Document rp92wrj8d4RLxQXban2Y0ryN0

FILE NAME Talc TALC DATE 1975 DOC TALC088 DOCUMENT DESCRIPTION Federal Register Notice RULES AND REGULATIONS 11865 Title Employees Benefits CHAPTER SOCIAL SECURITY ADMIN- ISTRATION DEPARTMENT OF HEALTH EDUCATION AND WELFARE Regs No. 5 further amended PART FEDERAL HEALTH INSURANCE FOR THE AGED AND DISABLED Part 405 of Chapter III of Title 20 of the Code of Federal Regulations is amended as follows Paragraph b of 405.912 is revised to read as follows 405.912 Collection of premiums while monthly benefits are suspended * * * * main categories One concerns provisions to decrease the potential for ingestion of asbestos fibers The other concerns pro- visions to decrease the potential for injection of asbestos fibers A discussion of each category of comments and the Commission's conclusions are set forth below A. Comments on provisions dealing 1965 b Collection of premiums where with ingestion potential of asbestos Subpart Premiums for Supplementary Medical Insurance Benefits SUPPLEMENTARY MEDICAL INSURANCE BENEFITS PREMIUM BILLING On October 2 1974 there was pub- lished in the FEDERAL REGISTER 39 FR 35577 a notice of proposed rulemaking with a proposed amendment to Subpart monthly benefit payments will not be resumed during the current taxable year Where an enrollee's monthly title II benefit payments other than age special payments sec 405.916 are being suspended for an indefinite period or for a definite period which will not permit collection of all premiums due from monthly benefits payable in the current fibers 1. The Commissioner proposed that any food food packaging material drug drug ingredient or drug packaging material containing tale that is not free from asbestos fibers as determined by a particular analytical method should be deemed adulterated in violation of section 402 of the Federal Food I Regulations No. 5. The proposed regulation permits beneficiaries whose title II benefits are not payable because of work or for other reasons to be billed taxable year the enrollee should pay his premiums by direct remittance when he is billed The first billing will be for whatever premiums are necessary to Drug and Cosmetic Act Nineteen comments related to the pro- posed analytical method for talc under 121.2006 21 CFR 121.2006 The com- quarterly for supplementary medical insurance SMI premiums but not neces- sarily as is provided under present regulations on a calendar basis Interested persons were given 30 days within which to submit written com- place him in a quarterly cycle Thereafter assuming such premiums are promptly paid the enrollee will be billed on a quarterly basis for 3 months premiums see 405.913 If the enrollee however wishes to pay premiums for ments were primarily from representatives of food drug and talc mining firms but also included four consultant laboratories and two other federal agencies Although it is apparent that most of these respondents did not actually use the de- ments or suggestions thereon The proposed regulation revises section 405.912 to permit the Social Security Administration at its option to bill monthly title II beneficiaries other than those receiving age special payments who are in suspense status for any 3 month quarter instead of restricting such billings to a calendar quarter basis A suggestion was received but not adopted that would allow individuals to be billed annually or semiannually if they so desired This is not within the scope of the proposed amendment which only conforms the SMI premium billing and collection procedures for beneficiary enrollees with those for nonbeneficiary enrollees Moreover experience has shown that most individuals find it con- venient to be billed for premiums on a quarterly basis In any event the regulation expressly provides and will continue to provide that any enrollee may pay more than 1 quarter's premiums at a time if he so chooses of course if his more than 1 quarter at a time he may do so FR Doc.75-6763 Filed 3-13-75 am Title Food and Drugs CHAPTER FOOD AND DRUG ADMINISTRATION DEPARTMENT OF HEALTH EDUCATION AND WELFARE SUBCHAPTER DRUGS PART DRUGS CURRENT GOOD MANUFACTURING PRACTICE IN MANUFACTURE PROCESSING PACKING OR HOLDING Asbestos Particles in Drugs for Parenteral Injection The Commissioner of Food and Drugs published in the FEDERAL REGISTER of September 28 1973 38 FR 27076 a notice proposing to restrict the utilization of asbestos filters in the manufacture of parenteral drugs and parenteral drug ingredients and to prohibit the use of containing tale signated method and were therefore reflecting their general experience with optical crystallography or a personal preference for other analytical methods none of the respondents supported the proposed method for compliance purposes The predominant objections to the proposed method were that it is difficult to use laborious and not practical for its intended purpose Several comments offered the opinion that only the most highly trained microscopists would be capable of using the method with any reasonable accuracy or precision Mem- bers of one trade association collabora- tively studied the method with 10 microscopists each examining seven samples of talc Four participants admittedly could not use the method to count the samples and there was obvious inconsistency in the results reported by other microscopists A number of alternative methods for determining asbestos particles in talc were suggested by the respondents Al- premium for a quarter has been paid he will not be billed for that quarter Accordingly the proposed amendment is adopted without change as set forth below Secs 1102 1840 1871 Social Security Act as amended 49 Stat 647 as amended 79 Stat 307 331 as amended 42 U.S.C. 1302 1395s 1395hh) Effective date These amendments will be effective on or before April 14 1975 as a food or food or drug ingredient or in food and drug packaging materials within certain analytical restrictions The notice provided for the filing of comments within 90 days Asbestos fibers are known to cause cancer when inhaled in large amounts Also asbestos and other fibers are considered likely to have a similar adverse effect if present in parenteral drugs although this has not been proven Because of this likelihood this order pro- though optical microscopy using dispersion staining was the most frequently suggested method others suggested ray diffraction spectrophotometry and seyeral electron microscopy and microprobe techniques as preferred or supportive analytical methods Many of the respondents additionally expressed their willingness to join a Food and Drug Administration analytical task force to evaluate applicable methodology Although the Commissioner cannot Catalog of Federal Domestic Assistance Program No. 13.801 Health Insurance for the Aged and Supplementary Medical vides that whenever possible asbestoscontaining or other releasing filters not be used in the manufacture proc- agree that the designated optical crystallographic method is unreliable when used by those experienced in the Insurance essing or packaging of drugs intended art he recognizes that an effective com- Dated February 24 1975 B. CARDWell for parenteral injection in humans Also it provides for measures to reduce the amount of fibers present in such prod- pliance method must have greater utility and acceptance than indicated by the comments on the proposed method Commissioner of Social Security ucts where it is not possible to elimi- The Commissioner has therefore Approved March 10 1975 nate these filters in the production of a drug decided to delay any final regulation for tale until an acceptable method for deter fi CASPAR W. WEINBERGER ne The comments made in response to the mining the presence of asbestos particles Secretary of Health Education en and Welfare . September 28 1973 proposal fall into two can be developed for this substance This gg ins ammem etree FEDERAL REGISTER VOL 40 NO FRIDAY MARCH 14 1975 a RULES AND REGULATIONS 11866 for talc used in the manu- man's overall exposure small The by these comment sub- con- area of rescarch currently is being acby the Food and Drug requirements in facture of paper and paperboard 121.101 h 21 CFR 121.101 h ) All of stances are tended that evidence is lacking to show of small amounts of tively pursued Administration these comments contended that asbestos that the ingestion and that the responsibil- 2. Several comments objected to the in containing talc does not mi- asbestos is safe and Drug Administra- purity limitattihoensprfoorpotsaelcd wmheitchhowderMeaensyby talc grate to packaged food when talc is used for this purpose One of these comments itics of the Food tion for promulgation of regulations to total human exposure to as- tablished thought that requirements that contained results of recently conducted lessen the not mitigated by the fact that amphibole be 99.9 percent and 99.99 unreasonable studies which were intended to prove this contention bestos were to asbestos cannot all human exposure by the agency percent chrysotile while others insisted that any limitation After a thorough review of submitted be regulated agrees that uniform unreasonable unless it could be de- was known hazard comments and examination and evaluadditional requested studies the ThecoCnosmimsitsenstionreergulations should be and industry basis In monstrated to reflect levels by ingestion While one respondent ation of concludes that this com- adopted on an lack of available re- calculated that 20,000 amphibole and producible micrometers Cmoemnmtishsaisondeermonstrated the validity of in a manner consistent this instance the methodology for determining beverages and 3,500 chrysotile fibers of 5 size should be permit- this contention In the con- asbestos fibers in to pro- x 1.7bmefiocrreomaentyertsalc sample exceeded the with available methodology ducted studies the comment has dem- other foods led the Commissioner the regulation of talc before han- ted respondent established limits another onstrated that dry packaged and shipped pose other related matters In any event observed that individual asbestos par- in size a million salt contains less than 0.01 part per bilasbestos when in direct and continu- dling has now become moot since the comment has decided to delay ticles often vary thus making it difficult to relate particle asbestos con- lion contact with uncoated paper con- ous to 6 percent tremolitic asbes- the Commissioner direct food or a final ruling on talc as a counts to the percentage of in talc . taining up detection was limited by drug ingredient also concludes that tamination the decision of the Com- tos Although recovered from other The Commissioner data on the addi- nonparenteral Although any final regulation on the bulk of ash wrapped and fro- neither the available missioner to delay these comments moot products such as fresh macaroni dried tion of fibers to foods and nor the talc has rendered the Commissioner wishes to respond to position on zen meat dry packaged milk rice and corn flakes the comment that these prod- drugs by use of asbestos filters the asbestos content of municipal data on to permit these comments to clarify his has also demonstrated bil- water are sufficiently reliable at posssible future talc regulations As indicated in the proposal the Com- evidence ucts contain less than 10 parts per lion asbestos under test and market con- of these of regulatory controls promulgation indicates a wide vari- this time Evidence in missioner recognizes that the the possible hazard from in- ditions studies The analytical details are on file with the Hearing ation of asbestos fiber tchoentcaimtiiensatoifonthe wa.er supply of concerning is contra- gestion of asbestos particleTshe method inconclusive Clerk Food and Drug Administration 5600 Fishers Lane Rockville the United States with some reports that of the San Francisco CA dictotryheraenfodre not proposed in order to Rm 4-65 the waters MN areas are among was known hazard from asbes- MD 20852 concludes that the and the Duluth content How- indicate any intended to establish a good The Commissioner study represents a the highest in asbestos of test meth- tos but was practice limitation for above reported salt limit of migration of as- ever the lack of consistency leads to ques- manufactoufritanlgc in food and drugs until practical uppcerontact paper and pa- ods and their applitchaetsieonsdata A recent tahne aussseessment of the hazard if any of epidemiological determined bestos froTmhis conclusion is based upon abrasive perboard of the extreme tions concerningstudy of cancer mortal- the last 14 years Ref ingested asbestos can be limitation accompanying consideration compared to other dry ity in Duluth over that up to this time The particlemethod represents the best municipal the proposed and Drug Admin- fnoatoudrseaonfdstalhte ausnusually high tremolitic the test paper 6 per- 2 has concluded effect could be demon- no carcinogenic of the assessment by the Food istration of the probability of occurrence asbestos content of levels of cent as compared to reported strated from ingestion been received waters Some reports have contact of such particles in natural talc deposits use 0.02-0.4 percent in claiming little or no asbestos addition the ability of the method to detect such and paperboard to the aforementioned products by the and the need to assign a limit paTpehre Commissioner therefore concludes of filters Ref 3 Other reports demonstrated ptaortdiecfliense the absence of asbestos The has also that that the commceonnttehnatsof talc used in the use from Canada which indicate some inin the asbestos content of bever- Food and Drug Administration tale samples of un- the asbestos of food- or contact creases 4 and 5 over background examined numerous in the past 2 years using defined grade and finds that manufacture does not represent paper and papceornbtoaamridnant of packaged awgaetserRsehf ow that the final levels are com- the background levels in areas the proposed methodology thirds of such sam- a potential as assessed by currently parable to States Therefore the Com- approximately within these limitations The food or drugs Accordingly the methodology of the United has decided to delay the pro- ples are therefore concludes that available is withdrawing the analyt- missioner of any regulation on the pro- Commpirsospioosneedrparticle limitations would Commissioner for talc in ical limitations proposed mhiubligtaitoinoonf use of asbestos filters for the the burden on unless new methodology or of foods and nonparenteral unreasonable not impose an of talc if these limitations 121.101 assessment requires further preparautnitoinl more reliable data can be toxicological manufacturers adopted of this question drugs on the background concentra- are ultimately Administration evaluation stated in the pro- Commissioner obtained asbestos in drinking water and The Food and Drug the possible extreme 4. Thtehat it had been decided not to tions of of asbestos filters in regard to has been aware of posal particle size that a proposed regulation gov- the role addition of fibers to ingestible variation in asbestos of talc promulgate of asbestos filters the may occur in natural deposits particles less than 5 microm- to erning the utilization in the processing of food and beverages that this was in- pro5.duMcatn s y comments endorsed or conparts of them Eliminating eters long or with less than a nar- One comment stated Commissioner's pro- demned the proposals or food and beverage length ratio considerably consistent with the asbestos content with respect to water most of these rows the range of permissmibeltehopadrtiCcolne-s the proposed that posg edrra egudlaetiotnalocn atnhde that attempts to of should apply ccoonmtmaemnitnsatdiiodnnoAtltshuopupglhy any additional current asbestos csioduenrtiendg tbhye variation in particle size limit asbestos ingestion data or information a Davis Ref 6 Commissioner's may yet be possiblemihcorwoemveetrers wtyepiigcha-l uniformly to all sources stated that the Another com- feeding study by J. M. G. and a 1967 study by G. M. Bonser and fur- particle of 300 cubic Ref 1 1 nanogram ment the use of as- D. B. Clayton Ref 7 were cited as ing approximately a purity of talc at decision not to regulate evidence of no harm from ingested was used to assure of amphibole types bestos filters in food beverage and non- ther Other comments cited the 1972 least 99.9 percent free was based asbestos fibers and at least 99.99 per- parenteral of asbestos asbestos fibers drug preparations notion that the amounts the unproven conclusion of the Advisory Committee Cancers Ref 8 that there cent free of chrysotile on comments from industrial which are contributed to on Asbestos fir3.ms Tohbrjeeected to the proposed analytical of asbesots NO FRIDAY MARCH 14 1975 FEDERAL REGISTER VOL 40 RULES AND REGULATIONS 11867 of asbestos fibers are months of the date of publication of this will be required to submit was no evidence of an increased risk of jection potential regulation from asbestos fibers in water as follows stated that monthly progress reports thereafter con- cancer and food or in fluids used for 1. A number of comments that cerning attempts to implement the re- beverages the administration of drugs and one Klein- there is no conclusive evidence asbestos filters add fibers to the filtrate quired procedures and any difficulties in maintenance of product quality comment cited a recent study by feld Messite and Zaki Ref 9 which or that asbestos has caused deleterious effects as a result of parenterally admin- 3. A large number of comments stated would reports no increase of gastrointestinal that many parenteral products and peritoneal cancer among talc istered drugs found in number suffer in safety and quality because of a workers exposed to talc dusts for a mini- Asbestos fibers were of samples of parenteral drugs by Nichol- requirement to replace containing filters in the manufacturing process mum of 15 years of the foregoing com- son et al Ref 10 and also by a sub- The Commissioner agrees that it is es- From analysis parenterals ments received concerning the limita- sequent Food and Drug Administration investigation of Although sential that there be no increase in risk result of this action tion of asbestos in talc from thorough avail- the Food and Drug Administration has to the public as a for continued use review of the scientific evidence concerning the adequacy of the demonstrated that filtration through as- of water sample highly contami- The regulation provides of asbestos filters where no alternative able available methodology to determine the bestos a with asbestos fibers can signifi- is feasible The responsibility for demon- amount of asbestos in talc and from nated the number of fibers pres- strating that the replacement of asbestos consideration of the controversial nature cantly reduce Administration filters or the utilization of a final non- releasing containing of evidence to demonstrate the hazard _ ent the Food and Drug the utill- to health presented by ingestion of the also has direct evidence that zation of asbestos filters can cause as- filter decreases product quality and effecof safety remains that of the amounts of asbestos fibers normally to bestos contamination The preliminary tiveness be expected in talc used in food or drugs latter study is on public manufacturer Evidence for such product in food or drug packaging materials report of the alteration must be submitted to the ap- or containing talc or in beverages other display in the office of the Hearing Clerk of propriate bureau of the Food and Drug foods and nonparenteral drugs prepared The evidence of the deleterious effects parenteral asbestos administration Ref Administration for approval of the conof the unmodified asbestos with the use of asbestos filters the Com- 1 11 12 and 13 requires that the tinued use missioner concludes that the promulgation of regulations on the limitations or amount of contamination in these prod- the filtration processes 4. One comment objected to the utili- of the use of asbestos filters ucts be minimized Consequently zation of the terms membrane filter prohibition for the preparation of foods and non- Commissioner has determined that it is fil- and releasing filter stating drugs and of the amount of important that containing that the former term was too limiting releasing parenteral in talc for use in food and ters be replaced with recommendation for a replacement asbestos fibers drugs or which might migrate into food filters unless it is demonstrated that it is not possible to manufacture a safe and as a of filters which may release asbestos and that the latter phrase should or drugs from containing packaging effective parenteral drug or parenteral fibers or materials is unwarranted until more without the use of such be changed to containing reliable data can be obtained concerning drug ingredient filter In the lat- migration filter This these matters an containing comment claimed that the term non- releasing The Food and Drug Administration in ter instance a final content releasing should be replaced since conjunction with other agencies is plan- filter shall be used to reduce the in the drug small quantities of the fibrous support ning extensive experiments to determine of any asbestos particles asbestos- used in many cellulose membrano if long term exposure to ingested asbestos or drug ingredient Use of an of filters as well as fibers and particles fibers represents a definitive hazard to containing filter with subsequent use from the manufacturing process for containing human health As noted until this study an additional cartridge and other type filters are re- is completed or other data become avail- releasing filter shall be permis- to leased by cleaning and flushing prior to able the Commissioner has determined sible only upon submission of evidence the appropriate bureau of the Food and marketing of the product Another comment stated that the proposed regula- that a prohibition of the use of asbestosfilters in the processing of Drug Administration that substitution did not contain a definition of a containing and of asbestos- for the asbestos filter of a fiber tions filter Comments also food and beverages food food additive leasing filter will or is likely to compro- releasing should not use the containing tale as a or mise the safety or effectiveness of the stated that $ 133.8 or in drugs or drug ingredients is unwarto lack of sufficient data In drug Use of an containing fil- of an addi- terms releasing and asbestos- containing interchangeably and one ranted due the interim maufacturers of food and ter without subsequent use comment objected to the synonomous drugs are urged to investigate all means tional containing nonreleasing filter shall be permissible use of the terms fiber and asbestos of eliminating the use of such filters and the Food and Drug only upon submission of evidence that fiber that the reg- talc and to keep Administration informed about changes neither the substitution for the asbestosfilter nor the use of a sub- The Commissioner agrees ulation should not specify only one type in formulation and processing of this containing filter can be of filter which would satisfy the new re- type sequent releasing accomplished without compromising the quirements and thus has deleted the membrane filter The Commis- B. In order to deal with the injection of asbestos fibers the Com- safety or effectiveness of the drug term concludes that for the pur- potential 2. One comment noted that although sioner also missioner proposed that the good manu- there have been several demonstrations poses of these regulations a fiber- facturing practice regulations for drugs of the addition of nonasbestos filters as releasing filter shall be defined as a non- be amended to require that filtration pro- final filters in the production of injecta- asbestos nonglass fiber filter which cedures for parenteral drugs shall utilize filter such ble biologics there remains concern that filters with after any appropriate pretreatment such as washing or flushing will not continue either a releasing as a membrane filter or if an asbestos- the replacement of asbestos to release fibers into the drug or drug containing filter is used because it is containing filters would up- which is to be filtered The necessary the procedures shall also set delicate filtration parameters of the preparation process An 18- ingredient distinction is therefore made between media mi- utilize an additional asbestos product the allow- filters which release fibers by filter such month period was suggested as to taining or releasing as a membrane filter to reduce asbestos able period of time for technical develop- gration i.e. continuous release due the nature of the filter and filters which fiber content to the minimum level fea- ment of the new processes that a spe- contain fibers from structural supports sible unless such a subsequent filter will The Commissioner agrees and The utilization of compromise the quality safety identity or purity of the cific period for process development modification should be provided in the months will be and contamination nonasbestos nonglass fiber filters in the strength regulations Therefore 18 latter category will be permitted pro- product pretreatment Comments received in response to this allowed for compliance Firms not conforming to these regulations within 12 vided that appropriate part of the notice dealing with the in- ry FEDERAL REGISTER VOL 40 NO FRIDAY MARCH 14 1975 RULES AND REGULATIONS which climinates fiber contaminant release has been accomplished As the similarity between the carcinogenicities of asbestos and fibrous glass has been noted fibrous glass filters have been added to this definition to prevent the widespread conversion from asbestos to this type of filter Ref 14 and 15 A fiber is defined as any particle with length at least three times greater than its width Ref 15 and 16 The Commissioner realizes that the definition of a releasing filter excludes the possibility of the use of an asbestos or fibrous glass filter locked into a matrix which precludes the release of fibers However no such technology was presented as feasible by any of the comments Therefore the Commissioner concludes that the definition of a fiber- releasing filter is appropriate for this regulation and that should a method for production of such a releasing asbestos or glass containing filter become available the definition will be subject to review 5. One comment suggested that the proposed requirement that no asbestoscontaining filter may be used unless it is not possible to manufacture a drug without the use of such a filter be replaced by when an containing filter is utilized a suitable filter must also be utilized to retain fibers The Commissioner concludes that such a change would be unacceptable since the purpose of these regulations is to minimize the amount of asbestos or asbestos fibers in parenteral drugs thereby minimizing the possibility of deleterious effects and although an afterfilter will substantially reduce the number of these fibers in the product it cannot be assumed that it will remove all of this material Hence the Commissioner has determined that the best means to eliminate asbestos contamination from parenteral drugs is by removal of the asbestos filters from the process whenever possible As stated in paragraph B.3 of this preamble the Commissioner agrees that there must be no increase in risk to the public from any product the manufacturing process of which is required to be changed However he reiterates that the use of an asbestos filter will be permissible only upon a demonstration by the manufacturer that the replacement of an asbestos filter by a releasing filter or the utilization of a final or filter is fiberreleasing adversely affects the quality safety and effectiveness of the product 6. One comment objected to the statement in the proposal that the use of asbestos filters in parenteral drug manufacturing is prohibited unless it is not possible to manufacture that drug or drug ingredient without the use of such a filter claiming that the lack of a more specific statement will lead to capricious regulatory decisions The Commissioner concludes that there is no more reasonable method by which to make a determination of the impossibility of achieving the desired product quality and effectiveness without the use of containing filters than by individual evaluation by knowledgeable scientists No automatic decision scheme was suggested in the comment Therefore the responsibility for submission of the evidence required for this determination will rest with the manufacturer and the responsibility for accepting or rejecting the request for use of containing filters will rest with the appropriate bureau in the Food and Drug Administration 7. Two comments objected to the fact that the regulations were limited to the release of asbestos and asbestos fibers and suggested that all extraneous material such as diatomaceous earth carbon silica fiberglass etc. also be regulated The Commissioner agrees that there is reason to be concerned about all particulate contamination in parenteral drugs but concludes that this problem should be considered separately from the subject regulations Therefore except for fibrous particulates the Commissioner has decided to await clarification of the degree of other types of contamination and the possible health effects of such other particulates prior to developing applicable regulations A call for scientific information in this regard will be published in the FEDERAL REGISTER in the future 8. One comment objected to the requirement of proof of reduction of asbestos fibers by the use of subsequent noncontaining filters in the manufacture of a parenteral drug or drug ingredient when submitting a request for approval of a process in which asbestos filters are used This and one other comment claimed that the National Institute for Occupational Safety and Health NIOSH analytical method as well as other analytical methods for determination of asbestos fibers in parenteral drugs is inadequate quantitatively to demonstrate reduction and is immensely difficult to perform The Food and Drug Administration and other government agencies are presently attempting to develop reproducible practical and useful methodologies for these analyses and amendments to these regulations will be promulgated upon the satisfactory completion of this research The Commissioner has decided that until these studies are completed the evidence for reduction of asbestos fiber content need not be obtained if adequate downstream filtration is accomplished Thus the requirement of proof of reduction of asbestos fiber content is omitted and the use of a nonreleasing filter of 0.22 micron maximum pore size is added to this regulation 0.45 micron maximum if the manufacturing conditions so dictate 9. One comment claimed that it is inappropriate to control all types of asbestos fibers uniformly as asbestos filters are composed primarily of chrysotile which is less hazardous to human health than amphiboles The Commissioner concludes that this differential in hazard has not been es- tablished for parenterally administered asbestos Studies by Reeves et al Ref 17 have demonstrated mesotheliomas in rats and rabbits from pleural and peritoneal injections of both chrysotile and crocidolite fibers Further studies have been initiated by the Food and Drug Ad- ministration on the effects of parenteral injections of chrysotile fibers in experimental animals 10. One comment indicated that in the study of parenteral administration of asbestos to animals by Schmahl Ref 11 the tumors that occurred were not related to asbestos since they were sarcomas rather than mesotheliomas Although mesotheliomas are closely related to inhalation of asbestos there also has been an association of carci- noma of the lung with asbestos inhalation As with other carcinogens several types of tumors may occur as a result of exposure to a particular carcinogen depending upon the route of exposure The Commissioner therefore concludes that the data in this reference are valid and may possibly implicate asbestos in the development of these malignant tumors of soft tissues namely sarcomas 11. One commenter presented data demonstrating that membrane filtration was capable of removal of all asbestos particles from his asbestos product beer as measured by electron mi- croscopy However even though the container for this product was subjected to a final rinse by municipal water the packaged product contained a significant number of asbestos fibers Similarly the Food and Drug Administration has found asbestos particles in parenteral drugs produced by manufacturers who do not use asbestos filters in their processes These indications of substantial con- tamination of the product from typical liquid containers have led the Commissioner to conclude that cleansing and rinse water for the containers for paren- teral drugs shall be filtered through nonreleasing filters equivalent to those required for asbestos filtration to remove inherent fiber contamination 12. The Environmental Impact Analysis Report EIAR and other relevant materials have been reviewed and it has been determined that the proposed use will not have a significant environmental impact Copies of the EIAR are available in the office of the Assistant Commis- sioner for Public Affairs Rm 15B or the office of the Hearing Clerk Rm 4 65 Food and Drug Administration Fishers Lane Rockville MD 20852 5600 The indications to references set forth in the preamble are to the following which are on display in the office of the Hearing Clerk 1. Parenteral Preparations Pyrogens in Remington's Pharmaceutical Sciences 14th ed Chapter 82 p 1542 1970 2. Mason T. J. F W. McKay and R. W. Miller Asbestos Fibers in Duluth Water Supply Relation to Cancer Mortality Journal of the American Medical Associa- tion 1020 May 20 1974 3. Comment from Asbestos Research Coun- cil March , 1974 4. Cunningham H. M. and R. Pontefract a Asbestos Fibers in Beverages and Drinking Water Nature 332-333 1971 FEDERAL REGISTER VOL 40 NO FRIDAY MARCH 14 1975 RULES AND REGULATIONS 11869 b Symposium on Industrial Chemicals as Food Contaminants Journal of the Association of Official Analytical Chemists 56 976-981 1973 products unless it is not possible to manufacture that drug product or component without the use of such a filter Filtra- 5. Pontefract R. and H. M. Cunningham tion as needed shall be through a non- Penetration of Asbestos through the Diges- releasing filter For the purposes tive Tract of Rats Nature 352 353of this regulation a releasing 1973 filter is defined as a nonasbestos non- 6. Davis J. M. G. Institute of Occupational Medicine Edinburgh Scotland unpublished report 7. Bonser G. M. and D. B. Clayton Feeding of Blue Asbestos to Rats 1967 Annual Report British Empire Cancer Campaign for Research p 242 8. Report of the Advisory Committee on glass fiber filter which after any appropriate pretreatment such as washing or flushing will not continue to release fibers into the drug product or component which is being filtered A fiber is defined as any particle with length at least three times greater than its width Asbestos Cancers to the Director of the In- 2 If use of a releasing filter is ternational Agency for Research on Cancer British Journal of Industrial Medicine 180-186 1973 9. Kleinfeld M. J. Messite and M. II Zaki Mortality Experiences Among Talc Workers A Follow Study Journal of Occupational Medicine 345-349 1974 10. Nicholson W H. C. J. Maggiare and required an additional releasing filter of maximum pore size of 0.22 microns 0.45 microns if the manufacturing conditions so dictate shall subsequently be used to reduce the content of any asbestos particles in the drug product or component Use of an I. J. Selikoff Asbestos Contamination of containing filter with or with- Parenteral 1972 Drugs Science 171-173 11. Schmahl D. Carcerogene Wirking von Asbest bel Implantation von Ratten Zeit schrift fur Krebsforschung 561-567 1958 out subsequent use of a specific nonreleasing filter is permissible only upon submission of proof to the apprapriate bureau of the Food and Drug Administration that use of a fiber 12. Roe H. R. L. Carter M. A. Walters leasing filter will or is likely to and J. S. Harrington The Pathological effects of Subcutaneous Injections of Asbestos compromise the safety or electiveness of the drug Fibers in Mice Migration of Fibers to Sub- mesothelial Tissues and Induction of Meso- theliomas International Journal of Can- cer 628-638 1967 13. Kanazawa K. S. Birbeck R. L. Carter and F. J. C. Roe Migration of As- bestos Fibers from Subcutaneous Injection Sites in Mice British Journal of Cancer 96 1016 970 14. Symposium on Occupational Exposure to Fibrous Glass sponsored by National Institute for Occupational Safety and Health University of Maryland June 26-27 1974 15. Stanton Mearl F. Fiber Carcinogenesis Is Asbestos the Only Hazard Journal of the National Cancer Institute 633 1974 3 Substitution for a releasing filter shall be achieved on or before September 14 1976. If such substitution is not achieved on or before March 14 1976 the manufacturer of the drug product for parenteral injection who requires the additional 6 months to develop new manufacturing procedures so as to utilize releasing filters in place of releasing filters shall submit monthly reports to the appropriate bureau of the Food and Drug Administration indicating progress in substituting the new filters Such a substitution shall be shown to have been effected without 16. Occupational Exposure to Asbestos loss of the safety or effectiveness of the Criteria document U.S. Public Health Serv- ice National Institute for Occupational Safety and Health Chapter VIII pg 6. 1972 17. Reeves A. J. H E. Puro R. G. Smith drug 2. By revising $ 133.9 to read as follows and A. J. Vorwald Experimental Asbestos Carcinogenesis Environmental Research 496-511 1971 133.9 Product components containers and their Therefore pursuant to provisions of the Federal Food Drug and Cosmetic Act secs 501 502 701 52 Stat 10491051 1055-1056 as amended 21 U.S.C. 351 352 371 and under the authority delegated to the Commissioner 21 CFR 2.120 Part 133 is amended as follows 1. By amending 133.8 by adding new paragraph j to read as follows 133.8 Production and control proce- dures + * * * * j Use of containing or other releasing filters 1 Filters used in the manufacture processing or packaging of components of drug products for parenteral injection in humans shall not release fibers into such products No Suitable specifications test methods cleaning procedures and when indicated sterilization procedures shall be used to assure that containers closures and other component parts of drug packages are suitable for their intended use Containers for parenteral drugs drug products or drug components shall be cleansed with water which has been filtered through a releasing filter equivalent to that indicated in 133.8 2 Product containers and their components shall not be reactive additive or absorptive so as to alter the safety identity strength quality or purity of the drug or its components beyond the official or established requirements and shall provide adequate protection against external factors that can cause deterio- containing or other fiber ration or contamination of the drug leasing filter may be used in the manufacture processing or packaging of such Effective date This fective April 14 1975 order shall ef- Secs 501 502 701 52 Stat 1049-1051 10651056 as amended 21 U.S.C. 351 352 371 Dated February 28 1975 A. M. SCHMIDT * Commissioner of Food and Drugs FR Doc.75-6733 Filed 3-13-75 am Recodification Docket No. 6 SUBCHAPTER DRUGS FOR HUMAN USE PART TESTS AND METHODS OF ASSAY OF ANTIBIOTIC AND ANTIBICONTAINING DRUGS Reorganization and Republication Correction In FR Doc 74 12338appearing at page 18921 in the FEDERAL REGISTER Of May 30 1974 the heading for 436.206 appearing on page 18959 is corrected to read " 436.206 Test for metal particles in ophthalmic ointments Dated March 11 1975 SAM D. FINE Associate Commissioner for Compliance FR Doc.75-6853 Filed 3-13-75 45 am PART OLIGOSACCHARIDE ANTIBIOTIC DRUGS PART TETRACYCLINE ANTIBIOTIC DRUGS Otic and Ophthalmic Preparations The Commissioner of Food and Drugs is amending Parts 444 and 446 to delete two sections that refer to drugs no longer being certified to delete a section that has been superseded and to amend a section to provide for a test method The final order for DESI 8583 et al published in the FEDERAL REGISTER of September 19 1974 39 FR 33665 revoked the provisions for otic use from 444.342g and 446.367c In addition it amended 446.367e by separating it into two sections 446.367e for the ophthalmic dosage form and new 446.467d for the otic dosage form However the document failed to account for sections describing products for both eye and ear use that appear twice in the regulations as recodified May 30 1974 39 FR 18922 in the subpart for ophthalmic dosage forms and in the subpart for otic dosage forms As a result Part 444 now contains 444.442e that refers to drug products that are no longer being certified Part 446 contains $ 446.467c that refers to drug products no longer being certified and 446.467b that has been superseded by a new section Therefore these three sections should be revoked In addition the amendment to 446.367e in the order of September 19 1974 inadvertently omitted the test method for sterility It is provided for below Therefore pursuant to provisions of the Federal Food Drug and Cosmetic Act secs 502 507 52 Stat 1050-1051 as amended 59 Stat 463 as amended 21 U.S.C. 352 357 and under authority delegated to the Commissioner 21 CFR FEDERAL REGISTER VOL 40 NO FRIDAY MARCH 14 1975