PROPOSED RULES 19225 2. A new § 989.210 is added, reading as gust 18, 1973. The data, views, and argu­ % , Dockage % Dockage follows: Substandard Factor Substandard Factor ments will be available for public in­ § 98 9 .2 1 0 Handling o f natural Thomp­ spection and copying at the Office of son Seedless raisins acquired pursu­ 8.0 or less..— No dockage... 15.1-15.5 .925 Standards located at the above address. ant to a weight dockage system. 8.1-8.5.......... .9 9 5 .----;:-—" 15.6-16.0 .920 Pursuant to 29 CFR 1911.11 (b) and 8.6-9.0___ — . .990__ 16.1-16 5 .915 (c), interested persons may, in addition (a) General. Subject to prior agree­ 9.1-9.5______ .985. 16.6-17.0 .910 9.6-10.0.......... .980.............. .- 17.1-17.5 .905 to filing written matter as provided ment between handler and tenderer, a 10.1-10.5....... . .975—______— 17.6-18.0 .900 above, file objections to the proposal, 10.6-11.0....... . .970________ 18.1-18.5 .895 handler may acquire as standard raisins 11.1-11.5......... .965................- 18.6-19.0 .890 requesting an informal hearing with re­ any lot of natural Thompson Seedless 11.6-12.0......... .960................- 19.1-19.5 .885 spect thereto, in accordance with the 12.1-12.5......... .955................. 19.6-20.0 .880 raisins containing more than 8 percent, 12.6-13.0.:___ .950................. 20.1-20.5 .875 following conditions: by weight, of substandard raisins under 13.1-13.5......... .945................. 20.6-21.0 .870 (1) The objections must include the 13.6-14.0......... .940................. 21.1-21.5 .865 name and address of the objector; a weight dockage system. The creditable 14.1-14.5......... .935................. 21.6-22.0 .860 14.6-15.0......... .930................... (2) The objections must be post­ weight of such lot acquired shall be that marked on or before August 18,1973. obtained by multiplying the net weight of N o t e : Percentages in excess of 22 percent shall be (3) The objections must specify with the raisins in the lot by the applicable expressed in the same increments as the foregoing, and particularity the provision of the pro­ the dockage factor for each such increment shall be .005 dockage factor from the dockage table less than the dockage factor for the preceding increment. posed rule to which objection is taken, prescribed in paragraph (g) of this and must state the grounds therefor; Dated July 13,1973. (4) Each objection must be separately section. C h arles R . B rader , stated and numbered; and, (b) Free and reserve tonnage per­ Acting Deputy Director, (5) The objections must be accom­ centages. Whenever free and reserve per­ Fruit and Vegetable Division. panied by a summary of the evidence centages are designated for natural [PR Doc.73-14701 Filed 7 -1 8 -7 3 :8 :4 5 am] proposed to be adduced at the requested Thompson Seedless raisins for a crop hearing. year, such percentages shall be applicable In § 1910.157(d) (4) (iii), Table L-3 is DEPARTM ENT OF LABOR proposed to be revised to read as follows: to the creditable weight of any lot of such raisins acquired by a handler pursuant Occupational Safety and Health § 1 9 1 0 .1 5 7 Portable fire extinguishers. Administration * * * * * to a weight dockage system. (c) Reserve tonnage. A handler may [ 2 9 CFR Part 1 9 1 0 ] (d) Inspection, maintenance, and hy­ hold as reserve tonnage raisins any lot, O CCUPATIONAL SAFETY A N D drostatic tests * * * H EALTH or portion thereof, of natural Thompson STANDARDS (4) Hydrostatic tests. * * * Inspection Intervals for Fire Extinguishers (iii) At intervals not exceeding those Seedless raisins acquired pursuant to a specified in Table L-3 and subdivision weight dockage system: Provided, That, with Aluminum Shells (iv) of this subparagraph, extinguishers only the creditable weight of such lot, or Pursuant to section 6(b) of the W il­ shall be hydrostatically tested. The first portion thereof, may be applied by the liams-Steiger Occupational Safety and hydrostatic retest may be conducted be­ committee against the handler’s reserve Health Act of 1970 (84 Stat. 1593; 29 tween the fifth and sixth years for those U.S.C. 655), Secretary of Labor’s Order with a designated test interval of 5 tonnage obligation» No. 12-71 (36 FR 8754) and 29 CFR Part years. (d) Assessments. Assessments on any 1911, it is hereby proposed to amend T a b l e L -3 lot of natural Thompson Seedless raisins Table L-3 in 29 CFR 1910.157 d) (4) (iii) as set forth below. HYDROSTATIC TEST INTERVAL FOR EXTINGUISHERS acquired by a handler pursuant to a weight dockage system shall be appli­ Table L-3 in paragraph (d) (4) (iii) T est cable to the free tonnage portion of the presently requires, among other things, interval that dry chemical extinguishers with Extinguisher typ e year creditable weight of such lot. aluminum shells, stainless steel shells or S o d a -a c id ______________ 5 (e) Payments for services on reserve sdldered-brass shells be hydrostatically Cartridge-operated water and/or anti­ tonnage. Payment to a handler for serv­ freeze _________________________ 5 tested at five year intervals. This table is ices performed by him with respect to derived from NFPA No. 10-1970, Stand­ Storage-pressure freeze _______ water and/or anti­ 5 reserve tonnage natural Thompson Seed­ ard for the Installation of Portable Fire W etting agent!________ :_________________ 5 less raisins acquired pursuant to a weight Extinguishers. On May 18, 1973, the Na­ F o a m ___________________________________ 5 dockage system shall be made on the tional Fire Protection Association revised Loaded stream__________________________ 5 its standard to place dry chemical fire Dry chemical extinguishers with stain­ basis of the creditable weight of such extinguishers with aluminum shells in less steel shells or soldered-brass lot and at the applicable rate specified the same class with dry chemical ex­ s h e ll s _________________________________ 5 for such services in § 989.401 of Subpart— Carbon dioxide extinguishers_________ 5 tinguishers with brazed-brass shells and Dry chemical extinguishers with Schedule of Payments. mild-steel shells, with the effect that the brazed-brass shells, mild-steel shells (f) Identification. Any lot of natural test interval for aluminum shells or aluminum shells_________________ 12 Thompson Seedless raisins acquired by a changes from five years to 12 years. (See Bromotrifluoromethane________________ 12 .1973 NFPA Technical Committee Re­ Dry powder extinguishers for metal handler pursuant to a weight dockage ports, Vol. B, P. 1273). hi order to con­ fires____________ ;______________________ 12 system shall be so identified by the in­ form Table L-3 of § 1910.157(d) (4) (iii) N o t e : Cylinders under jurisdiction of the spection service by affixing to one con­ to the revised NFPA Standard, it is pro­ U.S. Department o f Transportation (formerly tainer on each pallet, or to each bin, posed to revise Table L-3 so as to place Interstate Commerce Commission) may re­ in such lot, a prenumbered RAC control dry chemical fire extinguishers with quire hydrostatic testing at more frequent card (to be furnished by the Committee) aluminum shells with fire extinguishers periods. with brazed-brass shells and mild-steel * * * * * which shall remain affixed to the con­ shells and thus change the test interval (Sec. 6, Pub. L. 91-596, 84Stat. 1593 (29 tainer or bin until the raisins are proc­ for the former extinguishers from five U.S.C. 655, Secretary of Labor's Order No. 12- essed or disposed of as natural condi­ years to 12 years. 71, 36 FR 8754) tion raisins. The control card shall only All interested persons may submit Signed at Washington, D.C. this 12th be removed by, or under the supervision written data, views and arguments con­ day of July 1973. of, an inspector of the inspection service cerning the proposal to the Office of J o h n S tender , or authorized Committee personnel. Standards, Room 305, 400 First Street, Assistant Secretary of Labor. ( 8) D ockage tattle. NW., Washington, D.C. 20210 by Au­ [FR Doc.73-14823 Filed 7 -1 8 -7 3 ;8 :4 5 am] FEDERAL REGISTER, VOL. 36, NO . 138— THURSDAY, JULY 19, 1973 19226 PROPOSED RULES DEPARTM ENT OF HEALTH, EDUCA­ § 27 .31 Canned cherries; quality; label (D ), 512(b)(7), and 706(b) (5) (A) (iv) TION, AND WELFARE statement o f substandard quality. of the act. (a) * * * The Commissioner of Food and Drugs Food and Drug Administration (5) Not more than 15 percent by counthas determined that it would be in the [2 1 CFR Part 2 7 ] of the cherries in the container are blem­ public interest to set forth the principles Q U A LITY STAN DARD FOR CANNED ished with scab, hail injury, discolora­ involved in application of these safety CHERRIES tion, scar tissue or other abnormality. A provisions of the law with respect to the cherry showing skin discoloration (other adequacy of the sensitivity of the re­ Proposed Revision of Blemish Limitation than scald) having an aggregate area quired regulatory assay method for mon­ Notice is given that a petition has been exceeding that of a circle 9/32 inch in itoring compounds which may be admin­ filed by the National Canners Associa­ diameter is considered to be blemished. istered to food-producing animals, but tion, 1133 20th St., NW., Washington, DC A cherry showing discoloration of any for which no residue is permitted in hu­ 20036, proposing that the standard of area but extending into the fruit tissue man food. Therefore, a new regulation quality for canned cherries (21 CFR is also considered to be blemished. is proposed to establish the minimum 27.31) T«e amended by: * * * * * standards for determining the accept­ (1) Cnwiging the definition of a ability of assay methods used to assure Interested persons may, on or before the absence of residues in edible products blemished sherry; and y September 17, 1973 file with the Hearing of such animals. These proposed regula­ (2) Increasing the aggregate area of Clerk, Department of Health, Education, tions do not apply to drugs for which a the blemish from rfe torch to -is inch in and Welfare, Room 6-88, 5600 Fishers finite or negligible residue is established diameter. \ / Lane, Rockville, MD 20852, written com­ as safe for human food. Grounds set from in the petition in ments (preferably in quintuplicate) re­ The proposed new regulation will ap­ support of theriroposal are that: (1) garding this proposal. Comments may be ply to two classes of compounds admin­ The proposed/Change in the, definition accompanied by a memorandum or brief istered to food-producing animals: (1) of a blemish/wl unit wfcmld be consistent in support thereof. Received comments Exogenous compounds, defined as those with objections received to an order, pub­ may be seen in the above office during compounds which are not produced by lished in tile F ederal R egister on Febru­ working hours, Monday through Friday. the normal animal and are not required ary 23, ¿971 (36 FR 3364\ruling on a for normal animal body function (e.g., proposed cherry pie standard, of quality Dated: June 20,1973. diethylstilbestrol), and (2) Endogenous (21 CFR 28.2). These objections re­ V ir g il O . W odick a , compounds, defined as those compounds quested that the inch diameter limit Director, Bureau of Foods. which are present in and produced by for blemished units be changed to a A [FR Doc.73-14749 Filed 7 -1 8 -7 3 ;8 :4 5 am] the normal animal and are not required inch diameter limit. The Commissioner from an exogenous source (e.g., of Food and Drugs granted this request estradiol). in the F ederal R egister of June 13,1973 [2 1 CFR Part 1 3 5 ] In evaluation of the safety of com­ (38 FR 15503). COM POUNDS USED IN.FOOD-PRODUCING pounds of both classes the initial testing (2) Mechanical harvesting and bulk ANIMI L S must involve detailed metabolism stud­ handling in tanks o f water have replaced ies in the target species. Radiotracer the traditional hand picking and han­ Procedures 'foc>peternJining Acceptability studies are usually the method of choice. dling. As a result there has been a greatly of Assay Metnbds Used for Assuring the The purpose of these studies will be to increased problem with a mild form of Absence of Res» in Edible Products identify the metabolites of the com­ discoloration known as “tank or water of Such Animals pound, both qualitatively and quanti­ scald” which results in minor color vari­ The Federal Food, E rae, and Cosmetic tatively, and the concentrations of the ation but does not affect the tissues or Act requires that compounds admin­ compound and its metabolites in specific eating quality or the cherries. istered to animals as f< od additives, color tissues (“ tissues” include milk and eggs, (3) Since the present standard was additives, or animal dr lgs ba shown to be if applicable). Another aspect of these established 32 years ago, changes in cul­ safe for use. The tern “sare” refers to studies will be the determination of the tural practices have resulted in the pro­ the health of man or mimalVmder sec­ effect of the administration of the com­ duction of larger and softer cherries. tion 201 (u) of the act. In evaluating the pound on tissue levels of related endog­ Presently, there are as few as 100 to 110 safety of such compoi nds used in food- enous compounds. cherries per pound as compared to 140 producing animals, c msideration must For acceptable studies, it is necessary to 150 per pound when the standard was be given to the safety se animals which pound and/or its metabolites after aggravated the blemish problem because are a source of food fo *man. When there slaughter and during the period that they are more susceptible to blemishes is insufficient evidence to establish that a the edible ,tissue would normally be held and contain a greater surface area com­ finite or negligible residue of the com­ under storage conditions as well as to pared to the permitted area of skin dis­ pound is safe in hunan food, or when determine the impact of cooking at ap­ coloration. the anticancer clause 5 contained in sec­ propriate temperatures on the com­ (4) Increasing the area of the blem­ tions 4 0 9 (c)(3 )(A ), 112(d) (1) (H ), and pounds in question. ish to 9/32 inch would bring the quality 706(b)(5)(B ) of the [act are applicable, E xo g e n o u s C o m p o u n d s standard for canned cherries (21 CFR a zero tolerance (no residue) must be 27.31) into agreement with the present required. (Under the provisions of the Determination as to whether an exog­ voluntary U.S. Department of Agricul­ anticancer clauses no compound may be enous compound and/or its metabolites ture standard for grades of frozen administered to animals which are raised will require carcinogenicity testing will cherries. for food production if such compound be based on the results of the metabolism has been shown to induce cancer when studies, standard toxicity testing, struc­ (5) The proposed change will insure ingested by man or animal, unless such tural relationships of the compound and/ consumers a continued supply of canned compound will not adversely affect the or its metabolites to known carcinogens, cherries without significantly affecting animal and no residues, as determined modes of physiological actions and inter­ the quality. by methods of analysis prescribed or ap­ actions, and the intended use pattern of Therefore, pursuant to provisions of proved by the Secretary, are found in the compound. Tests for carcinogenicity the Federal Food, Drug, and Cosmetic the edible products of such animals will be routinely required for any new Act (secs. 401, 701, 52 Stat. 1046, 1055 under conditions of use specified in label­ compound for which a priori knowledge as amended by 70 Stat. 919 and 72 Stat. ing and reasonably certain to be followed is incomplete and which is intended to 948; 21 U.S.C. 341, 371) and under au­ in practice. A decision is then required as be used for disease prophylaxis and/or thority delegated to the Commissioner of Food and Drugs, it is proposed that Part to whether a practicable method exists production purposes (e.g., increased rate 27 be amended in § 27.31 by revising to determine the absence of such resi­ of weight gain, estrus synchronization, paragraph (a) (5) to read as follows: dues in food, under sections 409(b)(2) etc.). FEDERAL REGISTER, VOL. 38, N O . 138— THURSDAY, JULY 19, 1973 PROPOSED RULES 19227 If it is determined that tests for car­ and Pesticides (Toxicology and Applied consumption patterns, justified modifica­ cinogenicity are not required, or if the Pharmacology Vol. 20, pp 419-438, 1971) tions will be made on a conservative results of such tests are negative, con­ will be followed by the Pood and Drug basis. If a disease has a maximum in­ sideration leading to approval MU be Administration. cidence of 10 percent, then no more than based on standard toxicological proce­ If the results of the test for carcino­ 10 percent of the marketed animals dures. These procedures will include, in genicity establish that the compound or would have been treated with the drug. addition to subacute studies in a mini­ its metabolites will induce cancer in test Under these conditions, the probability mum o f two species, such studies as animals, the required sensitivity of the of continuous daily exposure for an in­ multi-generation reproduction studies, regulatory assay method will be deter­ dividual consumer could be very con­ teratological and any other special mined based on the Mantel-Bryan pro­ servatively estimated as 0.10. In this studies which may be indicated from the cedure described in the article entitled situation, the true probability of risk for nature o f the biological action of the “ Safety” Testing of Carcinogenic Agents the individual consumer would then compound, including life-tim e studies. (Journal o f the National Cancer Insti­ equal the probability of individual risk These studies will involve collecting data tute, Vol. 27, pp 455-470,1961). However, under conditions of continuous daily ex­ from appropriately designed dose-re­ rather than assuming a dose-response posure to the drug multiplied by the sponse experiments that demonstrate a relationship with a slope of one, as sug­ probability of an individual actually ex­ maximum “no harmful effect level” as gested in the reference, experimental periencing continuous daily exposure to well as a minimum “harmful effect level” data obtained from the carcinogenicity the drug. If a true exposure of 1/100,000,- in appropriate animal species. studies will be used to obtain a statistical 000 were deemed acceptable for an in­ Where a residue is permitted as safe in estimate of the slope of the dose-response dividual on the basis of risk-benefit con­ human food (either as a finite tolerance relationship. The lower 90 percent con­ siderations, this value could be held con­ level or as a negligible residue of less fidence limit of the estimated slope will stant by assuming a continuous exposure than a specified level), the sensitivity of be used for extrapolation to the required risk of 1/10,000,000 (1/100,000,000=1/ the assay method will be required to meet level of sensitivity of the regulatory assay 10,000,000 X 0.10) in the estimate of the the specified level, and the other provi­ method. If the data indicate that some Mantel-Bryan level. The true individual sions of this proposed new regulation linearizing transformation other than consumer risk would remain at 1/100,- relating to the required sensitivity of the the probit-log transformation used in the 000,000 since the consumer is only inter­ method will be inapplicable. Where no modified Mantel-Bryan procedure better mittently exposed to residues o f the com­ residue (zero tolerance) is permitted, the describes the observed response and has pound in food. provisions of this proposed new regula­ a biological rationale, then this other The maximum level of exposure as tion are fully applicable. linearizing transformation may be used estimated above, after standard adjust­ Under the proposed new regulation the for such extrapolation. Examples of the ment for the differences between daily dose-response slope estimated from the application of this technique are given food intake per unit of body weight of toxicological experiments will be used to in the above reference. the laboratory animal as compared with extrapolate to the required level of Absolute safety can never be conclu­ man, will be the required sensitivity of sensitivity of the method using appro­ sively demonstrated experimentally. The' the assay method for a compound. In priate confidence interval techniques in level defined by the Mantel-Bryan pro­ the event that both non-carcinogenic accordance with the concepts underlying cedure is an arbitrary but conservative harmful effects and carcinogenic effects the Mantel-Bryan procedure discussed level of maximum exposure resulting in a are observed during testing, the lowest below. Where such extrapolation is not minimal probability o f risk to an individ­ level for the regulatory assay sensitivity scientifically appropriate, e.g., if no dose- ual (e.g., 1/100,000,000), under those ex­ as determined for the different effects response slope can be estimated from the posure conditions of the basic animal will be adopted. data, other conservative methods will be studies. Such test conditions generally Withdrawal or post-medication pe­ invoked to determine an appropriate involve continuous daily lifetim e ex­ riods for exogenous compounds shall be safety margin based on a thorough posure to the compound in question. In based on data obtained from tissue deple­ evaluation o f the quality of the experi­ contrast, many types o f foods are con­ tion studies. The compound must be ad­ ments, their rigor as predictive tests and sumed only intermittently, e.g., turkey or ministered to test animals for a sufficient the nature and significance of the ob­ broiler kidneys, and therefore any drug time for concentration equilibrium to served biological effects. residues contained in such foods will be be achieved. On the basis of the developed Where tests for carcinogenicity are re­ consumed only intermittently. If the assay and/or other suitable methods, a quired for a compound there are two same procedure was used to determine determination must be made as to the basic objectives of the tests. The first is the level of exposure for turkey kidneys time When tissue levels of the parent to determine whether or not the com­ as was used to determine the level of ex­ compound and/or its metabolites and/ pound and/or its metabolites is a car­ posure for foods consumed more fre­ or any affected endogenous compounds cinogen. The second is to determine the quently, such as beef muscle, the popula­ are below the required level o f sensitivity relative potency o f the compound and/or tion would not be equally protected in for the regulatory assay method. its metabolites with respect to both its both situations. Consequently, it will be The withdrawal period shall be the carcinogenic and its noncarcinogenic but necessary to adjust the procedure for longer of: (1) The number of days for toxic effects, through appropriate oral establishing the exposure level to account tissue levels to be depleted to less than dose-response experiments. Test systems for usual as well as specific human con­ the maximum level of exposure extrap­ will be selected which maximize sensi­ sumption patterns. Any such adjustments olated by the modified Mantel-Bryan tivity to detect a minimal dose which in­ initially will be made on a conservative procedure plus a safety factor to account duces a carcinogenic effect. These sys­ basis. These adjustments will take into for animal to animal variation (as deter­ tems will include a sufficiently stable consideration the consumption expected mined by appropriate confidence interval control population to avoid false-positive by those who consume the greatest techniques) or (2) the number of days indications of carcinogenesis. amounts of food, not the average con­ for any affected endogenous compound There is a general lack o f agreement sumption of the food. More definitive in­ to return to normal levels plus a safety within the scientific community regard­ formation is being complied on food con­ factor to account for animal to animal ing appropriate protocols for determin­ sumption patterns by the Pood and Drug variation. (The normal level of the ing the dose-response relationship of Administration, and this information Will affected endogenous compound will be es­ carcinogenic compounds. Until they are be used to arrive at more refined adjust­ tablished as described below for endoge­ revised, the guidelines for protocols set ments as it becomes available. nous compounds.) For example, if excre­ out by the Pood and Drug Administra­ It will also be necessary to modify the tion data indicate that the average de­ tion Advisory Committee on Protocols procedure for establishing the exposure pletion time for an exogenous compound for Safety Evaluation: Panel on Car­ level to account for drug usage, patterns, is 72 hours with a safety factor of 27 cinogenesis Report on Cancer Testing in e.g., the administration of a drug in the hours, the withdrawal period becomes the Safety Evaluation of Pood Additives treatment of diseased animals. As with (72 hours+27 hours) -^24 hours or, after FEDERAL REGISTER, VOL. 38, NO . 138— THURSDAY, JULY 19, 1973 19228 PROPOSED RULES rounding upward, 5 days. Current live­ ground level plus a safety factor to ac­ gree of specificity, precision, and ac­ stock management techniques must be count for animal to animal variation (as curacy to preclude the occurrence of considered in establishing the withdrawal determined by appropriate confidence false negatives or false positives. period and may necessitate the lengthen­ interval techniques) shall be used to 3. The equipment, reagents and com­ ing o f this period* establish the required withdrawal pe­ pounds used in the assay must be com­ The provisions of the proposed new riod. Current livestock management mercially available. Any required spe­ regulation govern the required level of techniques must be considered in estab­ cialization in terms of equipment or per­ sensitivity o f the regulatory assay lishing the withdrawal period and may sonnel must be consistent with that nor­ method for those compounds for which necessitate the lengthening of this mally available in a modem well- a zero tolerance (no residue) is estab­ period. equipped analytical control laboratory. lished. If a regulatory assay method of A s s a y E v alu at ion C riteria 4. The time required for completion of lower sensitivity is later developed and the assay must not be so excessive as to validated, however, the Commissioner Prior to approval, the accuracy and delay regulatory action, when necessary. will adopt that more sensitive method reliability of the regulatory assay must and publish it in the F ederal R egister , be determined by validation of the 5. The assay must offer minimal haz­ even though its development was not re­ method in appropriate Food and Drug ard in the laboratory. quired under the law. Administration laboratories and other It is proposed that th e. requirements laboratories. The objectives of the vali­ contained in this regulation will be ap­ E n d o g en o u s C o m p o u n d s plicable to all NADA’s and supplemental dation will be to determine the feasibil­ It is proposed that animals shown to ity, specificity, accuracy, and precision NADA’s approved by the Food and Drug contain tissue levels of endogenous com­ of the method (including a determina­ Administration after the effective date pounds above the normal due to the ad­ tion of the amounts recovered as well as o f the new regulation. In determining ministration of such compounds will not an estimation of the variation associated the applicability of the provisions of the be permitted to be marketed for human with the recovered amounts). regulation to already-existing new ani­ consumption. Thus, neither tests for Prior to submission of a method for mal drug approvals, the Commissioner carcinogenicity nor standard toxicity evaluation and subsequent validation, it will first determine those drugs for which testing will be required for endogenous is recommended that the method be re­ a zero residue requirement now exists compounds. viewed and tested, both qualitatively and but fo r which a finite or negligible Naturally occurring (background) tis­ quantitatively, by independent labora­ residue should instead be permitted. sue levels of endogenous compounds tories. This evaluation should fulfill the The Commissioner recognizes that and/or their metabolites and/or other objectives of the validation as listed many of these zero tolerances were related endogenous compounds in the above. established several years ago, at a target species must be determined in time when detection methodology was The required sensitivity of the regula­ substantially less sensitive and the studies designed to show the effect of tory assay method as previously defined geographical location, stage of estrus, available toxicology information was not will be the regulatory action level and as extensive. For some of these zero age, etc., on normal animals receiving no will be published in the F ederal R e g is ­ external source of the endogenous com­ tolerances, it may now be possible and ter . Since any “positive” finding reported pound. The tissue distribution of the consistent with protection of the public at a level lower than the published level health, to establish a finite or negligible levels of the compound and/or its me­ o f sensitivity may actually be a false tabolites and/or other related endoge­ residue. Where a finite or negligible resi­ positive, regulatory action will be taken due is established on the basis of ade­ nous compounds will be estimated from only at or above the published level. This these studies. This distribution will be quate safety data, the provisions of the is necessary in order to assure that a new regulation will not be applicable. used to establish the required sensitivity residue is in fact a true positive. In the of the regulatory assay method. The re­ past the lack of such a procedure has led Where a zero tolerance is deemed quired sensitivity will be that level of the to finding violative samples in one necessary, either because of a determina­ tissue distribution which is exceeded by laboratory which could not be confirmed tion of carcinogenicity or because the only one percent of the normal animals. in a second laboratory. compound is a suspect carcinogen or is Tissue samples from animals at slaughter otherwise sufficiently toxic that a deter­ The assay method will be published or mination of a safe level of residue in hu­ will be considered suspect if a level is referenced in the F ederal R egister and found above normal background. For ex­ man food cannot be made at this time, will include a definition of the response the provisions of the new regulation will ample, if 99.0 percent of background criteria unique for each method which tissue levels for a parent endogenous be applicable. The Commissioner rec­ represents a reliable positive finding ognizes that these new requirements compound and/or its metabolites and/or based on the validation studies. The other related endogenous compounds are cannot be imposed immediately. Accord­ criteria will take into account adjust­ ingly, a determination will be made with below 16 ppt., then a tissue level greater ments based on the accuracy and pre­ than 16 ppt shall be considered suspect. respect to each drug as to a reasonable cision of the method. If the method is amount of time within which compli­ The final determination with respect to not specific for the identification of the regulatory action will be based on a field ance will be permitted. In those in­ compound or there are reasons to sus­ stances in which the Commissioner con­ investigation to determine if the ob­ pect the occurrence o f false positives due served value was due to a misuse of the cludes that a health hazard may exist, to interference, a practical confirmatory or where there is a failure to undertake compound or if it was due to normal bio­ test must be provided which will identify logical variability. the requisitie studies, the Commissioner the residue at the level of sensitivity will proceed immediately to withdraw Withdrawal periods following the last required. dosage for endogenous compounds shall approval o f the drug. Hence, the above In summary, the development and approach will permit a reasonable tran­ be established based on the time required validation of a regulatory assay method for the level o f the parent compound sition to the new requirements without for monitoring purposes must consider compromising the public health or dis­ and/or its metabolites and/or other the following criteria: related endogenous compounds in the rupting the use of drugs for which there tissue to return to the median back­ 1. The method must be capable of re- is no known health liazard. ground level of contemporary controls. producibly extracting, at the required Therefore, pursuant to provisions of The maximum approvable level of the level of sensitivity, the significant com­ the Federal Food, Drug, and Cosmetic compound shall be administered to tar­ pounds from target tissues obtained from Act (secs. 402, 403, 409, 512, 701(a), 706, get animals for a period of time suffi­ treated animals as well as from tissues .52 Stat. 1046-1048, 1055, 72 Stat. 1785- cient to establish equilibrium in tissues. containing known added amounts of the 1788 as amended, 74 Stat. 399-404, 82 The number of days required for tissue compounds. Stat. 343-351; U.S.C. 342, 343, 348, 706, levels of any affected endogenous com­ 2. The method must be capable of 360b, 371(a), 376), and under authority pounds to return to the median back­ measuring residues with a sufficient der delegated to the Commissioner (21 CFR FEDERAL REGISTER, V O L 38, N O . 138— THURSDAY, JULY 19, 1973 PROPOSED RULES 19229 2.120), it is proposed that Part 135 be mum of two species, such studies as a propriate adjustments to account for amended by adding the following new multi-generation reproduction studies, drug usage and human consumption pat­ section: teratology and any other special studies terns and for the differences between which may be indicated from the nature daily food intake per unit of body weight § 1 3 5.38 Compounds used in food- of the biological action of the compound, of the laboratory animal and of man. producing anim als; procedures for including lifetime studies. These studies (i) If the data indicate that some linear­ determining the acceptability o f .«than involve collection of data from ap­ izing transformation other than the assay methods used for assuring die propriately designed dose-response ex­ probit-log transformation used in the absence o f residues in edible prod­ ucts o f such anim als. periments that demonstrate a “maxi­ modified Mantel-Bryan procedure better mum no harmful effect level” as well as describes the observed response and has (a) The act provides that feed and a “ m in im u m harmful effect level” in ap­ a biological rationale, then this other drugs intended for animals shall be safe, propriate animal species. linearizing transformation will be used that food produced from animals, shall (i) Where a finite or negligible residue for the extrapolation, (ii) In the event be safe, and that any compound admin­ of the parent compound and/or its that both significant noncarcinogenic istered to a food-producing animal metabolites is determined to be safe in harmful effects and carcinogenic effects which is found to induce cancer when in­ food, the required level of sensitivity of are observed during testing, the lowest gested by man or animal is prohibited the regulatory assay method will be the level for the regulatory assay sensitivity from the food supply, unless it can be level of the tolerance published in the as determined for the different effects determined by methods of examination F ederal R egister and the remaining shall be adopted. prescribed or approved by the Secretary provisions of this paragraph shall be (7) The sensitivity of the regulatory by regulation, that no residues of any inapplicable. assay method as defined above, the such compound are found in the food (ii) Where no residue of the compound method, and a definition o f the criteria produced from such animals under con­ and/or its metabolites is determined to used to establish a reliable positive find­ ditions of use reasonably certain to be be safe' in food, the dose-response slope ing shall be published in the F ederal followed in practice. Petitions for use of estimated from the toxicological-experi­ R egister . a compound in food-producing animals ments will be used to extrapolate to the (8) The withdrawal period for the shall include data for determining the required level of sensitivity of the method compound shall be based, using the regu­ absence o f residues of any unsafe com­ using appropriate confidence interval latory assay method and/or other suit­ pounds in the food produced from such techniques in accordance with the con­ able methods, on the time required after animals. The provisions of this section cepts underlying the Mantel-Bryan pro­ the last dosage for tissue levels of the shall determine the required level of sen­ cedure described in paragraph (b) (6) of parent compound and/or its metabolites sitivity of the regulatory assay method this section. Where such extrapolation is and/or any affected endogenous com­ for any compound for which the Com­ not scientifically appropriate, e.g., if no pounds to fall below the required regula­ missioner of Pood and Drugs has estab­ dose-response slope can be estimated tory assay sensitivity. lished a zero tolerance (no residue) in from the data, other conservative meth­ (9) The withdrawal period shall be the food. ods shall be invoked to determine an ap­ longer of either (i) the number of days (b) Exogenous compounds, defined as propriate safety margin based on a thor­ required for tissue levels to be depleted those compounds which are not produced ough evaluation of the quality of the ex­ to less than the maximum exposure level by the normal animal and are not re­ periments, their rigor as predictive tests plus a safety factor to account for ani­ quired for normal animal body function, and the nature and significance of the mal to animal variation as determined by are subject to the following require­ observed biological effects. appropriate confidence interval tech­ ments: (5) If it is determined that testing for niques or (ii) the number of days required (1) Metabolism studies shall be con­ carcinogenicity is required, test proce­ for any affected endogenous compound ducted in the target species to identify dures shall be used which maximize to return to a normal level plus a safety and quantify metabolites of the par­ sensitivity to detect a minimal dose which factor to account for animal to animal ent compound and the concentrations of induces a carcinogenic effect and with a variation. Current livestock manage­ the compound and its metabolites in sufficiently stable control population to ment techniques may justify a longer specific tissues (“ tissues” to include milk avoid false positive indications of car­ withdrawal period. The normal level of and eggs, if applicable). The effect of cinogenesis. Appropriate dose-response any affected endogenous compound shall the exogenous compound on tissue levels experiments shall be conducted to (i) be established as described in paragraph of related endogenous compounds also clearly establish whether or not the (c) of this section. shall be determined. compound and/or its metabolites are car­ (10) Based on tissue depletion studies (2) Degradation of the compound cinogens, and (ii) determine the relative and animal management practices, con­ and/or its metabolites during the period potency of the compound and/or its ditions o f use that are reasonably certain of time after slaughter that edible tis­ metabolites with respect to both its car­ to be followed in practice shall be speci­ sue would normally be held under stor­ cinogenic and its other toxic effects. fied for the compounds so that, if fol­ age conditions and the impact of cooking (6) If it is determined that the com­ lowed, they assure that no residue shall on the compound and/or its metabolites pound is carcinogenic, the required sensi­ occur in food produced from treated in question shall be determined. tivity of the regulatory assay method animals. (3) Determination of whether an ex­ shall be established according to a mod­ (-11) Notwithstanding a determination ogenous compound and/or its metabolites ification of the Mantel-Bryan procedure. pursuant to this paragraph of the re­ shall be subjected to appropriate test­ (Mantel, N. and W. R. Bryan, “ Safety” quired level of sensitivity of the regula­ ing for carcinogenicity will be based on Testing of Carcinogenic Agents, Journal tory assay method, if a regulatory assay the results of the metabolism studies, of the National Cancer Institute, Voi. 27, method of lower sensitivity is later de­ standard toxicity testing, structural re­ pp, 455-470, 1961) / This modification veloped and validated the Commissioner lationships of the compound and/or its shall consist of using the lower 90 percent will adopt that more sensitive method metabolites to known carcinogens, modes confidence limit of the experimentally and publish it in the F ederal R egister of physiological actions and interactions, and the intended use patterns of the determined dose-response slope from the even though its development was not compounds. carcinogenicity studies for extrapolation required. (4) If it is determined that carcino­ to a maximum exposure level with ap- (c) Endogenous compounds, defined genicity tests are not required or if the as those compounds which are present in results of carcinogenic testing are nega­ 1 Copies may be obtained from : Director, and are produced by the normakanimal tive, consideration for approval shall be Division of Nutritional Sciences (V M -100), and are not required from an external based on standard toxicological proce­ Bureau of Veterinary Medicine, Food and source, are subject to the following dures. These procedures shall include in Drug Administration, 5600 Fishers Lane, addition to subacute studies in a mini­ Rockville, MD 20852. requirements: FEDERAL REGISTER, V O L . 38, NO . 138— THURSDAY, JULY 19, 1973 No. 138—pt. I------5 19230 PROPOSED RULES (1) Metabolism studies shall be con­ that are reasonably certain to be fol­ opinion of the Commissioner otherwise ducted in the target species to identify lowed in practice shall be specified for protect the ‘public health will be per­ and quantify the metabolites of the par­ the compound so that, if followed, they mitted to be put into effect in accord­ ent compound and the concentrations of assure that no residue shall occur in ance with § 135.13a(e) through (k). the compound and its metabolites in spe­ excess of the established normal level (g) The provisions of this section shall cific tissues (“tissues” include milk and in food from untreated animals. be applicable to existing approvals of eggs, if applicable). The effect of the (d) Prior to approval, the adequacy new animal drugs in accordance with the endogenous compound on tissue levels of the regulatory assay method shall be following priorities: of related endogenous compounds also determined by validation of the method (1) The Commissioner will review shall be determined. in appropriate Food and Drug Admin­ existing zero tolerances (no residues) to (2) Degradation of the compound istration laboratories and other labora­ determine whether the drugs involved and/or its metabolites during the period tories. The validation shall determine should be the subject of finite or negli­ of time after slaughter that the edible the feasibility, specificity, accuracy, and gible residues. Those drugs for which tissue would normally be held under stor­ precision of the method. This validation finite or negligible residues are estab­ age conditions and the impact of cook­ of an assay method used for regulatory lished are not subject to the provisions ing on the compounds and/or its metabo­ purposes shall be based on the following of paragraphs (b) or (c) of this section. lites in question shall be determined. criteria: (2) Those drugs for which the Com­ (3) Animals containing tissue levels of (1) The method shall be capable of missioner has determined the appropri­ endogenous compounds above thejiorm al reproducibly extracting, at the required ateness of a zero tolerance (no residue) due to the administration of endogenous level of sensitivity, the significant com­ will be the subject of a notice published compounds may not be marketed for hu­ pounds from target tissues obtained from in the F ederal R egister or a letter to man consumption. Thus, neither tests treated animals, as well- as from tissues every holder of a new animal drug appli­ for carcinogenicity nor standard toxicity containing known added amounts of the cation establishing a time within which testing shall be required for endogenous compounds. the provisions of this section shall be compounds. (2) The method shall be capable of satisfied. Notices already published in (4) The naturally occurring or back­ measuring residues with, a sufficient de­ the F ederal R egister and letters already ground tissue levels of endogenous com­ gree of specificity, precision, and accu­ sent by the Food and Drug Administra­ pounds and/or their metabolites and/or racy to preclude the occurrence of false tion requiring additional studies and/or other related endogenous compounds in negatives or false positives. a more sensitive regulatory assay method the target species shall be determined in (3) The equipment, reagents and com­ for a drug subject to a zero tolerance studies designed to show the effect of pounds used in the assay shall be com­ shall remain in effect, and the provisions geographical location, stage of estrus, mercially available. Any required special­ of this section shall be used in determin­ age, etc., on normal animals receiving no ization in terms of equipment or per­ ing compliance with the requirements of external source of the endogenous com­ sonnel shall be consistent with that the act pursuant to those notices and pound. The tissue distribution will be normally available in a modem well- letters. The Commissioner will immedi­ used to establish the required sensitivity equipped analytical control laboratory. ately proceed to withdraw approval of of the regulatory assay method. The re­ (4) The time required for completion^ any drug on the basis of data or infor­ quired sensitivity of the regulatory assay of the assay shall not be so excessive as mation indicating a health hazard or method will be that value of the distri­ to delay regulatory action. a failure to undertake studies necessary bution which is exceeded by only one per­ (5) The assay shall offer minimal haz­ to comply with the provisions of this cent of the normal animals. ard in the laboratory. section. (5) The sensitivity of the regulatory (e) After publication in the F ederal Interested persons may, on o f before assay method as defined above, the R egister of an assay method in accord­ September 17, 1973, file with the Hear­ method, and a definition of the criteria ance with paragraphs (b) through (d) ing Clerk, Department of Health, Edu­ used to establish a reliable positive find­ of this section, compliance shall be de­ cation, and Welfare, Room 6-88, 5600 ing shall be published in the F ederal termined as follows: Fishers Lane, Rockville, MD 20852, writ­ R egister. (1) Samples of the food produced from ten comments (preferably in quintupli­ (6) The withdrawal period for the appropriate animals will be routinely cate) regarding this proposal. Comments compound shall be based, using the regu­ collected and evaluated using the regula­ may be accompanied by a memorandum latory assay method and/or other suit­ tory assay method (s ). or brief in support thereof. Received able methods, on the time required after (2) Any sample subject to paragraph comments may be viewed in the above the last dosage for the tissue levels of the (b) of this section yielding a residue of office during working hours, Monday parent compound and/or its metabolites the compound at or above the published through Friday. and/or any affected other related endog­ level of sensitivity of the method will be enous compounds to return to the me­ liable to regulatory action. Dated: July 13,1973. dian background level of contemporary (3) Any sample subject to paragraph A. M. S chmidt, controls. The withdrawal period shall be (c) of this section yielding a residue of Commissioner o f Food and Drugs. the number of days required for tissue the compound at or above the published [FR Doc.73-14746 Filed 7 -1 8 -7 3 ;8 :4 5 am] levels of any affected endogenous com­ level of sensitivity of the method will be pounds to return to the median back­ subject to investigation. Any such resi­ ground level plus a safety factor to ac­ due which is determined to be the result Social Security Administration count for animal to animal variation as of improper use of the compound will be [ 20 ,CFR Part 405 ] determined by appropriate confiidence in liable to regulatory action. terval techniques. Current livestock [Reg. No. 5] management techniques may justify a (4) No regulatory action may be based on the measurement of a value which FEDERAL H EALTH INSURANCE FOR TH E longer withdrawal period. is below the established level of sensitiv­ AGED A N D DISABLED (7) The characteristics of the distri­ ity of the approved regulatory assay Payment for Services of Physicians in bution of tissue levels of the compound method (s) as published in the F ederal Teaching Hospitals, for Physician Costs normally found in animals not exposed R egister. to Hospitals and Medical Schools, and to external sources of the compound and (f) The provisions of this section shall for Volunteer Services the specified conditions of use shall be be applicable to all new animal drug published in the F ederal R egister as Notice is hereby given, pursuant to applications, including supplements, ap­ the Administrative Procedure Act (5 part of the approval of any endogenous proved by the Food and Drug Adminis­ drug compound. U.S.C. 552 et seq.) that the amended reg­ tration subsequent to the effective date (8) Based on tissue depletion studies of the final regulation, except that sup­ ulations set forth in tentative form below and animal management practices, a plemental applications meeting the re­ are proposed by the Acting Commissioner withdrawal period and conditions of use quirements of § 135.13a(d) or that in the of Social Security, with the approval of FEDERAL REGISTER, VOL. 38, NO . 138— THURSDAY, JULY 19, 1973