Document zz0qq8byY1Jme4vDr56akQO0a

FILE NAME: Talc (TALC) DATE: 1975 DOC#: TALC088 DOCUMENT DESCRIPTION: Federal Register Notice RULES AMD REGULATIONS 11865 Title 20-- Employees' Benefits rHAPTER III-- SOCIAL SECURITY ADMIN ISTRATION, DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE [B egs. No. 5,1f u r t h e r a m e n d e d ] PART 405-- FEDERAL HEALTH INSUR ANCE FOR THE AGED AND DISABLED (1 9 6 5 ........ ) P art 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 prem ium s while monthly benefits are suspended. * (b) Collection of premiums where main categories. One concerns provisions to decrease the potential for ingestion of asbestos fibers. The other concerns pro visions to decrease the potential for in jection of asbestos fibers. A discussion of each category of comments, and the Commission's conclusions, are set forth below. A. Comments on provisions dealing with ingestion potential of asbestos Subpart I-- Premiums for Supplementary monthly benefit payments will not be re fibers: Medical Insurance Benefits sumed during the current taxable year. 1. The Commissioner proposed th at S upplem entary M edical I nsurance Where an enrollce's monthly title II any food, food packaging material, drug, benefit payments (other than age-72 spe drug ingredient or drug packaging ma B enefits P rem ium B illino cial payments (sec 405.916)) are being terial containing talc that is not free On October 2, 1974, there was pub suspended for an indefinite period or for from asbestos fibers as determined by a lished in the F ederal R egister (39 FR a definite period which will not permit particular analytical method should be 35577 a notice of proposed rulemaking collection of all premiums due from deemed adulterated in violation of sec with a proposed amendment to Subpart monthly benefits payable in the current tion 402(a)(1) of the Federal Food, I, Regulations No. 5. The proposed regu taxable year, the enrollee should pay his Drug, and Cosmetic Act. lation permits beneficiaries whose title premiums by direct remittance when he Nineteen comments related to the pro I I benefits are, not payable because of is billed. The first billing will be for posed analytical method for talc under work or for other reasons to be billed whatever premiums are necessary to 121.2006 (21 CFR 121.2006). The com-' quarterly for supplementary medical in place him in a quarterly cycle. There ments were primarily from representa surance (SMI) premiums, but not neces after, assuming such premiums are tives of food, drug, and talc mining firms, sarily (as is provided under present regu promptly paid, the enrollee will be billed but also included four consultant labora lations) on a calendar-quarter basis. In on a quarterly basis for 3 months' pre tories and two other federal agencies. Al terested persons were given 30 days miums (see 405.913). If the enrollee, though it is apparent that most of these within which to submit written com however, wishes to pay premiums for respondents did not actually use the de ments or suggestions thereon. more than 1 quarter at a time, he may signated method, and were, therefore, re- The proposed regulation revises section do so. fleeting their general experience with 405.912(b) to permit the Social Security [FB Doc.75-6763 FLled 3-13-75:8:45 am ] optical crystallography or a personal Administration, at its option, to bill preference for other analytical methods, monthly title II beneficiaries (other than those receiving age-72 special payments), Title 21-- Food and Drugs none of the respondents supported the proposed method for compliance pur who are in suspense status, for any 3 CHAPTER I-- FOOD AND DRUG ADMINIS poses. The predominant objections to the month quarter instead of restricting such TRATION, DEPARTMENT OF HEALTH, proposed method were that it is difficult billings to a calendar quarter basis. EDUCATION, AND WELFARE to use, laborious, and not practical for its A suggestion was received but not SUBCHAPTER C-- DRUGS intended purpose. Several comments adopted that would allow individuals to PART 133-- DRUGS; CURRENT GOOD offered the opinion that only the most be billed annually or semiannually if MANUFACTURING PRACTICE IN MAN highly trained microscopists would be they so desired. This is not within the UFACTURE, PROCESSING, PACKING, capable of using the method with any scope of the proposed amendment, which OR HOLDING reasonable accuracy or precision. Mem only conforms the SMI premium billing and collection procedures for beneficiary Asbestos-Form Particles in Drugs for bers of one trade association collabora tively studied the method with (0 micros enrollees with those .for nonbeneficiary Parenteral Injection copists, each examining seven samples enrollees. Moreover, experience has The Commissioner of Food and Drugs of talc. Four participants admittedly shown that most individuals find it con published in the F ederal R eg ister of could not use the method to count the venient to be billed for premiums on a September 28, 1973 (38 FR 27076), a samples, and there was obvious incon quarterly basis. In any event, the regula notice proposing to restrict the utiliza sistency in the results reported by other tion expressly provides (and will con tion of asbestos filters in the manu microscopists. tinue to provide) that any enrollee may facture of parenteral drags and par A number of alternative methods for pay more than 1 quarter's premiums at a enteral drug ingredients, and to pro determining asbestos particles in talc time if he so chooses: of course, if his hibit the use of asbestos-containing talc were suggested by the respondents. Al premium for a quarter has been paid, he as a food, or food or drug ingredient, or though optical microscopy using disper will not be billed for that quarter. in food and drug packaging materials, sion staining was the most frequently Accordingly, the proposed amendment within certain analytical restrictions. suggested method, others suggested x-ray is adopted without change as set forth The notice provided for the filing of diffraction, spectrophotometry, and sev below. comments within 90 days. eral electron microscopy and microprobe Asbestos fibers are known to cause techniques as preferred or supportive (Secs. 1102, 1840(e), 1871. Social S ecurity Act, ns am en d ed ; 49 S ta t. 647, as am en d ed ; 79 cancer when inhaled in large amounts. analytical methods. Many of the re S ta t. 307. 331, os am ended; (42 U.S.C. 1302, Also, asbestos and other fibers are con spondents additionally expressed their 1395s(e), 1395hh)) sidered likely to have a similar adverse willingness to join a Food and Drug Ad Effective date. These amendments will effect if present in parenteral drags, although this has not been proven. Be ministration analytical task force evaluate applicable methodology. to be effective on or before April 14,1975. cause of this likelihood, this order pro Although the Commissioner cannot (C atalog of Federal D om estic A ssistance vides that, whenever possible, asbestos- agree that the designated optical P rogram No. 13.801, H ealth In su ra n c e fo r th e containing or oilier fiber-releasing filters crystallographic method is unreliable Aged an d D isabled--S u p p lem en tary M edical not be used in the manufacture, proc when used by those experienced in the Insurance.) essing or packaging of drags intended art, lie recognizes that an effective com Dated: February 24,1975. for parenteral injection in humans. Also, pliance method must have greater utility it provides for measures to reduce the and acceptance than indicated by the J. B. C ardw ell, amount of fibers present in such prod comments on the proposed method. - Commissioner 0/ Social Security. ucts, where it is not possible to elimi The Commissioner has. therefore, Approved: March 10,1975. nate these filte rs in the p ro d u c tio n of a decided to delay any final regulation for drug. talc until an acceptable method for deter Caspar W . W einberger, ' Secretary of Health, Education, The comments made in response to the mining the presence of asbestos particles and Welfare. September 28, 1973 proposal fall into two can be developed for this substance. Tills FEDERAL REGISTER, VOL. 40, NO. 51-- FRIDAY, MARCH 14, 1975 RULES AND REGULATIONS *118G6 man's overall exposure by these sub area of research currently Is being ac requirements for talc used in the manu facture of paper and Pa^ o a i d in stances are small. The comment con tended that evidence is lacking to show tively pursued by the Food and Drag 121.101(h) (21 CFR U1.101<h)) . All Of that the ingestion of small amounts of A dm inistration. , , . th . >. Several comments objected to the these comments contended that asbesto , in asbestos-containing talc, does not mi asbestos is safe and that the responsibil ities of the Food and Drug Admmistra- Durity limitations ior talc which were es grate to packaged food when talc is use tion for promulgation of regulations to tablished by the proposed n^eth ^ tM^ thought that requirements th at talc for this purpose. One of these comments contained results of recently conducted lessen the total human exposure to as bestos were not mitigated by the fact that be 99 9 percent amphibole-free and 99.99 percent chrysotile-free unreasonable. studies which were intended to prove this all human exposure to asbestos canno while others insisted that any Im itation was unreasonable unless it could be de monstrated to reflect known hazaid levels by ingestion. While one respondent calculated th at 20,000 amplubole and 3 500 chrysotile fibers (of 5 nucrometeis x'l 7 micrometers size) should be P^rm tted before any talc sample exceeded the established limits, another respondent observed that Individual asbestM ^ tieies often vary m size a million loin, tons making it difficult to relate particle counts to the percentage of asbestos con- ^ A ftor^ thorough review of submitted comments, and examination and evalu ation of additional requested studies, the Commissioner concludes that this com ment has demonstrated the validity o this contention in a manner consistent w lfeCavafiablc methodology. In ^ con ducted studies, the onstrated that dry packaged and snipped salt contains less than 0.01 part per bil lion asbestos when in direct a :^ continu ous contact with uncoatcd paper con taining up to 6 percent trcmolitic asbes iind consistent regulations should be dling other related matters. In any event B & : s s s s s b k x " n a ? S i . on talc a. a direct food o. ^ A l S S 1to 'd e c isio n of the Com m o n e r to delay any final regulation on talc has rendered these comments moot, tos. Although detection the bulk of ash recovered ficm other products such as fresh wrapped and from eat dry packaged macaroni, dried a" h e T . S `'lo,,cr also concludes that s "srcSrs the Commissioner wishes to rcsP ^ rice and corn flakes, the comment these comments to clarify his position on has also demonstrated that these prod- posssible future talc regulations unU contain less than 10 parts per on As indicated in the proposal, the Com missioner recognizes th at the evidence lion asbestos under test andl markeit con ditions. The analytical details of the e BationS'o^usSbestAos fibSer coSntai.nmatio*nm concerning the possible hazard ..(-,,mns are on file with the iieaiing gestion of asbestos particles is con" a Clerk Food and Drug Administration, U n i t e d ita te s !Pwith some reports that dictory and inconclusive T te method Rm. 4-65, 5600 Fishers Lane, Rockville, the waters of the San Francisco, CA, was therefore not proposed m older to and the Duluth, MN. areas are among indicate any known hazard from asbes ^ The Commissioner concludes _^at the the highest in asbestos content. How tos but was intended to establish a good above reported salt study presente' ever the lack of consistency of test meth- manufacturing practice limitation for practical upper limit of migration of as the S e of talc in food and drugs until an assessment of the hazard, if any, o ingested asbestos can be deteimmed. The particle limitation accompanying the proposed method represents the best by the Food and Drag Admin- 9J has concluded that, up to this time, no c a rc in o g e n ic effect could be demon strated from ingestion of the municipal IrtraUon of the S S * of such particles in natur,a\ 0^ the ability of the method to detect sucti ia rtto le fa n d the need to assign a hmi to define the absence of asbestos, rne Food and Drug Administration has also examined numerous talc samples of un defined grade in the past 2 yeais, using the proposed methodology, and finds tliat approximately two-thirds of such sam ples are within these limitations. The Commissioner therefore concludes that P r o p o s e d particle limitations would not impose an unreasonable buiden on m a n S u r e r s of talc if these limitations are ultimately adopted. . . , , -inn S n u tM tides le than 5 that the comment h ^ m o n s U ated th^t the asbestos content of t o l c u s e d ^ ^ creasestn'the' S s t o s content of bever- paper andpaperboard does not r t P ^ n t to available methodology. Accordingly, the Commissioner is withdrawing the analyt- a l e f f f i f" and 5) over background water show that the final levels are comnarab'le to the background levels in aieas of the United States. Therefore, the Com missioner has decided to delay the pro mulgation of any regulation on the pro 5 i ! assessment requites turtlier evaluation of this question. st? s? .sSs. 4-f i S S T S 0^ w " ? S S U S t o totoosed / S a U = s s z s v z oOnnee ccoommmmceint statedcomthmatistshioisnewr'asspmro- p o se fr tia tio n ^ on toe asbestos content of food-grade talc, and that attempts to hmit asbestos ingestion should apply hibition of use of asbestos filters foi the preparation of foods and nonparenteial drugs until more reliable data can be obtained on the background conccntiaUons of asbestos in drinking water ana the role of asbestos filters in lcgard to the addition of fibers to ingestible P15d Many comments endorsed or con demned the proposals or parts of with respect to water, food, and beverage ^nntnmination. Although most of tnese comments did not supply anJ ^d^ 1es1^ data or information, a cuncnt asbestos 3 Three comments from mdustual firms^objected to the proposed analytical uniformly to all sources. Another cornr a n t stated that the Commissioners decision not to regulate the use of as bestos filters in food, beverage mid no parenteral drug preparations was based orrthe unproven notion that the amounto of asbesots which are contributed to feeding study by \ and a 1967 study by G. M. Ensei ai n B Clayton (Ref. 7) were cited as fur ther evidence of no harm from meet, e asbestos. Other comments cited the conclusion of the Advisory C o m m itte e on Asbestos Cancers (Ref. 8) th at theie -FRIDAY. MARCH 14, 1975 nrff& l REGISTER, VOL. 40, NO. 51- RULES AND REGULATIONS 11867 was no evidence of an Increased risk of jection potential of asbestos fibers, are months of the date of publication of this regulation will be required to submit cancer from asbestos fibers In water, beverages, and food, or in fluids used for as follows: , , . .. . 1. A number of comments stated tnav monthly progress reports thereafter con cerning attempts to implement the re the administration of drugs, and on there is no conclusive evidence that quired procedures and any difficulties in asbestos filters add fibers to the filtrate, comment cited a recent study by Klemfeld. Messite. and Zaki (Ref. 9) which or that asbestos has caused deleterious maintenance of product quality. 3. A large number of comments stated reports no increase of gastrointestinal effects as a result of parenterally admin that many parenteral products would and peritoneal cancer among talc workers exposed to talc dusts for a mini istered drugs. . , Asbestos fibers were found m a number suffer in safety and quality because of a requirement to replace asbestos-contain mum of 15 years. . osofnsaemtpalel.s o(Rf epfa.re1n0)teraanlddraulgsos bbyyNaicshuobl ing filters in the manufacturing process. From analysis of the foregoing com ments received concerning the limita sequent Food and Drug Administration The Commissioner agrees that it is es sential that there be no increase in risk tion of asbestos in talc, from thorough investigation of parenterals. Although the Pood and Drug Administration has to the public as a result of this action. re-review of the scientific evidence avail demonstrated that filtration through as The regulation provides for continued use able concerning the adequacy of the available methodology to determine the bestos of a water sample highly contami of asbestos filters where no alternative is feasible. The responsibility for demon amount of asbestos in talc, and from nated with asbestos fibers can signifi cantly reduce the number of fibers pres strating that the replacement of asbestos coof nesvidideernatcieontoofdtehme oconnsttrraotveertshieal hnaaztuarred, ent, the Food and Drug Administration filters or the utilization of a final non fiber-releasing, non-asbestos-containing to health presented by ingestion of the also has direct evidence that the utili zation of asbestos filters can cause as filter decreases product quality and effec amounts of asbestos fibers normally to be expected in talc used in food or drugs, bestos contamination. The preliminary tiveness of safety remains that of the manufacturer. Evidence for such product or in food or drug packaging materials report of the latter study is on public display in the office of the Hearing Clerk. alteration must be submitted to the ap containing talc, or in beverages, other foods and nonparenteral drugs prepared The evidence of the deleterious effects of propriate bureau of the Food and Drug Administration for approval of the con with the use of asbestos filters, the Com parenteral asbestos administration (Ref. 1, 11, 12, and 13) requires that the tinued use of the unmodified asbestos missioner concludes that the promulga tion of regulations on the limitations or amount of contamination in these prod filtration processes. ' 4. One comment objected to the utili prohibition of the use of asbestos filters ucts be minimized. Consequently, the Commissioner has determined that it is zation of the terms "membrane filter" for the preparation of foods and non parenteral drugs and of the amount of important that asbestos-containing fil and "non-fiber-releasing filter," stating that the former term was too limiting asbestos fibers in talc for use in food and ters be replaced with non-fiber-releasing filters unless it is demonstrated that it is as a recommendation for a replacement drugs or which might migrate into food or drugs from talc-containing packaging not possible to manufacture a safe and of filters which may release asbestos fibers and that the latter phrase should materials is unwarranted until more effective parenteral drug or parenteral drug ingredient without the use of such be changed to "asbestos-containing or reliable data can be obtained concerning an asbestos-containing filter. In the lat media-migration-exhibiting filter." This these matters. The Food and Drug Administration, in ter instance, a final non-fiber-releasing comment claimed that the term non fiber-releasing" should be replaced since conjunction with other agencies, is plan filter shall be used to reduce the content of any asbestos-form particles in the drug small quantities of the fibrous support ning extensive experiments to determine or drag ingredient. Use of an asbestos- used in many cellulose-ester membrane if long term exposure to ingested asbestos fibers represents a definitive hazard to containing filter with subsequent use of filters, as well as fibers and particles from the manufacturing process for human health. As noted, until this study an additional non-asbestos-containing, non-fiber-releasing filter shall be permis cartridge and other type filters, are ie- is completed or other data become avail able, the Commissioner has determined sible only upon submission of evidence to leased by cleaning and flushing prior to marketing of the product. Another com th at a prohibition of the use of asbestos- the appropriate bureau of the Food and Drug Administration that substitution ment stated th at the proposed regula containing filters in the processing of food and beverages, and of asbestos- for the asbestos filter of a non-fiber-re tions did not contain a definition of a non-fiber-releasing filter. Comments also containing talc as a food or food additive leasing filter will or is likely to compro mise the safety or effectiveness of the stated that 133.8 should not use the or in drugs or drug ingredients is unwar drag. Use of an asbestos-containing fil terms "fiber-releasing" and "asbestos- ranted due to lack of sufficient data. In the interim, maufacturers of food and ter without subsequent use of an addi containing" interchangeably, and one comment objected to the synonomous drugs are urged to investigate all means tional non-asbestos-containing, non fiber-releasing filter shall be permissible use of the terms "fiber" and "asbestos of eliminating the use of such filters and talc, and to keep the Food and Drug only upon submission of evidence that fitThe Commissioner agrees that the reg Administration informed about changes neither the substitution for the asbestoscontaining filter nor the use of a sub ulation should not specify only one type in formulation and processing of this sequent non-fiber-releasing filter can be of filter which would satisfy the new re ^B. In order to deal with the injection accomplished without compromising the quirements, and thus has deleted the term "membrane filter." The Commis potential of asbestos fibers, the Com- safety or effectiveness of the drug. 2. One comment noted that, although sioner also concludes that, for the pur missioner proposed that the good manu there have been several demonstrations poses of these regulations, a non-fiber facturing practice regulations for drugs be amended to require that filtration pro of the addition of nonasbestos filters as releasing filter shall be defined as a non asbestos, nonglass fiber filter which, cedures for parenteral drugs shall utilize final filters in the production of injecta ble biologies, there remains concern that after any appropriate pretreatment such either a non-fiber-rclcasing filter such as a membrane filter or, if an asbestos- the replacement of asbestos filters with non-asbestos-containing filters would up as washing or flushing, will not continue to release fibers into the drug or drug containing filter is used because it is necessary, the procedures shall also set delicate filtration parameters of the ingredient which is to be filtered. The distinction is, therefore, made between utilize an additional non-asbestos-con product preparation process. An 18month period was suggested as the allow filters which release fibers by media mi taining or non-fibrr-rcleasing filter such as a membrane filter to reduce asbestos able period of time for technical develop gration, i.e., continuous release due to the nature of the filter, and filters which fiber content to the minimum level fea ment of the new processes. The Commissioner agrees that a spe contain fibers from structural supports sible unless such a subsequent filter will compromise the safety, identity, cific period for process development and and contamination. The utilization of strength, quality, or purity of the modification should be provided in the regulations. Therefore. 18 months will be nonasbestos, nonglass fiber filters In the latter category will be permitted pro product. Comments received in response to this allowed for compliance. Firms not con vided that appropriate pretreatment, part of the notice, dealing with the in forming to these regulations within 12 FEDERAL REGISTER, VOL. 40, NO. 51-- FRIDAY, MARCH 14, 1975 RULES AND REGULATIONS which eliminates fiber contaminant re lease, 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 fiber-releasing filter ex cludes 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 com ments. 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 non-fiber-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 with out the use of such a filter" be replaced by "when an asbestos-containing filter is utilized, a suitable after-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-form fibers in parenteral drugs thereby minimizing the possibility of del eterious eflects, and although an after filter will substantially reduce the num ber of these fibers in the product, it can not 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 when ever 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 re quired to be changed. However, he re iterates th at the use cf an asbestos filter will be permissible only upon a demon stration by the manufacturer that the replacement of an asbestos filter by a non-fiber-releasing filter or the utiliza tion of a final or after-filter is non-fiber releasing adversely affects the quality, safety, and effectiveness of the product. 6. One comment objected to the state ment in the proposal that the use of asbestos filters in parenteral drug manu facturing 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 asbestos-containing filters than by individual evaluation by knowl edgeable scientists. No automatic de cision scheme was suggested in the com ment. 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 asbestos-containing filters will rest with the appropriate bureau in the Pood and Drug Administration. 7. Two comments objected to the fact that the regulations were limited to the release of asbestos and asbestos-form fibers and suggested that all extraneous material such as diatomaceous earth, carbon, silica, micro-fiberglass, etc., also be regulated. The Commissioner agrees that there is reason to be concerned about all par ticulate 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 scien tific information in this regard will be published in the F ederal R eg iste r in the future. 8. One comment objected to the re quirement of proof of reduction of asbes tos fibers by the use of subsequent non asbestos-containing filters in the manu facture 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 com ment claimed that the National Institute for Occupational Safety and Health (NIOSH) analytical method, as well as other analytical methods for determina tion of asbestos-form 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 pres ently 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 un til these studies are completed, the evi dence for reduction of asbestos-form fiber content need not be obtained if adequate downstream filtration is ac complished. Thus, the requirement of proof of reduction of asbestos fiber con tent is omitted and the use of a nonfiber-rcleasing filter of 0.22 micron maximum pore size is added to this regu lation (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 amphibolcs. The Commissioner concludes that this diiferential 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 peri toneal 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 experi mental 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 re-lated to inhalation of asbestos, there also has been an association of carci noma of the lung with asbestos inhala tion. As with other carcinogens, several types of tumors may occur as a result of exposure to a particular carcinogen de pending 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-filtered prod uct (beer) as measured by electron mi croscopy. However, even though the con tainer 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 m 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 Commis sioner to conclude that cleansing and rinse water for the containers for paren teral drugs shall be filtered through non fiber-releasing filters equivalent to those required for post-asbestos-filter filtration to remove inherent fiber contamination. 12. The Environmental Impact Anal ysis 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-42, or the office of the Hearing Clerk, Rm. 4-65, Food and Drag Administration, 5600 Fishers Lane, Rockville, MD 20852. 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. " P a re n te ra l P re p ara tio n s, P yrogens," in R em ington's P harm aceutical Sciences, 14th ed.. C h a p te r 82, p. 1542, 1970. 2. M ason, T. J ,, P W. M cKay an d R. W. M iller, "A sbestos-Like Fibers In D uluth W ater Supply R elation to Cancer M ortality," "Jo u rn al of th e A m erican M edical Associa tio n ," 228:1020. May 20, 1974. 3. C om m en t from A sbestos R esearch C o u n cil, M arch 1, 1974. 4. C u n n in g h am , H. M. an d R. P o n te fra c t: (a) "Asbestos Fibers in Beverages and D rinking W ater," "N ature" 232:332-333, 1971. . FEDERAL REGISTER, VOL. 40, NO. S I -- FRIDAY, MARCH 14, 1975 RULES AND REGULATIONS 11869 (b) "Sym posium on In d u strial Chem icals as Food C o n tam in an ts," "Jo u rn a l of th e As so ciatio n of Official A nalytical C hem ists," 56:976-081, 1973. 5. P o n te fra c t, R ,, an d H. M. C u n n in g h am , "P en etratio n of Abestos through th e Diges tive T ract of R ats," "N ature," 243:352-353, 1973. 6. Davis, J. M. G.. I n s titu te of O ccu p atio n al M edicine Edinburgh, Scotland, unpublished report. 7. Bonder, G. M .f an d D. B. C layton, "F eed in g o f B lu e A sbestos to R a ts ," 1967 A n n u a l R eport, B ritish Em pire Cancer C am paign for R esearch , p. 242. 8. " R ep o rt of th e A dvisory C o m m ittee o n A sbestos Cancers to th e D irector of th e In tern atio n al Agency for Research on Cancer," "B ritish Jo u rn al of In d u strial M edicine," 30:180-186, 1973. 9. K le in fe ld . M., J. M csslte, a n d M. II. Z akl, "M ortality Experiences Among Talc W ork ers: A Follow -up S tu d y ," "Jo u rn al of Oc c u p a tio n a l M e d icin e," 16:345-349, 1974. 10. N ich o lso n , W H., C. J . M aggiarc a n d I. J . SelikofF, "A sbestos C o n ta m in a tio n of P a re n te ra l D rugs," "Science," 177:171-173, 1972. t 11. S ch m ah l, D., " C arcerogene W irking von Asbest bei Im plantation von R atten," "Zeit sc h rift fu r K rebsforschung," 62:561-567, 1958. 12. R oe, F . n. C., R. L. C a rter, M. A. W a lte rs an d J. S. H arrington, "The Pathological ef fects of Subcutaneous Injections of Asbestos F ibers in Mice: M igration of Fibers to Sub- m esothclial Tissues and Induction of Meso theliom as," "In ternational Journal of Can c e r," 2:628 -6 3 8 , 1967. 13. K an a z a w a , K . M. . C. B irbeck, R . L. C a rter and F. J. C. Roe, "M igration of As bestos Fibers from S ubcutaneous Injection S ites In Mice," "B ritish Jo u rn a l of C ancer," 24:96 -1 0 6 . 1970. 14. "S ym posium on O ccu p atio n al E xposure to Fibrous G lass," sponsored by N ational In stitu te for O ccupational Safety and H ealth, U n iv e rsity o f M a ry la n d . J u n e 26-27, 1974. 15. S ta n to n , M carl F , "F ib e r C a rc in o g e n e sis: Is Asbestos th e Only yazarcl?" "Jo u rn al of th e N ational C ancer I n s titu te ," 52:633 (1974). 16. " O c c u p a tio n a l E x p o su re to A sbestos," C riteria d o cu m en t, U.S. P ublic H ealth S erv ice, N ational In stitu te for O ccupational S a fe ty a n d H e a lth , C h a p te r V III, pg. 6. 1972. 17. Reeves. A. J., H E. P u ro , R. G. S m ith a n d A. J . V orw ald, " E x p e rim e n ta l A sbestos Carcinogenesis," "E nvironm ental Research," 4:496-511,1971. Therefore, pursuant to provisions of the Federal Food, Drug, and Cosmetic Act (secs. 501, 502, 701, 52 Stat. 1049 1051, 1055-1056, as amended; 21 U.5.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.il Production and control proce dures, ***** (j ) Uso of asbestos-containing or other fiber-releasing filters: (1) Filters used in the manufacture, processing or pack aging of components of drug products for parenteral injection in humans shall not release fibers into such products. No asbestos-containing or other fiber-re leasing filter may be used in tire manu facture, processing or packaging of such products unless it is not possible to man ufacture that drug product or component without the use of such a filter. Filtra tion, as needed, shall be through a non fiber-releasing filter. For the purposes of this regulation a non-fiber-releasing filter is defined as a nonasbestos, non glass fiber filter which, after any appro priate pretreatment such as washing or flushing, will not continue to release fibers into the drug product or compo nent which is being filtered. A fiber is de fined as any particle with length at least three times greater than its width. (2) If use of a fiber-releasing filter is required, an additional non-fiber-releas ing filter of maximum pore size of 0.22 microns (0.45 microns if the manufac turing conditions so dictate) shall sub sequently be used to reduce the content of any asbestos-form particles in the drug product or component. Use of an asbestos-containing filter with or with out subsequent use of a specific non fiber-releasing filter is permissible only upon submission of proof to the appro priate bureau of the Food and Drug Ad ministration that use of a non-fiber-re leasing filter will, or is likely to. compromise the safety or electiveness of th drug. (3) Substitution for a fiber-releasing filter shall be achieved on or before Sep tember 14, 1976. If such substitution is not achieved on or before March 14, 1976, the manufacturer of the drug prod uct for parenteral injection who requires the additional 6 months to develop new manufacturing procedures so as to uti lize non-fiber-releasing filters in place of fiber-releasing filters shall submit monthly reports to the appropriate bu reau of the Food and Drug Administra tion indicating progress in substituting the new filters. Such a substitution shall be shown to have been effected without loss of the safety or effectiveness of the drug. 2. By revising 133.9 to read as follows: 133.9 Product containers and tlicir com ponents. 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. Con tainers for parenteral drugs, drug prod ucts or drug components shall be cleansed with water which has been fil tered through a non-fiber-releasing filter equivalent to that indicated in 133.8Cj) (2). Product containers and their com ponents 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 ration or contamination of the drug. Effective date. This order shall be ef fective April 14, 1975. * (Secs. 501, 502, 701, 52 S ta t. 1049-1051, 1055-' 1050, os am ended; (21 U.S.C. 351, 352, 371)) Dated: February 28, 1975. ' A. M. Schmidt^ '. ' Commissioner of Food and Drugs. (PR Doc.75-0733 F iled 3-13-75;8:45 am j [R ecodiflcatlon D ocket No. 6] SUDCHAPTEF1 D-- DRUGS FOR HUMAN USE PART 436-- TESTS AND METHODS OF ASSAY OF ANTIBIOTIC AND ANTIBI OTIC-CONTAINING DRUGS Reorganization and Republication; Correction In FR Doc. 74-12338 appearing at page 18921 in the F ederal R egister 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. S am D. F in e , Associate Commissioner for Compliance. [FR Doc.75-6853 Filed 3-13-75;8:45 am ] PART 444-- OLIGOSACCHARIDE ANTIBIOTIC DRUGS PART 446-- TETRACYCLINE ANTIBIOTIC DRUGS Otic and Ophthalmic/Otic 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 F ederal R egister of September 19, 1974 (39 FR 33665), re voked 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 ophthal mic dosage form and a new 446.467d for the otic dosage form. However, the docu ment failed to account for sections de scribing products for both eye and ear use that appear tv ice in the regulations, as recodified May 30, 1974 (39 FR 18022), in the subpart for ophthalmic dosage forms and in the subpart for otic dosage forms. As a result, Part 444 now con tains 444.442e that refers to drug prod ucts that are no longer being certified. Part 446 contains 446.467c that refers to drug products no longer being cer tified and 446.467b that has been super seded 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. 51-- FRIDAY, MARCH 14, 1975