Document n9YX6pmk1nm2bQYD7kD8OdVOR

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY ENCLOSURE 1 subject: EPA - FOA Meeting Held on January 7, 1976 DATE: JANB76 /ROM: TO: Alan Levin --* Special Assistant for Water Supply & Pesticides Memorandum of Record Participants FDA Sam D, Fine Sherwin Gardner Terry Coleman Robert Angelotti Howard R. Roberts Robert M. Schaffner Bob Lake Gerad L. McCowin Richard J. Ronk John R. Wessel Associate Comm, for Compliance Deputy Conmissioner Associate Chief Counsel for Food Associate Dir. Compliance, Bur. Foods Acting Director, Bureau of Foods Assoc. Director for Technology, Bur. Foods Reg. Coord. Staff 8ureau of Foods Division of Food and Color Additives Director, Div. of Food and Color Additives Scientific Coordinator, Office of the Associate Commissioner for Compliance EPA William M. Upholt Alan Levin Andrew Breidenbach Christopher Little Victor J. Kimm Senior Science Advisor, Office of Water and Hazardous Materials Special Assistant for Water Supply and Pesticides Assistant Administrator for Water and Hazardous Materials Assistant General Counsel Deputy Assistant Administrator for Water Supply 1. The purpose of the meeting was a get acquainted session for Commissioner Schmidt and Dr. Breidenbach and to explore areas of mutual interest to our two agencies. Commissioner Schmidt was unable to attend and Deputy Conmissioner Gardner substituted for him. 2. Dr. Breidenbach made an opening statement indicating a number of areas where EPA and FDA regulatory responsibilities may overlap. Among these are: PA Fi<m J320-4 (lb*. 4.72) SPI-25982 a. Pesticides that may contaminate food or feed, b Pesticides which may also be drugs. c. Toxic Substances d. Domestic Water Supplies. Dr. Breidenbach pointed out that relations between our two agencies have generally been good and have resulted in a number of Interagency agreements, particularly in the area of pesticides. He indicated that he preferred to limit the discussion at this meeting to water supply. 3. Deputy Comnlssioner Gardner responded that he endorses the Idea of an Interagency agreement on water supply matters. 4. Mr. Kimm outlined the principal problems involving drinking water as they relate to FDA: a. Enforcement of Interstate carrier watering points; b. Regulation by product or food additives (such as pipe); c. Water supplies not covered by the Safe Drinking Water Act; d. Bottled water 5. It was agreed that Mr. Kimm and Dr. Angelottl would take the lead to form a task force consisting of representatives of EPA and FDA to Identify Issues requiring top level decision In the area of water supply, with Item 4b. above receiving the highest priority. 6. Additional task forces on other problems such as pesticides and toxic substances would be formed as needed. 7. There was mention made of the need for further consultation on regulatory philosophies. EPA Indicated their Increasing use of risk/benefit evaluation as a basis for regulation and expressed a need for a degree of understanding, if not agreement, between the regulatory agencies, especially FDA and EPA but eventually probably OSHA and CPSC as well. FDA Indicated a willingness to discuss It further at a later date. cc: Participants 2 SP1-25983 January 7, 1976 MEMORANDUM OF CONFERENCE ENCLOSURE 2 Present : EPA Participants: Dr. Andrew W. Breidenbach, Assistant Administrator for Water and Hazardous Materials Dr. William M. Upholt, Senior Science Advisor, Office of Water and Hazardous Materials Alan Levin, Special Assistant for Water Supply and Pesticides Christopher Little, Assistant General Counsel Victor J. Kimm, Deputy Asst. Administrator for Water Supply FDA Participants: Sherwin Gardner, Deputy Commissioner Sam D. Fine, Associate Commissioner for Compliance John R. Wessel, Scientific Coordinator, Office of the Associate Commissioner for Compliance Terry Coleman, Associate Chief Counsel for Food Dr. Robert Angelotti, Associate Director for Compliance, Bureau of Foods Dr. Howard R. Roberts, Acting Director, Bureau of Foods Dr. Robert M. Schaffner, Associate Director for Technology, Bureau of Foods Bob Lake, Regulations Coordination Staff, Bureau of Foods Richard J. Ronk, Director, Division of Food and Color Additives, Bureau of Foods Gerad L. McCovin, Division of Food and Color Additives, Bureau of Foods Dr. Breidenbach and his associates met with Deputy Commissioner Sherwin Gardner and members of the staff of the Food and Drug Administration in Che Commissioner Conference Room in FB-8 on January 7, 1976, as a follow-up to Dr. Breidenbachfs letter of November 7, 1975, to Dr. Alexander M. Schmidt, Commissioner of Food and Drugs. Dr. Breidenbach explained that he had just recently been appointed Assistant Administrator for Water and Hazardous Materials, and chat he realized there were several areas of concern which require a close working relationship between EPA and FDA. He listed the following areas: 1. Water Supply - Interstate Carrier Program 2. Pesticides a. Contamination of food and animal feed - setting of tolerances and action levels. b. Pesticides as drugs for both man and other animals. SPI-25984 Pege 2 3. Toxic Substances Dr. Breidenbach referred to the current problem with PCB's and the new legislation now In the Congress on toxic substances. He said he was aware of the cooperation there has been In the past between Glen Sweitzer, Coordinator, Office of Toxic Substances, EPA and Mr. Wessel on problems dealing with toxic substances. 4. Philosophy of regulation Dr. Breidenbach made reference to the generation of data on which regulations are based. He also called attention to EPA's publication in the Federal Register of December 24, 1975, under the new Safe Drinking Water Act, of National Interim Primary Drinking Water Regulations. He stated that Mr. Train was sending to FDA through Secretary Mathews an official communication on the work required by FDA on bottled drinking water as a result of the new EPA regulations. (Later during 'the meeting Dr. Upholt said that he meant, under term "philosophy of regulation," the kind of philosophy FDA follows due to the Delaney Clause of the Food Additives Amendment). 5. HCTR Dr. Breidenbach referred to the cooperative program of the two agencies at Pine Bluff, Arkansas. It was Dr. Breidenbach's view that the main concern at the moment for both agencies is the problem of water supply. He asked Victor Kimm to discuss the interface between the two agencies on this problem. Mr. Kimm referred to the interchange of information required because of overlapping jurisdiction under the various laws administered by the two agencies. He noted the difficult judgments required on the problem of contaminants, such as chloroform in the water supply of New Orleans, Louisiana. He pointed out the Impact of FDA's publication of its proposed regulation on PVC, which Included the problem of migration of vinyl chloride from PVC pipe to water. The need for.the public and the regulated industries to know who does what on the Interstate Carrier Program was emphasized by Mr. Kimm. He also referred to what he identified as "products problems." * SP1-25985 Pegs 3 / AC Mr. Gardner's request, Dr. Angelotti reviewed for the EPA visitors FDA's concerns with water problems under both the Food, Drug and Cosmetic Act and the Public Health Service Act. Reference was made to the problems that arise when EPA applies the term "Use Prohibited" to water supplies, when there are administrative deficiencies or there la no standard. It was pointed out that in some instances where EPA has applied this designation, FDA has made a determination that the water Is safe, and thus FDA allows it to go on interstate carriers, and further . allows it to be used for manufacturing foods. Reference was made to the meeting held by Messrs. Fine, Angelottl, Kacevicz and McNamara with Mr. Klmm and other EPA staff members in June of 1975, where there was a discussion of the new authority granted to EPA under the Safe Drinking Water Act on control of water on interstate carriers. It was pointed out that under the old Public Health Service, where FDA had hot been Involved, there had been no concern with food additives in water (Mr. Klmm's "products problems"). The problem with PVC caused FDA to look at vinyl chloride migration to water; this logically could lead to FDA looking at liners for reservoirs, etc. After Dr. Angelotti'a review there was a general discussion, with a consensus being reached that there should be additional formal agreements between the two agencies to deal with problems caused by overlapping jurisdiction. It was agreed that the problems in the pesticide area would be handled by Mr. Wessel with the current EPA staff members that he has been working with. Mr. Wessel gave a brief review of the status of the agreements with EPA on pesticides. It was agreed that a task force would be set up, headed by Dr. Angelottl and Mr. Kimm, to deal with the water supply -- interstate carrier problems. It was agreed that at intervals of 2 to A months on an as--needed-basis. Dr. Breldenbach would telephone Mr. Fine to arrange for discussions at the Commissioner/ Assistant Administrator level. cc: HF-1 HF-2 HFC-1 HFC-2 HFC-13(Wessel) GCF-1 GCF-l(Coleman) HFF-300 HFF-1 HFF-400 HFF-302 HFF-330 HFF-330(McCowin) SDFine:br:eh 1/9/76 SPI-25986 1804 NOTICES ENCLOSURE 3 DEPARTMENT OF HEALTH, EDUCATION. AND WELFARE Food Mid Drug Administration [Docket No. 76P-9M9) MONSANTO CO. FUing o( Petition for Food Addtttva Correction In PR Doe. 75-30100. appearing at page 3437. in the Issue for Monday. Novem ber 10. 1075. change the seventh Une of the second paragraph to read as follows: "slderad In a draft environmental Im pact". [Docket Me. 76W-000S) CLANCO PRODUCTS CO. ET AL. Dlethytstilboetrol; Notice of Opportunity for Hearing on Proposal To Withdraw Ap proval of New Animal Drug Applications The Food and Drug Administration (FDA) !ls proposing to withdraw approval of all outstanding new animal drug ap plications for use of diethylstubestrol in anitweic. used for food for Human con sumption on the ground that use of the drug results In residues that have not been shown to be safe within the meaning of the act and that render continued approval of the drug unlawful under the Delaney anticancer clause of the Federal Food, Drug, and Cosmetic Act Holden of approved applications have until Feb ruary 11. 1979 to submit requests for hearing in accordance with 1314.200 (31 CFR 514.200). Such requests should be Identified with the Hearing Clerk docket number found In brackets In the heading of this notice. Backsaouna Diethylstubestrol (DBS), a synthetic estrogen used by feeders of cattle and sheep as a growth promotant has been shown to cause a statistically significant Increase of cancer In female CH mice at the lowest levels at which it was tested, 1a., 6.23 parts per billion <ppb>. In hu mans. a statistically significant relation ship has been identified between the ad ministration of DES to pregnant women and the appearance In daughters born of these pregnancies of a rare type of cancer--adenocarcinoma of the vagina. Since 1938, any new drug for use la animals. Just as any new drug for human use. has been required to be shown to be safe for Its intended uses. Even be fore the enactment of the Food Additives Amendment of 1938 (sec. 409. Pub. L. 8S-929. September . 1938. 73 Stat 17831788 (21 U.S.C. 348)). FDA had Inter preted this basic safety requirement as demanding proof that drugs Intended for use In animals used for human food would not cause barm If ingested by humans; DES was first approved for use In cattie feed In November 1954. A new drug application (NDA) for the drug wag per mitted to become effective on the basis of data demonstrating that, using the so- called mouse-uterine assay test, no real- dues could be detected in edible tissue 48 hours after withdrawal of DES. NDA'a for DES Implants In cattle became ef fective in December 1965. again on the basis of mouse-uterine assay data dem tlon published In the Fxbsial Rsonna of March 37, 1975 (40 FR 13902). These methods have remained In effect since 1983, although significant Improvements in sensitivity and reliability of other onstrating "no residue" under the per mitted conditions of use. Applications became effective for DES in feed for sheep and as Implants for sheep In 1937 and 1959. The current standards for approval of new animal drugs, set forth In eection 512 of the act as added by Pub. L. 90399. July 13. 1968. 82 Stat. 343-351 (21 U.S.C. 360b>, include several criteria. In addition to requiring substantial evi dence of efOcacy. sectljn 5l?.id> maites very clear that the sponsor of any animal analytical methods have occurred In the intervening years. Since publication of the detection methods In 1963, numerous new animal drug applications (NADA's)* for the use of DES have been approved by FDA.-In each Instance, the agency concludedthat If, when used in accordance with the conditions of use prescribed In the label ing. DE3 residues could not be detected in edible tissue by the approved methods, the requirements of the law were satis fied. Experience with the use of DES and drug has the burden of demonstrating advances In detection methodology have that the drug Is safe for humans If en demonstrated that this conclusion Is no countered in food produced from the ani longer supportable. mal. and causes no adverse effect to the Since their original approval, no data animal. Section 513(d) (D(H> Imposes have been submitted by the holders of ap additional restrictions on the approval proved NADA's for DES that cast doubt of animal drugs that have been shown to on the finding that the drug causes can cause cance'r. That provision requires cer in test animals. Furthermore, radio that FDA shall refuse to approve a drug active tracer research studies using " C-- If the Commissioner finds that "such labeled DES. conducted by the United drug Induces cancer when Ingested by States Department of Agriculture man or "imai or. after tests which are' <USDA), have ahown that radioactive appropriate for the evaluation of the residues attributable to the use of DES safety of such drug, Induces cancer In can result even when the prescribed con man or animal * * *.*' This language Is ditions of use are strictly followed, l.e., the codification In section 512 of the withdrawal 7 days prior to slaughter for Delaney anticancer clause that was DES in feed or Implantation of DES added to the act by the Food Additives 120 days prior of slaughter. See Amendment of 1938. T. S. Rumsey et aL. "Depletion Patterns In 1962, Congress enacted an excep of Radioactivity and Tissue Residues In tion to the anticancer clause. The focus Beef Cattle after the Withdrawal of of Congress at that time was so clearly Oralu C-DiethylstUbestrol," Journal of on DES that this exception has ever Animal Science, 40(3) : 539-549, 1975, since been known as the "DES clause." and T. 3. Rumsey et al.. "Fate of Radio This exception, now also part of section carbon In Beef Steers Implanted With u 512(d) (l) iH> of the act. permits approv C-Dlethylstilbestrol." Journal of Animal al of the use of a carcinogen as a drug Science. 40(3): 550-560. 1975 (available In animals only If the Secretary (by dele for public examination at the office of gation under f 2.120 (21 CFR 2.120). the the Hearing Clerk, Food and Drug Ad Commissioner of Food and Drugs) finds ministration) . These radioactive residues that: were at levels that are below the sensi under the-conditions of uee specified In proposed labeling end reasonably certain tivity of the previously approved methods and that have not been shown to be safe to be followed la practice (I) such drug will ; within the meaning of the act not adversely affect the for which In 1972 and 1973, the FDA, acting on It is intended, and <U) no residue of such these reports (then unpublished) of res drug will be found (by methods of examinei idues discovered by the tJSDA In radio tlon prescribed or approved by tbe Secretary active tracer studies, withdrew all ap by regulations, wbleb regulations ahaU not be aubject to subsections (c), <d), and (h|) ' (of section). in any edible portion of sucb animals after slaughter or in any food provals of DES for use in animals used for human food. These actions were challenged by sponsors of NADA's for yielded by or derived from the living anl- DES and ultimately vacated by the United States Court of Appeals for the In accordance with the foregoing pro vision, FDA In 1993 approved methods for the measurement and identification of DES residues: the mouse-uterine method, which measures total estrogenic activity at 2 ppb, and the so-called "paper chromatography" method, which is Incapable of differentiating DES from other estrogens at levels below 10 ppb. Originally codified under If 1358.29 (b) and (e) and 121.241 (e) and (f) (21 CFR 1359.29 (b), <c> and 121.241 (e), (f)), the approved methods published in District of Columbia Circuit in Hess ft Clark v. Food and Drug Administration, 495 F. 2d 975 (1974), and chemetron v. Department of Health. Education, and Welfare, 493 F. 2d 995 (1974) 'on the ground that the notice of withdrawal of approval Issued by FDA had not afforded the sponsors adequate opportunity to demonstrate the need for a hearing, as required by 21 UB.C. 360b<eHl>. Since the resumption of the use of DES following the Court of Appeals' rein statement of the NADA's, residues havp Fart 133 were recodified under Part 538 been found in samples of edible tissues without substantive change by a regula- (livers) taken from cattle presented for FIOttAl ttCISTM, VOL 41. NO. 7--MONDAY, JANUAIT 12, 197* SPI-25987 aUofbUi'. In 8 U8DA objective --npltof program of cattle slaughtered through- ' gut the country, 11 residues were detected In 3,184 samples In 1974 using gse liquid ehromatogrmpble (OLC) methods. Dur ing the flnt 3 quarters of 1978, 23 reel- due* were detected in 1.71? samples, to diesting an increase in the percentage of samples containing DES residues from 0.41 percent to 1.46 percent. Two addi tional residues detected by U6DA dur ing the fourth quarter of 1978 in edible tissues of beef cattle are not include In the percentage calculation because the fourth quarter sample else Is not yet known. - Hubs calculations likewise do not in clude 17 additional DES residues found during 1974 and the first a quarters of 1676 in the UBDA selective ssmpllng pro gram. This program samples on a non- random basis both animals presented for slaughter by raisers who have pre viously presented residue-carrying ani mals as well ss >nl1"*1* that are suspect ed, on some other basis, of containing DBS residues, In the selective ssmpllng program, as would be expected, the In cidence of residues Is considerably high er. Only 1 of the 36 residues detected In the USDA objective sampling program was st a level (greater than 10 ppb) that could have been both detected and iden tified as DES If the currently approved mouse-uterine and paper chromatog raphy methods had been used. Further more, although FDA investigation of the causes of these residues indicates that several may have resulted from DES contamination of withdrawal feed or fail ure to follow the prescribed conditions of use of DES, a substantial number of the residues cannot be attributed to misuse. In the face of these findings. It Is clear that the central assumption underlying the previous approvals by FDA of DES for use in used for human food. Le., that no residues would be detected when the drug was used in accordance with the currently approved conditions of use. Is no longer valid. The currently ap proved methods for DES have been shown to be Inadequate to detect signifi cant residues. Residues being detected by other methods have not been shown to be safe within the meaning of the act. Tbls showing was not previously required of the applicants since a common premise of all previous DES approvals was that no residues would occur. Moreover, since, no level of DES residues has been proven to be safe within the meaning of the act, the Commissioner concludes that no new method for the detection of DES can now be approved pursuant to the 1963 excep tion to the anticancer clause. f Zhaskousct or Amoves Msthods The Commissioner issued. In the FeoeasL Rgozsm of March 27, 1974 (39 FR 11399), a proposal to revoke the ap proved methods for Identification and measurement of residues of DES. and in vited Interested persons to comment within 30 days (extended 10 days to the close of business of May 0, 1974 by a NOTICfS 1803 notice published In the Pnuu Riumi of April 20,1974 <39 FR 14611) >. Sixteen comments were received on the proposal within the extended com ment period: 8lx from manufacturers of DES, four from individuals, two from between feed tad implant uses of DE8 with respect to the adequacy of detection methodology. The Commissioner further observes that, whatever the deficiencies of other detection methods, there ba been no showing that the approved cattle Industry organisations, two from methods art adequate to Justify con cattle feeders, and one each from a citi- tinued approval of DES. Neither com sens* association, and a scientific society. ment submitted or referred to data that Bight additional comments were received show that levels of DES below the sensi after the comment period doted. Several tivity of the approved methods kre safe comments supported the proposed- revo within the meaning of the act. cation of the detection methods and urged the Commissioner to set to termi nate the use of DES in food-producing animals, while other comments objected 4. Two comments stated that final action on the revocation of methods proposal should await resolution of the proposal on sensitivity of the method to the Commissioner's proposed action. None of the comments received supplied published in the Prbkral Rioistir of July 19. 1973 (36 FR 19236). data or studies adequate to support the approval of any new analytical method(s>, much less data or studies to dem onstrate that the methods previously approved are adequate to detect residues of DES now known to occur. All the comments may be semi at the office of the Bearing Clerk,-Food and Drug Administration. The comments received and the Com missioner's responses are discussed below. 1. Nine comments suggested that the official methodology might be an issue for a hearing rather than the subject of a revocation before a hearing. The CommlMloner notes that the des ignation of officially approved method ology does not Independently require a hearing under the act. However, oppor tunity for bearing is required on the proposal to withdraw approval of the NADA's for DES, and any hearing held could Include the issue of whether a practicable analytical method exists that is adequate to detect DES residues. 3. Eight comments stated that the use of DES was Important to the revenue of cattle raisers and to the reduction of the cost of cattle production. Two comments stated that the revocation of DES ap provals could affect consumer prices for beef. The Commissioner notes that the eco nomic importance of diethybtllbestrol to a particular Industry or even its effect on consumer beef prices is not relevant to or determinative of the acceptability of detection methods offered to Justify exception of the drug from the anticancer clause, nor is it relevant to the safety of residues resulting from the use of the drug. 3. Two comments stated that the pres The Commissioner notes that despite continuing efforts of FDA since that pro posal to determine aoproorlate criteria for levels of sensitivity, the complexity and scope of the scientific and legal is sues have combined to prevent comple tion of a final regulation to resolve the Issues of methodology. No final regulation based on the Mantel-Bryan procedure is anticipated within the next 6 months. The Commissioner has concluded that the public and FDA should no longer await final action on that proposal before resolving the status of DES. 9. One comment contended that the OLC method, coupled with mass spec trometry Identification, was superior to the present procedures, but the comment did not state that these procedures would be adequate to detect DES residues or provide data to support their adequacy. Another comment, while opposing any action to revoke existing methodologies, urged that If present methods were re voked they should be replaced with the OLC method as the official method and claimed that this method Is sensitive to 0.6 ppb. This comment did not provide -any Information or data to demonstrate that levels of DES below 0.3 ppb are safe within the meaning of the act. Another comment stated that the OLC method reliably detects residues of DES as low as 1 ppb md noted that information describing thu method had previously been submitted with an NADA. This comment, too, failed to provide data showing that a sensitivity of 1 ppb is sufficient to meet the requirements of the act or to show that residues of DES below 1 ppb are safe within the meaning of the act. ent approved test-methods for DES are The CommlMloner acknowledges that adequately sensitive. One of these com the results of USDA's OLC sampling pro ments limited Its claim of adequacy to gram supply part of the basis on which the use of the drug in Implant form. he is proposing to withdraw approval of The other stated that the sensitivity of outstanding NADA's for DES. These re the present methods is sufficient because sults clearly demonstrate that the cur the radioactive tracer studies that rently approved methods for DES, Le.. showed residues below the limits of the the mouse-uterine method and the paper mouse-uterine test were discredited In chromatography method, are inade court proceedings arising out of the quate. The Commissioner concludes, agency's previous efforts to withdraw ap- however, that no showing has been made proval of these NADA's. that the OLC method, whether used The Commissioner concludes that nei alone or in conjunction with mass spec ther the scientific data cited in the pro trometry, may be approved In their place. posal nor any Information provided by 6. One comment stated that the bur this comment establishes any difference den of {woof to demonstrate the safety of FfDCtAl RfOUTfR. VOL. 41. NO. 7--MONOAT, JANUARY 13, 147* SPI-25988 1806 / v NOTICES t DCS should rest with ttaoa* who with to market the drug. Tta* Commissioner concun with this comment and notes that Congress has placed the burden on the applicant to demonstrate the safety of any animal drug <31 UJ.C. Sb).- 7. Three comments refsrrsd specifically to ths Oass study cited In the propoeal to revoke the methods for DU: Gas*. Coats, end Oraham. "Carcinogenic DoseResponse Curve to Oral DlethylstflbestroL" Journal of the National Cancer Imtitute. 33:971-977, 1994 (available for public examination at the office of the Hearing Clerk. Pood and Drug Adminis tration). The Gass study found that 6.33 ppb DCS caused cancer In teat animals (C>H mice). Two of them comments claimed that this finding was a "false positive.- one of them suggesting that another teat animal should have been used Instead of the mice that were used.Nelther of these two comments provided data to demonstrate that DES does not cause caneer at levels of 6.3S ppb. The third comment questioned whether the Oass study was statistically sound and quoted two scientists who drew from that study widely divergent conclusions as to the lowest levels of DES capable of caus ing cancer. This comment concluded that this disparity of scientific opinion means that the present data are Inadequate to determine safe levels and supports a re quest for additional funds to conduct more studies. ' The Commissioner Is of the opinion that. In the absence of convincing scien tific evidence that the Oass study was in error or that there Is some level at which DES Is not carcinogenic, the determina tion that DES Is carcinogenic in CH mice at 6.25 ppb cannot be Ignored. The Commissioner agrees that data are not adequate to establish the lowest level at which DES causes cancer In test *im*i* The Commissioner Is aware of no evi dence that a level of DES that doee not cause cancer in test animals can neces sarily be assumed otherwise to be safe within the meaning of the act. On the basis of data currently available, the Commissioner questions whether any of the available analytical methods for the detection of DES residues affords ade quate assurance that residues below the level of detection are safe within the meaning of the act. 8. One comment stated that one pos sible solution to the method suitability Issue that should be explored would be to discard, the livers of animat* treated with DES. The Commissioner Is of the opinion that whether or not specific edible tis sues may be discarded is not material to determining the adequacy of a meth od to detect DES residues in those or other edible tissues. It has not been dem onstrated, for example, that DES resi dues In the liver mmy not serve as an Indicator of resdues present, albeit at lower levels. In other edible tissues. 9. Two comments suggested that the basic question of whether DES repre sented a public health threat as car cinogen remained unanswered. The Commissioner notes that the earetnogenlclty of DES has long been rec ognised by scientists, and concludes FDA need not await demonstration of a danger to public health before en forcing the act's requirements that ani mal drugs be shown to be safe and that any cancer-causing drug be demonstrated to leave no detectable residues. 10. Other comments, which opposed the administration of DES to cattle or Its presence in any foods, pointed out that the Canadian Government had ex cluded United States beef falling to bear USDA certification that the animal had never received DES. and expressed hope that FDA would move expeditiously to remove DES from the food supply. Although these comments are not di rectly relevant to ths adequacy of the previously approved DES detection methods, they do support the agency's liming of this notice of opportunity for hearing on the withdrawal of approval of NADA'S for DES. 11. One comment suggested that In enacting section 512(d)(1)(H). Con gress intended that carcinogens could be used Injood animal* and obliged the Secretary of Health, Education, and Welfare to establish some matiwt of The Commissioner disagrees. Section 512(d)(1)(H) of the act prohibits the use of any carcinogenic drug un less the Secretary makes certain affirm ative finding*, including a finding that no residue of the drug will be found In edible tissue by officially designated methods. Congress did not intend the Secretary to designate a method when no adequate method was available. Rather, the act. requires that an *"immi drug not be approved unless an adequate detection method can be designated. To be approvable a detection method must be both practicable, In the sense that It must be adaptable for use as a regula tory tool, and It must be sufficiently sen sitive. The Commissioner concludes that any method approved In accordance with section 512(d) (1) (H) must at least be capable of detecting residues at a level that has been shown to be safe within the meaning of the act. Because no such showing has been made with respect to residues of DES well below the com bined sensitivity of the currently ap proved methods, the Commissioner twaintain* that those methods can no longer serve as the basis for approval of the use of DES In animals used for hu man food. The Commissioner Intends to revoke these methods at the time of final ac tion based upon this notice of oppor tunity for hearing. If no hearing on the proposal to withdraw approvals for the use of DES Is required, either because FDA recieves no request(s) for hearing or because any request(s) for hearing fails to demonstrate a genuine ang sub stantial Issue of fact requiring a hearing, the approved methods will be revoked simultaneously with the announcement of that fact If a hearing U held, the currently approved method will be re voked. and any replacement method(s) demonstrated to be adequate will be des ignated at the time the Commissioner issues a final order based upon the hear ing reoord and the decision of the Ad ministrative Law Judge. PaorosKD Aenow On the basts of the comments received In response to the propoeal to revoke the detection methods for DES. the data cited In the March 1974 proposal, and evidence that DES residues continue to be found In edible tissues of nirw-if slaughtered for human food, the Com missioner concludes that: 1. DES has been shown to cause can cer In test animals and has been asso ciated with the occurrence of cancer In humans. 2. Residues of DES have been and are being detected in the edible tissue of animals at levels that have not been shown to be safe within the meaning of the act. 3. The authority conferred by section 512(d)(1)(H) of the act to approve methods of examination allows, but does not require, the Commissioner to desig nate a method. 4. Any method designated by the Commissioner pursuant to section 512 (d) (1) (H) must be practicable and ca pable of detecting drug residues regard less of the route of administration used for a drug. 5. The approved methods for detection of DES residues In edible tissue are Dot adequate to demonstrate that, within the meaning of the act. no residues wtU be found when the drug is used accord ing to the approved conditions of use. < 6. Data are lacking to Justify the ap proval of any other analytical method(s) for detection of DES residues because no currently available method Is capable of detecting residues at levels that have been shown to be safe within the mean ing of the act. Therefore, under the Federal Food. Drug, and Cosmetic Act (sec. 512(e) (1). 21 U.S.C. 360b(e) (1)), the Commis sioner proposes to withdraw approval of all existing NADA's providing for the use of DES In animals used for human food on the following grounds: 1. Information and data available since these applications were approved, together with earlier data reevaluated In the light of current scientific knowledge, demonstrate that DES Is not shown to be safe for use as approved. 2. The anticancer clause In section 512(d) (1) (H> of the act Is applicable. This notice applies to all outstanding NADA's for the use of dlethylstilbestrol In animal* used for food for human con sumption. All such applications now known to FDA are listed below by NADA number and by each applicant's name and last known address In FDA records. Copies of this notice are being forwarded by registered or certified mail to each of these known applicants. Notice to other applicants or holders of such NADA's whose Identity is not known to FDA is given by this publication. FiOfiAAi REGISTER, VOL 41, NO. 7--MONDAY, JANUARY 12, 197* SPI-25989 Nonas 1807 MADA No, me.......... 97*7-------------- *770________ 798_____ ... 10190..._____ 10356_______- , 10361 -- . 10431 10666 10664.________ 11080________. uses______ 11846 uses 11466..._____ 13448_________ 1*773__________ 1S374_________ 41446_________ S4739_________ 8*816 69017 S9018 S6819_____... S6479 96454. 96671__________ 96876________ _ 97146__________ 87441.________ 97868....____ 34607_________ 98408_____... S8410_____... 48683 Mom* sad addr*m Banco Produet* Oo. P.O. Box mo. Tnfiunxpom. md. 4MM. Pfimr. ine. S3* lut 4M St. H*w Tort, H.T. 10017. Sm HADA 9787. 8m HADA 0707. Walnut Oror* Ptoducte, 901 Liu at. DtTteton of W. 8. One* Oo. Atlantic, low* OOSS. Am*rtea& Cyanamid Co. P.O. Box 400, Princatoa. NJ. 06440. Marsh Sharp * Dotun* Bo- March LabeeatoriM. DmMOB of uk A Co. me. Bahway. HJ. 07060. Dawm LeborrtorlM. 490 Stat* 8L, Chicago Halghta, Hi. *0411. mmoaiMB Manufacturing Co. Qtuaoy, Iowa 91048. Vlnaland LaboratorM*. Zne. BnbddUry of Damon. 3389 Xaat laiwlii At*. Vineland, HJ. 06960. 8m HADA 8809. Haaa a Clark, Dlrlalan of Bhodt*,' Inc. 7th and Oranga St. Aahland, Ohio 44809. 8m HADA 9797, X. B. Squibb * Sons., Inc. P.O. BOX 4060, Princeton, HJ. 08840. 8M HADA 10431. 8M HADA 11389. Pater Hand Foundation. Inc. 3 S. Madtoon St. waukagan. ZU. 60084. o. m. Franklin arum Co. .P.O. Box 33999. D*nT*r, Oolo. Port Dodg* Lnboratortaa. Port Dodg*. Xowa 90601. Standard Manufac turing Co. 701 8. 43d BL, Omaha. Nabr. saios. Sm HADA 10431. Tbompaon-Hayward Chemical Co. 6300 Spaakar Bd. Kan sas City, Kan*. 06106. BM HADA 99017. Paad AddiUTsa, Inc. nusetit, Habr. 68034. 8. B. Panlek Co. 100 Church 8U Haw Tort. H.T. 10008. Dais Allay Co. P.O. Box 444. 8t. Joaaph. Mo. 64903. Sea HADA 96694. 8m HADA 84736. national Oat* Co. 1991 Baugh At*. Cast St. Leu!*, X1L 63304. Sm HADA 87146. SM HADA 86313. Tax** Nutrition A Serrlc* Co. P.O. Box 4378, Fort Worth, T*>. 76108. Sm HADA 38907. SM HADA 98907. Ultra Llf* Laboratories. Inc. No. l Ultra Way DrlT*, juiu**. - - - - - - - r~i iiirin 0717--------------- 0M HADA *0710. 0710_________BM HADA 90710. 07TS--_____ >M IfADA laaoi. M014--------------- wwura pm svppiMBoato, nto&xburt- Waah. MOM. 43169-------------- 80* IfADA 0036. 43946-------------- Cbtnttton Corp. Chicago, HL 60611. 43703_________ TkiBiBia Induatrtea, KiBBA 43640--------... 44944-------------44436--.... City. Mo. Ml)A 8m HAOA 10361. 8m HADA 11304. wum nmm A--edition. 6MttU, VulL Mill. 44709.------------ Falctaff Brewing Carp. 90M 46061--------------40063-------------- Oakland At*. 89. Lena*. Mo. 69166. BM HADA 11368. 8m HADA 11384. Any holder of An Approved applica tion that elects to avail itself of the op portunity for hexring pursuant to section 513(e)(1) (31 U.S.C. 360b(6)(l)> And | 514.300 (31 CPR 514.300) must file with the Hearing Clerk. Pood and Drug Ad ministration, Rm. 4-65, 5600 Fishers Lane, Rockville. MD 30653, a written Ap pearance requesting such hraring by February 11, 1976, giving the reasons why approval of the application should not be withdrawn, and providing a wellorganised and full-factual analysis of the scientific and other Investigational data such holder Is prepared to prove In support of Its opposition to the-Commls1oner's proposal. A request for hearing may not rest upon mere allegations or denials, but must set forth specific facts showing there Is a genuine and substan tial issue of fact that requires a bearing. Responses to this notice may be seen In the office of the Hearing Clerk during regular business hours, Monday through Friday. If a hearing Is requested and Is Justi fied by any holder's response to the no tice of opportunity for a hearing, the is sues will be defined, an Administrative Law Judge will be assigned, and a written notice of the time and place at which the hearing will commence will be issued as soon as practicable. Any hearing on the withdrawal of ap proval of the foregoing NADA's win be open to the public. If, however, the Com missioner finds that portions of the ap plications that serve as a basis for such a hearing contain information concern ing a method or proces that Is entitled to protection as a trade secret, the part of the Hiring involving such portions win not be public, unless the respondent so specifies. The Commissioner has carefully con sidered the Inflation Impact of this pro posed action and a major inflation Im pact has been found, ss defined in Execu tive Order 11131, OMB Circular A-107, and Interim guideline* la*ud by the Departomit of Health. Education, and Wel fare. Copies of the Inflation Impact state ment an on file with the Hearing Clerk Food and Drug Administration. The major conclusions found In tbs <nflstion Impact statement are: 1. There are no satisfactory alterna tives to the agency's proposed action that an consistent with the legal constraints Imposed by the Federal Food. Drug "< Cosmetic Act. as amended. 3. Operating expenses to feed lot pro ducers of cattle for feed and other Items an estimated to increase by 6156 million (hiring the first year following a DES ban. These increased costs are expected to fall substantially over the long term as sub stitutes to DES become available in greater quantitive*. 3. Retail prices of beef are estimated to rise by about 2 cents per pound, mean ing the per capita cost of beef to con sumers at current levels of consumption would increase approximately $2 to 93 annually. The aggregate consumer Im pact Is estimated at 9503 mi|on. 4. A ban on DBS would not cause major Inflation Impacts, as defined by the HEW/OMB criteria, in the areas of com petition. productivity, supply of ma terials, or use of energy. 5. The benefits from Implementing the proposed action will be the elimination of any risk of cancer associated with the consumption, via the edible tissues of food-producing animals, of residues at tributable to DES. This notice U Issued under the Federal Food, Drug, and Cosmetic Act (sec. 513. 63 Stat. 343-351 as amended (21 U.S.C. 360(b)), and under authority delegated to the Commissioner (31 CFR 3.120). Dated: January 7.1976. A. M. SCHMZPT. Commissioner of Food and Drugs. (FB Doc.76-660 FU*d 1-0-76:6:44 am] ADVISORY COMMITTEE Notice of Meeting This notice announces a forthcoming meeting of a public advisory committee of the Food and Drug Administration. It also sets out a summary of the proce dures governing the committee meeting and the methods by which interested persons may participate in the open pub lic hearing conducted by the committee. The notice la Issued under section 10(a) <1> and (3) of the Federal Advisory Com mittee Act (Pub. L. 93-463, 66 Stat. 770776 (5 U.S.C. App. I)). The following ad visory committee meeting is announced: 99161__________ XXL 83348- Square Deal Fortification Co. Kouta, lad. 46347. wiiwn Date, Uzm, pUe Type af msatlag acd contact pmo 98481........ 98719.. 38716_____... Brealf-Koallng, In*. Ord. Habr. 68363. PMd Products, Zne. 1000 Wact 47th At*. Danrar, Oolo. 0311. BM HADA 39718. AnUWoUei la Animal Psada Jaa. Si aa4 SS, am. Can* Opaa cannntUsa dlscoMon fan. 30, a.m. to < p.a.i SabemimlUM sf tba Na- Imm Boom B, Park- p* pvtoU haarinf Jan. 9. j p.m. U4S0 p.m-: opa tianal Advisory Food and lava Bide., MOT FUban eomnittaa dlmuMtoa Jan. SO, S km. unit! iJIkiMm Drag Cmmniltaa. Lena, RcekTtUe, Md. ot Uada went date: ctaasd aommlttea deUberatloaa )u. SS, dlacuMon of tmda went data to adjourn- mant; WiUam V. WNtaham. M.D. <UPOD. MOO Flaban Lana, JLockrUta, Md. 20843, Kn-4tS-it7. PIDCBAl 8EOISTM, VOL 41, NO. 7--MONDAY, JAMUA1V 13, IV74 SPI-25990