Document XG6EdZQMbx0yz3O1GLNrMeYx

i v-' 1 C\ pi/ c I (ferJH^A l*w omen JOSEPH I. IIU.1I J1E0MB K. XECEMxlT rECE"^ Kelleh and Heckman CHILIS M KlIKAl' WILLIAM a.SOBOBESAXl, JX. ISS'/iSST' JM12S1976 us6 irw iTaxxT, *, w. IUITI 1003 WA5HIKOTON, D-C- 20036 DAVTD L. HILL 'cSOllP kaxtiw w. Mxco^c^p^j CHEM- (jKUuri | -FITXB M. JflMBOV JOBXPH 1 HABLST CREOLE C. HiHlIS LAW dept. January 26, 1976 PETES THOMAS SMITH MICHAEL r MOmiOKE LAS ST *. SOLOMOK No. 14 TELZFIOSI aoa o-arco CABLE ADDHEBS"EELMaK" TO: All Members of PVC/VCM Mailing Lists Ladies and Gentlemen: The purpose of this letter is to keep you up to date on the regulatory situation as regards the Pood and Drug Administration (FDA), Environmental Protection Agency (EPA) and the Occupational Safety and Health Administration (OSHA). PDA In our last letter we advised that we would attempt to bring you information as promptly as we could regarding any further moves towards resolution of the jurisdictional question between FDA and EPA, particularly with reference to PVC pipe. Only after Letter No. 13 went out did we learn so that we can now report that a "first meeting" was held on January 7, 1976 between high level groups from FDA and EPA. Although a number of different subjects were explored, the question of jurisdictional responsibilities for drinking water and water distribution systems was referred to a task force to be headed by Dr. Robert Angelotti of the Pood and Drug Administration and Mr. Victor Kimm of EPA. We are enclosing copies of two different memoranda on this conference, one prepared by Alan Levin of EPA (En closure 1), and one prepared by Sam Fine of FDA (Enclosure 2). Although not reflected in either of the memoranda, it is our understanding that Mr. Kirnm suggested EPA might be prepared to acquiesce in FDA responsibility for "food additives" that might enter the water supply in light of FDA's greater ex pertise in this area. This is somewhat disturbing news but all it really means at this stage is that additional explora tory work and discussion is required. Along this line, we are planning to try to follow up on the activities of the newly designated task force as they relate to the jurisdictional AP00053904 January 26# 1976 Page Two \ * problem, hopefully so that our views can be more force fully made known. In any case, we will keep you informed as to any developments. Not directly related to VCM/PVC matters but never theless a matter of some concern, was the Notice published in the Federal Register on January 12, 1976 proposing to withdraw approval of all of the New Animal Drug Applications for diethylstilbestrol (DBS). The reason for our concern is that we have been informed by our contacts at the Bureau of Foods that they are worried about the way the Commissioner of Food and Drugs has stated, in the enclosed proposal (En closure 3), that, with regard to the sensitivity of an analytical method for DES it "must be both practicable, in the sense that it must be adaptable for use as a regulatory tool, and it must be sufficiently sensitive." As you will see, the Commissioner concluded 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. Then, the Notice states that "Data are lacking to justify the approval 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 meaning of the Act." On this basis he has, in effect, concluded that DES must be banned as an animal drug. The law with respect to new animal drugs is not the sane as that with respect to food additives. Nevertheless, the Commissioner has here set as a requirement for an ana lytical sensitivity for the detection of a carcinogen an assurance that it would detect the substance at a level shown to be safe within the meaning of the Act. Since the Act has sometimes been interpreted to legislate that car cinogenic food additives have no safe level, the application of a similar standard could lead to the adoption of the HRG position, i.e. PVC is made from VCM so some must get in, no level has been proven safe, ergo no data is acceptable to preclude a ban on the basis of the "no migration" concept. Since some Staffers in the Bureau of Foods have ex pressed concern about whether the DES action might have to AP00053905 January 26, 1976 Page Three govern treatment of the polyvinyl chloride situation, we thought it would be advisable to bring this matter to your attention. At the same time, we urge you not to overreact on the basls"~of thie informationThe fact is that there are Important distinctions between the two situations. In deed, I eo indicated last Friday in an informal talk I had with the Staff member most concerned. In so doing, the following distinguishing features were called to hie atten tion: 1. I pointed out with some vigor that it should be more difficult for the Commissioner to go the DBS route aa regards polyvinyl chloride in light of the willingness of the Occupational Safety and Health Administration (OSHA) and the Environmental Protection Agency (EPA) to at least implicitly accede to the existence of a "safe level" by the adoption and proposal, respectively, of their Standards. 2. X reminded him that, while all New Animal Drugs have to be specifically approved to be legally marketed, a po tential indirect food additive need not even be cleared if there is no reasonable expectation of migration and the burden of proving reasonable expectation of migration is on the Government. 3. I also reminded him that further toxicological work is being done and there is every reason to believe a no effect level will be shown at perhaps as high as 100 parts per million (As far as we are aware, Maltoni has had no problem with the rats he is feeding 3.3 mg/kg. of VCM), while DES has apparently been proven a carcinogen at a level as low as 6.5 parts per billion. AP00053906 s January 26, 1976 Page Four 4. 1 further reminded the 8tafer that the Commissioner has thus far recognized that there is & whole group of PVC applications where he has con ceded the validity of a "no reasonable expectation of migration" posture and no data, or even language, has been filed to contest this view. 5. Finally, I pointed out that the animal drug regulations, like the pes ticide provisions, speak in terms of a flat "no residue," rather than in the hard fought for "no reasonable expecta tion of migration" language of the Food Additives Amendment. We hope the foregoing list of concepts advanced will have a helpful impact. The only other information I can pats along is that the Staff member involved told me that the Bureau now has a target date of "sometime next spring" for action on the PVC situation. I think I need not tell any of you that there is very little we can do to expe dite the process--our having been advised that the data is still under scientific review. The fact that there will be some delay could conceivably be helpful since another Maltoni report is expected soon* This is not to gainsay the fact that we know many of you would like a prompt favorable decision ao as to remove the cloud on PVC food contact products. We do have both points of view fully in mind but all ve can really promise is that we will try to keep you informed about the shifting tides. EPA The VCM/PVC Producers Group met on January 23 and approved plans for an appearance at the Hearing scheduled for February 3, and for the preparation of Comments to be filed in connection with EPA's proposed rulemaking on vinyl chloride emissions. It has been determined that any statements at the AP00053907 January 26, 1976 Page Five Hearing should be general in nature. In addition to a dis cussion of specific points at issue, a recommendation for additional joint research programs sponsored by EPA, industry, and labor will be presented. With respect to the more detailed Comments which must be submitted by February 23, the various technical, legal, health and economic arguments are now being gathered for a timely, comprehensive written filing. OS HA In a previous letter we reported that OSHA was inter preting the definition of fabricated product so as to include resins with a residual vinyl chloride level low enough so that employee exposure at or above the action level without regard to the use of engineering controls could not occur. Another recent letter from the Department of Labor addressed to Mr. R. R. (sic) Wheeler, Jr., Union Carbide Corporation, repeats the same opinion, states that there are no plans to amend the vinyl chloride standard, and notes that a revised Program Directive is contemplated. Since the letter refers to other matters which could be of general interest we are, with the permission of Union Carbide Corporation, sending each of you a reproduction of the December 17, 1975 communication from the Department of Labor (Enclosure 4). General In previous correspondence we have also made reference to an article in Rolling Stone magazine. The B. F. Goodrich Company has now written to Rolling Stone to correct inaccura cies in the story. Again, as an item we think you will find worth having and reading, we are herewith transmitting a copy of what we feel is a very thorough analysis of major errors in the Rolling Stone story, the same having been sent to the publication by Thomas B. Nantz, Executive Vice President of the B. F. Goodrich Company (Enclosure 5). * ** We are Bomewhat at a loss to know exactly how to characterize the news release issued by the American Chemical Society in connection with a paper published in the January, AP00053908 January 26, 1976 Page Six 1975 issue of Analytical Chemistry. The paper by D. Hoff man, C. Patrianakoa, and K. D. Brunnemann reporta that vinyl chloride has been found in tobacco smoke. A copy of the ACS news release and Table II from the paper itself is attached (Enclosure 6). The fact that ACS issued a general news release about this article and that it was picked up rather widely by the lay press is indicative of the public interest the Society sees in the entire vinyl chloride situation. * * To end on one bright note, we are pleased to report that the California Assembly's Ways and Means Committee, at its hearings last Friday, January 23, on Assemblyman Car penter's bill that would have permitted state regulation of PVC food packaging materials, voted 10 to 4 against the bill. In short, the defeat in Coxunittee of this measure, the details of which were described in our last letter (No. 13), brings to an abrupt end another piece of threatening anti-PVC legis lation? credit in this instance goes to the whole SPI Public Affairs Committee team, and especially to all those on the scene in California. * ** We shall continue to keep you as fully informed as possible on all these matters. Cordially yours. Enclosures AP00053909 UNITED S.^TES ENVIRONMENTAL PROTECTS - AGENCY ENCLOSURE 1 SUBJECT: epa - FDA Meeting Held on January 7, 1976 DATE: 1Z jam 1976 .-ROM: TO: Alan Levin Special Assistant for Water Supply & Pesticides Memorandum of Record Participants FDA Sam 0. Fine Sherwin Gardner Terry Coleman Robert Angelotti Howard R. Roberts Robert M. Schaffner Bob Lake Gerad L. HcCowIn Richard J. Ronk John R. Wessel Associate Corm. for Compliance Deputy Comnlssloner Associate Chief Counsel for Food Associate Dir. Compliance, Bur. Foods Acting Director, Bureau of Foods Assoc. Director for Technology, Bur. Foods Reg. Coord. Staff Bureau of Foods Division of Food and Color Additives Director, Div. of Food and Color Additives Scientific Coordinator, Office of the Associate Comniss loner for Compliance William M. Upholt Alan Levin Andrew Breldenbach 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, Breldenbach and to explore areas of mutual Interest to our two agencies. Commissioner Schmidt was unable to attend and Deputy Comnlssloner Gardner substituted for him. Z, Dr. Breldenbach made an opening statement Indicating a number of areas where EPA and FDA regulatory responsibilities may overlap. Among these are: PA Fin 1J2Q4 (fcv. 4.7:) AP00053910 a. Pesticides that may contaminate food or feed. b. Pesticides which may also be drugs. c. Toxic Substances d. Domestic Water Supplies. Dr. Breldenbach 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 tr^cusslon at this meeting to water supply. 3. ' Deputy oirmlssloner Gardner responded that he endorses the Idea of an Interagency agreement on water supply matters. 4. Mr. Klim 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. Hater supplies not covered by the Safe Drinking Water Act; d. Bottled water 5. It was agreed that Mr. Klmm and Dr, ngelottl wcr d take the lead > form a task force cons-; ing of repr-entatlves of EPA ano FDA to Identify Issues r^uirlng 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 agree ment, 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 AP00053911 January 7, 1976 MEMORANDUM OF CONFERENCE ENCLOSURE 2 Present : EPA Participants: Dr. Andrew W. Breidenbach, Assistant Adniniatrator 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. Wassel, 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. Schaffoer, 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 Cerad L. MeCowin, Division of Food and Color Additives, Bureau of Foods Dr. Breidenbach and his associates met with Deputy Conmissioner Sherwin Gardner and members of the staff of the Food and Drug Administration in the Commissioner's Conference Roora in FB-8 on January 7, 1976, as a follow-up to Dr. Breidenbach's 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 that 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. AP00053912 Prge 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. Vessel 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 :sr Regu :.cions. He stated that Mr. Train was sen. ag 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. NCTR Dr. Breidenbach referred to the cooperative program of. the two agencies ac Pine Bluff, Arkansas. It was Dr. Breidenbach's view that the main concern at the moment fox both agencies Is the problem of water supply. He asked Victor KItdxd to discuss the interface between the two agencies r>. this problem. Mr. Kinsa 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 c-f 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." ` AP00053913 Page 3 / At Mr. Gardner'* request, Dr. Angelotti reviewed for the EPA visitors FDA** concern* with water problems' under both the Pood, Drug and Cosmetic Act end 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 sdninistrativs deficiencies or there is no standard. It vaa pointed out that in some instances where EPA has applied this designation, PDA has made a determination chat the water ia 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, Angelotti, Kacewicx and McNamara with Mr. Kimm 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 PDA had not been Involved, there had been no concern with food additives in water (Mr. Kimm's "products problems"). The problem with PVC caused FDA to look at vinyl chloride migration to water; this logically could lead to PDA looking at liners for reservoirs, etc. After Dr. Angelotti's 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 Che Agreements with EPA on pesticides. 1c was agreed that a task force would be set up, headed by Dr. Angelotti and Mr. Kimra, to deal with the water supply -- interstate carrier problems. It was agreed that at intervals of 2 to 4 months on an as-needed-basls, Dr. Breidenbach would telephone Mr. Fine to arrange for discussions at the Commissioner/ Assistant Administrator level. cc: HF-1 HF-2 HFC-1 HFC-2 KFC-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 AP00053914 im NOTICES ENCLOSURE 3 department of health, due* could be detected In edible tissue tlon published in the PiixaiL Exasrit EDUCATION, AND WELFARE 48 hours after withdrawal of DES. NDA's of March 27, 1975 (40 PR 12803). These for DES Implants in cattle became ef methods have remained In effect slnee Feed end Drug Admtnietrtttan fective In December 1955, again on the 1985. although significant improvements [Doc**tnio.75*-woei MONSANTO CO. basis of mouse-uterine essay data dem in sensitivity and reliability of other onstrating "na residue" under the per analytical methods have occurred In the mitted conditions of use. Applications Intervening year*. Filing of Petition fer Feed Additive became effective for DES In feed for Sine* publication of the detection Correction sheep and as Implants for sheep In 195T methods In 1983, numerous new animal and 1959. drug applications (NADA's)' for the use In pr Doe. 15-30109, appearing at page The current standards for approval of of DES have been approved by FDA. In 12421. In the issue lor Monday, Novem new eaimal drugs, set forth in section each Instance, the agency concluded that ber 10, 1918, change the seventh line of 512 of the act as added by Pub. L. 90- If. when used in accordance with the the second paragraph to read u follow*: 999, July 13. 1958. 82 Stat. 343-951 (21 conditions of use prescribed in the label "stderad in a draft environmental Im D.8.C. 360b, include several criteria. In ing. DE3 residues could not be detected pact". addition to requiring substantial evi In edible tissue by ths approved methods, dence of efficacy, seetim 515 id) makw the requirements of the Law were satis [DodMtNo.TBN-OOO* ] very clear that the sponsor of any animal fied. Experience with the use of DES and CLANCO PRODUCTS CO. ET Al. drug has the burden of demonstrating advances in detection methodology have that the drug Is safe for humans U en demonstrated that this conclusion is no DlethyHtilbettrol; Notice of Opportunity fer countered in food produced from the ani longer supportable. Haarlng on Propose! To Withdraw Ap mal. and causes no adverse effect to the Since their original approval, no data prove) of New Animal Drug Application* animal. Section 512(d)(1)(H) imposes have been submitted by the holders of ap The Food and Drug Administration (FOX) Is proposing to withdrew approval of all outstanding new animal drug ap plications for use of dlethylstilbestrol in animals 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 mean ing 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. Holdere of approved applications have until Feb ruary 11, 1970 to submit requests for hearing In accordance with I 614.300 <21 CFR 514-200). Such requests should be identified with the Hearing ClerK docket number found In brackets In the beading of this notice. additional restrictions on the approval of animal drjigs that have been shown to cause cancer. That provision requires that FDA shall refuse to approve a drug If the Commissioner finds that "such drug Induce* cancer when ingested by man or animal or, after tests which are appropriate for the evaluation of the safety of such drug, induces cancer In man or animal * * V" This language Is the codification in section 512 of the Delaney anticancer clause that was added to the act by the Food Additives Amendment of 1958. In 1902. Coogrea enacted an excep tion to the anticancer clause. The focus of Congress at that time was so clearly on DES that this exception has ever sine* been Imovn a* the "DES clause." This exception, now also part of section proved NADA's for DES that cast doubt on the finding thit the drug causes can cer in test animals. Furthermore, radio active tracer research studies using u CIsbeled DES. conducted by the United States Department of Agriculture (USDA). have shown that radioactive residues attributable to the use of DS8 can result even when the prescribed con ditions of use are strictly followed, I.e., withdrawal 7 days prior to slaughter for DES in feed or Implantation of DES 120 days prior of slaughter. See T. S. Rumaey et a!., "Depletion Patterns of Radioactivity and Tissue Residues In Beef Cattle after the Withdrawal of Oral1* C-Dletfajl*tilbe*ttol," Journal of Animal Science, 40(3): 539-549, 1975, and T. fl. Rumsey et al.. "Fate of Radio carbon in Beef Steers Implanted With u Bacxaaomm 512(d)(1) iH) of the act. permits appiov- C-Dtethylatllbestrol" Journal of Animal DiethyIstubestral (DES), a synthetic estrogen used by feeders of cattle and sheep as a growth promotant, baa been shown to cause a statistically significant Increase of o*"c<r in female C mlee at the loweet levels at which it was tested. I.e., 6J5 parts per billion (ppb). In hu mans. a statistically significant relation ship haa been identified between the ad ministration of DES to pregnant women and the appearance In daughter* born of these pregnancies of rare type of cancer--adenocarcinoma of the vagina. Slnee 1938, any new drug for us In animals, Just as any new drug for human use, has been required to be shown to be safe for its Intended use*. Even be fore the enactment of the Food Additives Amendment of 1958 <sec. 409. Pub. L. 85-929. September 6, 1958. 73 Stat. 17801788 (21 U.S.C. 348> >, FDA hid Inter preted this basic safety requirement as demanding proof that drugs intended for us* In animals used for human food would set cause harm If Ingested by humane. DES was first approved for use In cat tle feed in November 1954. A new drug application <NDA> for the drug was per mitted to become effective on the basis of al of the use of a carcinogen as a drug in only If the Secretary (by dele gation under | 2.120 (21 CFR 2.120), the Commissioner of Food and Drugs) finds that: under the-oondltlena of use specified in proposed labeling and ressonably certain to be followed In practice (1) such drug wUl not adversely effect the enlmale for which It ts intended, and (111 no residue of such drug will be found (by methods of ssamtaev tioiv prescribed or spproved by the Secretary by regulations, wbteh regulations shell not be subject to subjections (c), id), and (b)) (of section). In any edible portion of such after slaughter or in any food yielded by or derived from tbs living ani mals. In accordance with the foregoing pro vision. FDA In 1983 approved method! for the measurement and identification of DES residue*: the mouse-uterine method, which measure* total estrogenic activity at 3 ppb. and the ao-called "paper chromatography'* method, which ia Incapable of differentiating DE8 from other estrogens at level* below 10 ppb. Originally codified under tl 1352.36 (b> and <e) and 121.241 (> and (f) (21 CFR 139C.28 (b). (C and 121.241 (e). (f)), the approved methods published in Science, 40(3) : 660-560. 1975 (available for public examination at the office of the Hearing Clerk, Food and Drug Ad ministration) . These radioactive residue* were at level* that are below the sensi tivity of U>e previously approved methods and that have not been shown to be safe -within the meaning of the act. In 1972 and 1973, the FDA. acting on these reports (then unpublished) of rafdues discovered by the USDA In radio active tracer studies, withdrew all ap provals of DES for use In animals used for human food. These actions were challenged by sponsor* of NADA's for DELS and ultimately vacated by the United States Court of Appeal* for the District of Columbia Circuit in Hess it Clark v. Food and Drug Administration. 495 F. 2d 975 (1974), and chemetron v. Department of Health. Education, and Welfare. 495 F. 2d 995 (1974) 'on the ground that the notiee of withdrawal of approval issued by FDA bad not afforded the sponsors adequate opportunity to demonstrate the seed for a hearing, a* required by 21 U.&.C. 360b<e)(l>. Since the resumption of the use of DES following the Court of Appeals' rein statement of the NADA's, residues harp data demonstrating that, nmy tn* lo Part 135 wer* recodified under Part 858 been found is samples of edible tissues cated mouse-uterine assay test, no real- without substantive change by a regula- (livers) taken from cattle presented for AMtAl ixemil* VOL 41, NO. 7-MONQAT, JANUAtV 11, 1*74 AP00053915 Nonets 1805 slaughter. In n USDA objective sampling program ot estate Uu|hUrl toreugtaut to* country, 11 residues wire detected In i,IB4 sample* to 1974 ueing iu liquid hromatographie (OLC) method*. Dur ing to* first S quarters of 178, 98 reel- dues were detected to 1,717 sample*. In dicating an increase in tot ptretnUtt of sample* ocnUlntng DES residua* frees e.41 percent to l.a percent. Two addi notice published in tot Pcstin Ricuna Of April 2S, 1974 (39 FR 14411) >. Sixteen comments war* received on toe proposal within toe extended com ment period: Six from manufacturer* of DBS, four from Individuals, two from oattlc industry organisations, two from cattle feeders, and one each from a olUtens' association, and a scientific society. Bight additional comments were received between feed tad implant use* of bes with respect to the adequacy of detection methodology. Tha Commissioner further observes that, whatever toe deficiencies of other detection methods, there has been no showing that the approved methods are adequate to justify con tinued approval of DES- Neither com ment submitted or referred to data that show tost levels of DES below ths sensi tional residue* detected to USHA dur after toe comment period dosed. Several tivity of toe approved methods are safe ing tot fourth quarter of 1971 la edible comments supported the proposed- revo within ths meaning of the act. Umum of besf cattle are sot Include to tot perctnUft calculation because tot fourth quarter hidpit tot# is not yet known. cation of the detection methods and urged the commissioner to act to termi nate the use of DSS In food-producing animals, while other comments objected 4. Two comments stated that final action on ths revocation of method* proposal should await resolution of the proposal on sensitivity of the method These calculations likewise do not tn- to toe Commissioner'* proposed action. published in toe Fspesax, Rionrti of eludt 17 additional DES rttlduec found None of to* comments received supplied July 19. 1979 <91 FR 19238). during 1974 and toe Snt a quarter* of 1*79 to tot CiSDA selective sampling protram. Till* program sample* on a nonrandom baala both animal* presented for alaufthter to raiser* who have pre viously prtaeated residue-carrying ani mal* at veil a* *nimai that are suspect ed, on icme other basis, of containing DBS realduea. In toe selective eempllng data or studies adequate to support the approval of any new analytical meth od (i), much lea* data or studies to dem onstrate that the method* previously approved are adequate to detect residues of DBS now Luqwu to occur. All the comments may be seen at the office of the Hearing Clerfc,-Food and Drug Administration. The CommHtioner notes that despite continuing efforts of FDA since that pro posal to determine anproortate criteria for levels of eensltlvity, the complexity and scope of tha scientific and legal is sue* have combined to prevent comple tion of a final regulation to resolve the laeue* of methodology. No final regulation baaed on the Mantel-Brysn procedure Is procram, a* would he expected, toe In cidence of residues is considerably high er. Only 1 of the at residue* detected in the USDA objective sampling program was at a level (greater than 10 ppb) that could have been both detected and iden tified a* 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 teed or fail ure to follow toe prescribed condition* of tue of DSS, a substantial number of the residue* cannot be attributed to misuse. In the face of these findings, It is clear that the central assumption underlying toe previous approvals by FDA of DES for use in animals used for human food, t*.p that no residues would be detected when the drug was used to accordance with the currently approved conditions of use, la no longer valid. The currently ap proved methods for DES hare been shown to be Inadequate to detect signifi cant residues. Residue*: being detected by other methods have not been shown to be safe within the meaning of the act. This showing was not previously required of the applicants since a common promise of all previous DES approvals waa that no residues would occur. Moreover, since no level of DES residues has been proven The comments received and toe Com missioner's responses are discussed below. 1. Nine comments suggested that the official methodology might be an issue for a hearing rather than toe subject of a revocation before a heating. The Commissioner note* that toe des ignation of officially approved method ology does not Independently require a hearing under the act. However, oppor tunity for hearing 1* required co the proposal to withdraw approval of the KADA's for DES, and any hearing held could include toe issue of whether a practicable analytical method exists that is adequate to detect DES residues. 3. Eight comments stated that toe use of DES was Important to toe revenue of cattle raisers and to the reduction of the cost of cattle production. Two comments stated that the revocation of DES ap proval* could affect consumer prices for beef. The Commissioner notes that the eco nomic Importance of diethylstllbeetrol to a particular Industry or even Its effect on consumer beef prices is not relevant to or determinative of toe acceptability of detection methods offered to justify exception of the drug from the anticancer clause, nor 1* It relevant to toe safety of residues resulting from the use of the drug. 9.Two cemmente stated that toe pres ent approved test-methods for DES are anticipated within the next 8 months. The Commissioner ha* concluded that the public and FDA should no longer await final action on that proposal before resolving the atatus of DES. 5. One comment contended that the GLC method, coupled with man spec trometry identification, was superior to the present procedures, but the comment did not state that these procedure* 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 GLC method as the official method and claimed that this method Is sensitive to 0.5 ppb. This comment did not provide -any information or data to demonstrate that levels of DES below 0.5 ppb are safe within the meaning of the sot Another comment stated that the GLC method reliably detects residue* of DES as low as 1 ppb and noted that information describing this 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 toe act The Commissioner acknowledges that to be safe within toe meaning of the act, adequately sensitive. One of these com the results of USDA'i GLC sampling pro the Commissioner concludes that no new ments limited Its claim of adequacy to gram supply part of the best* oo which method for the detection of DES can now the use of the drug In implant form. he la proposing to withdraw approval of be approved pursuant to the 1982 excep The other stated that to* sensitivity of outstanding NADA'c for DES. These re tion to the anticancer clause. the present method* Is sufficient because sult* dearly demonstrate that toe cur the radioactive tracer studies that rently approved methods lor DES. Le.. XvAosqvacT or Atfsovd Mxthom showed residues below toe limits of the the mouse-uterine method and the paper The Commissioner Issued, to the Fn- mouse-uterine test were discredited in chromatography method, are inade BUt Rsorsts* of March 27, 1974 (39 FR court proceedings arising out of the quate. The Commissioner concludes, 11999), a proposal to revoke the ap agency's previous efforts to withdraw ap however, that no showing has been made proved methods for identification and proval of these NASA's. that the GLC method, whether used measurement of residue* of DES, and in The Commissioner concludes that nei alone or In conjunction with mas* spec vited Interested persons to comment ther the scientific data cited in the pro trometry, may be approved In their place. within 30 day* (extended 10 days to the posal nor sny information provided by I. One comment stated that the bur close of business of May l, 1974 by a this comment establishes any difference den of proof to demonstrate toe safety of PtbfgAl UOItm, VOL 41, NO. 7--MONDAY, MNUAIT 12, 1474 AP00053916 NOT1CIS f DES should rtit with tboag who wife to market tht dm*. Tba Commissioner coaeura wttti this comment and notes that Congress ha* placed toa burden on the applicant to -demonstrate ths safety of any animal drat (7i U.8.C. 3Mb>.~ T. Three comments referred ^eetfleiBy to the Gass study cited to the propoeal to revoke the methods for DB: Gam, anted a public health threat a* a earotoogen remained unanswered. The Commissioner notes that the car cinogenicity of DBS has lone been t*eognlaart by selantute, and conclude* that FDA need not await demonstration of a dancer to public health before en forcing the act's requirement* that ani mal drugs be shown to be safe and that any eancer-oaustog drug be demons&ated of that fact. If a hearing la held, to* currently approved method will ba re voked, and any replacement methodts) demonstrated to be adequate will be dm-. Lfnated at the time the Commissioner Issues a final order based upon tot hear ing record and toe decision of toe Ad- I mlnlstrauvs i*tw Judge. Fkoposn Acnow 1 Coats, and Oraham, "Carctaogenle Doee- to leave no detectable residues. On toe basis of toe comment* received Response Curve to Ora] Dtetoytstfl- 1ft. Other comments, which opposed to raspoxue to the propose! to revoke bestroU " Jcental o! tke National Cancer the administration of DBS to cattle or to* detection methods for DBS, the data Institute, *3:971-977,1H4 (availabt# for its presence to any foods, pointed out cited to the March 1974 proposal, and public examination at the office of toe that the Canadian Government had ex evidence that DES residues continue to Hearing Clerk, Food and Drue Adminh- cluded United States beef falling to bear be found to edible tissues of tratton). The Oas* study found that US UHDA certification that the animal had slaughtered for human food, tot Com ppb DEfl caused earner to tost animate naver received DES, and expressed hope missioner concludes that: (CJ mice). Two of tome comments that ^DA would move expeditiously to 1. DBS been shown to cause can claimed that this finding was a "false remove DBS from the food supply. eer to teat animal* and has been asso positive,* one of them suggesting that Although these comments an not dl- ciated with too occurrence of n^r in another test animal should have been rscUy relevant to the adequacy of toe humans. used Instead of the mice that were used.- previously approved DES detection 3. Residues of DS3 have been and are Nelther of theee two comment* provided methods, they do support the agency's being detected In the edible tissue of data to demonstrate that DES doee not of this notice of opportunity for animals at levels that have not been cause cancer at levels of 6.35 ppb. The hearing on the withdrawal of approval shown to be safe within the meaning of third comment questioned whether the of NADA's for DBS. the act Gass study was statistically sound and 11. One comment suggested that to 3. The authority conferred by section quoted two scientist* who drew from that enacting section 512(d) <1) IH), con 812(d)(1)(H) of the act to approve study widely divergent conclusion* as to gress intended that earetoogens could methods of examination allows, but docs toe lowest levels of DES capable of caus be used lnjood animals and obliged toe not require, the Commissioner to desig ing cancer. This comment concluded that Secretary of Health. Education, and nate a method. this disparity of scientific opinion means Welfare to establish some method, of 4. Any method designated by the that the present data are Inadequate to analysis. Commissioner pursuant to section 513 determine safe levels and support* a re The Commissioner disagrees. Section (d)(1)(H) must be practicable and ca quest for additional funds to conduct 513(d)(1)(H) of the act prohibits toe pable of detecting drug residues regard more studies. The Commissioner is of toe opinion that. In the absence of convincing scien tific evidence that the Gass study was In error or that there Is some level at which DBS is not carcinogenic, toe determina tion that DBS is carcinogenic In CJX mice at <.25 ppb cannot be ignored. The Commissioner agrees that data are not adequate to establish Che lowest level at which DBS causae cancer la test animal*. The Commissioner Is aware of no evi dence that a level of DBS that does 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, toe Commissioner questions whether any of the available analytical methods for the detection of DB9 residues affords ade quate assurance that residues below the level of detection an; 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 animals treated with DBS. The Commissioner li of the opinion use of any carcinogenic animal drug un less toe Secretary makes certain affirm ative findings. Including a finding that no raildue of the drug will be found in edible tissue by officially designated method*. Congress did not intend the Becretary to designate a method when no adequate method was available. Rather, the act requires that an animal 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 a* a regula tory tool, and It must be sufficiently sen sitive. The Commissioner concludes that any method approved to accordance with aactlon 512(d)(1)(H) must at least be capable of detecting residues at a level that bat been shown to be safe within the meaning of the act. Because no such showing has been made with respect to residues of DE9 well below the com bined sensitivity of the currently ap proved methods, toe Commissioner maintain* that those methods can no longer serve as the basis for approval of toe use of DES to animals used for hu man food. The Commissioner Intends to revoke less of the route of administration used fora drug. 5. The approved methods for detection of DES residues to edible tissue are not' adequate to demonstrate that, within the meaning of the act, no residues will be found when toe drug U used accord ing to the approved conditions of use. 8. Data are lacking to justify the ap proval of any other analytical methodts) 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 Coemetic Act (sec. 513(e) (l), 21 UJS.C, 350b<e)(l)), the Commis sioner proposes to withdraw approval of all existing NADA'i 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 to the light of current scientific knowledge, demonstrate that DBS 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. that whether or not specific edible tis these methods at the time of final ac This notice applies to all outstanding sues may be discarded 1* not material to determining the adequacy of a meth od to detect DBS residues in tooas or other edible tissues. It Idas not been dem tion based upon this notice of oppor tunity for hearing. If no hearing on the proposal to withdraw approvals for too use of DES Is required, either because NADA's for the use of dlethylstilbestrol in animals 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 onstrated, for example, that DBS resi FDA reeieves no request(e) for hearing and last known address to FDA records. dues in the liver may 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 DBS repre- or because any requeatd) for hearing falls to demonstrate a genuine and -ubstantlal issue of fact requiring a hearing, the approved methods will be revoked simultaneously with the announcement Copies of this notice are being forwarded by registered or certified mall to of these known applicants. Notice to other applicants or holders of such NADA's whose identity is not known to FDA Is given by tola publication. 1 m*iAi taoism, vol *i, no. t--Monday, januaiy 13, IV74 AP00053917 AP00053918 ISO* / ' Nonas * DXfl should rat with tbo* who wish to mtrkst the dm. Th* Commissioner eoneon wtito this comment and notes that Copgrea has placed the burden on tos applicant to demonstrate th safety of any animal drug <ai O.B.C. 3#0b>.- 1. Three comamit* rtferred ^aetfleaBy aanted a public health threat ss a car cinogen remained unanswered. The Commissioner notes that tht earctnogsnlcUy of DES has long been reeognieed by setaatlsU, and concludes that IDA need nog await demonstration of a danger to public health before en forcing the act's requirements that ani of that fact Xf a hearing la held. th currently approved method will be re voked. and any replacement method(s) damoastrated to be adequate will be dtoIgnated at the time the Commissioner Issue* a final order based upon the bear ing reoord and the decision of the Ad- j minlstrauvs Law Judge. to the Oeas study cited to the proposal mal drugs b* shown to be safe and that to revoke the methods (or DCS: Oaa, any ea&cer-causlng drug be demonstrated Tkovossp Acnoai | Coats, and Oreham, MCarctnotrate Das*- to leave do detectable residue*. On the basis of the comments received Bosponse Curve to Oral Dtethylitfl- 10. Other comments, which opposed In response to the proposal to revoke bestrot" Journal of tiu National Cancer the administration of DBS to cattle or the detection method' for DES. the data Iutttvte. J9:971-5T7,1*4 (available (or Its presence in any foods, pointed out cited In the March 1974 proposal, and public examination a t the office of the that Use Canadian Oovernment had ex evidence that DES residues continue to Hearing Clerk. Pood and Drue Admin*, cluded United States beef tailing to bear be found in edible tissues of tratlon), The Oaas study found that 195 UEDA certification that the animal had slaughtered far human food, the Cccn- ppb DCS eaused cancer in test animals never received DES, and expressed hope mletioner concludes that: (C.H mice). Two o:f that comments that EDA would move expeditiously to 1, Des has been shown to cause can claimed that this finding was a "falsa remove DE3 from the food supply. cer In tot animals and has been asso positive." one of them suggesting that Although theee eemments are not di ciated with the occurrence of eanesv in another test animal aboold have been rectly relevant to the adequacy of the humans. used instead of the mice that weT* used.- previously approved DES detection 3. Residues of DES have been and an Neither of these two commtote provided methods, they do support the agency's being detected In the edible tissue of data to demonstrate that DBS does not issuing of this notice of opportunity for animals at levels that have not been cause cancer at levels of 6.35 ppb. The bearing on the withdrawal of approval shown to be safe within the meaning of third comment questioned -whether the of NADA'a for DES. the act Oass study was statistically sound and 11. One comment suggested that In 3. The authority conferred by section quoted two scientists who drew from that enacting section 513(d)(1)(H), Con 512(d)(1)(H) of the act to approve study widely divergent conclusions as to gress intended that carcinogen* could methods of examination allows, but doe* the lowest levels of DEa capable of caus- be used Ingood animals and obliged the not require, the Ccmmialoner to dmlg- tag cancer. This comment concluded that this disparity of scientific opinion means that the present data are Inadequate to determine safe level* and support* a re quest for additional funds to conduct mote studies. The Commissioner is or the opinion that. In the absence of convincing scien tific evidence that the Oaas study was in error or that there is some level at which DEB U not carcinogenic, the determina tion that DES Is carcinogenic in CJ! mice at 8.25 ppb cannot he ignored The Commissioner agrees that data are not adequate to establish the lowest level at which DES cause* cancer In teat ^mai The Commissioner is aware of no evi dence that a level of DBS that does not cause cancer in test animals can neces sarily be assumed otherwise to be sale 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 DBS residues affords ade quate assurance that residues below the level of detection are sale 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 treated with DBS. The Commissioner is of the opinion that whether or not cipeelfic edible tis Secretary of Health. Education, and Welfare to establish some method of aaalysla. Tbs Commissioner disagree*. Section 512(d)(1)(H) of the act prohibits the use of any carcinogenic animal 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 animal drug not be approved unless an adequate detection method can be designated. To be approvable a detection method must be both practicable, in the sence 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 action 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 DBS well below the com bined sensitivity of the currently ap proved methods, the Commissioner maintains that those methods can no longer serve as the basts 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 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- lea of the route of administration uafi for a drug. 5. The approved methods for detection of DBS residues in edible tissue are not adequate to demonstrate that, within the meaning of the act, no residues will be found when the drug la used accord ing to the approved conditions o! use. , 5. Data are lacking to justify the ap proval of any other analytical method(s) for detection of DE3 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 Aet (sec. 512(e) U), 21 U.S.C. 960b(e)(i>), 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 DBS is not shown to be safe for use as approved. 2. The anticancer clause in section 512(d)(1)(H) of the act la applicable. This notice applies to all outstanding 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 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 NADA's for the use of diethylstilbestrol In animals used for food for human con sumption. All such applications now koown to FDA are listed below by NADA number and by each applicant * name onstrated, for example, that DES resi FDA recleves no request(s) for hearing and last known address In FDA records. dues in the liver may not serve as an indicator of resdues present, albel. at lower levels. In other edible tissues, 3. Two comments suggested that the basic question of whether DBS repre- or because any request(i) for hearing falls to demonstrate a genuine and sub stantial Issue of fact requiring e hearing, the approved methods will be revoked simultaneously with the announcement Copies of this notice are being forwarded by registered or certified mall 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. nociai Btoimx, voc si, no. r--Monday, januaiy 12, >V7* AP00053919 ___ __ . m QCD l. KMV VS. DEPARTMENT OF LABOR Oettljviiuiul Safety anJ Health /ulminutraiion Washington, o.C. amo i ENCLOSURE 4 Nr. R. R. Khealar, Jr. Vinyl Chloride Resins-Manager Onion Carbido Corporation 270 Park Avenue New*York, New York 10017 _. JMiM'975 V/HtEV-Et^ JR- ft Dear Hr. Wheeler* This is in response to your joint letter with Mr. John Whittlesey dated June 17, 1975, petitioning for modifi cations of the Exposure to Vinyl Chloride Standard, 29 CFR 1910.1017 (formerly 1910.93 recodified May 28, 1975) There are no plans presently to amend the Vinyl Chloride Standara. a revisea program directive is contemplated, although we are not certain as to the date it will be available. Please be assured that your comments and suggestions are greatly appreciated and they will be considered fully in the revision of the program directive. In the meantime, the following administrative decisions have been made: 1. 29 CFR 1910.1017(a) and (b)(6) Scope and application (^)7 (3) and (b) Definitions (6) .( The standard defines a fabricated product as being one which is "made wholly or partly from polyvinyl chloride, and which does not require further processing at temp eratures, and for times, sufficient to cause mass melting of the polyvinyl chloride resulting in the release of vinyl chloride." "Release of vinyl chloride" means the release of an amount of vinyl chloride which would likely result in employee exposure at or above the action level without regard to the use of engineering controls. Products which can be classified as fabricated products are exempt from the provisions* of the vinyl chloride standard. All other products are subject to the re quirements of the standard, if the employer uses or manufactures a product v/hich is not a fabricated product, he must initiate monitoring procedures. If the monitoring reveals that the employees arc not exposed to vinyl chloride at or above .the action level, the employer's operations will be exempt from the AP00053920 2 provisions of the standard. However, if the monitoring reveals exposure at or above the action level, the employer must implement tho procedures specified In the standard. 2. 29 CFR 1910.1017(b) Definitions (5). The petition requests that the definition of "emergency" be revised to include specific examples, such as fire and explosion. We agree that the definition might well be expanded to include examples. Again, this matter will be addressed in a program directive and not as an nnendiaenU to the standard. The definition of a "massive release" as being "greater than 100 parts per million (ppm)u found in tho current Program Directive 200-35, will also be addressed in a revised directive. We agree that the 100 ppm should be changed. 3. 29 CFR 1910.1017(d) Monitoring (4) - The intent of paragraph (d)(4) is that the employer shall be 95% confident that his monitoring result is within 25%, 35% or 505 of the actual value depending On the concentration. * Therefore, .-an employer using a* method which has proven vinyl chloride detection accuracy of 25% or less need take only onetmeasure ment regardless of the actual vinyl chloride monomer concentration. In concentration ranges where accura cies of 35% or 50% are required, the employer need take only one measurement if the method accuracy is less than the specified accuracy. With methods of unknown accuracy or having errors greater than the specified accuracy requirements, repeated measure ments are necessary. In these cases, one may use the coefficient of variation (CV) as a parameter to judge whether or not a sampling procedure is adequate to. meet the standard. The CV in percentage units is defined as the standard deviation of the method, times 100, divided by permissible exposure limit. The required CV of the procedure is obtained by dividing the required accuracy by 1.96 (2 value for 95% confidence). Thus* for accuracies of 25%, 35% and 50%, method CV valuer, should bo less than 12.8%, 17,5%, and 25.5% respectively. AP00053921 3. * To repeat, there are no plans presently to amend the standard but. your comments on monitoring will be con sidered in the program directive revision and also in future rulemaking where monitoring is a requirement, 4. 29 era 1910.1017(3) Training. The standard does not specify a level of exposure to trigger training activities. Section 6(b)(7) of the Occupational Safety and Health Act of 1970 provides that employees shall be apprised of the nature of the hazardous substances with which they come in contact. The evidence we have compiled on vinyl chloride has indicated that it is sufficiently hazardous to warrant training for all personnel who have any possibility of coming in contact with vinyl chloride. There is always the opportunity for accidents to occur and em ployees should be aware of the possible consequences. There has also been some indication that storage con tainers may yield high concentrations of vinyl chloride when opened after transporting. ' Therefore, It is not likely that the training provisions will be amended. For those operations covered by the Standard, training is a requirement. 5. 29 CFR 1910.1017(e), Signs and labels (4) If there are situations where the blended polyvinyl chloride must be labeled yet contains less than 0.5 ppra residual vinyl chloride monomerf the following' wording may be used: BLENDED iOLYVINYL CHLORIDE (1?VC) CONTAINS TRACE AMOUNTS ( 0.5 pp;ft) OF VINYL CHLORIDE. VINYL CHLORIDE IS A CANCER-SUSPECT AGENT. AP00053922 He hope that the above clarifications will satisfy your petition for modification and amendment of the vinyl chloride standard. As previously stated, there are no plans presently to formally amend the standard. There will be an addendum or modifica tion of the Program Directive #200-35. Should you wish to discuss any matter further do not hesitate to contact me or members of my staff. Sincerely, Barryyfrj/Khite Associate Assistant Secretary for Regional Programs AP00053923 ENCLOSURE 5 900 SOOTH MAIN STREET TU B. F. Goodrich company A K R 3 N. OHIO <43(1 RHONE III*J7I-23II THOMAS I N A N T 2 .ic.January 16, 1976 Mr. Jans S. Wenner Editor ROLLING STONE 625 Third Street San Francisco, California 94107 Dear Mr. Wenner: We have read with considerable interest the article, "The Plastic Coffin of Charlie Arthur", in your January 15 issue. Because of the seriousness of this subject, we believe your readers are entitled to know the facts in regard to several inaccuracies in this story. The article contains errors of fact and omissions but, more importantly, it accuses B.F.Goodrich officials of trying to cover up a critical problem. The fact is, Goodrich moved swiftly and openly to solve this problem. The following corrections of some of the more important inaccuracies indicate the flaws in your article. ITEM: "Maltoni was working for a group of European chemical manufacturers who wanted his findings kept secret. The American companies were all too happy to agree -- so for the year before the Goodrich announcement the companies covered up Maltoni's findings that vinyl chloride caused cancer." (Page 44, Col. 4) FACT: In late 1972 companies in the Manufacturing Chemists Association were planning research studies to evaluate previous findings that rats subjected to massive exposures to vinyl chloride in air (30,000 parts per million), had developed tumors. ` It was learned that European manufacturers were sponsoring similar studies in Italy. Representatives of American companies visited Dr. Cesare Maltoni in Bologna in January, 1973, to learn about his program. At that time JJaltoni told them that preliminary results had found cancer in some test rats. Maltoni's work at that time was not complete enough to reach firm conclusions. AP00053924 J Pag# 2 Ur. Jann 8. tenner San Francisco, California January 16, 1976 U.S. government scientists knew of M&ltonl'a preliminary results early la 1973 but considered them to be as preliminary as did U.S. industry. Umberto Saffiotti, associate director of carcinogenlais at the U.S. National Cancer Institute, attended a symposium at Bologna, Italy, April 9 to.13, at which Dr. Ualtoni showed a table giving preliminary results linking vinyl chloride with cancer in rats. 0.; iorll 17, 1973, members of the Manufacturing Chemists As elation asked the European sponsors of Ualtoni*s work to Br joint presentations to U.S. and European governments. Th i.S. National Institute of Occupational Safety and Health (h JH) set up a meeting for July 17. One European and four Uv- industry representatives presented NIOSH Information that malignant tumors had been found in animals exposed to vinyl chloride. At that time no human cancer cases had been reported, Ualtoni*s studies had not been completed and he had not issued a full report. ITEU: The story reports that Dr. Peter Infante, then of the Ohio Department of Health, had found that three Northern Ohio communities with polyvinyl chloride plants had higher than average birth defects. (Page 45, Col. 2) FACT: Dr. Infante, in his report to the New York Academy of Science, stated that there is not sufficient evidence to link vinyl chloride to birth defects. The Center for Disease Control of the U.S. Public Health Service, In Its weekly Mortality and Morbidity report for July 19, 1975, reports Its own study of this subject. The report states that the study "coul; not establish any relationship between cases (birth defects) and vinyl chloride exposure." ITEU: The story quotes a worker, only identified as "Harry", who charged that a supervisor had "pulled the plug" on a Goodrich plant monitoring system, so that work could continue during periods of higher exposure. The story correctly states that the company denied these charges. (Page 46, Col. 3) FACT: First, Goodrich PVC plants have two monitoring systems -- a computerized area monitoring system, and personal monitoring systems. One backs up the other. OSHA requires that all records must be kept and made available to both federal inspectors and employees. It would have been very easy to verify Harry's allegation. A recent check of these records shows no gap. AP00053925 Page 3 Mr. Jann S. Wenner San Francisco, California January 16, 1976 ITEM: The story quotes "other workers" as saying that when government inspectors visited our Ohio PVC plant, the company shut down most of the vinyl chloride lines, claiming that maintenance work was being done on them. (Page 46, Col. 3) FACT: Uoder the OSHA inspection system, inspectors visit plants without prior notice, and therefore could arrive when maintenance operations are occurring. Since it takes some time to shut down and restart PVC reactions, this rumor is not only untrue, it Just doesn't make sense. ITEM: The ROLLING STONE story quotes a WALL STREET JOURNAL story of October 29, 1975 which reported that nine PVC workers at the Shawinigan plant of BFG Canada had died from angiosarcoma, "but the company bad chosen not to make an official announcement." (Page 47, Col. 3) FACT: The WALL STREET JOURNAL story, which itself resulted from a company announcement, states: Goodrich Canada announced in a news release last December that four cases of liver angiosarcoma had been uncovered from death records of former Shawinigan workers.... The U.S. parent company said in its annual report last spring that the Shawinigan angiosarcoma toll had climbed to eight deaths." Only one of these men ever worked at the Shawinigan plant after it was purchased by Goodrich Canada. None of the rest were Goodrich workers, although the article said they were. The WALL STREET JOURNAL also reported, correctly, that we had reported all these cases to the U.S. National Institute of Occupational Safety and Health. The cases also were reported to Quebec authorities and to all PVC employees in Canada. The Shawinigan release was carried in the U.S. by the Associated Press. Since Joe Klein, your reporter, apparently had the WALL STREET JOURNAL story, we cannot understand his allegation that the company "chose not to make an official announcement." ITEU: The report states that "...hearings were called on a proposed permanent standard of 1 ppm", and goes on to say that at the public hearings, the chemical manufacturers threatened that the whole industry would be forced to shut down if the standard was implemented. (Page 46, Col. 1) AP00053926 Page 4 Mr. Jinn S. Wenner San Francisco, California January 16, 1976 FACT: The proposed standard called for "no detectable" level of vinyl chloride in the work atmosphere, not 1 part per million on a time-weighted average as in the final standard. This may seem like a minute difference, but it is important in correctly reporting the Industry's objection to the proposed standard. The proposed "no detectable" provision was ambiguous. If it had been interpreted as "no detectable" by any test method -- in other words, zero -- it would indeed have shut down the industry. Klein was at a Goodrich press briefing on December 4 when the industry position was explained in detail but he chose to ignore the explanation. Just as important as these individual Inaccuracies, however, is the overall impression created by the ROLLING STONE article. The article clearly implies that B.F.Goodrich executives, managers, and foremen conspired to suppress information relating to employees' health and then to prevent implementation of safe guards to resolve this most serious situation. This implication is unfounded. -- - ........ Omitted from Klein's story are such facts as: Goodrich freely and voluntarily publicized its findings of the first angiosarcoma cases when they were discovered. The company supplied detailed information to employees, state and Federal officials and the industry. Goodrich has conducted the largest research program in its history, and is spending an estimated $42,000,000 to prevent exposure to vinyl chloride in plants, in the environment and in products. The company has stated that it can operate within all present and expected regulations. Klein sat: in the front row at the press briefing where all these programs were explained in detail, and all questions fully answered, and he was given all supporting material to substantiate the open manner in which Goodrich has handled the entire matter. The fact that he did not choose to use any of this positive information is a clear indication of his lack of objectivity. Tours very truly. THE B.F.GOODRICH COMPANY T_______-. __________ Executive Vice President k AP00053927 FOR IMMEDIATE RELEASE u74 --TA La 4 M ENCLOSURE 6 NIWS SIRVICS 11U SIXTItNTH *T,, N.W. Washington, o.c. aooaa TSfc.. (SOS) IT1-44IO The flrsc report of vinyl chloride* known to produce cancer, in test animals and In humane, In mainstream cigarette smoke Is detailed In the current (JANUARY) Issue of Analytical Chemistry a monthly publication of the American Chemical Society. In minute amounts, the vinyl chloride la formed during combustion and the amount is correlated with the inorganic chloride in the tobacco. Revealing a new class of carcinogens In cigarette smoke and the flrsc environmental appearance of vinyl chloride unrelated to its deliberate manufacture. or use, this report raises the possibility that vinyl chloride and related substances, possibly cancer-causing, may be formed not only in burning cigarettes but also in other burning plant materials. Dts. Dietrich Hoffmann of the American Health Foundation (AHF)t Vahalla, N.Y. and Gto B. Gori of the National Cancer Institute, Bethesda, Md. arc authors of the report, with AHF's Constantin Patrianakos and Klaus D. Brunnemann. Charco-' filte-s were particularly effective in abstracting much of the vinyl chloride from the mainstream smoke of cigarettes, they say. -oore- Ifl/G AMI RICAN CtUMlC'U 'iOCICfv CCNHNN1AI 10/l? AP00053928 VINYL CHLORIDE FOUND IN CIGARETTE SMOKE -2- The highest vinyl chloride concentration measured in the study w.is about 30 parts per billion in the smoke of a standard nonfilter cigarette or ^ "little cigar." This amount per cigarette is difficult to relate to the 5C pcrts per million (more chan 1000 times more) that has been found to produce turners v inhalation in test animals (number and length of exposures not specified). \. the significance, if any, of any added burden of the vinyl chloride to the It' known load in smoke of polynuclear aromatic hydrocarbons, Such as cancer-causing benzfa]pyrene, is not clear. Although Dr. Hoffmann pointed oxtt in a telephone interview that the amount of vinyl chloride measured in cigarette smoke is probably too minor to be a significant contributor to the known carcinogenicity of tobacco smoke, he acknowledged that vinyl chloride from burning tobacco does contribute to public exposure to the substance and chat it conceivably could interact with other carcinogens in the environment to increase cancer-causing potency. "Based on human data and results from animal studies, it appears to us that these minute amounts of vinyl chloride will not contribute to a measurable degree to the carcinogenic activity of tobacco," the authors write. Vinyl chloride is widely used in manufacture of polyvinyl chloride plastics and has been labelled the cause of a high incidence of liver angiosarcoma in those who work with it. The vinyl chloride content of the tested commercial cigarettes and cigars varied considerably, they report. Smoke frcuu ordinary c i^are t tes contained from 5.(i to 15.8 unnogrnms (billionths of j gram) per cigarette. with an average of 11.7 nanograms. Ordinary filters had little effect on vinyl chloride content of smoke:, but charcoal filters cut the gas by about two thirds. -more- AP00053929 VINYL CHLORIDE FOUND IN CIGARETTE SMOKE -3- A charcoal filter brand received the lovesc score with 1.3 nanograms per cigarette. Smoke from the same brand without the filter contained 4 oanograms per "smoke," according to the report. Marijuana cigaratces tested relatively low at 5.4 nanograms. Since vinyl chloride has not been found in nature previously, the authors conclude that the vinyl chloride in cigarette smoke is not due to contamination of the tobacco itself, but forms through interaction of hydrocarbons and chlorine, a normal plant constituent, at the 800 or more degrees Celsius (1500 Fahrenheit) of the cigarette cone. "It should be realized, however," they write, "that we have directed our analysis only toward the identification and quantitative determination of vinyl chloride and that tobacco smoke may also contain other unsaturaced chlorinated hydrocarbons with carcinogenic activity. This may include the suspected human carcinogen 2-chlorobutadiene (chloroprene) as well as chlorinated products of unsaturated isoprene, the major unsaturated hydrocarbon in tobacco smoke." Possibly a more serious problem chan the presence of such small amounts of vinyl chloride in cigarette smoke. Dr. Hoffmann said, is the indication that chlorinated hydrocarbons may form when other plant materials are burned. He cited burning of trash, especially trash enclosed In polyvinyl plastic bags, as an example of a practice that ought to be examined in light of the new findings. mu 1/21/76 AP00053930 Figure S. OC retention and resolution data far a mixtir* or da- and ezns-t-octadeeane* on a 12.5% EOS polyettar on sianizad silver utfobenzyl Poras* C column uaing 99.9999% hefcen carrier at (lew of 30 cmVmin. Column temperature. 180 *C anca of H} in tha carriar gas. Zero Gas grad# helium con tains about 1 ppm of Hj (12) which reduced the Ag* to Ag0 in 10 days of operation at 180 *C under tha conditions of chromatography. The packing was removed from the col umn, extracted with CHjCI* and Ag removed with 5 N HNOiw About 70% of initial capacity of the ionogenic groups remained. In order to determine the effects of H-* in the carrier, Aiico No. 6 grade helium was utilized. Each day for 44 day*, over a total period of 10 weeks, two samples of a mixture of the cis- and from-9-cxtadecenes were injected into the column. Figure S summarizes the experiment and depicts an initial decrease in retention time, relative reten tion, and resolution although an adequate separation was achieved throughout the course of the study. When the col umn was operated above 180 *C, alkene retention times decreased, but bleeding of the ECS polyester increased rapid ly with temperature and loss of resolution was accelerated. When this loan of resolution becomes excessive, the column packing may be removed and regenerated at the Ag* form. The extent of interaction of solutes with the surface of the supposedly inert support in GLC is often debated. On the basis of this s' \ thera can he no Hooht that the uir> face does interact -- ia evidenced hy the effect of HMDS upon retention. Ir addition, the difference in interaction of AgSP with respect In the hydrogen-form support indicates that solutes penetrate tha liquid coating and approach near to the surface. Tha surprising extent of cuatiug (tenet ration wee apperent whan c\- and trana-d-iKUtdecanes were **parated in 30 min at 188 *C with H 1.45 on HMDS.treated AfSP at 15% loading of ECS. When a column with idi**, EGS was used, a resolution of 0.57 at )W *0 was obtained. Thus, the approach described here has utility for analytical operations, provides e probe for the study of the migration of a solute through liquid phase, and may be used to mea sure interactions of volatile solutes with surface-bonded groups. ACKNOWLEDGMENT The authors thank T. Foglia of our Center for the samplee of cii- and tre/u-9-octadecenes, and M. A. Kaiser. M. O'Brien, and R. L. Grob, Villanova University, for deter mining tha surface areas reported herein. LITERATURE CITED (1) 0. K. Quha nC J Jsrlk. j. Oromafepr.. SI. 325(1*72). (2) J. J. Outlets sod L 8 Roger*. Anti. Ctiam.. 3*. 1193 l !952| (3) ft. F. Hrtcn. h. C. Sloeer. W. Koaoisnsky. F. N. nuorwr. and A. w O'Cdnne*. Anti. Cfotri, *1. 210) (1973) l*| J j. VoSmer snd S. A GorOon. Chemairy, *7, S|19 7*i IS) ft. A. Bwlord. L. T Olsziwskl. D. ti. SjukOvi. ft. Magumin, snd H l. fto**art, J. Cvomerepr. Set., 12. 555 (1974) (8) K. Skkto. Y. Tskede. and 2. Kiooqiwa, J. Am. Cfiam. See, S3, 531 (1941). (7) O. H. Severn, ft. a. Barlonl. P. Ms.jaSmsn, l. T Otuawwi. snd M L. ftoeoan. Anti. Own, *, 504 (1974) (I) 0. Seylerw, ft Suiu*.. C. J. MvcCiy. and C. ft. Seoet, j. CVpencnwr Own.. 3.431(1944). (SI U. A. Kaiser. U. O'&nen. snd A.l. Sroe. A met Led. Jgne-Aiy (1975) (10) K. linger, Ary* Cham.. M. d Sntf.. 11. 257 (1972). (11) V. Y. Davydov. L. T. Zhuralev. snd A. V. KisiHv. J. Phyi Crem USSft, J*. 1101(1944). (12) Private eommon-ittien from Liquid Csrtenie Corp.. Oiity * Lara. 0i- mgwn.Nj.d974). RECEIVED for review June 27, 1975. Accepted October 2. 1975. Mention of commercial product* does not constitute an endorsement by the United Stales Department of Agri culture over others of s similar nature not mentioned. Chromatographic Determination of Vinyl Chloride in Tobacco Smoke Dietrich Hoffmann/ Constantin Patrianakot, and Klaus D. Brunnemann Drvisjcn ofEnvinwntntMi Gareinoganatit, American HmW Foundation, Vahata, N. Y. 1059S Glo B. Gorl DMaJon of Canear Causa ana Pravantion. national Cancer Ihslitvtm, Sathasda. Md. 20014 A ehemical-arialytleal method has bsan developed for the quantitative determination of vinyl ehlorid* (VC) In tobacco smoke. VC from the mainstream smoke Is trapped on char coal, extraetud. and subsequently converted lo 1,2-dlbromo-1-chloroethan# (DB-VC). Hie Utter it enrfehad by column chromatography and determined by gas liquid chro matography using an electron capture detector wllh high sensitivity for 0B-VC. From the mainstream smoke of a popular 65-ntm cigarette without Idler tip, we Isofnled 12.2 ng ol VC per cigarette. The VC content In the smoke of some domestic and foreign cigarettes and llltla cigars ranged from 5 to 27 ng, and that of a marijuana cleared* was 5.4 ng. The analytical dala suggest that the total inor ganic chloride In tobacco Is a determining (actor lor the amount of VC In the smoke. VC may also bo released into ow respiratory environment during the burning ol other chlorine-containing organic matter. Yinvl thli-riili- lV(`) i -imulk hsah-ihIihI willi luuiin.s.if umm f Mu- liver in VC wtrki*r* \ I. .). C.\|hrsire >>i nmv, ANALYTICAL CHEMISTRY. VOL. 48. NO t. JANUAflY t9?6 . 47 AP00053931 now* t. Gas Chromatogram Of COrvrttra of vinyl cNorWaai 1.2-dibeamo-1-ch<OfOthflria (DB-VC) bam cjaren* smok Paalc 1 t Sbromoceooafla: 2 a awomoyopra: 3 a tSbtomobitw: * 2,lxJ*romo-/vCtaar*: S dbronubuuna and a tNsrofnofcjtana; 6iihouid*rj adferornobuian*; 7 (laji pasJc) 1.2-ditrBmo-t-ctNQroatnaft# |D-VC1 rata, and Syrian golden hamsler* to VC in concentrations aa low as 50 ppm leads to the induction of various types of tumors, including angiosarcoma of the liver (1-3). Until now, VC has been identified only in environments and ma terials related to vinyl chloride and polylvinyl chloride) U, 2). The relatively high reactivity of VC, as well as its pre sumably tow concentration in nan-occupational respiratory environment*, requires special analytical methods and sen sitive detection techniques. This study reports a quantita tive method for the determination of nanogram amounts of vinyl chloride in tobacco smoke. EXPERIMENTAL Apparatus. A Hewlett-Packard gas chromatograph Model 7260A with 'tl\'i-ECD was used fur the analysis. Cigarettes wer smoked individually with a nO-pnrt, automatic imukar- (Heinrich Borgwtldu Hamburg. Germany). Mass spectra wer* determined un a Hiiachi:/Perkin-Elmer RMU-tiD instrument by the Mass Spectroscopy Laboratory of the Massachusetts Institute of YtH.lv nulogy and on Hewlett-Packard S?lU-5ddOA OC/MS instrument. Condition* during analysis were: ion source. 185 *C; ieitertac*. t*d *C. NMR spectra were obtained with a Hilnchi/Perkin-Klim-r Model K.24 instrument. The elemental ehlorine aiiah.-d* ! carfil'd out by lliilbr.iifh l.iilmr.ilnrics. K no*'. ille. Tetirv Hi-agem*. o-Hi'timi' ivtHHingriulid w.i* Ifrxlilv diviilled over N,l St', *anh\ drcii-l prior to use Itrumme nos cat fueloil with coo * nil r.uI'd 11 Si >, t i> it nl i liorvool w;i oliimiuil I rum tin- 1'ilts hnrp)* Nimaiiil t'arUm l'o ll'l'U - 12 Y W). i.ili. : grl tim-.li lit Util I roil* .1. T linker Chcmn'.d I *. . 11V-1? ml i!< t'liroin Q lme<h S> lH train Applied Science l^ilmrniiiries. pure viml chloride gas Imm MnllnrMio toe* I'rodtu-t*. unit vinyl i-lilnriili- imxittrr Hhv ppm in .nr) tram Scott Rot-arch l.nUiralurii-s i I'lum'.li-mh ilte. Pa.). [All ripi-rimi'itt* with NT' rcferi'ine* were performed under well veniiliitrd IiihmIs}. Cigarettes. Ibnncstir and foreign cigarette!* were |iuri`hused on the open market in New York City ami Westchester < *mnlv, N.Y.. during 1974-73. The cigarettes were selected by weight (20 mg of average weight uf 200 cigarette*) rtd by draw resistance (*.v\ ,,i average value of 50 weight selected cigarettes). Before smoking, the cigarettes wert stored at 22 2 *C for at least 24 hr in a cham ber with a relative humidity of hi) I-Chloro-I^-Dibromoethanc (reference compound). Twenty ml of bromine were dissolved in liH) ini <>: n.nriwit. Under magnetic stirring at -5 (*, pur* vinyl chloride /a. w* bub bled slowly through the solution until the color rti.vappeared. Mu.-t of the solvant win distilled at atmospheric pressure, and the re mainder under reduced pressure. I -Chloro-l^-dihromoethane IHibromuvtnyl chloride. HB-VC) ww distilled at 52 *C under I 2 rum Hg pressure. It won sealed under dry nitrogen, covered with dark paper, and stored .it 0 *C. Under these vomtitinn*, UR-YC remains unchanged for up In tt*n rr<s The known l)R-YC wa* ehjraclerixed by NMR: 4.1) ppm. H. 2H: .Yi> ppm. t. I H; and liv MS im.i . rel. ini.): 145 (251. 14il, HI*)). Nl |5tb, IU.T |i)7; Ty. ai [The parent peaks t`220. 222, 224. 22l>) of UK-YC are nol nliwerved under mir conditions; **e Figure 2|, the ratio, ol the major fragment* are curto\t*ru with the natural abundum-e i-f Hr and Cl ioilo|- The |n.|. rtly of th compound was ascertained by go* chromatograph* Gas Chromatography. The mM Niiiid'actufv Ntpur.iiioii of l>B-NV from a cigarette smoke ciiiicenifute wa obtained ot rin T on a 12-ft by 2-mm i d. gU column piled with )ir\. I>V 1 7 uii tia> Chruiu Q luursh #0-ltX)h .Vs. Mel hane in argon was u.setl j' i lie i nrrirr and purge gas with ,i il-.w rate ol 22 inl/mti*. T'lie reirntooi time for UR-VC wan .12.5 mu* UMug n '"Ni-KCU at 2i"> *ti lu To lection limit w,i> lf> ,!g till 1 -o > |u-r inirc|i<n Tin- Toiiator re .(amsc w.iw linear in t lie range c it .*>U TIH) yg Miufel Sitliiii-s. In hmhIi I li 'l', it .oulil lx- T../ii..n.lfi.l. it Ui.il I i) g i'l .all* ,n id . fiar. o,il |i,n keii in ,> I:! i m *. i> n.io id gin.. IuIh- li'llils clos'd Willi L>,|VS w i. ill ri'l.iMlK Yl' 11 ;* * 1111. I VI - (V. ol t.-:l-l up III 2tat ug ,'t NT ' I nun a si rein.I ol mr I2U inlAei I i .oil .1 imng It) 5 P|'> ol N t'. NT* reinniii* mo liaiigcti on i li.in iutl lor .n ten.i it lif.) The M-pafuliun inelhod w.iv developed be blowing an .nr .irmni I (low rule 20 nil/vce) of 4 I. eonljining 21H nl NT ilirmign ,i Cambridge filler tCM lITAJ Imided with tr of in iig.iretles (*->4|g| lug), und throtigli I d g of charienl with llie guv pilule drpe*ika Itnni th* eipuTelti**. Alter loading with VC, the i hnrvoai was 41 ANALYTICAL CHEMISTRY, VOL. 48. NO. 1. JANUARY t7$ AP00053932 a. mrxMHct fc-ovov 40 t* ---IL 40 *0 CO ao mo & IfOCATCO o Luviu, ., ,ii, 40 60 SO 100 120 40 *0 Figure 2. Mata spectra of 1,2-d*xorno-i-chtoroethane <Dfl-VC) (pwwrt Ion* 220. 222. 224. 226 are istit>*a and not delected) poured into a flask which wai kept at -30 *C and which contained Oh ml of bromine and 11 ml of n-hixsne. The daurraination of DB-VC by GLC from iha solution after column chromatocraphy gsv* recovery rates of more than 95%. Two control rum 'as out lined under Procedure), one involving extraction with n-hexsne of charcoal with smoke gas-phase deposits (no bromination) and the other involving bromination of charcoal without imoke (blank teat), produced no signals at the retention time of DB-VC. (All equipment used was the same as under Procedure). Procedure.`halation of Vinyl Chloridi. An amount of the con- 1 renlrale frum cigarette imuke sufficient (a>20 wg) for mau spec tral identification of the 1.2-dibromo at hvative of VC was collect ed by several runs following the procedure for quantitative analy sis of VC (see below), Each successive run was quantitatively and qualitatively monitored by gas chromatography. Quantitative Anolyti*. Thirty cigarettes (selected by weight and draw resistance) were smoked with a JO'port automatic smoking machine at a tale of one puff of 2-sac duration per min, a puff vol ume of 35 ml, to a butt length of 23 mm. The mainstream smoke area drawn through a Cambridge filter (CM-113A; 92-mm diame ter) and subsequently through a glass tube (12-em X 6-mm i.d.l containing 1.0 g of activaud charcoal (glass wool at both ends of tha tube). Immediately after smoking, the contents of two such tubes were poured into a flask [Rtacti-flask with screw cap and Teflon-faccd dick iPieree Chemical Co.)] which was kept at --30 *C And contftined 0.5 ml of bromin* in It ml of TH flask was sealed and covered with dark paper, and the contents were magnetically stirred for 7 min, An aliquot of the reaction mix ture wa chrumaiographtd with n-hexane on silica gel (mesh .SO SO) 1.0 x 60-cnt it a column temperature of 0 *C. Fractions (aver age T,,'l ml) were collected every 2 min. Fractions 13-15 were com bined and concentrated slowly under nitrogen at 45 *C to a 7-ml volume. This solution was rechromatngraphed with n-hexane <>n silica gel mesh 60-80 (column I.:! X 75-cm) at room temperature: Tci-ml fractions were collected every 1.25 min. An aliquot of fraction .'4 was analyzed by gas chromatography. (To ensure maximal recov ery. neighboring fractions were also analyzed Tor DB-VC and, if needed, combined with frmetiun 24). Quantitative Analysis of Inorganic Chloride in Tobacco. The technique employed was the Caldwell and Moyer modification of the Volhard method (4>, with the further change of filtering the simple solution with Norite prior to titration. Cl" was extracted from tobacco samples according to Yamasaki and Yamasaki (it. RESULTS AND DISCUSSION A gas chromatogram of a vinyl chloride (VC) concentrate from cigarette smoke as 1.2-dibromo derivative (DB-VC) is shown in Figure l. The column ellluenl. which by retention time corresponded with DB-VC, was identified by il* mass spectrum iFigure 2). 'I'he main peaks in l!e gas chromnlogram (Figure I' with retention times lower than that of DB-Vt' were identified by mass s|c tn>mi try as dihmmnpropane* nnd tlihronmlnitane*: however, lieemi** of a lack of reference rim|M>und*. we were unable to assign struc ture* with tin- exception of une case. Five analyst** of 60 Tlbte L Vinyl C Ida In Cigarette Smoke, ngfeigy Me. uf frelriM l t t 4 5 Average Std dev Dar coefficient Vtayl chlonU* u.hrej* 12.6 11.4 12.9 10.8 19.1 12.2 0.90 7.4 % Commercial, 85 mm. nonfiker eigaretle. A Not corrected for toeaes. Table IL Vinyl Chloride in Cigarette Smoke Preduct- *filth. mm butt kri|(h. mm Vmvl chloride. nr,mi- Reference eigarette IRI Cigarette A NF Commercial cigarettes 35 23 12.4 Cigarette A F Cigarette B F Cigarette C F Cigarette D NF Cigarette E NF Cigarette G F Cigarette H NF Commercial Tittle cigar: 85 23 56 SS 23 W.1 95 23 11.4 70 23 It.9 70 23 15.3 86 23 35 23 09 2.2 Little cigar A F Little cigar B F Charcoal filter cigarettes6 'as 23 14.4 85 23 27.3 Cigarette A with F 85 35 5.1 Cigarette A with F cut off 60 10 15.3 Cigarette B with F 85 35 13 Cigarette B with F cut off 60 10 4.0 Marijuana cigarette 85 23 5.4 F: Filter; NF: nonftlter.* Cigarette column smoked 50 mm. cigarettes each yielded an average of 12.2 ng VC isolated as DB-VC from the mainstream smoke of an 85-mm lr.S. blended cigarette without filter tip (Table l). The recovery rate was found to he at least dn%. The minimum recovery rate was calculated by directing known amount* of VC in air through charcoal which was earlier loaded with the gas eous phase of the mainstream smoke of 10. 20, or :I0 stan dard cigarettes, respectively. After completing the analysis, we calculated the recovery rate. In addition to the standard nunflller cigarettes, we ana lyzed the mainstream smoke of some domestic and foreign cigarette*, of two little cigars, and a marijuana cigarette. The results are summarized in Table II and indicate signif icant differences in the concentration of Y(' in (he main stream smoke of commercial cigarettes. As expected, the smoke of cigarettes with charcoal filler ti()s contains signif icantly tower amounts of Y(! than doe* the smoke of ciga rettes without this type of filter lip. CH radicals are long known to lw generated during the burning of tobacco products (f>). Since many tobacco con stituents give rise to CH radicals, a seufeh for jxis-ibli- -ptcific precursors fur the I'jHn moiety of V(` ap|>e:ifs r.ithi-T futile. On the oilier hand, tobacco conlains (races of resi due* of chlorinated posltcidi-s (7), some unknown, chlorin.iled organic ininfhitmd* (t>, HI, and op (o :t*\ of inorganic chloride (fri. lt is. thmTnn*. reasonable (o assume that (be inorganic chloride in tobm-co cootribolcs signilirmillv lo the concentraiion of VC in (he smoke. This hvpoil. . is supported by the oliscrvAtion that the anunmt of : ivl chloride in cigarette smoke is determined by tin* cot<> iru- ANALYTICAL CHEMISTRY. VOL. 48. NO. 1, JANUARY 1975 49 AP00053933 II1! 5 10 15 mg Cl "I o 1, mg CM A > per g Of) Tobacco Flour* S. Correlation between Inorganic chloride end total eHotiw in tobacco and vinyl chfooda in cigarette smoke tion of inorgsnie chloride in tobacco (JO). Figure 3 indi cates that water soluble chloride, aa well as total chlorine, in tobacco may contribute to the concentration of VC in the smoke. We realize that detailed studies are needed to ensure the nature of the major precursors in tobacco for the chlorine of VC in the smoke. Nevertheless, we should not disregard the possibility that also during the burning of other plant materials, and in fact of ail organic matter which contains chlorine, vinyl chloride can be generated and can be released into our respiratory environment, ai demonstrated for marijuana smoke. This study has shown that smoke contains up to 16 ng of vinyl chloride per cigarette, and 27 ng of VC per little cigar. This amount corresponds to s concentration of about 30 ppb. Based on human data and result* from animal studies, it appears to us that these minute amounts of VC will not contribute to a measurable degree to the carcinogenic ac tivity of tobacco smoke. It should be realized, however, that we have directed our analysis only toward the identifica tion and quantitative determination of vinyl chloride and that tobacco emok -nay also contain other unaalurated. chlorinated hydrcx ns with carcinogenic artivitv. This Buy include the suspected human carcinogen 2-chlun.UiUdlana ichloruprene; II. I'D as well chlorinated printucta of isopr*na, the major unaetured hydrocarbon in to bacco amoke. Note Added in Proof. This Study wu presented at the 29th Tobacco Chemist*' Research Conference (College Park, Md., Oct. S-10, 1975). Two questions arose. 1) How much VC is in ambient air? Ming ihe above methiwl. t different times we passed 20 t. of amhirnt laboratory air through charcoal. The extract of the charcoal was each time free of VC. 2) la VC artificially formed from the ethyl ene of the smoke (trapped on charcoal) and the trace amounts of chlorine possibly present in the bromine? To answer this question, we led 400 ml of ethvlene (CP-Matheaon Gas Products) through charcoal and, using the same bromine, we processed it in the usual way. VV did not ob serve a signal in the gle at the retention time of D8YC using the CCD at twice the usual sensitivity. ACKNOWLEDGM E NT The authors thank C. Costello of the Mass Spectroscopy Laboratory, Massachusetts Institute nfTechndogy, for her cooperation in obtaining and interpreting mass spectral data on DB-VC. LITERATURE CITED (1) SitemeOona! Agency (Or Research on Cancer. Monogr r, 29111974) (2) I. J. SeSkOlf and 6. C. Hammond. 'TenieitY Of Vinyl Cmorida-Potywiyt OYerkJe". Am. N.Y. Ac** Sc.. 248, 1 (1975). (3) C Uattora. a. Latemir*. 9. Cisaco. and D Canerb. Oipadava Ssttena *e*. 1 ($-). 1 0974). (4) J..R. CeUwMendH. V.Moyor. An*1. Chem.. t. 3eoMS> |5) M Yamasaki end J. Yamataki, Sd. Pag Central flat Inst, jpn Mongfio. lyCorp.. 174, *5 (1972). (6| E. t.. VTynder end D. Hoffmann Tobacco and Tooaeeo Seka. Stuoai n ip*rimamai CardnogeoMi*". Ac*aa*r*e Pres*. Hew York, n Y 1947. (7) P. F. GuthrieandP. 0. Sowary. ResAePav. 7*. 31 (1947) IS) R. L. Stedman, Chem. flaw. SI. 153 (1968). (9) T, C. tso. "Ptryjloiogi' and eocneimtry of ToOecco Plant*", Oowden. Hutchinson, and Rost. Sl/eudJburg. Pa , 1972. (10) R. R. Johnson and T. . Smith. Abatr. 24th Totsaccg Chernaia' Res Can/., 24 (197C). (11) E. A. Khaekstryan. Qig Tr. final. ZiteJ ll, S4 (1973) (12) 6. A. KhsChalryan. OUOA Once* uss*.. H. 85 (1972) RECEIVED for review August 5, 1975. Accepted September 22, 1975. This is No. XXXVI of "Chemical Studies on To bacco Smoke". It was supported in part by American Can cer Society Grant BC-56T and by Public Health Service Contract ECl-SHP-T-t-106. Thin Layer Chromatography/Densitometry with Transferable Calibration Factors H, Bethke and R. W. Fr#i` Analytical Research ary) Development. Ptigrmecevticsl Drvisicn. SanOoz Ud , 4002 Bash. Switzerland The principle at transferable calibration technique It dlscussed and Introduced with examples of dlhydroergotsmlne. The quantitation of spots Is carried out with direct UV re flectance speetrometrlc measurements of methyiergobasin# on different series of ehromalopiatss. The applicanttty of this tame calibration transfer model lo In sllu fluores cence measurements which require a derlvsilzallng raac- tlon after separation it demonstrated with sample* of dlgoxIn. Th# reproducibility ol Ihe results obtained It comparable to Individual calibration carried out for each ptale (rei std dev about 2%). With Ihe use of transferable calibration, S analyses can be carded out on one 20 X 20 cm plato which represents an Increase in capacity of 60% comparod lo a previously discussed method. 50 ANALYTICAL OCMSTRY, VOL. 44. NO. 1. JANUARY 1976 AP00053934  ^2 Tfce 5lsr iw.i Vinyl Chloride Found! In Cigarette Smoke- Vinyl cfclcr.ie. i ciac*r aoiin* chert::*!. ha* b~trt tend for tie tint tirse in t riprett* iirs.r.t, possibly : Indicating similar cr.er.s' c*U form when ot-.*.- p;*:M * rotlerial it burned, scien tist* tiy. < The researcher* said ve*. tcrtay ti amour.: o', vsnvi chipnde measured in c-.esrmte *m*ke u pronely :*> cnall ta be 4 major factor in cigarettes causing tin- , CtT. But one o! the scientist* ` ssid viayl chlcnie , iobacco smoke ::-.tr.b-t io public exposurt *3 - chemical. and n*ctvai;r cajld interact w;:a otser caicer-ctviir.g agasts m the cm* ire r. men* it - ttsCerriJk. The study, published in the American Citemi.-al fscety'i jsu.na] Ar.&.\mcai Cterr.iirry. u-as *; ".dueled by Dr. b.eir.ch Hastean Cor.itxrnn Pitnsr-skas ui Kiiii* D. Brunremanfl at the American Hei;\h FouoCanon. Viha.ia. N V. Dr. G'> B Gor. <: Lie National Cancer institute. irr.evts. Me., ccautr.orej the retvrt. Vinyl < blonde ;* vtdely used m rtaiirc plastics and, hat hesn Iterd to a h.cner t it uv?r rancer u | mesa tha -*crk '.ta it. i c.x7os:re also has procured I v2_-.r.i r,*7** o: cancers a The mw cudy m.arfcj the first ccvirenmen;*! appear* iru c-f vinyl chloric uare* its rury* f::hi:eer`sr. The highest vinyl chloride concentration measure *a* 35 par;* per r:i::oa m the srr.^kt cf a r.oriilierrt eigarer^. This i.r.curt per cigarette it `.irr.et ip.sb fn-.d :s produce tumors in c.'.ma_s iaiai.'uug ice ccimv1 c ilL <'