Document R26RZ08ZMoL6YjvN5rNgneVZB

Dr. K. S. Lane Mr. J. L. Myers'^ Mr. P. J. Morgan c a . to --SS' --- - Oefobar 3, 1973 The attached correspondence Is self-explanatory. On Initial reading. It Is my opinion that the proposed FDA rule changes are sufficiently remote from our business interests to make comments unnecessary. However, if you have thoughts to the contrary, please advise me so that I may submit the proper response either to the A|A or directly to the FDA. Please advise me by November 1st. W.r.TKurTer Asbestos Information Association/North America 52SXBfiXJ9HXSKS{$CX aXMKXaKXXKXfoOXRKX Uig9tJH 1660 L Street, N. W. Washington, D. C. 20036 October 1, 1973 MEMORANDUM TO MEMBERS SUBJECT: FDA Proposed Rulemaking "Asbestos Particles in Food and Drugs" Attached is the announcement of the Food and Drug Administration notice of proposed rulemaking on "Asbestos Particles in Food and Drug as appeared in the Federal Register, Vol. 38, No. 188, Friday, September 28, 1973. The Association proposes to comment on this matter and encourages comments by individual members as well. Deadline of the FDA for receiving comments is December 27. 1973. It is requested that information to assist in the preparation of the Association response be received by November 5. R. H. Mereness Executive Director Attachment RECEIVED OCT 3 1973 WM. C. THUS3ER 27076 PROPOSED RULES DEPARTMENT OF HEALTH. EDUCATION, AND WELFARE Food and Drug^dministration 121 CFR Parts 121,128.133 ] ASBESTOS PARTICLES IN FOOD AND DRUGS Notice of Proposed Rulemaking The Commissioner of Food and Drugs has received a petition from the Center for Science in the Public Interest, 1779 Church Street NW.. Washington, D.C. 20036, and the Environmental Defense Fund. 1525 18th Street NW.. Washing ton, D.C. 20036, requesting promulgation of regulations under the Federal Food. Drug, and Cosmetic Act to prohibit the adulteration of food and drugs with as bestos. Petitioners request that the Com missioner publish in the Federal Regis ter "Immediately (within 30 days)" the following proposed regulations: 1. Subpart P of Part 121 Is amended by adding the following section: 121._- Filters containing asbestos. "Foods that have come Into contact with filters made wholly or partially of nsbestos may reasonably be expected to become con'laminated with asbestos particles which insy bp Injurious to health when ingested. Ac cordingly. any food or food additive produced, manufactured, processed or prepared using a filter made wholly or partially of atbestoa shall be deemed to be adulterated in violation of section 402(a) of tbe Act. 2. Part 133 is amended by adding the fol lowing sections: A i Uou3 9 133.... Fillers remaining asbestos. Drugs passed through fillers made wholly or partially of n.sljesuis may reasonably be expected to become contaminated with asbestos particles which may tie Injurlj-.ts to health when injected or ingested. Accord ingly, any drttc or drug component produced, manufactured, processed or prepared using a filter made wholly or partially of asbestos shaU be deemed to be adulterated In viola tion of section 401 (a) of the Act. 9133.... Talc containing asbestos. Tate Is a naturally occurring hydrous magnesium silicate which may reasonably be expected to be contaminated with asbestos particles. Asbestos particles may be Injurious to health when ingested or Injected. Accord ingly. It Is not considered good manufactur ing practice to add talc, directly or Indirectly, as a component in the production, manu facture. processing or preparation of any drug, unless the manufacturer or processor of tbe drug first demonstrates by appropriate teste that the tale so used Is free of asbestos particles. Any drug or drug com ponent containing tale which has not' been demonstrated to be free of asbestos particles shall be deemed to be adulterated in viola tion of section SOI (a) of the Act. Petitioners also request that the Com missioner "immediately (within 30 days from the receipt of this petition)*' promulgate as a final regulation a zero tolerance for asbestos particles in talc intended for use as a food additive, pur suant to the proposal published in the Federal Register of August 12. 1972 (37 FR 16407), and take whatever other ac tion the Commissioner deems necessary to eliminate contamination of food and drugs with asbestos. A complete copy of the petition and its attachments may be reviewed at the office of the Hearing.Clerk, Food and Drug Ad ministration. Rm. 6-86. 5600 Fishers Lane, Rockville. MD 20852. during work ing hours, Monday through Friday. The Ccnan issioner has carefully re viewed the petition, its attachments, and other available information, and has reached the following conclusions. Each conclusion indicates the source reference upon which the conclusion is based and copies of all referenced material are available from the office of the Hearing Clerk. "Asbestos" is a generic term for a num ber of hydrated silicates that, when crushed or processed, separate into flexi ble fibers made up of fibrils. Although there are many asbestos minerals, only six are of commercial importance. Chrysotilc, a tubular serpentine mineral, accounts for 95 percent of the world's production. The others, all amphiboles (crystals with 3 groups of metal ions). are amositc. crocidolite. anthophyllite. tremolito and actlnollte. These asbestos minerals differ in their metallic ele mental content, range of fiber diameters, flexibility, harshness, tensile strength, surface properties, and other attributes that determine their Industrial uses and which may affect their rcspirability, dep osition. retention, translocation and biologic reactivity (Ref. 1). Many products such at cement, floor ing, shingles, pipes, filters, textiles, etc, contain asbestos of one kind or another. FEDERAL REGISTER, VOL 31, NO. 118--FRIDAY, SEPTEMBER 2B. .1VP3 PROPOSED RULES 27077 ntcro arc great variations among such products with respect to the chances of fiber release during the use of the prod uct. The likelihood of such liber release depends predominantly on the case with which the fibers can be dislodged and on the degree to which the use of the prod uct destroys the- Abel's. Almost all as bestos fiber used In the United States for manufacturing products becomes mesothelioma, occur at rates greater than in persons not so occupationally exposed. There is a 5 to 7 fold increase in lung cancer in asbestos workers which is noted as early as 10 to 14 years alter onset of exposure and is significant at 20 years (Refs. 0 through 15). Seven per cent of deaths in asbestos workers are caused by pleural and peritoneal meso thelioma (ltcfs. 10 through 33). This is a were totally cleared by the gastrointes tinal tract in 48 hours and no asbestos was detected In the animal tissues at the end of 1 week. The gastroinstcstmal tract of the rat seemed to provide an cifecuvc barrier to penetration. In a published study by W. E. Smith. et at. (Ref .41). hamsters maintained on a diet of 1 percent chrysotile or amosito through life had no gastrointestinal tightly bound within the products and marked increase since this tumor is ex tumors. usually undergoes little actual abrasion or wear before being discarded. Asbestos cement products (accounting for most of the asbestos used in the United States), shingles and floor tiles arc in this cate gory. Some asbestos-containing products, tremely rare in the general population. There is suegestivo evidence concerning an increase m me rate of gastrointestinal malignancies in asbestos workers (Ref. 34). There is considerable evidence that A report by Westlake, Spjut and Smith (Ref. 42) indicates that the rat colonic mucosa is penetrated by chryso tile after feeding a diet containing 5 per cent asbestos for 3 montlis. Cunningham and Pontefract (Ref. 43 such as brake linings, arc subjected to most human lungs harbor thousands or and 44) injected chrysotile fibers (9.4 great friction; their rate of wear is con millions of asbestos fibers although most and 94 x 10') directly into stomachs of siderable. and at times they are almost people do not have asbestosis (Refs. 35. rats. Fibers were found in blood and completely worn away. In the case of through 37). This is due to the ubiquity other organs, 2-4 days after treatment. brake linings, the application of force is of the substance. Some of these fibers are Control rats, although having no asbes so Intense and the heat created so great chrysotile asbestos, and amphiboles are tos in blood, also had high levels of that most chrysotile fibers are destroyed probably present also. This number of asbestos in tissues. by being converted into another sub fibers is relatively small in most persons These workers found that, whereas the stance which is non-fibrous. Neverthe not occupationally exposed to asbestos tap water in Ottawa (having a filter less. an appreciable percentage (1 to 3 compared with the numbers found in the plant) contained about 2 million fibers percent) remains as fibrous asbestos, occupationally exposed. The systematic per liter, the quality of fibers in soft and fiber release from products such as application of quantitative techniques, drinks and alcoholic beverages purchased asbestos, cloth, paper and sprayed fire measuring both coated and uncoatcd in the Ottawa area ranged from 1 to 12 proofing materials Is a serious source of fibers, is needed to define a gradient of million fibers per liter. Even with the emission. Tills usually occurs in densely accumulated fibers for correction with technical problems of methodology, this populated areas. Most of the pipes de incidence of disease, on the one hand, seems to indicate that in some beverages livering drinking water are of a mixture and history of environmental exposure, the asbestos content may be about the of cement and asbestos. on the other. same as in water, whereas, in others, it Solid wastes produced during manu The methodology for quantification of may be increased. Thus, it is reasonable facture of asbestos-containing products, asbestos fibers of varying sizes is such to conclude that water and many other use of such products, and demolition that the results obtained in one labora beverages for human consumption con can be emission sources. These waste ma tory may vary substantially from those tain substantial amounts of asbestos terials ore usually disposed of without in another. An inter-agency govern fibers. regard to their potential as emission mental task force together with other There is some evidence that asbestos sources. Alternate methods of disposal scientists working in this field is cur filters may remove some asbestos mate often result in commingling of asbestos- rently attempting to develop standard rial. In a preliminary experiment per containing wastes with municipal wastes technology which can be applied to the formed by the Food and Drug Adminis in open dumps and thus create a long identification and qualification of asbes tration. asbestos was added to distilled term emission source. tos fibers. The Environmental Protection water and dispersed evenly by the action Asbestos fibers thus are ubiquitous in Agency is currently investigating four of an ultrasonic generator. Electron air, water and a large percentage of the separate techniques in order to establish microscopy of this material clearly earth's crust. The amount of this ma the best method for identification, quan showed large numbers of asbestos fibers. terial which additionally is added to the tification, sizing and typing of asbestos This material was then filtered through environment and to food and drugs by particles and fibers. At present, the Na an asbestos filter, and electron micro the use of asbestos filters is not known. tional Institute for Occupational Safety scopic examination of the filtered mate Therefore it is obvious that the presence and Health (NIOSH) recommends, as a rial showed a reduction in the number of or aspestos in these products is only one technique for sampling of air. a method asbestos fibers. small suurcB umxposnre: based on counting fibers greater than 5 Nicholson and his colleagues (Ref. 45) ASDestos inhalation has been known to microns in length using phase contrast Investigated a number of samples of par be an occupational hazard in workers in asbestos mines. The asbestos is inhaled and lodges in the lungs causing the de velopment of a fibrotic disease known as "asbestosis." Asbcstosis. or abcstotic pneumonoconiosis, was the first clearly illumination at 430x magnification with a 4 millimeter objective (Refs. 38 and 39). This technique Is currently recom mended for liquid materials until more accurate and sensitive practical methods are developed. However, os indicated be enteral drugs and found asbestos fibers. Based on their report a study was under taken by the Food and Drug Administra tion concerning contamination of par enteral drugs with asbestos. Although the data are still preliminary, the following demonstrated adverse ctfcct of asbestos In man. It is characterized by a pattern of rocntgcnographic changes in the lung low, another method is proposed for analysis of asbestos fibers in a material sucli as talc. observations are pertinent. Parenteral drug samples were collected from a num ber of firms. Based on phase contrast consistent with diffuse interstitial fi The evidence concerning the possible microscopy. 11 of 13 Samples had clear- brosis of variable degree and at times hazard from ingestion of asbestos par cut evidence of the presence of asbestos, with fibrosis and calcification of the ticles is contradictory and inconclusive: one sample was questionably positive, pleura;.clinical changes that include line rales, finger clubbing and shortness of breath, each of which may be absent in an individual case; and physiologic changes consistent with a restrictive lung disorder (Refs. 2 through 8). In an unpublished study by L. M. Swinbum (Ref. 40), asbestos particles were fed once a week to SPP Wistar rats for 1G and 18 weeks. The material was adminlslcrcdln butter. Although the par ticles were of llic size range known to and one was negative. The number of fibers ranged from 2 to 27 in the positive specimens of variable sample size. Using electron microscopy. 12 of the 12 samples examined were positive. Quantitation is not yet complete. In these workers in asbestos mines, produce tumors by other modes of ad In this survey, seven of 13 manufac malignancies of the lung and of the body ministration. no tumorgcnic cllcct was turers of parenteral drugs do not use as lining tissues, namely lung cancer and noted. With a single large dose, the fibers bestos filters; four firms use such lifters FEDERAL REGISTER, VOL 3B. NO. 1_|OAT, SEPTEMBER 31, 1973 .27078, PROPOSED RULES ' followed by final membrane type flllcra fORC of ther-c uses xibor.tos filters for Its rinse water without final filtration of such wnterl: and two firms use .T.-,hc;:tos filters otilv for their rinse water, without final filtration. kidneys and occasionally to brain llssuo suggesting that some asbestos tnay enter the circulation. Tims, there is experimental evidence that pnrrntcral administration of asbes tos fibers may lead to wide dissemination 8. Soper, W. D., "Pulmonary Asbestosis: A report of a ease and a review," Am. Rev. Tuberc.. 22:571-501. 1930. 9. Lyuch. K. M.. and W. A. Smith. "Pul monary Asbestosis III: Carcinoma of lung in nsbcsto-slllcosls." Am. J. Cancer, 24:50-04. 1935. The preliminary retwirt of these stiultes Is on display at the OiTicc of the Hearing Clerk. Any other .scientific data in this record should be submitted to the Hear ing Clerk. Certain parenteral drugs. such as blood fractionation products, may be littered several times through asbestos inters. Thus far, it is not known with certainty whether the more viscous products could be successfully processed through ter minal membrane Alters without com promising safety, identity, strength. . quality or purity. The precise ctTect of asbestos pad filtration on removal of pyrogens (Ref. 46 and 47) is not com pletely known at the present time. Currently the Food and Drug Adminis tration Is surveying the industry for information concerning the use of asb estos filters. Results of this survey will be Incorporated in the public record. Although the major experimental studies of asbestos have involved Inhala tion of fibers so as to simulate occupa tional exposure, several studies have been performed to investigate the cirect of parenteral inoculation of asbestos fibers. In 1958, Schmahl (Ref. 48) reported that Implantation of asbestos fibers and crumbs in cither the subcutaneous tissue or in the peritoneum lead to the develop ment of malignant tumors (sarcomas) -in 11 of 30 rats which survived longer than 15 months after such implantation. Roe and his colleagues (Ref. 49. 50, 51) of such fibers in animals and to the de velopment of local malignant tumors as well as malignant mesotheliomas of the pleura and peritoneum similar to those that occur after inhalation of asbestos fibers. The problem of asbestos In the total environment, to which the worldwide scientific commimity is addressing itself, is very complex. The Environmental Pro tection Agency has published in the Federal Register of April 6,1973 (38 FR 8820) national emission standards lor asbestos milling and manufacturing based on the determination that asbestos is a hazardous air pollutant. This stand ard has been developed despite the fact the EPA also recognizes that a "stand ardized reference method has not been developed to quantitatively determine the content of asbestos in a material." The present status of this problem is summarized by the report of a committee prepared subsequent to a meeting spon sored by the International Agency for Research on Cancer (Ref. 52). The Food and Drug Administration's review of this report indicates the following areas of further research are necessary: (1) Further epidemiology, particularly with respect to past exposure to asbestos and cancer of sites other than lung, pleura, and peritoneum.' (a) Assessment of excess cancer risks following exposure to only one type of fiber. 10. Doll. R.. "Mortality from Lung Cancer In Asbestos Workers." Brit. J. Induitr. Med,, 22:81-80, 1955. 11. Buchanan. W. D.. "Asbestosis . and rrlmory Intralhoraele Neoplasms." Ann. N. Y. Acad. Set.. 2J2:507-518. 1905. 12. Cordova. J. F.. H. Tesluk and R. P. Knudtson. "Asbestosis and Carcinomas of the Lung." Cancer, 15:1181-1187. 1902. 13. Gross. P.. R. T. P. dcTrcville, E. B. Toker, M. Kasenak and M. A. Babyak. "Experimental Asbestosis. The development of lung cancer In rau with pulmonary deposits of ehrysottle asbestos dust." Arch. Environ. Health, 25:343-355, 1967. 14. SeltkofT. I. J.. J. Churg and E. C. Ham mond. "Asbestos Exposure and Neoplasia," JAMA. 128:23-20. 19G4. 15. Borow. M- A. Conston, L. L. Llvornese and N. Schalet. "Mesothelioma and Its Asso ciation with Asbestos," JAMA, 202:587-591. 1907. 10. Elmes, P. C.. W. T. E. McCaugbey and O. L. Wade, "Diffuse Mesothelioma of' the Pleura and Asbestos," Brit. Med. 2, 2:350353. 1965. 17. Elmes. P. C. and O. L. Wade. "Relation ship Between Exposure to Asbestos and Pleura Malignancy In Belfast," Ann. N.Y. Acad. Set.. 232:549-557, 1965. 18. Entlcknap. J. B. and W. N. Smlther. "Peritoneal Tumor In Asbestosis." Brit. J, Ind. Med., 21:20-31. 1964. 19. Fowler. P. B. S.. J. C. Sloper and E. C. Warner. "Exposure to Asbestos and Meso thelioma of the Pleura," Brit. Med. J., 2:211313, 19G4. 20. Hammond-E. C.. I. J. Sellkoff and J. Churg. "Neoplasia Among Insulation Workers In the United States with Special Reference to Intraa'odomlnal Neoplasia." Ann. N.Y. have performed a number of studies in (b) Investigation of whether reduc Acad. Sci.. 132:519-525. 1305. . which asbestos fibers were injected sub tion of asbestos exposure in lungs below 21. Hourlhane, D. O B.. "The Pathology of cutaneously (Ref. 49) into the flanks of those causing asbestosis abolishes excess Mesothelioma and an Analysis of Their As mice. In the first experiments, crocidolite, amosite and chrysotlle asbestos fi bers were used and each animal was in jected twice subcutaneously in both risk of carcinoma. (c) Investigation of evidence of an in creased risk of cancer resulting from as bestos in water, beverages, food, or sociation with Asbestos Exposure." Thorax. 19:268-278. 1964. 22. Licben. J. and H. Plstawka. "Meso thelioma and Asbestos Exposure." Arch. En viron. Health, 14:559-503. 1967. flanks with 10 milligrams of fibers in liquids used for the administration of 23. Mann, R. U- J. L. Grosh and W. IS. saline with an interval of five weeks be drugs. O'Donnell. "Mesothelioma Associated with tween the Injections. Seven of seventyone mice which survived 40 weeks or more developed Injection site tumors. In addition, one mouse developed a meso thelioma of the peritoneum underlying (2) Development of methods of quan titative assessment, size analysis and characterization of particles and fibers. Raiuxca Asbestosis," Cancer, 19:521-526, 1906. 24. McCaughey, W. T. E.. O. L. Wade and P. C. Elmes. "Exposure to Asbestos Dust and Diffuse Pleural Mesotheliomas." Brit: Med. .2, 2:1397. 1962. 25. McDonald, A. D,, A. Harper. O. A. El at the injection site. The injection site 1. "Asbestos, the need end feasibility of air tar and J. C. McDonald. "Epidemiology of sarcomas were produced by all three pollution controls." Report of the Committee Primary Malignant Mcsotheltal Tumors tn types of fibers. In addition. Roe ct at (Ref. 49) showed that the asbestos fibers were widely disseminated from the local - Injection sites being deposited rather selectively on the serosal surfaces of the abdominal organs and tire retroperi toneal structures as'well as on the peri cardium. diaphragm, pleura and adja cent parts of the lunr.s and heart. These serosal surfarcs reacted vigorously to the presence of the asbestos fibers and in 10 of 71 mice, malignant mesotheliomas of on Biologic Effects of Atmospherte Pollutants. National Academy of Sciences, 1971. 2. Coolce. W. E., "Fibrosis of the Lungs due to the Inhalation of Asbestos Oust," Brit. Med. J.. 2:147. 1924. 2. Cooke. W. E.. "Pulmonary Asbestosis," Brit. Med. J.. 2:1021-1025. 1927. 4. Dreessen. W. C.. J. M. Dallavalle. T. L. Edwards. J. W. Miller, and n. R. Sayers. "A Study of Asbestos In the Asbestos Textile Industry," Public Health. UulU 241, Washing* ton. US. Government rrlntlng OUlce, 1928, 126 pp. 5. McDonald. S.. "History of Pulmonary Canada." Cancer, 22:914-919. 1970. 26. Newhouse. M. L. and H. Thompson, "Epidemiology of Mcsotheltal Tumors In the London Area." N.Y. Acad. Scf, 232:579-588, 1965. 27. Owen. W. O., "Mcsotbellal Tumors and Exposure to Asbestos Dust," Ann. N.Y. Acad. Sci., 132:674-079. 1905. 28. Sellkoff. L. J., J. Churg and E. C. Ham mond. "Relation Between Exposure to As bestos and Mesothelioma." New Eng. J. Med, 272:500-505, 1965. 29. Wright. O. W.. "Asbestos and Health In the thorax and/or abdomen developed. Asbestosis." Brit. Med. J.. 2:1025-102G. 1927. 1909" Am. Rev. Reap. Die., 100:407-479, 1909. In a Inter study (Ref. 51) Kanazawa 0. Mrrewether. E. It. A.. `"The Occurrence 30. Sellkoff. L. J., E. C. Hammond and J. et at showed that, after subcutaneous of ridmomiry Fibrosis and Ollier Pulmonary Churg: "Asljestoa Kxjmsurc. Smoking, and i injection of xsbestos fibers in mice, fibers could be found to have disseminated to regional and distant lymph nodes, spleen. Affections In Asbestos Workers," J. Ind. llyg* 22:190-222 and 22 :239-257. 1930. 7. Mills, It. G.. "Pulmonary Asbestosis: Re port of a cose." Minn. Med, 22:495-499.1930. NvopbLSla," JAMA. 204:100-112. I9G8. 31. Wngner, J. C.. C. A. Slcggs and P. Marchand. "Diffuse Pleural Mesothelioma and Asbestos Exposure lu the North Western Cape FEDERAL REGISTER, VOl. 38. NO. t88--fRIOAY, SEFTEMBER 21, 1973 A i Uou8 PROPOSED RULES 27U7U province," flrlf. J. /ini. Med., 17:200-271, JMO. 32. Champion. r.. "Two C.'W'B of nnt Mcoolliclliiinn uficr Eiposnro to As bestos," Am. /lev. Jlesp. 3JU.. 303:831-026, 1971. 33. iicllkoir. L. J. nn<] E. C. ir.immond. "En vironmental Eputrnilolocy. III. Community flfecl.t of Nonocciip-iUoiml Environmental Asbestos Exposure," Am. J. Pub. Health, Si: 1G58-ICCG. 1963. 34. Wagner. J. C., "Epidemiology of Diffuse Mcsothcll.il Tumors: Evidence of nn Asso ciation from -Studies In South Africa and the United Kingdom," Ann. N.Y. Acad. Set, 332:575-578. IOCS. 35. Churp. J, E. C. Hammond. A. M. Lances. W. J. Nicholson. L. J. Sclikoff and Y. Suzuki. "Biological ElTccts of Asbestos.'* presented at the National Institutes of Health. Feb. 1, 1973. 3G. Anvllvel, L. and W. M. Thurlbcck, "The Incidence of Asbestos Bodies In the Luncs at Random Necrospslcs In Montreal," Con. Med. Assoe.J, 35:1173-1182. 10C6. 37. Cauna, D.. R. S. Totten and P. Cross, 'Asbestos Bodies in Human Lungs at Au topsy," JAMA. 192: 371-373. 1965. 38. "Crlterta for a Recommended Stand ard--Occupational Exposure to Asbestos." Report of Review Committee, National In stitute for Occupational Safety and Health, Publication No. HSM 72-10207 (1972). 39. Lynch, J. R. and II. E. Ayer, "Measure ment of Asbestos Exposure," J. Oeeup. Med., 10: 21-24.19G8. 40. Swinburne. L. M.. "The Ingestion of as bestos by rats (unpublished data)." personal communication to Bureau of Foods. FDA. 41. Smith. W. E.. L. Miller. R. E. Elsasscr and D. D. Hubert. "Tests for Carcinogenicity of Asbestos." Ann. N.Y. Accd. Set., 132:450-488. 1965. 42. Westlake. G. E.. H. J. Spjut and M. N. Smith. "Penetration of Colonic Mucosa by Asbestos Particles. An Eleelrou Microscopic Btudy in Rats Fed Asbestos Dust," Lab. In vest., 14:2029-2033. 1965. 43. Cunningham. H. M. and R. Pontefract: (a) "Asbestos Fibers In Beverages and Drinking Water," Nature, 232:332-333. 1971. (b) "Symposium on Industrial Chemicals as Food Contaminants." Journal o/ the AOAC. 56:976- 001. 11)73. 44. Pontefract. R. and IT. M. Cunningham: "Penetration of Asbestos through the Diges tive Tract of Rats." Nature, 243:352-353, 1973. 45. Nicholson, W. J., C. J. Maggtare and I. J. Sclikoff, "Asbestos Contamination of Parenteral Drugs, .Science, 377:171-173, 1972. 46. Tui. C. and A. M. Wright, "The Pene tration of Non-Pyrogen Infusion and Other Intravenous Fluids by Absorptive Filtration," Anna/s Surg.. 336:412-125. 1942. 47. Remington's Pharmaceutical Sciences, "Parenteral Preparations, Pyrogens," Chap ter 82. 14th Ed. (pg. 1524). 1970. 48. Schmahl, D, "Canccrogene Wlrkung on Asbest bel Implantation von Ratten." Zeitsehri/t fur Krebsforschung, 62:561-567, 1958. f 49. Harlngton. J. S. and F. J. C. Roe. "Stud ies of Carcinogenesis of Asbestos Fibers and their Natural Fibers." Annals of the N.Y. Academy of Sciences, 332:439-450,1965. 60. Roe. F. J. C.. R. L. Carter. M. A. Walters and J. S. Harlngton. "The Pathological Ef fects of Subcutaneous Injections of Asbestos Fibers In Mice: Migration of Fibers to Sub- mesoihcllal Tissues and Induction of Mesothcllomata." Int. J. of Cancer, 2:028-638, 1907. 51. Kanazawa, K.. M. 5. C. Btrbeck. R. L. Carter nud P. J. C. Roc. "Migration of Asbes tos Fibres from Subcutaneous Injection Sites In Mice." British Journal of Cancer, 24:06100.1070. 02. "Report of the Advisory Commit! re on Asbestos Canrers to the Dlrrctor of the In ternational Aocncy for Re-'nrrh on Cancer." liril.J. tndustr. Med, 30:100-106.1973. The Commissioner recognizes that It is brnne filters. Is also requested. Finally, comment on methods of quantitative assessment, size analysis, and char acterization of particles and fibers, is essential In order to develop final not possible to eliminate ail sources of methods on which accurate and fair asbestos contact with food and drugs. compliance can be based. Asbestos is used In virtually all pipes Therefore, pursuant to provisions of carrying drinking water, in buildings in the Federal Food. Drug, and Cosmetic which food and drugs arc manufactured, Act (secs. 402. 502, 701. 52 Stat. 1046- and in many filtering systems used in the 1047. as amended. 1050-1051, as amended. manufacture of food and drugs, and is 1055-1056, as amended; 21 U.S.C. 342. found ifi some substances, notably water 352. 371) and under authority delegated and talc, used in the manufacture and to him (21 CFIt 2.120). the Commissioner processing of'food and drugs. Neverthe of Food and Diaics proposes to amend less. the Commissioner also recognizes Title 21 of the Code of Federal Regula that asbestos fibers perform no functional tions as follows: purpose in talc and are an unnecessary 1. In Part 121 by amending 3 121.101 contaminant. It is therefore reasonable (d)(8) by alphabetically adding to the to require precautions to be taken in the table a new item and in paragraphs ill) manufacure of food and drugs, as part of good manufacturing practices, to assure that the amount of asbestos fibers in any food or drug is reduced to the minimum feasible level. Accordingly, the Commis sioner has concluded to take the follow and (I) by revising the entry for "talc", to read as follows: 121.101 Substances that are generally recognized a* safe. ing action: (d) 1. In view of the demonstrated hazard in animals from injection of asbestos fibers, the Commissioner is proposing that Product Tobruco Limitation! or rauictionj the good manufacturing practice (GMP) regulations for drugs be amended to re quire that filtration procedures for pa rental drugs shall utilize either a non- l*) Miscflltneotu ind.'or geoeral purpose food asbcstos-containing or non-fiber-releas additive* ing filter such as a membrane filter or. If an asbestos-containing Alter is neces sary. shall also utilize an additional non asbestos-containing or non-fiber-releas Tale (fre* ofasbestos fibers u dtter* minM in 1 ui.rux). In (hrwlr.c rum bow tod os xn oaUstUkicr own In forms liv'd in ing filter such as a membrane filter to reduce asbestos fiber content to the min imum level feasible unless such a subse molding load abapro. quent filter will compromise the safety. Identity, strength, quality or purity of (h) the product. Talc (free of asbestos fibers os determined 2. The Commissioner Intends to pro In i 121.2006). mulgate a final regulation for taic under S 121.200G as soon as a method for deter mining asbestos fibers in food-grade talc via* (!)* Is validated. Such a method is proposed Talc (free of asbestos fibers os determined below, as part of a republication of the earlier proposal in which no methodology In { 12151006). was specified. The Commissioner con 2. In Part 121 by amending Subpart E cludes that a final regulation for talc by adding the following new section: under Part 121 cannot be promulgated until a reproducible and accurate method 121.2006 Talc. can be specified for compliance purposes. (a) Talc is a naturally occurring 3. The Commissioner is also proposing hydrous magnesium silicate subject to that any talc used in the manufacture or a prior sanction for use in coating pol processing of drugs meet the specifica ished rice. It is found in natural deposits tions for this substance that will be im that may be contaminated with asbestos posed by i 121.2C06. fibers... ------------------- -- 4. The Commissioner realizes that the . (b) Good manufacturing practice re issues raised in tills notice arc complex . and have widespread ramifications. Com-'' ment is requested on all aspects of th6 public health significance of ingcstlqii quires that talc be free from asbestos fibers to the maximum extent prac ticable. Accordingly, any food or food- and injection of asbestos fibers. Sintc packaging material containing talc~IHat adoption of any new filtration requiremerits may require me of additional equipment, comment on tire availability of ajiproprlatc equipment, trie need for use of asbostos-conlamin;: filters as con is TO l lrci: UffiTh asbestos fibers as determined by the method set out in para graph (c) shall be deemed to be adul terated In violation of section 402(a) (1) trasted with filters which contain no of the act. _ ____ .--------- -- - asbestos, and trie time needed to ob- (c) The following method shall be tain and becin using non-asbestos- used to determine compliance with tills containing final filters such as mem- section: No. 188--Pt. x> FEDERAL REGISTER, VOL. 31, NO. 188--FRI0AT, SEPTEMBER 38, 1973 oJ J 27080 PROPOSED RULES \ <1) The various ktmls of asbestos are distinguished from talc and from each other by lhc:r refractive indices, other optical crystallographic properties, and morphology as determined with a polar izing microscope (Methods of the Asso ciation of Official Analytical Chemists. Ilth Ed.. 1970. Sections 36.541-36.543. p. 717-721).1 Talc occurs mainly in the form of thin plates, which may appear fibrous when seen edgewise in micro scopic view. Beta and gamma indices of talc vary from about 1.575 to 1.590. beta being very close to gamma. All of the principal refractive indices of chrysotile are less than 1.590. Chrysotile asbestos is therefore distinguishable from fibrous looking talc particles in a 1.574 refractive index liquid and the other five amphibole types of fibrous asbestos from talc in a 1.590 refractive Index liquid. The table of optical crystal lographic properties for talc and the asbestos minerals in subparagraph (3) shows refractive indices which are usually encountered in these minerals, but occasional samples may have indices which are somewhat higher or lower. For practical measurement of optical prop erties shown in the table, particles iden tified by this method should be at least 5 lira or longer. (2) Weigh out 1 milligram of a repre sentative portion of talc on each of two microscope slides. Mix the talc with a needle to spread evenly over the suitable area on one slide with a drop of 1.574 refractive index liquid, and then the other with 1.590 liquid, and place on each a square or rectangular cover glass suffi ciently large so that the liquid will not run out from the edge (ca. 18 mm. square) and will provide a uniform par ticle distribution. Fibers counted by this method should meet the following cri teria: (i) Length to width ratio of 3 or greater <U> length of 5 .m or greater fill) width of 5 lira or less. Count and record the number of asbestos fibers found in each 1 milligram as determined from a scan of both slides with a polariz ing microscope at a magnification of ap proximately 400 X. In the 1.574 refrac tive index liquid, chrysotile fibers with Indices less than 1.574 In both extinction positions may be present: in the 1.590 refractive index liquid, the other five amphibole types of asbestos fibers with Indices exceeding 1.590 in both extinc tion positions may be present. Check the extinction and sign of elongation for tentative identification. For specific identification of asbestos fibers, make ad ditional mounts in appropriate refractive Index liquids, and refer to the optical crystallographic data in the table. A count of not more than 1000 amphibole types of asbestos libers and not more than 100 chrysotile asbestos fibers per tnilllgram-sildc constitutes the maximum Copies may bo obtained from: Association of Oitlctal Analytical Chemists P.O. Dox 640. nenjiimln Franklin Station Washington, DC 20044 limit for the presence of these asbestos fibers in talc. Tlicso limits assure a purity of talc at least 99.9 percent free of amphibole types of asbestos fibers and at least 99.99 percent free of chrysotile asbestos fibers. <3> Optical crystallographic charac teristics of asbestos minerals and talc: ltZAKrui or Rxnucnv* Ismriu (n) Bututono* M n4 dt EiUncUoa Elon{tloa Actlnollta ................... A1O05U*. Anthopliyllits................... . Inclined.. Positive. Positive. Clirysotil*. Positive. Crocidollta..______ ___ ____ _____ Tale______........................ Nt$etive. Farm**. Tremollte. Positive. n4-n. 3. In Part 133 by adding the following new paragraph (1). to 133.6 to read as follows: 133.6 Components. (1) Talc is a naturally occurring hy drous magnesium silicate which may reasonably be expected to contain as bestos fibers which may be injurious to health. Current methodology cannot as sure the absence of asbestos in talc. Accordingly, any drug, drug ingredient, or drug packaging matenST"containing talc tnat fails to meet the specifications of paragraph (c) of i 121.2006 of this chapter as determined by the method set out in that paragraph shall be deemed to be adulterated in violation of section 501(a) of the Act. 4. By adding the following new para graph (j) to i 133.8 to read as follows: 5 133.8 Production and control proce dures. e (j) Use of asbestos-containing filters: Filters used In the manufacture of a parenteral drug or parenteral drug in gredient shall not release fibers into such products. No asbestos-containing or fi ber-releasing filter may be used in the manufacture of a parenteral drug or par enteral drug Ingredient unless it is r.ot possible to manufacture that drug or drug Ingredient without the use of such a filter. If use of such a filter is required, an additional non-asbestos-containm; or non-flber-relcasing filter such as a membrane filter shall subsequently be used to reduce the content of any asbes tos-form particles in the drug or drug in gredient. Evidence for reduction shall be based on the use of the methods de scribed. in "Criteria for a Recom mended Standard--Occupational Expo sure to Asbestos." Report of Review Com mittee. National Institute for Occupa tional Safety and Health. Publication No. HSM 72-10267 (1972).* Use of an asbes tos-containing filter without subsequent use of nn additional non-asbcstos-containlng membrane filter Is permissible only upon submission of proof to the Food and Drug Administration that us* of a non-asbestos-containing membrane Copies may be obtained from: Superintendent ot Documents U S. Government Printing Omce Washington. DC 20402 FEDERAL RCGISTCR, VOl. 38, NO. 188--FRIDAY, SEPTEMBER 28, 1973 I filler will, or is likely to. compromise the safety or effectiveness of the drug. Interested persons may.'on or before December 27. 1973, file with the Hearing Clerk. Food and Drug Administration. Rm. 6-86, 5600 Fishers Lane. Rockville, MD 20S52, written comments (prefer ably In quintuplicate) regarding the pe tition and the Commissioner's proposal. Comments may be accompanied by a memorandum or brief in support thereof. The petition, background information re ferred to in this proposal, and comments received may be seen in the above office during working hours. Monday through Friday. Dated September 24, 1973. A. M. Schmidt, Commissioner of Food and Drugs. ' IFR Doc.73-20711 Filed 9-27-73:8:45 am) Social and Rehabilitation Service [ 45 CFR Part 221 ] FAMILIES, CHILDREN. AGED, BLIND, OR OlSABLED INDIVIDUALS Service Programs; Correction FR Doc. 73-19242, published at page 24872 In the issue dated Monday, Sep tember 10,1973, is corrected by changing: 1. The number "233" in item number two of the preamble, fifth line, to "233$4"; 2. The code designation "221.6(a)(3) (1) " in Item number two of the preamble, seventh line, to "221.G(c) (3) (i) "; 3. The code designation "211.6(a)(3) (111)" In item number three of the pre.amble, fourth line, to "221.6(c) (3) (111) 4. The code designation "211.6(a)(3) (vll)" In item number four of the pream ble, fourth line, to "221.6(c) (3) (vii) 5. The code designation "211.7(b)" in Item number five of the preamble, fourth line, to "221.7(b)"; 6. The code designation "211.9(b)(3)" In Item number seven of the preamble, sixth line, to "221.9(b) (3)"; 7. The code designation "221.6(a) (3>" In the words of issuance, number three, firstline: and in 9 221.6(a)(3) itself, first line, to "221.6(c) (3)": 8. The number "8" in 9 221.6(a)(4), (now corrected to 9 221.6(c) (4)), fourth line, to "6"; and 9. The word "secured" in 9 221.9(b) (5). fourth line, to "secure". Approved September 24, 1973. Thomas S. McFce. Deputy Assistant Secretary for Management Planning and Technology. |FR Doc.73-20728 Filed 9-27-73:8:43 m| A 1 037 1