 (Santomsrsc no. 3)** 350 Dodccyl peltate1* 50* Dodinc4*** 30* Endosulphan* 5* EPN* Epoxidized soybean oil (Paraplex 25,000 C-CG)*1 Epoxidized soybean oil (Paraplcx 5000 G-62)41 4-Ethoxyphenyiureft (Sucrol, dulein)” <1000 120* Ethoxyquin* 100 Ethyl acrylate*1 50* Ethyl 4,4<-dichlorobcnzi1&te* 40.000 2-Ethyl hexnnediol-1,3'* 2-Ethylhcxyl diphenyl phosphate 1250 (Santicizcr 141)** 5000 Ethyl phthalyl ethyl glycolate* 10,000 Fast Green FCr** 5000 FD & C Blue No. lw low FD & C Blue Mo. 2” 200* Ferbam4 100,000 Glycerol** 250,0W Glycerol monostcaratc4* 5000 Gum suaiac14 500 Gum rosin, pale41 0-5* Heptachlor epoxide* Compound No-e fleet level (ppm) 2-Hcptadecyl glyoxatidine acetate (Glyodin)* 210* n-Hcptyl-p-hydroxybenzoale** 1500 1-I5*{3a,4,5,6,7,7a-Hcxahydro-4,7methanoindanyl))-3,3-dimethylcrr* (Herban)1 500* Hydroxyethylecllulose41 10,000 Hydroxypropylmethykcllulosc1 50,000 Hydroquinone” 10.000T d-Isoascorbic acid*1 10.000 rf-Jsoascorby) palmitaic” 2500 Isopropyl A'-(3 chlorophenyl) carbamate (CIPQ11 2000* 4,4'-Jsopropylidcn* bis(2-Iiopropy}« phenol)1 1000 Light Green SF Yellowish** 10,000 Malathion* 100* Maleic hydrazide* 20,000* Maneb* 24* _ Melamine-formaldehyde resin (Pares 607)** 50,000 Mercaptobenzothia2ole* 120* Mercury acetate* 2-5* hlethortychlor1*** • 200* O-MethyNC?-(4-/m-bulyI-2-chlorophenj'0 methylphosphoroninidothioate (Ruclene)'*4* 30* O*MethyI-0-(2,4-dichlorophenyt) 10* isopropylphosphorumidothloate* Methyl ^-hydroxybenzoate41 20,000 Methyl methacrylate91 100 Methyl ruiphthalenaaceiic acid* 2500* MelhylpolysiJoxanc1 3000 Methyl salicylate*1 10,000 Monuron* 250* l-N’aphtn>i-A-n«thyl cat hamate* 200* o-Naphthylihiourea** 50* Nicotine* 62 Norriihydrocu.tixretic acid** 2500 Nylon (Zytel)** 100,000 Octadecylarnine** 500 350 Octyl galiate'* p-fer/-Octylp!icr.oxy-po!yethoxy ethanol* ffriton X-405)** 14,000 Parathion4 1* 50,000 Petrolatum1* Petroleum wax no. 211 100,000 100,000 Petroleum ww no. S11 Petroleum wax no. 12** 100,000 Petroleum wax no. 15** 100,000 Petroleum wax no. 20'* 100,000 630 PhenaeetiR11 Phenol” 10,000 O-l* Phenyl mercuric acetate* e-Phcnylphcnol44 2000* 500 Pimarictn” Piperonyl buio\idc* 700* RSV 0012037 FOOD-PACXAGlNG CONTROL 30$ Appendix (comd) Compound No-effeet level (ppm) polyacrylamide (Scparan AP30)** 10.000 polyacrylamide (Ssparan NPlOi” 10,000 polyethylene glycol (mol wt 200)' 40,000 polyethylene glycol (mol wt 400)' 20.000 2000 polyethylene glycol (mol v.t 1500)* Polyethylene glycol (mol wt 1540)* 40,000 polyethylene glycol (mol wt 4000)' 40,000 Polymerized turpentine resin* 2000 Po]yox)-etliylene(20)sorbttan monolaumte (Tween 20)** 50,000 PoJyoxycthylenc(20)sorbi tan tnonoolcats (Twrtn 80)** 50,000 Polyoxycthylene(20)sorbitan monopalmiutc (Tween 40)** 50,000 Folyoxycthyl«ne(20) sorbitan monostearate (Tween 60)** 50.000 « Polyoxyethylcrtc(20)sorbitan tristearate (Tween 63)** 50,000 Polyoxyethylcnc(S)stearate (Myrj 45)*, 20.000 J*olyoxycthylcne(40)sccaratc (Myrj S2)*1 30,000 Ponceau 3R (Cl. (1936) No. 16,155)** 5000 Ponceau SX (C.I. (195G) No. 14,700)** 50,000 627 Potassium bromate** l-n-Propoxy-2-amino-4-ikitrobenzene (P-4000)** <1000 Propyl gallatc** 10.000 Propyl p-hydroxy benzoate11 20,000 Pyreihrum* 1000* Rosin, disproportionated** 500 Rosin, fully dimerized1* 500 Rosin, partially dimerized'* 500 Rotenone* 2* Saccharin** 10,000 Selenium* <3* Sodium alginate** 50,000 Sodium alkylbenzcnesulphonatc** 5000 Sodium bisulphite** 500 300* Sodium chromate** Sodium cyclamate4* 10,000 Sodium 2,2-dicliloropropionate1 300 Sodium dioctyl sulphoxuccinate*1 5000 Sodium hexametaphosphate** 5000 Sodium lauryl glycerylsulphonate** 5000 No-e/Tcct ^1 Compound (ppm) Sodium lauryl sulphate*1 10,000 Sodium lauryl trioxyethylcne sulphonate** 5000 Sodium monofluoracetate* <5* Sodium nitrate** 10,000 Sodium l-sulphoproptonamidc* 10.000 Sodium tripoiyphosphate** 5000 Sorbic acid'* .50,000 Sorbitan monopalmitate (Span 40)** 50,000 Sorbitan monostcarate (Span 60}** 50,000 Sorbitan tristearate (Span 65)** *50,000 Sulphenone (p-chtorophenyl phenyl tulphone}* 100* Tall oil rosin, pale** 2000 Tartar emetic (Potassium antimony! tartrate)1 3 <5001Tartaric acid** 12,000* Tartraiine** 10,000 Tcrpcne polychlorinatcs (Strobane)* 50* Tetradifon* 300* Thiodipropionic acid** 30,000 Thiourea** SOO* Thiram* 200* Toxaphene* 25* 2,4,5-TricUlorophenoxyethyl sulphate. sodium salt1 200 TrKpolynonylphenyf) phosphite (Polygard)** 3300 Tylosin** 10,000 Vinyl chloiido-vinyl acetate copolymer** 120,000 Vinylidcne chloridc-vinyl chloride copolymer* 50.000 Wood rosin, dark** 500 Wood rosin, fully hydrogenated** 500 Wood rosin, hydrocarbon insoluble residue1* 500 Wood rosin, pale4* 2000 Wood rosin, partially hydrogenated" 2000 Yellow AB** 500 Yellow OB** 500 ZineV 500* Ziram* 250* REFERENCES 1. Wei). C S .it McCoUister, V. D. (1963). Relationship between short- and long-term feeding studies in designing an effective toxicity test. J. opric. Fd Chcm. II, 486. 2. Davis, KJ. & Fttzliugh, O. G. (IP62).Tumorigenic potential of aldrin and dicldrin for mice. Toxic, oppl. Pharmac. 4, 1ST. 3. Hercules Incorporated (Unpublished data). 4. Lehman, A. J. (196$). Summaries of Pesticide Toxicity. The Association of Food and Drag Officials of the United States. Kansas. 5. Hazleton, L. \Y., Paynter, O. E. & Weir. R. J. (1961). Safety evaluation studies on 2,5dichloro3-aminobenzoic acid (Amiben). 7bx/e. oppl. Pharmac. 6, 349. 6. Sherman, H. A Stula, E. F. (1965). Toxicity studies on ammonium sulfainate. Toxic, oppl, Pharmac. 7, 497. 7. Lehman, A. J. (1932). In Chemicals in Foods: A Report to the Association of Food and Drug Official* on Current Developments, Part //. Pesticides. Vo!.- XVI, No. 2. p. 47. The 906 J. P. FRAWLEY Association of Food mnd Drug Official* of the United States. I. Prior. R. F„ Nee*. P. O. & Dcrsc. P. H. (1963). The toxicity of an organic arsenical. 3-nitro-4hydroxyphenylarsonic acid. II. Chronic Toxicity. Toxic, appl. Phormac. 5. 526. 9. Fitzhugh. O. C. & Nelson. A- A. (1946). Subacute and chronic toxidties of ascorbyl palmitates. Proc. Soc. exp. Slot. Med. 61, 195. 10. Joint FAO/WHO Expert Committee on Food Additives—Sixth Report (1962). Evaluation of the Toxicity of a Number of Antimicrobial* and Antioxidants. Tech. Rep. Ser. Wld HUh Org. 228. _ 1). Oser, B. L., Oser. Mona A Morgareidge, K. (196$). Studies of the safety of azodicarbonamidc as a flour-maturing agent. Toxic oppl. phormac. 7, 445. 12. Deichmann, W. B., Ckrruner, l. 3„ Rakoczy, R. & Bianchine, J. (1955). Toxicity of ditertiarybutyimethylphenol. AJ4~A. Arehs ind. HUh 11,93. 13. Joint FAO/WHO Expert Committee on Food Additives—Ninth Report (1966). Specifica­ tions for the Identity and Purity of Food Additives and tltcir Toxicological Evaluation: Some Antimicrobial*, Antioxidants, Emulsi­ fiers, Stabilizers, Flour-Treatment Agents, Acids and Bases. Tech. Rep. Ser. Wld filth Org. 339. 14. Lehman, A. J. (1955). Insect Repellents. Yol. 19. p. 87. The Association of Food and Drug Officials of the United States. * 15. Scale, R. A. A Payntcr, O. E. (1964). Safety evaluation studies on 1,3-butylene glycol. Toxic, appl. Phormac. €, 358 16. Oser, B. L. & Oser, Mona (!962). 2-(p-tertButy|phenoxy)isopropy] 2-chiorocthly] sulfite (Aramite). II. Carcinogenicity. Toxic, appl. Pharnwc. 4, 70. 17. Oser, B. L., Oser, Mona A Spencer, M. C. (1963). Safety evaluation studies of calcium EDTA. Toxic, appl. Phormac. 5, 142. IS. Oser, B. L-. Morgareidge, K., Weinberg, M. S. & Oser, Mona (1966). Carcinogenicity study of carbanone. Toxic, oppl. Phormac. 9, 528. 19. Shclanski, H. A. A dark, A. M. (1948). Physiological action of sodium carboxymethyloellulose on laboratory animals and humans. Ftl Res. 13, 29. 20. Bagdon, RZbindcn, C. St Studer, A. (I960). Chronic toxicity studies of 0-carotene. Toxic, appl. Phormac. 2, 225. 21. Lehman, A. J., Fitzhugh, O. G., Nelson, A. A. St Woodward, G. (1951). The pharmacological evaluation of antioxidants. Ad*. fd Res. 3,197. 22. Delahunt, C. S., P*an, S. Y., Dardin, V. J. A Schneider, 3. A. (I960). Prolonged administra­ tion studies with chlorpropamide. Toxic. appU Phormee. 2, 195. 23. Dessau, F. 1. A Sullivan, W. J. (1961). A iwo- * * year study of the toxicity of chlortctracycline hydrochloride in rats. Toxic, appl. Pkurnwt 3, 654. 24. Dacrc, J. C. (1965). Chronic toxicity ani carcinogenicity studies on Citrus Red Ke. ' Proc. Unit. Otago med. Sch. 43, 31, 25. Hansen, W. H., Davis, K. J. A Fitzhugh, O r, (196$). Chronic toxicity of cube. Toxic. «•*./ Phormac. 7, 535. ‘ ' 26. Industrial Bio-Test Laboratories (Unpublislwd data). 27. Davis, K. J. St Fitzhugh, O. G. (19«2i. Pathologic changes noted in rats fed D 4 c Red No. 9 for two years. Toxic, appl, Phatawt 4,200. * 28. Davis, JC. J. St Fitzhugh, O. G. (1961). Pathologic changes noted in rats fed D A c Red No. 10 [monosodium salt of2-(2-h)'dro«y1-naphthylazoH-naphthalenesulfonic acid] for two years. Toxic, appl. Pharnwc. 5, 728. 29. American Cyaoamid Company (Unpublished data). 30. Hodge, H. C, Maynard, E. A., Downs, W. 1.., Salerno, Lillian A Packer, 3. T. (1962). Chronic oral toxicity studies of dw/-hexyl a relate n rats and dogs. Toxic, oppl. Phormac. 4? 247. 31. Smyth, H. F., Jr., Carpenter, C. P. A Wei. C. S. (1966). Toxicologic studies on JJdimethyhetrahydro-1,3,5, 2/f-lhiadiaiiic-2* thione, a soil fungicide and siimicidc. ToxU. appl. Phamtoc. 9, 521. 32. Kerr, K. B., Abrahamson, P. R. A Ipson, J. K. (1S65). Evaluation of the safety of 3,5-diniiro* benzamide. Toxic, oppl. phormac. 7, 4SS33. Ambrose, A. M., Booth, A. N., DeEds, F. & Cob, A. J., Jr. (I960). A toxicologies! study of biphenyl, a citrus funeislaL Fd Res. 25. 3IS. 34. Paymer. O. E. & Weir, R. J., Jr. (I960! Chronic toxicity of Santomenc No. 3 from Olefin (dodecyl benzene sodium sulfonate). Toxic, oppl. Pkanrtac. 2, 641. 35. Levinskas, G. J., Vidone, Lena B., O’Gnuly, J. J. & Shaffer, C. B. (1961). Acute and chruaU toxicity of dodine (w^lodecylguaaidine acetate). Toxic, appl. Pharmac, 3, 127. 36. Larson, P. S., Finnegan, J. K., Haag, II. B-. Smith, R. B., Jr., & Hcnnigar, G. R. (I960). ' Chronic toxicity studies on two epoxidized soybean oils in the rat and dog. Toxic, oppl. Pharinec. 2, 649. 37. Fitzhugh, O. G., Nelson, A. A- & Frawlcy. J. P. (1951). A comparison of Ihe ehronic toxicities of synthetic sweetening agents. J. Ant. pltarm. Ass, ScI Ed. 40, 583. 38. Dorzelleca, J. F., Larson, P. S., Henrugar. G. R.t Jr., Huff, E. C., Crawford, L M- A • Smith, R. B., Jr. (1964). Studies on the chronic oral toxicity of monomeric ethyl acrylate and methyl methacrylate. Toxic, appl. phormac. 6,29. 39. Trcon, J. F„ Dutm, F. R. A Cleveland, F. **■ (1953). Toxicity of 2-cthylhexyl diphenj1 phosphate. Add*4. Arelu but. Jlyg• 8> 170. RSV 00X2039 c ( V I FOOD-PACKAGING CONTROL I l » ( ! i>w > * < -■ !•' **■ J J { t | ; ( 40. JIansen, W. H., Lone. Eleanor L., Davis, K. J, Nelson, A. A- & Fitzhugh, O. O. (1966). Chronic toxicity of three food colourings: Guinea Green B, Light Green SF Yellowish and Fast Green FCF in rats, dogs and mice. Fd Cosmet. Toxicol. 4, 3$9, 41. Hansen, \Y. H, Fitzhugli, O. G., Nelson, A. A. & Davis, K. J. (1966). Chronic toxicity of two food colours. Brilliant Blue FCF and Indigotinc. Toxic, oppl. Pharmac. 8, 42. Hine, C H., Anderson, R JL, Moon, R D, Dunlap, M. K. & Morse, M. S. (1953). Comparative toxicity or synthetic and natural glycerin. AJ-fui. Archs ind. Uyg. 7, any 43. Ames, S. R., O’Grady, M. P., Embree.'N. D. A Harris, P. L. (1951). Molccularly distilled monoglycerides, 11L Nutritional studies on monoglycerides derived from cottonseed oil. J. Am. OU Chem. Soc. 28, 31. 44. Johnson, V., Carlson, A. J., Kkitman, N. Sc Bergstrom, P. (1933). Action of gum guaiaeum upon the animal organism. Fd Res. 3, 335. 45. Frawley, J. P. (1963). Investigations estab­ lishing the safety of rosin products for food, food packaging applications. A’or. Stores Ary. Ter. Chem. 74 (12), 4. 46. Paymer, O. E., Hazleton, L. W. St Gariock. E. A. (1966). Toxicologic evaluation of the ir-hcptyl ester of p-hydroxybenzoic add. Toxic, Oppl. Phartnac. 8, 3 SO. 47. Smyth, H. F., Jr., Carpenter, C. P. St Well, C. S, (1947). Chronic toxicity of hydroxyethyl cellulose for rats. /. Am. pharm. Ass. 36, 333. 48. Larson, P. S., Crawford, E. M., Smith, R. B., Jr^Hennigar, G. R., Haag, H. B. St Finnegan, J. K. (1960). Chronic toxicologic studies on isopropyl A'-(3-chlOTOphenyl) carbamate (GJPC). Toxic, oppl. Pharmac. 2, 6S9. 49. Hodge H. CL, Maynard, E. A. A Blanchet, R J„ Jr. (1952). Chronic oral toxicity tests of methoxyclitor [2, 2-di-(p-methoxypheny1)*l,l, l-trichlorocthanc] in rats and dogs. J. Pharmac. exp. Thtr. 104, 60. 50. McCollister, D. D., Oyen, F., Olson, K. J. St Rowe, V. K. (1965). Toxicology of 4-tertbutyl-2-chlorophcnyl methyl methylphosphoramidate (Ruelene). Toxic, oppl. Pharmac. 7, 490. 51. Matthews, CL, Davidson, Jn Barren. 1L, Morrison, J. L. Sc Richardson, A. P. 0956). p-Hydroxybenzoic acid esters as preservatives, IX: Acute and chronic toxicity in dogs, rats and mice. /. Am. pharm. Ass. 45,260. 52. Webb. W. K. St Hansen, W. H. (1963). Chronic and subacute toxicology and pathology of methyl salicylate in dogs, rats, and rabbits. Toxic, oppl. Pharmac. 5, 576. S3. Fitzhugh, O. G. St Nelson, A. A. (1947). Chronic oral toxicity of alpha-naphthyl tliiourea. Proc. Soc. exp. Biol. Med. 64, 305. 54. Haskell Laboiatorhs. DuPont Company (Un* published data). V 307 55. MaeDonald, W. E^ Deichmann, W. B., Radomski, J. L. St Austin, B. S. (1962). The chronic toxicity of octadecylaminc in the rat— a supplemental report. Toxic, oppl. Pharmac. 4,610. 56. Larson, P. S., Borzdleca, J. F., Bowman, E. R., Crawford, E. M., Smith, R. B., Jr., A Hennigar G. R. (1963). Toxicologic studies on a prepara­ tion of p-tertiary octylphenavy-polyethoxy ethanols (Triton X-405). Toxic, oppl- Pharmac. 5,782. 57. Oser, B. L, Oser, Mona A Carson, S. (1965). Toxicologic studies of petrolatum in mice and rats. Toxic, oppl. Phannac. 7, 3S2. 58. Shublk, P., Saifiotti, U., Lijinsky, W., Pietra, G„ Rappaport, H, Toth, B„ Raha, G. R« Tomatis, L, Feldman, R. A Ramahi, R (1962). Studies on the toxidty of petroleum waxes. Toxle. oppl. Pharmac. (Supp.) 4, 49. 59. Woodard, G., Post, K. F, Cockrell, K. O. A Cronin, M.T.L(1965).Phcnacetin: Long-term studies in rats and dogs. 7bxfe. oppl. Pharmac. 7,303. 60. Hodge, H. C. Maynard, E, Blanchet, R Jr., Spencer, RCA Rowe, V. K. (1952). Toxicological studies of ortho-pbcnylphenof in (Dowiddc 1). J. Pharmac. exp. Thcr. 104, 202 61. Levinskas, G. J., Ribelin, W. E. A Shaffer, G B. (1966). Acute and chronic toxicity of pimaricin. Toxic. oppl. Pharmac. 8, 97. 62. McCollister, D. D„ Hake, C Sadek, S. E. A Rowe, V. K. (1965). Toxicologic investiga­ tions of polyacrylamide. Toxic, appl. Pharmac. 7,639. 63. Joint FAOAVHO Expert Committee on Food Additives-—Seventh Report (1964). Specifica­ tions for the Identity and Purity of Food Additives and Their Toxicological Evaluation; Emulsifiers, Stabilizers, Bleaching and Matur­ ing Agents. Tech, Rep. Ser. 1VM tilth Org. 281 64. Fitzhugh, O. G., Bourke, Anne R.a Nelson, A. A. A Frawley, J. P. (1959). Chronic oral toxicities of four stearic add emulsifiers. Toxic, appl. Pharmac. 1, 315. 65. Hansen, W. R, Davis, K. JL, Fitzhugh, O. G. A Kelson, A. A. (1963).'Chronic oral toxicity oT Ponceau 3R. Toxic, appl. Pharmac. 5, 103. 66. Davis, K. J„ Nelson, A. A_, Zwickey, R. E., Hansen, W. H. A Fitziiugh, O. G. (1966). Chronic toxicity of Ponceau SX to rats, mioe and dogs. Toxic, appl. Pharmac. 6, 306. 67. Nihon, R A Wagner. J. E. (1931). Feeding tats with some algiri products. Proc. See. asp. BioL Med. 76,630. 68. Tusing, T. W„ Payntcr. O. E. A Opdyke. D. U (1960). The chronic toxicity of sodium alkyl* benzenesulfonate by food and water admini­ stration to tats. Toxic. oppl. Pharmac. 2, 464. . . RSV 0012040 308 J. P. FRAWLEY 69. Fitzhugh, O. C, Knudscn, L S. & Nelson, A. A. (1946). Chronic toxicity of sulfites. J. Pharmae. exp. Titer. 86, 37. 70. Food And Drue Administration (Unpublished data). 71. Fitzhugh, O. C. A Nelson, A. A. (1948). Chronic oral toxicities of surface-active agents. J. Am. pharni. Asm. Sci. Ed, 37, 29. 72. Tusing, T. \V„ Paynter, O. E., Opdyke, D. L. A Synder, F. H. (1962). Toxicologic studies on sodium lauryl glyceryl ether sulfonate and sodium busy! trioxyeihylene sulfate. Toxic. eppl. Pharmae. 4,402. 73. Lehman, A. J. (I9JS). Nictates and nitrites in meat products. Q. Bull. Au. Fd t>rut Off. V.S. 22, 136, 74. Fitzhugh, O, G. & Nelson, A. A. (1947). The comparative chronic toxicities of fumaric, tartaric, oxalic and maleic acids. J. Am. phorm. Ass. Sei. Ed. 36,217. 73. Davis, JC J., Fitzhugh, O. G. A Nelson, A. A. (1964). Chronic nt and dog toxicity stud** on tartrazine. Toxic, appl. pharmae. 6, 621. 76. Fitzhugh, O. G. A Nelson, A. A. (194S). (iter tumours in rats fed thiourea or thioaectamide Science, tf.Y. IDS, 626. 77. Carson, S., Oser, B. L. A Oser, Mona (19641 Toxicologic studies with the antioxidur.i • Polycard. 7b.v