Document K6kjD88zMn6yzX0QLwv3eaO4X

DEPARTMENT OF HEALTH, EDUCATION, AN FOOD AND DRUG ADMINISTRATION [21 CFR PARTS 121, 128, 133] ASBESTOS PARTICLES IN FOOD AND DRUGS NOTICE OF PROPOSED RULE MAKING L A ^ 7 0 7 Co The Commissioner of Food and Drugs has received a petition from the Center for Science in the Public Interest, 1779 Church Street, NW., Washington, DC 20036, and the Environmental Defense Fund, 1525 18th Street, NW. , Washington, DC 20036, requesting promulgation of regulations under the Federal Food, Drug, and Cosmetic Act to prohibit the adulteration of food and drugs with asbestos. Petitioners request that the Commissioner publish in the FEDERAL REGISTER "immediately (within 30 days)" the following proposed regulations: "1. Subpart F 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 asbestos may reasonably be expected to become contaminated with asbestos particles which may be injurious to health when ingested. Accordingly, any food or food additive produced, manufactured, processed or prepared using a filter made wholly or partially of asbestos shall be deemed to be adulterated in violation of section 402(a) of the Act. # 2I . "2. Part 133 is amended by adding the following sections : " 133.____ Filters containing asbestos. "Drugs passed through filters made wholly or partially of asbestos may reasonably be expected to become contaminated with asbestos particles which may be injurious to health when injected or ingested. Accordingly, any drug or drug component produced, manufactured, processed or prepared using a filter made wholly or partially of asbestos shall be deemed to be adulterated in violation of section 401(a) of the Act. " 133.____ Talc containing asbestos. . "Talc 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. Accordingly, it is not considered good manufacturing practice to add talc, directly or indirectly, as a component in the production, manufacture, processing or preparation of any drug, unless the manufacturer or processor of the drug first demonstrates by appropriate tests that the talc so used is free of asbestos particles. Any drug or drug component containing talc which has not been -3- demonstrated to be free of asbestos particles shall be deemed to be adulterated in violation of section 501(a) of the Act." Petitioners also request that the Commissioner "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, pursuant to the proposal published in the FEDERAL REGISTER of August 12, 1972 (37 FR 16407), and take whatever other action 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 Adminis tration, Rm. 6-86, 5600 Fishers Lane, Rockville, MD 20852, during working hours, Monday through Friday. The Commissioner has carefully reviewed 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 number of hydrated sili cates that, when crushed or processed, separate into flexible fibers made up of fibrils. Although there are many asbestos minerals, only six are of commercial importance. Chrysotile, a tubular serpentine mineral, accounts for 95 percent of the world's production. The # -4- others, all amphiboles (crystals with 3 groups of metal ions), are amosite, crocidolite, anthophyllite, tremolite and actinolite. These asbestos minerals differ in their metallic elemental content, range of fiber diameters, flexibility, harshness, tensile strength, surface properties, and other attributes that determine their industrial uses and which may affect their respirability, deposition, retention, translocation and biologic reactivity (Ref. 1). Many products such as cement, flooring, shingles, pipes, filters, textiles, etc., contain asbestos of one kind or another. There are great variations among such products with respect to the chances of fiber release during the use of the product. The likelihood of such fiber release depends predominantly on the ease with which the fibers can. be dislodged and on the degree to which the use of the product destroys the fibers. Almost all asbestos fiber used in the United States for manufacturing products becomes tightly bound within the products and 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 are in this category. Some asbestos-containing products, such as brake linings, are subjected to great friction; their rate of wear is considerable, and at times thay are almost completely worn away. In the case of brake linings, the application of force is so intense and the heat created so great that most chrysotile fibers are destroyed by being converted into another substance which is non-fibrous. Nevertheless, an appreciable percentage (1 to 3 percent) remains as fibrous asbestos, and ?r release from products such as asbestos cloth, paper and sprayed fireproofing materials is a serious source of emission. This usually occurs in densely populated areas. Most of the pipes delivering drinking water are of a mixture of cement and asbestos. Solid wastes produced during manufacture of asbestos-containing products, use of such products, and demolition can be emission sources. These waste materials are usually disposed of without regard to their potential as emission sources. Alternate methods of disposal often result in commingling of asbestos-containing wastes with municipal wastes in open dumps and thus create a long-term emission source. Asbestos fibers thus are ubiquitous in air, water and a large percentage of the earth's crust. The amount of this material which additionally is added to the environment and to food and drugs by the use of asbestos filters is not known. Therefore it is obvious that the presence of asbestos in these products is only one small source of exposure. Asbestos inhalation has been known to be an occupational hazard in workers in asbestos mines. The asbestos is inhaled and lodges in the lungs causing the development of a fibrotic disease known as "asbestosis." Asbestosis, or asbestotic pneumonoconiosis, was the first clearly demonstrated adverse effect of asbestos in man. It is characterized by a pattern of roentgenographic changes in the lung consistent with diffuse interstitial fibrosis of variable degree and at times with fibrosis and calcification - 6- of the pleura; clinical changes that include fine 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 these workers in asbestos mines, malignancies of the lung and of the body lining tissues, namely lung cancer and 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 after onset of exposure and is significant at 20 years (Refs. 9 through 15). Seven percent of deaths in asbestos workers are caused by pleural and peritoneal mesothelioma (Refs. 16 through 33). This is a marked increase since this tumor is extremely rare in the general population. There is suggestive evidence concerning an increase in the rate of gastroin testinal malignancies in asbestos workers (Ref. 34). There is considerable evidence that most human lungs harbor thousands or millions of asbestos fibers although most people do not have asbestosis (Refs. 35 through 37). This is due to the ubiquity of the substance. Some of these fibers are chrysotile asbestos, and amphiboles are probably present also. This number of fibers is relatively small in most persons not occupationally exposed to asbestos compared with the numbers found in the occupationally exposed. The systematic application of quantitative techniques, measuring both coated and uncoated fibers, is needed to define a gradient of accumulated fibers for correlation with incidence of disease, on the one hand, and history of environmental exposure, on the other. tI - 7- The methodology for quantification of asbestos fibers of varying sizes is such that the results obtained in one laboratory may vary substantially from those in another. An inter-agency governmental task force together with other scientists working in this field is currently attempting to develop standard technology which can be applied to the identification and quantification of asbestos fibers. The Environmental Protection Agency is currently investigating four separate techniques in order to establish the best method for identification, quantification, sizing and typing of asbestos particles and fibers. At present, the National Institute for Occupational Safety and Health (NIOSH) recommends, as a technique for sampling of air, a method based on counting fibers greater than 5 microns in length using phase contrast illumination at 430x magnification with a 4 millimeter objective (Refs. 38 and 39). This technique is currently recommended for liquid materials until more accurate and sensitive practical methods are developed. However, as indicated below, another method is proposed for analysis of asbestos fibers in a material such as talc. The evidence concerning the possible hazard from ingestion of asbestos particles is contradictory and inconclusive: In an unpublished study by L. M. Swinburn (Ref. 40), asbestos particles were fed once a week to SPF Wistar rats for 16 and 18 weeks. The material was administered in butter. -8- Although the particles were of the size range known to produce tumors by other modes of administration, no tumorgenic effect was noted. With a single large dose, the fibers were totally cleared by the gastrointestinal tract in 48 hours and no asbestos was detected in the animal tissues at the end of 1 week. The gastro intestinal tract of the rat seemed to provide an effective barrier to penetration. In a published study by W. E. Smith, et_ al_ (Ref. 41), hamsters maintained on a diet of 1 percent chrysotile or amosite throughout life had no gastrointestinal tumors. A report by Westlake, Spjut and Smith (Ref. 42) indicates that the rat colonic mucosa is penetrated by chrysotile after feeding a diet containing 5 percent asbestos fo.r 3 months. Cunningham and Pontefract (Ref. 43 and 44) injected 9 chrysotile fibers (9.4 and 94 x 10 ) directly into stomachs of rats. Fibers were found in blood and other organs, 2-4 days after treat ment. Control rats, although having no asbestos in blood, also had high levels of asbestos in tissues. These workers found that, whereas the tap water in Ottawa (having a filter plant) contained about 2 million fibers per liter, the quantity of fibers in soft drinks and alcoholic beverages purchased in the Ottawa area ranged from 1 to 12 million fibers per liter. Even with the technical problems of methodology, this seems to indicate that in some beverages the asbestos content may be about the ; in water 1.areas in others, it may be increased. Thus, it is reasonable to conclude that water and many other beverages for human consumption contain substantial amounts of asbestos fibers. , There is some evidence that asbestos filters may remove some asbestos material. In a preliminary experiment performed by the Food and Drug Administration, asbestos was added to distilled water and dispersed evenly by the action of an ultrasonic generator. Electron microscopy of this material clearly showed large numbers of asbestos fibers. This material was then filtered through an asbestos filter, and electron microscopic examination of the filtered material showed a reduction in the number of asbestos fibers. Nicholson and his colleagues (Ref. 45) investigated a number of samples of parenteral drugs and found asbestos fibers. Based on their report a study was undertaken by the Food and Drug Adminis tration concerning contamination of parenteral drugs with asbestos. Although the data are still preliminary, the following observations are pertinent. Parenteral drug samples were collected from a number of firms. Based on phase contrast microscopy, 11 of 13 samples had clear-cut evidence of the presence of asbestos, one sample was questionably positive, 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. 10 - In this survey, seven of 13 manufacturers of parenteral drugs do not use asbestos filters; four firms use such filters followed by final membrane type filters (one of these uses asbestos filters for its rinse water without final filtration of such water); and two firms use asbestos filters1only for their rinse water, without final filtration. The preliminary report of these studies is on display at the Office of the Hearing Clerk. Any other scientific data in this regard should be submitted to the Hearing Clerk. Certain parenteral drugs, such as blood fractionation products, may be filtered several times through asbestos filters. Thus far, it is not known with certainty whether the more viscous products could be successfully processed through terminal membrane filters without compromising safety, identity, strength, quality or purity. The precise effect of asbestos pad filtration on removal of pyrogens (Ref. 46 and 47) is not completely known at the present time. Currently the Food and Drug Administration is surveying the industry for information concerning the use of asbestos filters. Results of this survey will be incorporated in the public record. - 10a - Although the major experimental studies of asbestos have involved inhalation of fibers so as to simulate occupational exposure, several studies have been performed to investigate the effect of parenteral inoculation of asbestos fibers. In 1958, Schmahl (Ref. 48) reported that implantation of asbestos fibers and crumbs in either the subcutaneous tissue or in the peritoneum lead to the development 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) have performed a number of studies in which asbestos fibers were injected subcutaneously (Ref. 49) into the flanks of mice. In the first experiments, crocidolite, amosite and chrysotile asbestos fibers were used and each animal was injected twice subcutaneously in both flanks with 10 milligrams of fibers in saline with an interval of five weeks between the injections. Seven of seventy-one mice which survived 40 weeks or more developed injection site tumors. In addition, one mouse developed a mesothelioma of the peritoneum underlying the injection site. The injection site sarcomas were produced by all three types of fibers. In addition, Roe et al (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 abdomenal organs and the retroperitoneal structures as well as on the pericardium, diaphragm, pleura and adjacent parts of the lungs and heart. These serosal surfaces reacted vigorously to the presence of the asbestos fill rs and in 10 of 71 mice, 11 malignant mesotheliomas of the thorax and/or abdomen developed. In a later study (Ref. 51) Kanazawa et aJL showed that, after subcutaneous injection of asbestos fibers in mice, fibers could be found to have disseminated to regional and distant lymph nodes, spleen, kidneys and occasionally to brain tissue suggesting that some asbestos may enter the circulation. Thus, there is experimental evidence that parenteral adminis tration of asbestos fibers may lead to wide dissemination of such fibers in animals and to the development 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 world wide scientific community is addressing itself, is very complex. The Environmental Protection Agency has published in the FEDERAL REGISTER of April 6, 1973 (38 FR 8820) national emission standards for asbestos milling and manufacturing based on the determination that asbestos is a hazardous air pollutant. This standard has been developed despite the fact the EPA also recognizes that a "standardized 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 sponsored 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: - 12 - (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 follow ing exposure to only one type of fiber. (b) Investigation of whether reduction of asbestos exposure in lungs below those causing asbestosis abolishes excess risk of carcinoma. (c) Investigation of evidence of an in creased risk of cancer resulting from asbestos in water, beverages, food, or liquids used for the administration of drugs. (2) Development of methods of quantitative assessment, size analysis and characterization of particles and fibers. REFERENCES 1. "Asbestos, the need and feasibility of air pollution controls," Report of the Committee on Biologic Effects of Atmospheric Pollutants, National Academy of Sciences, 1971. 2. Cooke, W.E., "Fibrosis of the Lungs due to the Inhalation of Asbestos Dust," Brit. Med. J ., :147, 1924. 3. Cooke, W.E., "Pulmonary Asbestosis," Brit. Med. J ., 2^:10241025, 1927. s 4. Dree^en, W.C., J.M. Dallavalle, T.L. Edwards, J.W. Miller, and R.R. Sayers, "A Study of Asbestos in the Asbestos Textile Industry," Public Health Bull., 241, Washington, U.S. Government Printing Office, 1938, 126 pp. 5. McDonald, S., "History of Pulmonary Asbestosis," Brit. Med, J ., 2:1025-1026, 1927. 6. Merewether, E.R.A., "The Occurrence of Pulmonary Fibrosis and Other Pulmonary Affections in Asbestos Workers," J. Ind, Hyg., 12:198-222 and 12:239-257, 1930. 7. Mills, R.G., "Pulmonary Asbestosis: Report of a case," Minn. Med., 13:495-499, 1930. 8. Soper, W.B., "Pulmonary Asbestosis: A report of a case and a review," Am. Rev. Tuberc., 22_:571-584, 1930. 9. Lynch, K.M., and W.A. Smith, "Pulmonary Asbestosis III: Carcinoma of lung in asbesto-silicosis," Am. J. Cancer, 24:56-64, 1935. 10. Doll, R., "Mortality from Lung Cancer in Asbestos Workers," Brit. J. Industr. Med., 1_2:81-86, 1955. 11. Buchanan, W.D., "Asbestosis and Primary Intrathoracic Neoplasms," Ann. N.Y. Acad. Sci., 132:507-518, 1965. 12. Cordova, J.F., H. Tesluk and R.P. Knudtson, "Asbestosis and Carcinomas of the Lung," Cancer, 15:1181-1187, 1962. 13. Gross, P., R.T.P. deTreville, E.B. Toker, M. Kaschak and M.A. Babyak, "Experimental Asbestosis. ' The development of lung cancer in rats with pulmonary deposits of chrysotile asbestos dust," Arch. Environ. Health, 15:343-355, 1967. 14. Selikoff, I.J., J. Churg and E.C. Hammond, "Asbestos Exposure and Neoplasia," JAMA, 188:23-26, 1964. 15. Borow, M . , A. Conston, L.L. Livornese and N. Schalet, "Mesothelioma and Its Association with Asbestos," JAMA, 201:587-591, 1967. 16. Elmes, P.C., W.T.E. McCaughey and O.L. Wade, "Diffuse Mesothelioma of the Pleura and Asbestos," Brit. Med. J ., l_:350-353, 1965. 17. Elmes, P.C. and O.L. Wade, "Relationship Between Exposure to Asbes to- >-'<'-TiTP m .-=1 o - . y Be1fert," Ann N.Y. Acad. Sci., 122: 549- 557, 1965. 13 18. Enticknap, J.B. and W.N. Smither, "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 Mesothelioma of the Pleura," Brit. Med. J ., 2:211-213, 1964. 20. Hammond, E.C., I.J. Selikoff and J. Churg, "Neoplasia Among Insulation Workers in the United States with Special Reference to Intraabdominal Neoplasia," Ann. N.Y. Acad. Sci., 132:519 525, 1965. 21. Hourihane, D. O'B., "The Pathology of Mesothelioma and an Analysis of Their Association with Asbestos Exposure," Thorax, 19:268-278, 1964. * 22. Lieben, J. and H. Pistawka, "Mesothelioma and Asbestos Exposure,' Arch. Environ. Health, 1A:559-563, 1967. 23. Mann, R.H., J.L. Grosh and W.M. O'Donnell, "Mesothelioma , Associated with Asbestosis," Cancer, l_9:521-526, 1966. 24. McCaughey, W.T.E., O.L. Wade and P.C. Elmes, "Exposure to l Asbestos Dust and Diffuse Pleural Mesotheliomas," Brit. Med, J ., 2:1397, 1962. 25. McDonald, A.D., A. Harper, O.A. Elattar and J.C. McDonald, "Epidemiology of Primary Malignant Mesothelial. Tumors in Canada,' 16 26. Newhouse, M.L. and H. Thompson, "Epidemiology of Msothlial Tumors in the London Area," N.Y. Acad. Sci., 132:579-588, 1965. 27. Owen, W.G., "Msothlial Tumors and Exposure to Asbestos Dust," Ann. N.Y. Acad. Sci., 132:674-679, 1965. 28. Selikoff, L.J., J. Churg and E.C. Hammond, "Relation Between Exposure to Asbestos and Mesothelioma," New Eng. J Med., 272:560-565, 1965. 29. Wright, G.W., "Asbestos and Health in 1969," Am. Rev, Resp. Pis., 100:467-479, 1969. 30. Selikoff, L.J., E.C. Hammond and J. Churg, "Asbestos Exposure, Smoking, and Neoplasia," JAMA, 204:106-112, 1968. 31. Wagner, J.C., C.A. Sieggs and P. Marchand, "Diffuse Pleural Mesothelioma and Asbestos Exposure in the North Western Cape Province," Brit. J, Ind. Med., 17:260-271, 1960. 32. Champion, P., "Two Cases of Malignant Mesothelioma after Exposure to Asbestos," Am, Rev. Resp. Pis., 103:821-826, 1971. 33. Selikoff, L.J. and E.C. Hammond, "Environmental Epidemiology, III. Community Effects of Nonoccupational Environmental Asbestos Exposure," Am. J, Pub. Health, 58^1658-1666, 1968. 34. Wagner, J.C., "Epidemiology of Diffuse Msothlial Tumors: Evidence of an Association from Studies in South Africa and the United Kingdom." Ann. N.Y, Acad. S c i ., 13_2:575-578, 1965. - 17 r 35. Churg, J., E.C. Hammond, A.M. Langes, W.J. Nicholson, L.J. Selikoff and Y. Suzuki, "Biological Effects of Asbestos," presented at the National Institutes of Health, Feb. 1, 1973. 36. Anvilvel, L. and W.M. Thurlbeck, "The Incidence of Asbestos Bodies in the Lungs at Random Necrospsies in Montreal," Can. Med. Assoc. J ., 95_:1179-1182, 1966. 37. Cauna, D., R.S. Totten and P. Gross, "Asbestos Bodies in Human Lungs at Autopsy," JAMA, 192:371-373, 1965. 38. "Criteria for a Recommended Standard - Occupational Exposure to Asbestos," Report of Review Committee, National Institute for Occupational Safety and Health, Publication No. HSM 72-10267 (1972). 39. Lynch, J.R. and H.E. Ayer, "Measurement of Asbestos Exposure," J. Occup. Med., 10:21-24, 1968. 40. Swinburne, L.M., "The ingestion of asbestos by rats (unpublished data)," personal communication to Bureau of Foods, FDA. 41. Smith, W.E., L. Miller, R.E. Elsasser and D.D. Hubert, "Tests for Carcinogenicity of Asbestos," Ann. N.Y. Acad. Sci., 132:456-488, 1965. 42. Westlake, G.E., H.J. Spjut and M.N. Smith, "Penetration of Colonic Mucosa by Asbestos Particles. An Electron Microscopic Study in Rats Fed Asbestos Dust," Lab, Invest., 14_:2029-2033, 1965 4 18 ! 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 of the AOAC, 56_:976-981, 1973* 44. Pontefract, R. and H.M. Cunningham: "Penetration of Asbestos through the Digestive Tract of Rats," Nature, 243:352-353, 1973. 45. Nicholson, W.J., C.J. Maggiare and I.J. Selikoff, "Asbestos Contamination of Parenteral Drugs, Science, 177:171-173, 1972. 46. Tui, C. and A.M. Wright, "The Penetration of Non-Pyrogen Infusion and Other Intravenous Fluids by Absorptive Filtration," Annals Surg., 116:412-425, 1942. 47. Remington's Pharmaceutical Sciences, "Parenteral Preparations, Pyrogens," Chapter 82, 14th Ed., (pg. 1524), 1970. 48. Schmahl, D., "Cancerogene Wirkung von Asbest bei Implantation von Ratten," Zeitschrift fur Krebs fors chung, j52:561-567, 1958. 49. Harington, J.S. and F.J.C. Roe, "Studies of Carcinogenesis of Asbestos Fibers and their Natural Fibers," Annals of the N.Y. Academy of Sciences, 132:439-450, 1965. 50. Roe, F.J.C., R.L. Carter, M.A. Walters and J.S. Harington, "The Pathological Effects of Subcutaneous Injections of Asbestos Fibers in Mice: Migration of Fibers to Submeso- thelial Tissues and Induction of Mesotheliomata," Int. J. of Cancer, 2:628-638, 1967. # - 18a 51. Kanazawa, K., M.S.C. Birbeck, R.L. Carter and F.J.C. Roe, "Migration of Asbestos Fibres from Subcutaneous Injection Sites in Mice," British Journal of Cancer, 24:96-106, 1970. 52. "Report of the Advisory Committee on Asbestos Cancers to the Director of the International Agency for Research on Cancer," Brit. J. Industr, Med., 0:180-186, 1973. V - 19 - The Commissioner recognizes that it is not possible to eliminate all sources of asbestos contact with food and drugs. Asbestos is used in virtually all pipes carrying drinking water, in buildings in which food and drugs are manufactured, and in many filtering systems used in the manufacture of food and drugs, and is found in some substances, notably water and talc, used in the manufacture and processing of food and drugs. Nevertheless, the Commissioner also recognizes that asbestos fibers perform no functional purpose in talc and are an unnecessary contaminant. It is therefore reasonable to require precautions to be taken in the manufacture 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 Commissioner has concluded to take the following action: 1. In view of the demonstrated hazard in animals from injection of asbestos fibers, the Commissioner is proposing that the good manu facturing practice (GMP) regulations for drugs be amended to require that filtration procedures for parenteral drugs shall utilize either a non-asbestos-containing or non-fiber-releasing filter such as a membrane filter or, if an asbestos-containing filter is necessary, shall also utilize an additional non-asbestos-containing or non-fiber-releasing filter such as a membrane filter to reduce asbestos fiber content to the minimum level feasible unless such a subsequent filter will compromise the safety, identity, strength, quality or purity of the product. 20 - 2. The Commissioner intends to promulgate a final regulation for talc under 121.2006 as soon as a method for determining asbestos fibers in food-grade talc is validated. Such a method is proposed below, as part of a republication of the earlier proposal in which no methodology was specified. The Commissioner concludes that a final regulation for talc under Part 121 cannot be promulgated until a reproducible and accurate method can be specified for compliance purposes. 3. The Commissioner is also proposing that any talc used in the manufacture or processing of drugs meet the specifications for this substance that will be imposed by 121.2006. 4. The Commissioner realizes that the issues raised in this notice are complex and have widespread ramifications.' Comment is requested on all aspects of the public health significance of ingestion and injection of asbestos fibers. Since adoption of any new filtration requirements may require use of additional equipment, comment on the availability of appropriate equipment, the need for use of asbestos-containing filters as contrasted with filters which contain no asbestos, and the time needed to obtain and begin using non-asbestos-containing final filters such as membrane filters, is also requested. Finally, comment on methods of quantitative assessment, size analysis, and characterization of particles and fibers, is essential in order to develop final methods on which accurate and fair compliance can be based. # - 20a - Therefore, pursuant to provisions of the Federal Food, Drug, and Cosmetic Act (secs. 402, 502, 701, 52 Stat. 1046-1047, as amended, 1050-1051, as amended, 1055-1056, as amended; 21 U.S.C. 342, 352, 371) and under authority delegated to him (21 CFR 2.120), the Commissioner of Food and Drugs proposes to amend Title 21 of the Code of Federal Regulations as follows: - 21 - 1. In Part 121 by amending 121.101(d)(8) by alphabetically adding to the table a new item and in paragraphs (h) and (i) by revising the entry for "talc", to read as follows: 121.101 Substances that are generally recognized as safe. * *** (d) * * * * Product Tolerance Limitations or restrictions *** *** *** (8) MISCELLANEOUS AND/OR GENERAL PURPOSE FOOD ADDITIVES *** *** *** Talc (free of asbestos fibers as determined in 121.2006). *** ----*** In chewing gum base and as an antisticking agent in forms used in molding food shapes. *** (h) * * * Talc (free of asbestos fibers as determined in 121.2006). * *** (i) * * * Talc (free of asbestos fibers as determined in 121.2006). * *** * * - 22 - 2. In Part 121 by amending Subpart E by adding the following new section: 121.2006 Talc. (a) Talc is a naturally occurring hydrous magnesium silicate subject to a pripr sanction for use in coating polished rice. It is found in natural deposits that may be contaminated with asbestos fibers. (b) Good manufacturing practice requires that talc be free from asbestos fibers to the maximum extent practicable. Accordingly, any food or food-packaging material containing talc that is not free from asbestos fibers as determined by the method set out in paragraph (c) shall be deemed to be adulterated in violation of section 402(a)(1) of the act. (c) The following method shall be used to determine compliance with this section: (1) The various kinds of asbestos are distinguished from talc and from each other by their refractive indices, other optical crystallographic properties, and morphology as determined with a polarizing microscope (Methods of the Association of Official Analytical Chemists, 11th Ed., 1970, Sections 36.541-36.543, p. 717-721).^ Talc occurs mainly in the form of thin plates, which may appear fibrous when seen edgewise in microscopic 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 ^Copies may be obtained from: Association of Official Analytical Chemists P. 0. Box 540, Benjamin Franklin Station Washington, DC 20044 - 23 - 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 crystallographic 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 properties shown in the table, particles identified by this method should be at least 5 pm or longer. (2) Weigh out 1 milligram of a representative 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 sufficiently large so that the liquid will not run out from the edge (ca. 18 mm. square) and will provide a uniform particle distribution. Fibers counted by this method should meet the following criteria: (a) length to width ratio of 3 or greater (b) length of 5 pm or greater (c) width of 5 pm 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 polarizing microscope // - 24 - / vilification of approximately 400 X. In the 1.574 refrat ex liquid, chrysotile fibers with indices less than 1.574 ii extinction positions may be present; in the 1.590 refractive ii liquid, the other five amphibole types of asbestos fibers with exceeding 1.590 in both extinction positions may be present. I the extinction and sign of elongation for tentative identifies For specific identification of asbestos fibers, make additions in appropriate refractive index liquids, and refer to the opti crystallographic data in the table. A count of not more than amphibole types of asbestos fibers and not more than 100 chrysi asbestos fibers per milligram-slide constitutes the maximum lii presence of these asbestos fibers in talc. These limits assun purity of talc at least 99.9 percent free of amphibole types o: asbestos fibers and at least 99.99 percent free of chrysotile ; fibers. \ Actinolite Amosite Anthophyllite *n + n 2 - 25 - (3) Optical crystallographic characteristics of asbestos minerals na 1.614 1.615-1.655 1.663* 1.675* 1.598 1.598 1.598-1.674 1.608 1.619 1.619-1.633 1.629 1.633 Examples of refractive indices (n) n3 1.630 nT 1.641 Extinction Inclined 1.625-1.665 1.64-1.68 -- 1.680 -- 1.623 1.702 -- Parallel -- 1.623 1.605-1.685 1.615-1.697 -- 1.631 1.630 1.630-1.642 1.640 1.640-1.657 1.635 1.640 1.638 1.652 Substance Chrysotile Crocidclite - 26 - nCC 1.493 1.508 1.529-1.559 1.53-1.54 1.542 1.542 1.546 1.546 1.548 -- 1.693 1.697 Examples of refractive indices (n) n3 n r Extinction 1.504 1.517 Parallel 1.512 1.522 1.530-1.564 1.537-1.567 -- 1.54-1.55 -- 1.555 1.543 (calc.) 1.555 1.550 1.557 1.557 1.557 1.560 1.695 1.560 -- Parallel 1.695 1.697 1.700 1.703 - 27 - Substance Talc Tremolite nC 1.538-1.545 1.539 1.539 1.539 1.540 1.541 1.544 -- 1.545 1.599 1.599 1.599-1.612 1.600 1.602 ne -- 1.589 1.589 1.589 nearly - n 1.585 1.592 1.594 1.584 1.613 1.613 1.613-1.626 1.616 1.614 nT Extinction 1.575-1.590 Parallel 1.589 or 2 or 3 1.589 1.589 1.575 1.585 1.592 1.594 1.584 1.625 Inclined 1.625 1.625-1.637 1.627 1.635 - 28 - Examples of refractive indices (n) Substance______________no_____________ nfi n r __________ Extinction____________ Elongation 1.602 1.618 1.631 1.602-1.623 1.613-1.638 1.624-1.650 1.604 1.612 1.628 1.604 1.617 1.630 1.609 1.622 1.636 1.609 1.623 1.636 1.613 1.621 1.634 . - 29 - 3. ' In Part 133 by adding the following new paragraph (i) to 133.6 to read as follows: 133.6 Components. AA A A A (i) Talc is a naturally occurring hydrous magnesium silicate which may reasonably be expected to contain asbestos fibers which may be injurious to health. Current methodology cannot assure the absence of asbestos in talc. Accordingly, any drug, drug ingredient, or drug packaging material containing talc that fails to meet the specifications of paragraph (c) of 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 paragraph (j) to 133.8 to read as follows: 133.8 Production and control procedures. AA AA A - 30 - (j) Use of asbestos-containing filters: Filters used in the manufacture of a parenteral drug or parenteral drug ingredient shall not release fibers into such products. No asbestos-containing or fiber releasing filter may be used in the manufacture of a parenteral drug or parenteral drug ingredient unless it is not 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-containing or non-fiber-releasing filter such as a membrane filter shall subsequently be used to reduce the content of any asbestos-form particles in the drug or drug ingredient. Evidence for reduction shall be based on the use of the methods described in "Criteria for a Recommended Standard Occupational Exposure to Asbestos," Report of Review Committee, National Institute for Occupational Safety and Health, Publication No. HSM 72 2 10267 (1972). Use of an asbestos-containing filter without subsequent use of an additional non-asbestos-containing membrane filter is permissible only upon submission of proof to the Food and Drug Administration that use of a non-asbestos-containing membrane filter will, or is likely to, compromise the safety or effectiveness of the drug. 2 Copies may be obtained from: Superintendent of Documents U. S. Government Printing Office Washington, DC 20402 Interested persons may, on or before (insert date 90 days after date of publication in the FEDERAL REGISTER), file with the Hearing Clerk, Food and Drug Administration, Rm. 6-86, 5600 Fishers Lane, Rockville, MD 20852, written comments (preferably in quintuplicate) regarding the petition and the Commissioner's proposal. Comments may be accompanied by a memorandum or brief in support thereof. The petition, background information referred to in this proposal, and comments received may be seen in the above office during working hours, Monday through Friday. . .I. Schridt' Commissioner o f Food and Drugs CERTIFIED TO BE A TRUE COPY OF THE ORIGINAL