Document xzwnJe304aKgaEG5Dex81DbQJ

THE DISCOVERY COMPANY UNION CARBIOE CORPORATION MINING & METALS DIVISION P.O. BOX 579 NIAGARA FALLS. N. Y. 14302 TEL: 716-278-3376 July 18, 1975 Mr. Peter Zschunke Grace GmbH 6520 Worms Rh. Postfach 449 In der Hollerhecke Germany PLAINTIFFS EXHIBIT " UC-1354 Dear Peter: Bob Byrne has asked me to respond to your letter of June 24, 1975 on the subject of the use of asbestos in filter equipment and packaging material for pharmaceuticals and food. This has been an emotional and controversial subject in the United States ever since Nicholson, Maggiore, and Selikoff published their data and publicly expressed their concern. Basically two different problems have been examined by the FDA: 1. The use of asbestos filters for the processing of injection drugs, foods, and beverages. 2. The use of asbestos contaminated talc in foods. After much debate and testimony, the FDA decided to put severe restrictions on filters and packaging for injection drugs only. No restrictions have been placed at this time on talc contaminated with asbestos in foods or on the use of asbestos filters for processing foods and beverages. Extensive research on the effects of injected asbestos are planned to deter mine if such restrictions are necessary. The essentials of these decisions are summarized in the attachment. "Consumer Health." A copy of the complete regulations from the Federal Register is also provided if you want more details. You may also be interested in an excellent suranary of the facts on the problem that was submitted to the FDA by the Asbestos Information Association. The AIA concluded that there was no evidence of any danger in the use of asbestos filters for injection drugs but did not object to the requirement of an after-filter as an extra precaution. I hope this gives you the information you need for the customer. If you have any further questions, please let us know. Very truly yours HBR:pcr Enclosures H. B. Rhodes Technology Manager uPaCfe ufTiDn July 18, 1975 Added Notes: 1. A copy of the J. L. Myers paper which you requested is also enclosed. 2. Mine Safety Appliances tells us that they have offices in most of the principal cities in Europe. We are enclosing a list of addresses. H. B. Rhodes HBRrpcr Enclosures cc: R. E. Byrne, Jr. J. L. Myers A. Dambach, W. R. Grace, Lausanne, Switzerland CONSUMER HEALTH. FDA/Asbestos Filter Regulations (David L. Mallino) On March 14, 1975,the Food and Drug Administration promulgated regula tions governing the use of "asbestos-containing or other fiber-releasing filters" in the manufacture offparenteral drugs?} (Federal Reqister, March 14, 1975, pp. 11865-11869 ) s--------------------- According to the regulations: No asbestos-containing or other fiber-releasing filter may be used in the manufacturing, processing or packaging of parenteral drugs unless it is not possible to manufacture the drug product or compo nent without the use of such a filter. Filtration shall be through a non-fiber releasing filter. For the purposes of this regulation a "non-fiber releasing filter" is defined as "a nonasbestos, nonqlass fiber filter,"which after any appropriate pretreatment will not continue to release fibers into the drug product. If use of a fiber-releasing filter is required, an additional non fiber releasing filter of maximum pore .size of 0.22 microns (0.45 microns if the manufacturing conditions so dictate) shall be subse quently used to reduce the content of any asbestos-form particles. If the use of a fiber-releasing filter is necessary, proof of its necessity must be submitted to FDA. Substitution for a fiber-releasing filter shall be achieved on or before September 14, 1976, with more time allowed if necessary. Drug packages, containers and components shall be cleansed and made suitable for their intended purpose. FDA/Asbestos-Containing Talc in Food (David L. Mallino) On March 14, 1975, the FDA acknowledged that available scientific and medical information does not v/arrant banning talc-containing asbestos in foods. (Federal Reqister, March 14, 1975 ) The Agency also rejected its original proposal to tie the "generally recognized as safe" use of talc in food packaging to the absence of asbes tos particles. At the same time, the FDA reaffirmed its original decision not to propose any restrictions on asbestos-containing filters used in the processing'of food or beverages. FDA stated that, in conjunction with other agencies, it plans to con duct extensive research into the potential health hazards of ingested asbes tos. Until such time that positive data is available, FDA concluded that "a prohibition on the use of asbestos-containing filters in the processing of food and beverages, and of asbestos-containing talc as a food or food additive... is unwarranted due to a lack of sufficient data." ASSESTOS INFORMATION ASSOCIATION KOniH AUSCCA 1650 L Streei. N W. vVajtvrc'c-.. u C. 00036 (002) 223-'-d35 20 December 1973 Hearing Clerk Food and Drug Administration Room 6-86 5600 Fishers Lane Rockville/ Maryland 20852 Dear Sir: The following comments are respectfully submitted by the Asbestos Information Association/North America in reference to Department of Health, Education and Welfare: Food and Drug Administration (21 CFR Parts 121, 128, 133), proposed rulemaking on Asbestos Particles in Food and Drugs, as printed in the Federal Register, Vol. 38, No. 188, Friday, September 28, 1973. The Asbestos Information Association/North America consists of 22 member companies and associations v/hich represent approximately three-quarters of the asbestos mining, milling manufacturing and importing industries in the-United States. The members of the Association are listed on a sheet which has been attached. The adverse health effects of inhaling large quantities of asbestos fiber over a substantial period of time are docu mented in technical literature. Some researchers have reported an increased rate of gastrointestinal cancer among some long-term asbestos industry employees. Other researchers have been unable to support an increase in cancer of the GI tract among populations with above normal exposure to asbestos particles. In 1971, the seven-man Panel on Asbestos of the National Academy of Sciences' Committee on Biologic Effects of Atmospheric Pollutants examined all of the relevant data and concluded: "Associa tions between asbestos exposures and malignancies of the ... gastrointestinal tract and of other sites have been reported but the data are still inconclusive". Reviewing the situa tion two years later, the Advisory Committee on Asbestos Cancers of the International Agency for Research on Cancer Hearing Clerk Food and Drug Administration 20 December 1973 Page 2 of the World Health Organization concluded that for some .exposed populations, such an increase does exist, but that the excess is relatively small, that further research is needed, and that there is no cancer hazard resulting from the ingestion of "asbestos fibres present in water, bever ages, food or in the fluids used for the administration of drugs." If the human evidence as to a possible relationship between asbestos exposure and an increased risk of gastrointestinal cancer is scanty and contradictory, animal experimentation performed to date is even more so. As is pointed out in the proposed rulemaking, the major feeding (as exposed to injection) experiments of L. M. Swinburn (your reference number 40) and W. E. Smith (your reference number 41) produced no tumors in the gastrointestinal tracts of the animals, even though the amounts of fiber fed to the animals were massive when compared with human occupational exposures known to result in respiratory disease. These findings have been further confirmed by the work of . J. M. G. Davis of the Institute of Occupational Medicine, Edinburgh, Scotland, whose feeding experiments with rats have thus far produced no GI tumors. A 1967 paper by G. M. Bonser and D. B. Clayton ("Feeding of Blue Asbestos to Rats," 1967 Annual Report, British Empire Cancer Campaign for Research, p. 242) likewise reported no tumors in 40 rats fed crocidolite asbestos throughout their lifetime. Since it has been suggested that mesothelioma might be caused in some instances by a migration of asbestos fibers from other parts of the body, including the gastrointestinalsystem, it should be pointed out that no mesothelial tumors . were found in any of the animals involved in the various feeding experiments. While some injection experiments have produced site and meso thelial tumors in test animals, the amount of fiber used in each case was so large as to render any attempted trans lation to human experience completely inappropriate.-. In addition, the work of M. F. Stanton of the National Cancer * Institute ("Some Aetiologic Considerations of Fiber Carcino genesis," as presented at the World Health Organization Conference on the Biological Effects of Asbestos,'Lyon, France, October 2-5, 1972, Paper 43A) and of P. Gross ("The Locus of Pathogenicity of Asbestos Dust," Archives of Environ mental Health,.Vol. 27, October 1973, p. 240) strongly suggest that injection or implantation cancers in test animals are directly related not only to dose but, even more Hearing Clerk Food and Drug Administration 20 December 1973 Page 3 importantly, to the size of the fiber used in the experi ment. Electron microscope sized fibers did not produce .tumors in the test animals. This is extremely relevant to the proposed rulemaking in that the vast majority, 'if not all, of the asbestos fibers found in air, water, beverages, drugs and food in the United States are in this apparently non-carcinogenic size range. On the basis of the human and animal studies contained in the literature, one would have to conclude that the rela tionship between asbestos exposure and an increased risk of gastrointestinal cancer remains tentative. Because of the known respiratory health hazards of asbestos, there has been a tendency among some researchers to ascribe to asbestos sole blame for an excess mortality from any cause experienced by an exposed cohort, even if that cohort was exposed to recognized toxic substances. It is theoreti cally possible that some other substance or agent is re sponsible for the excess GI cancer rate found among some asbestos-exposed populations. This would explain why Other exposed cohorts have shown no such increase and also why animal feeding experiments have failed to demonstrate an increased risk. Until further research is completed, this possibility cannot be excluded from consideration. Even if it is eventually proven that a relationship be tween asbestos exposure and an increased risk of gastro intestinal cancer does exist, the animal feeding experi ments performed to date would have to cast serious doubt on the proposition that the ingestion of asbestos fibers is the cause of this increase. It should also be pointed out that despite the long-term use of asbestos filters in this country, there is no evidence that anyone in the United States -- or in the world, for that matter -- has ever contracted either GI cancer or mesothelioma from drinking a beverage filtered through an asbestos filter or by being injected with a drug filtered in the same fashion. In fact, the GI cancer rate in the United States is on the decline, and if we were going to see an epidemic of these diseases because of asbestos filter contamination, certainly we would have had some evidence of it before now. With regard to the question of asbestos-related disease, it must be borne in mind that all of the human groups studied to date have had occupational, para-occupational, neighborhood or household exposures of a magnitude far greater than that which could reasonably be expected to Hearing Clerk Food and Drug Administration 20 December 1973 Page 4 exist to affect the general public. V7hile precise compari sons are impossible because of different measurement techni ques used to quantify asbestos concentrations in the work place and in ambient air and water (occupational exposures are measured in fibers per cc while ambient exposures are measured in nanograms per cubic meter of air or micro grams per liter of water), rough approximations indicate that even safe occupational exposures are many thousands of times higher than those to which the general public is or has been exposed. Asbestos is ubiquitous in our environment. It exists naturaiLly-rin small, though detectable, amounts in serpen tine.'rock formations throughout the world and is constantly being released into the atmosphere through erosion by wind and water. Asbestos is natural to our environment and -- . as analysis of dated ice from the polar caps has revealed -- has been for thousands or even millions of years. Man, therefore, evolved into his present form in an atmosphere containing a natural background of asbestos -- both in the air he breathed and in the water he drank. While precise comparisons are impossible, today's atmospheric levels of asbestos, even in urban settings, are still only marginally higher than in the distant past. Most speculation as to the health hazards of the minute amounts of asbestos that have been demonstrated to exist in air, water and in bever ages or drugs completely ignores these two most-important factors -- the differences in magnitude between occupation al and ambient concentrations, and the ubiquitous' nature of asbestos in the environment. To conclude, therefore, as some have done, that because exposure to heavy concentrations of asbestos fiber in the workplace is a recognized health hazard, general public exposure to infinitesimally smaller quantities of the same material must also be a hazard, flies in the face of logic, especially since man has survived such exposures for millions of years. It is reasonable to conclude that the general public is not at risk from infinitesimal quantities of asbestos. Such is the conclusion in the "Report of the Advisory Committee on Asbestos Cancers to the Director of the International Agency for Research on Cancer" (your reference number 52). On the question of fiber release from asbestos-containing filters into the finished product, it is important once again to comment upon the ubiquitous nature of asbestos in our environment. A number of studies have been undertaken in the United States, Canada, and in the United Kingdom to Hearing Clerk Food and Drug Administration 20 December 1973 Page 5 determine the so-called "natural background" level of asbestos in ambient air and water. Because of the different analytical techniques employed, the results of the various studies are not 100 percent comparable. However, it would appear that the average background level in water in the U.K. is in the vicinity of 4x10" grams per gallon? and in the United States and Canada, somewhere between 2 and 5 micrograms (lxI0" grams) per gallon. Because of the com plexity of the analytical techniques used to measure the asbestos content in water, an error factor of from 400 to . 500 percent must be assumed in evaluating the results. The higher background found in North America is probably . due to the greater quantity of asbestos-bearing serpentine rock found on the continent -- especially on the Eastern seaboard, where the samples were collected. To place the results in perspective, one microgram per gallon equals one ounce in 2.84 billion gallons. If these background levels can be considered "normal" for human ingestion, the question must then be raised: how do these levels compare with' beverages, drugs, etc. filtered through asbestos-containing filter pads? Research into . this aspect of the problem has been conducted by Cunning ham and Pontefract (your reference number 43); Nicholson, Maggiore and Selikoff (your reference number 45); Badami and Rickards (unpublished data submitted to FDA on May 1, 1973 by S. Holmes of the Asbestosis Research Council); J. P. Leineweber (unpublished summary of asbestos fiber content in United States commercial beers -- copy attached);. Dr. Philip McGrath (FDA memorandum to-Dr. Armand Casola); and Dr. J. R. Crout (FDA Preliminary Results of Special Survey). The results of the Cunningham et al^, Badami et a]L, and Leineweber studies all showed tKe asbestos fTFer content of the various soft drinks, beers, wines and parenteral drugs tested to be no more than, or in many cases, less than the natural background level of asbestos that one would expect to find. Badami and Leineweber could find no correlation between the use of asbestos-containing filter-pads and an increase of asbestos fiber in the finished product. Only Nicholson et a_l found levels of asbestos in'parenteral drugs higher than would be considered normal.. This is not particularly surprising, because the Mount Sinai laboratory has consistently reported higher asbestos levels in ambient air and water than have been found by other laboratories in the United States and abroad. Professional speculation is either that the Mount Sinai electron microscopy technique is faulty to some extent, or that improper attention is being Hearing Clerk Food and Drug Administration 20 December 1973 Page 6 paid to achieving true clean room conditions so that the samples are not contaminated prior-to measuring. When seeking to obtain accurate measurements of such infinitesi mally small quantities, even the slightest contamination could throw the results off considerably. Of special interest with regard to the proposed rulemaking are the reports of McGrath and Crout. While only prelimi nary in nature, the Crout survey shows that the use of asbestos-containing filters bears no relationship to the presence of asbestos fibers in the finished product. In this respect, it confirms the studies of Badami and Leineweber, and throws considerable doubt on the proposition that the elimination of asbestos filters for parenteral drugs would result in any reduction in asbestos content of the finished product. In fact, the McGrath survey could lead to the conclusion that asbestos filters should be required for all filtration systems, since, to quote the McGrath memorandum, "Filtration through an asbestos filter demonstrated the remarkable capacity of this device to reduce the amount of asbestos in a given sample". It would be highly ironic, in light of the controversy that this subject has generated, if it turned out that the bast method for the reduction of natural background levels of asbestos in base liquids would be the use of an asbestos filter! To summarize briefly: 1. The evidence for a relationship between asbestos exposure and an increased risk of gastrointestinal cancer is inconclusive. 2. If such a relationship could be established, the evidence to date casts serious doubt on the pro position that the ingestion of asbestos fibers causes either gastrointestinal cancer-or mesothe lioma. 3. The size range of fiber most commonly found in beverages, drugs, etc. doss not appear to be carcinogenic. ..... . 4. Asbestos is ubiquitous in our environment and has been for millions of years. 5. With the exception of the Nicholson et al study, which has been the object of serious criticism, none of the studies done to date shows an unnatural Hearing Clerk Food and Drug Administration 20 December 1973 Page 7 5. (Continued) . level of asbestos fibers in the finished product. 6. No correlation has been demonstrated between the use of asbestos filters and the presence of excess asbestos fibers in the finished products. 7. It is unlikely that the elimination of asbestos filters for parenteral drugs will result in a reduction in the asbestos content of the drugs. 8. The levels of asbestos found in beverages, drugs, etc. have not been shovzn to be hazardous to human health. On the basis of the above, the following comments and recommendations are offered: 1. The FDA acted properly in not placing restrictions of any type on the use of asbestos filters in the food and beverage processing industries. . This decision should not be altered. 2. In light of (a) the available medical evidence (b) the proven value of asbestos filters in remov ing pyrogens from parenteral drugs, and (c) the unlikelihood that asbestos filters contribute significantly, if at all, to the asbestos content of the final product, it is our recommendation that the FDA delete from Section 133.8 (j) of the pro posed regulations, that portion prohibiting the use of asbestos filters "unless it is not possible to manufacture that drug or drug ingredient without the use of such a filter". \. 3. Applying the "prudent person" approach, we support the precautionary measure of requiring a non-asbestoscontaining after-filter whenever an asbestos filter is used for filtering parenteral drugs, even though' ' it is highly unlikely that this is necessary either from the public health or drug purity standpoint. 4. Because of the extreme complexity of the technology involved and the possibility of substantial error, we further recommend that the requirement for proof of reduction be eliminated from the proposed regula tion. Since the sampling method as described in the NIOSH document is useful only for detecting light-sized fibers, and not those in the EM range. Hearing Clerk Food and Drug Administration 20 December 1973 Page 8 4. (Continued) which constitute the vast majority of all asbestos fibers likely to be found in a parenteral drug, the method is in-appropriate and misleading for evaluating the asbestos burden of a particular drug. In addition, it would appear from the studies des cribed above that the asbestos content of the pre filtered solution is more important in determining the content of the final product than whether or not an asbestos filter with or without an after f* ilter is used. 5. We support that portion of Section 133.8 (j) with regard to the use of an asbestos-containing filter without an after-filter. We believe these recommendations will provide the public with the health protection as required in the proposed regulations. In addition, the elimination of the sampling requirement and of that portion of the regulations pro hibiting the use of an asbestos filter unless it is not possible-to.manufacture the drug in any other fashion, will considerably ease FDA's administrative enforcement of the standards. It would be much simpler for an FDA inspector to merely check to see that an after-filter was being used to assure compliance with the regulations than it would be to set up some type of permit system that could create confusion and serve neither the FDA nOr the companies involved in the joint interest of best public service. The Association appreciates the opportunity to submit this letter and requests that the recommendations and comments herein be given fullest consideration in the development of final standards on the use of asbestos-containing filters by the Food and Drug Administration. M Attachments: Summary of Asbestos Fiber Content in Commercial Beers, J. P. Leineweber Member list Asbestos Information Association/ North America * SUMMARY OF ASBESTOS FIBER CONTENT IN COMM * i^ J. * V 1 '-D Brand SCHLITZ (regular) Sample 1 SCHLITZ (regular) Sample 2 SCHLITZ draft Filtration Fiber Content (^qArai.) * (Primary - diatomite only (Polish - asbestos-cellulose precoat + diatomite body feel 0.23 2.50 Same as regular + Millipore 2.50 RHEINGOLD extra dry (Primary - diatomite only (Polish - asbestos-diatomite precoat + diatomite body feel 0..61 SCHMITZ Same as Schlitz regular * 1.39 . NARRAGANSET (Primary - diatomite only (Polish - diatomite only 1.14 OLD BOHEMIAN * KAIERS PIELS regular PJELS draft (Primary - two stage diatomite (No polish (Primary - diatomite only (Polish - diatomite only . 7 3.07 0.24 3.96 0.74 *1 ^5/gal. = 1 gram in 1,000,000 gallons = 1 ounce in 2,84 0,000,000 gal. * * .All values determined by electron microscope observation. No fibers were visible in any of the samples under optical microscopic observation at 450X magnification. J. P. "LEINEWEBER / P.H.D., Assistant Director Central Research Dept., 10-15-68 Johns-Manville Corp. FRIDAY, MARCH 14, 1975 WASHINGTON, D.C. Volume 40 3 Number 51 Pages' 11359-12066' . .,, . r' --- - PART I HIGHLIGHTS OF THIS ISSUE This listing dees not affect the legal status of any document published in this issue. Detailed table of contents appears inside. NONHUMAN PRIMATES--Hr,V proposes restricting im portation; comments by 4--14--75___________________ 11 37 EXHAUST EMISSION STANDARDS--EPA grants auto manufactures suspension request for 1977 mode/ year___________________________________ 11900 HIGHWAY SAFETY--DOT criteria for incentive grants to States for annual fatality rate reductions; effective 3-14-75:-------------------------------- --- 11870 CAREER EDUCATION PROGRAM-- HEW/OE announces closing date of 4-21-75 for receipt- of funding applications__ ___________________ 11930 HEW/OE proposes fund criteria foe FY 1976; comments , by 4-14-75--------------------- 11923 FOREIGN LANGUAGE AND AREA STUDIES-- HEW/OE sets closing date of 4-15-75 for receipt of applications11931 HEW/OE proposes funding criteria for FY 1976; com- ments by 4-14-75.___ 11930 SUPPLEMENTARY EDUCATIONAL CENTERS-- HEW/OE sets closing date of 4-25-75 for receipt of applications ______________________________________ 11931 HEW/OE proposes funding criteria for FY 1976; com- " merits by 4-ia--75 11885 ANTIBIOTIC DRUGS--HEY//FDA provides test method y^for Tetracycline; effective 3-14--75__________________ 11869 yy ASBESTOS PARTICLES--HEW/FDA restricts use in man- w ufacture of parenteral injection preparations; effective 4-14-75 11865 BIOLOGICS--HEW/FDA proposal changing testing re quirements for Smallpox Vaccine. Live; comments by 4-14-75_____________________________ _______ _____11884 {Continued Inside) PART If: DRINKING WATER--EPA proposes Interim pri mary standards; comments by 5-16-75__- 11989 PART 111: MINIMUM WAGES--Labor/ESA determinations for Federal and federally assisted construction____ 11999 . THSo21--Fond and Drugs ! CHAPTER 1--FOOD AND DRUG ADMINIS TRATION, DEPARTMENT G" HEALTH, ' EDUCATION. AND WELFARE j SUBCHAPTTR C--DRUGS | PART 133--DRUGS; CURRENT GOOD 1 MANUFACTURING PRACTICE IN MAN- ; UFACTURE. PROCESSING, PACKING, I OR HOLDING | Asbestos-Form Particles In Drugs for I ' Parenteral Injection | The Commissioner of Food and Drugs ! published In the FsosRAt Rrcis--a of t September 28. 1073 (33 FR 27070, a. notice proposing to restrict the utilira- 1 tion of asbestos filters In tha manu- 1 facture of parenteral drugs and par enteral drug ingredients, and to pro- : hlbit the use of asbestos-containing talc 1 as a food, or food or drug ingredient, cr . In food and drug packaging materials, i within certain analytical restrictions. . The notice provided for the filing of t comments within 00 days. i Asbestos fibers' are known to cause | cancer when inhaled In large amounts. 1 Also, asbestos and other fibers are con sidered likely to have a similar adverse effect If present in parenteral drugs, although this has not been proven. Be cause of this likelihood, this order pro vides that, whenever possible, asbestos- containing or other fiber-releasing filters not be used in the manufacture, proc essing or packaging of drugs intended for parenteral injection in humans. Also. It provides for measures to reduce the amount of fibers present in such prod ucts, where it is not possible to elimi nate these filters in the production of a ( drug. The comments made In response to the j September 28,1973 proposal fail into two I main categories. One concerns provisions to decrease the potential tor ingestion. of asbestos fibers. The other concerns pro visions to decrease the potential for lnJecUon of asbestos fibers. A discussion o* each category of comments, anti tha Commission's conclusions, are set iorth below. A. Comments on provisions dealing with ingestion potential ot asbestos fibers: 1.The Commissioner proposed that any food, food packaging material, drug, drug Ingredient or drug packaging ma terial containing talc that is not free from asbestos ficers as determined by a particular analytical method should bo deemed adulterated in violation of sec tion 402(a)(1) of. the Federal Feed. Drug, end Cosmetic Act. Nineteen comments related to the pro posed analytical method loc talc underi 121.2006 (21 CFR 121-2006). The com ments were primarily from representa tives of food, drug, ar.d talc raining firms, but also included lour consultant labora tories and two other federal agencies. Al though It is apparent that most cf theserespondents did not actually use the de signated method, and were.there!ore-, re flecting their general experience- with optical crystallography or a personal preference for other analytical methods, none oi the respondents supported theproposed method for compliance pur poses. The predominant objections to tha proposed method were that it is did;-nit to use. laborious, and not practical for its Intended purpose. Several comments offered the opinion that only the most highly trained microscopists. would be capable of using the method with any reasonable accuracy or precision. Mem bers of one trade association coliacoratively studied the method with 10 micrcscopists. each examining seven samples of talc. Four participants admittedly could not use the method to count the gampies, and there was obvious incon sistency in the results reported by other microscopists. A number of alternative methods for determining asbestos particles in talc were suggested by the respondents. Al though optical microscopy using disper sion staining was the most frequently suggested method, others surges ted x-ray diffraction, spectrophotometry, ar.c sev eral electron microscopy and microprobe techniques as preferred or supportive analytical methods. Many of the re spondents additionally expressed their willingness to Join a Food and Drug Ad ministration analytical task force to evaluate applicable methodology. Although the Commissioner cannot agree that the designated optical crystallographic method Is unreliable when used by those experienced in the srt. ho rccogniccs that an effective com pliance method must have fnreater utility and acceptance than indicated by the comments on the proposed method. The Commissioner has. therefore, decided to delay any final regulation for talc until au acceptable mcUicd for deter mining the presence of asbestos particles can be developed -for this substance. TIUs FEDERAL REGIJTM, VOL 40', NO. 51--FRIDAY, MARCH 14. uses RULES ANO REGULATIONS area of research currently Is belnsr ac requirements for talc used in the manu man's overall exposure by these sub tively puii.'isci ty the Food and Drug facture of paper and paperboard in stances are small. The comment con /.drain titration. f 121.101th) (21 CFR 121.101(h)). .Ml of tended that evidence is lacking to show 2. Several comments objected to the these comments contended that asbestos, that the ingestion of small amounts of purity limitations for talc which v/ere es in asbestos-containing talc, does not mi asbestos is safe and that the responsibil tablished by the proposed method. Many grate to packag'd foot! when talc is used ities of the Food and Drug Administra thought that requirements that talc for this purpose. One of these comments tion for promulgation of regulations to be 23.9 percent amphiboie-free and 99.99 contained rcsul;.> of recently conducted lessen the total human exposure to as percent chrysotile-free unreasonable, studies which were intended to prove this bestos were not mitigated by the fact that while others insisted that any limitation contention. nil human exposure to asbestos cannot was unrra.or.abie unless It could be de After a thorough renew of submitted be regulated by the agency. monstrated. to reflect known hazard comments, and examination and evalu The Comimssioner agrees that uniform levels by ingestion. While one respondent ation of additional requested studies, the and consistent regulations should be calculated that 20.0G0 nmpvibole and Commissioner conduces that tins com adopted on an industry-wide basis. In 3.50G chrysctilc fibers (of 5 micrometers ment has demonstrated the validity of this instance, the lacs oi available re x 1.7 micrometers size) should be permit this contention in a manner consistent producible methodology for determining ted before any talc sample exceeded the with available methodology. In the con asbestos-farm fibers in beverages and established limits, another respondent ducted studies, the comment has dem olher foods led the Commissioner to pro observed that Individual asbestos par onstrated that dry packaged and shipped pose the regulation of talc before han ticles often vary in size a million-fold, salt contains less than C.01 part per bil- dling ether related matters. In any event, thus making it circuit to relate particle il.ni asbestos when in c.rect anc continu the comment has new become mcot since counts to tiie percentage of asbestos con ous contact with urcoated paper con the Commissioner has decided to delay tamination in talc. taining up to G percent t rentoillie asbes a final ruling on talc as a direct food or Although the decision of the Com tos. Although detection was limited by drug ingredient. missioner to delay any final regulation on the bulk cf ash recovered frem other The Commissioner also concludes that talc has rendered these comments moot, products, such as fresh wrapped and fro neither the available data on the addi the Commissioner wishes to respond to zen meat, dry packaged macaroni, dried tion of fibers to foods and r.onparentcral these comments to clarify his position on milk, rice, and corn flakes, the comment drags by use of asbestos fillers nor the posssible future talc regulations. has also demonstrated that these prod data on the asbestos content of municipal As indicated in the proposal, the Com ucts contain less than 19 parts per bil water are sufficiently reliable to permit missioner recognizes that the evidence lion asbestos under test and market con promulgation of regulatory controls at concerning the possible hazard from in ditions. The analytical details of these this time. Evidence indicates a wide vari gestion of asbestos particles i3 contra studies are on file with the Hearing ation of asbestos fiber contamination in dictory and inconclusive. The method Clerk, Food and Drag Administration, the water supply of the cities of the was therefore not proposed in order to Rm. 4-63, 3600 Fishers Lane, Rockville, United States, with some reports that Indicate any known hazard from asbes hXD 20352. the waters of the San Francisco, CA, tos, but was intended to establish a good The Commissioner concludes that the and the Duluth, MN, areas are among manufacturing practice limitation for above reported salt study represents a the highest in asbestos content. How the use of talc in food and drugs until practical upper limit of migration of as ever, the lack of consistency of test meth an assessment of the hazard, if any, of bestos from food-contact paper and pa ods and their applications leads to ques ingested asbestos can be determined. perboard. This conclusion is based upon tions concerning these data. A recent The particle limitation accompanying consideration of the extreme abrasive epidemiological study of cancer mortal the proposed method represents the best nature cf salt as compared to other dry ity in Duluth over the last 14 years (Ref. assessment by the Food anti Drug Admin loods, and the unusually high trcmcktic 2) has concluded that, up to this time, istration of the probability of occurrence asbestos content of the test paper (6 per no carcinogenic'eflcct could be demon of such particles in natural talc deposits, cent) as compared to reported levels of strated from incastion of the municipal the ability cf the method to detect such use (0.02-0.4 percent) In food-contact waters. Some reports have been received, particles, and the need to assign a limit paper and paperboard. chiming little or no '.asbestos addition to define the absence of asbestos. The The Commissioner therefore concludes to the aforemehtlanetf'jiroducts by the Food and Crus Administration has also that the comment has demonstrated that use of filters (Ref. 2\\ Other reports examined numerous talc samples of un the asbestos Conte..: of talc used in the from Canada, which indicate some In defined grade in the past 2 years, using manufacture of food- or drug-contact creases in the asbestos content of bever the proposed methodology, and finds that paper and paperboard doe3 not represent ages (Ref. 4 and 5) over background approximately two-thirds of such sam a potential contaminant of packaged water, show that the final levels are com ples are within these limitations. The feed or drags, as assessed by currently parable to the background levels in areas Commissioner therefore concludes that available methodology. Accordingly, the of ihe United States. Therefore, the Com the proposed particle lirtiitat-.oiis would Commissioner is withdrawing the analyt missioner has decided to delay the pro not Impose an unreasonable burden on ical i.mitations proposed for talc In mulgation of any regulation on the pro manufacturers of talc if these limitations 5121.101(h), unless new methodology or hibition of use of nsbestes filters for the are ultimately adopted. toxicological assessment requires further preparation of foods and r.onparenteral The Food and Drug Administration has been aware of the possible extreme variation in asbestos particle size that may occur in natural deposits of talc. Eliminating particles less than S microm eters long or with less than a 3-to-l length-to-wicUh ratio considerably nar rows the range of permissible particles counted by the proposed method. Con sidering the variation in particle .size that may yet be possible, however, a typical particle of non cubic micrometers, weigh ing approximately 1 nanogram iRef. 1) was used to assure a purity of talc at least 93.9 percent free oi amphibole types of asbestos fibers and at least 99.03 per cent free of chrysolile asbestos fibers. evaluation of this question. 4. The Commissioner stated in the pro posal that it had been decided not to promulgate a proposed regulation gov erning the utilization of asbestos filters in the procc'sin;: of iced and beverages. One comment s:..ted that this was in consistent with the Commissioner's pro posed regulation on the asbestos content of food-grade talc, mid that attempts to limit asbestos ingestion should apply uniformly to all sources. Another com ment stated that the Commissioner's decision not to regulate the use of as bestos filters in food, beverage and r.on- parcr.teral drag preparations was based drags until more reliable data can be obtained on the background concentra tions of asbestos in drinking water and the role of asbestos filters in regard to the addition of fibers to lngcstlble products. 5. Many comments endorsed or con demned the proposals, or part:; of them, with respect to water, food, and beverage contamination. Although mest of these comments did not supply any additional data or Information, a current asbestos feeding study by J. M. G. Davis (Ref. 0) and a 1967 study by G. J.I. Jtaiiscr and D. B. Clayton (Ref. 7) were cited as fur ther evidence of no harm from ingested asbestos. Other comments citc-d the 1972 3. Three comments from industrial on the unproven notion that the amounts conclusion of the Advisory Committee firms objected to the proposed analytical of fisbesots which arc contributed to on Asbestos Cancers (Ref. 8) that there FEDERAL REGISTER, VOt. 40, NO. 31--FRIDAY, MARCH 14, 1973 jincer Irom nsacstcs fioer-, :n water, leverages. and food, or In fluids used for the administration ol drugs, nr.d one ' comment cited a recent study by Klemir - / Xcld. Messite, and ZukI (Itel. O) whiicch reports no Increase of Gustrolatteestltnaal / end peritoneal cancer actons taic workers exposed to talc dusts for a mini mum of 15 years. From analysis of the foregoing com ments received concerning the limita tion of asbestos in talc, from thorough re-review of the scientific evidence avail as follows: X. A number of comments stated that there is no conclusive evidence that asbestos filters add fibers to tire filtrate, or that asbestos has caused deleterious effects as a result of parenterally admin istered drugs. Asbestos fibers were found in a number of samples of parenteral drum by Nichol son et al. (Ref. 10) and also by a sub sequent Feed and Drug Administration investigation of parcncerals. Although the Food and Drug Administration has regulation will ce rcauircc. to s'..err..: mon:hi7 prepress reports t.-.ereafter con cerning attemois to imnlemer.t the re quired procedures and nr.y difficulties in maintenance of product quality. 3. A large number of comments stated that many parenteral products would suffer in safety and quality because of a requirement to replace asbestos-contain ing filters in the manufacturing process. The Commissioner agrees that it is es sential that there be no increase in risk to the public us a result of this action. able concerning the adequacy of the demonstrated that filtration through as The regulation provides for continued use available methodology to determine the bestos of a water sample highly contami of asbestos filters where no alternative amount of asbestos in talc, and from nated with asbestos fibers can signifi is feasible. Tne respor.sibdity for demon . consideration of the controversial nature cantly reauce the number of fibers pres strating that the replacement of ar-aestes of evidence to demonstrate the hazard ent. the Food and Drug Administration filters or the utU-zation of a final non- to health presented by ingestion of the also has direct evidence that the utili fiber-releasing. non-asbestos-ccn taininy amounts of asbestos fibers normally to zation of asbestos filters can cause as- filter decreases product quality and effec be expected in talc used in food or drags, bestos contamination. The preliminary tiveness of safety remains mat o: the or in food or drug packaging materials report of the latter study Is on public manufacturer. Evidence for such product containing talc, or In beverages, other display In the ofiice of the Hearing Clerk. alteration must be submitted to the ap loods and nonparenteral drugs prepared The evidence of the deleterious effects of propriate bureau of the Food and Drug with the use of asbestos fillers, the Com parenteral asbestos administration (Ref. Administration for approval of the con missioner concludes that the promulga 1. IX, 12, and 13) requires that the tinued use of tiie tmmocified asbestos tion of regulations on the limitations or amount of contamination in these prod filtration processes. prohibition of the use of asbestos filters ucts be minimized. Consequently, the 4. One comment objected to the utili for'the preparation of food3 and noa- Commissioner has determined that It is zation of the terms "membrane filter" parcnteral drugs and of the amount of Important that asbestos-containing fil and. "nort-fiber-releasing filter." stating asbestos fibers in talc for use in food and ters be replaced with non-fiber-re'easing that the former term was too limiting drugs or which might migrate into food filters unless it is demonstrated that it is as a recommendation for a replacement qr drugs from talc-containing packaging not possible to manufacture a safe and of filters which may release asbestos materials is unwarranted until more effective parenteral drug or parenteral fibers and that the latter phrase saauid reliable data can be obtained concerning drug ingredient without the me of such be changed to "asbestos-containing or these matters. an asbestos-containing filter. In the lat media-migraiion-ex-hi'citir.g filter." Thus The Food and Drug Administration, in ter instance, a final non-::ber-re!easing comment claimed that the term "nan- conjunction with other agencies, is plan filter shall be used to reduce the content fiber-rcleasing" should be replaced since ning extensive experiments to determine o: any asbestos-form particles in the drug small quantities of the fibrous support if long term exposure to ingested asbestos or drug ingredient. Use of an asbestos- used in many cellulose-ester membrane fibers represents a definitive hazard to containing filter with subsequent use of filters, as well as fibers and particles human health. As noted, until this study an additional non-asbestos-containing, from the manufacturing process for Is completed or other data become avail non-fiber-releasing filter shall be permis cartridge and other type niters, are re able. the Commissioner has determined sible only upon submission of evidence to leased by cleaning and pushing prior to that a prohibition of the use of asbestes- the appropriate bureau of the Food and marketing of the product. Another com contaming filters in the processing of Drug Administration that substitution ment stated that the proposed regula food and beverages, and of asbestos- for the asbestos filter of a non-fiber-re- tions did cotf-contam a definition of a containing talc as a food or food additive leasing filter will or is likely to compro non-fiber-releasing filter. Comments also or in drugs or drug ingredients is unwar mise the safety or effectiveness of the stated that $ 103.8 should net use the ranted due to lack of sufficient data. In drug. Use of an asbestos-containing fil terms "fibcr-releasin?)' ar.d "asbestos- the interim, maufacturers of food and ter without subsequent use of an addi containing" interchangeably, and one drugs arc urged to investigate all means tional non-asbeatos-containir.g. non comment objected to the synoncmaus of eliminating the use of such filters and fiber-re!easing filter shall be permissible use of the terms "fiber" and "asbestos talc, and to keep the Food and Drug only upon submission of evidence that fiber." * Administration informed about changes- neither the substitution for the asbestos- The Commissioner agrees that the reg In formulation and processing of this containing filter ner the use of a sub ulation shouid.iiot speedy only one type 7< type. 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 potential of asbestos fibers, the Com safety or effectiveness of the drug. term "membrane filter." The Commis missioner proposed that the goad manu 2. One comment noted that, although sioner also concludes that, for the pur facturing practice regulations tor drugs there have been several demonstrations poses of these regulations, a non-ncer- be amended to require that filtration pro cf the addition of nonasbestos filters as rcleasing filter shall be defined as a con- cedures for parenteral drugs shall utilize final filters in the production of injecta asbestos, nonglass fiber filter which, cither a non-fibrr-relcasing filter such ble biologies, there remains concern that alter any appropriate pretreatment such as a membrane filter cr, if an asbestos- the replacement of asbestos filters with as washing cr flushing, wiil not continue containing filter is used because it Is r.cn-nsbestos-contnining filters would up to release fibers into the dims or drug necessary, the procedures shall also set delicate filtration parameters of the ingredient which is to be filtered. Tha utilize an additional non-asbestos-ccn- product preparation process. An 13- distinction is. therefore, made between talnhig or non-fiber-releasing filter such month period was suggested as the allow filters which release fibers by media mi as a membrane filter to reduce asbestos able period of time for technical develop gration, l.e., continuous release due to fiber content to the minimum level fea ment of tiie new processes. the nature of the filter, and filters which sible unless such a subsequent filter will The Commissioner agrees that a spe contain libers from structural supports compromise the strength, quality, product. safety. Identity, or purity of the cific period for process development and modification should be provided in the regulations. Therefore. 13 months will be and contamination. The utilization of nonasbestos, nonglass fiber filters in the Comments received in response to this allowed for compliance. Firms not con latter category will be permitted pro part of the notice, dealing with the in- forming to these regulations within 12 vided that appropriate prctrcr.lmcnt. FEDERAL REGISTER, VOL 40, NO. 51--FRIDAY, MARCH 14, 1975 --_i L..:r,,r.a:cj fit>er contaminant re than by individual evaluatien by knowl 17) have demonstrated mesotheliomas In lease. has bron accomplish*-. As the edgeable scientists. No automatic ce- r.ns nr.a rabbits from pleural ar.d peri .similarity bet.vren the carcinogenicities cision scheme was suggested in the com toneal in.cctior.s o: both chrysolite red of asbestos and fibrous glass has been ment. Therefore, the responsibility for crocidclite fibers. Further studies have noted, fibrous glass filters have b^en su'omissiar. of the evidence required for been initiated by the Food ar.d Dru* Ad added to this difinition to prevent the tills determination will rest with the ministration cn the cilects of parenteral widespread cunveisioa from cofcesi.es to manufacturer and the responsibility for injections of chrysotUe fibers in experi this type c' filter (Ret. 14 and 15>. A accepting or rejecting the request for use mental animals. fiber is define-:! ns "any particle with of asbestos-containing filters will rest 10. One comment indicated that, in length at least tluco times greater than with ike appropriate bureau in the Food the study of parenteral administration of its width" <R:f. 15 raid 16). and Drug Aiim.nistration. asbestos to animals by Schmahl (Ref. The Commir-iic.ier realizes that the T. Two comments objected to the fact 11), the tumors that occurred were not definition cr a fiber-releasing filter ex that the regulations were limited to the related to asbestos since they were cludes the possibility of the use of an release of asbestos and askestes-form sarcomas rather than mesotheliomas. Bsbesics or fibrous glass filter locked into fibers anti suggested that ah extraneous Although mesotheliomas are closely re a matrix which precludes the release of material such as diatomaceous earth, lated to inhalation of asbestos, there fibers. However, no such technology was carbon, silica, micro-fiberglass, etc., also r.Jso has been an azseciation cf carci presented as feasible by any of the com be regulated. noma of the lung with asbestos inhala ments. Therefore, the Commissioner The Commissioner agrees that there is tion. As with other carcinogens, several concludes that tire definition of a fiber- reason to be concerned about all par types of tumors fiiay occur as a result of releasing filter is appropriate for this ticulate contamination in parer.fcral exposure to a particular carcinogen de regulation and that, siiouid a method for drugs, but concludes that this problem pending upen. the route of exposure. The production of such a non-fiber-releasing should be considered separately from the Commissioner therefore concludes th3t asbestos or glass containing filter become subject regulations. Therefore, except for the data in this reference are valid ar.d .available, the definition wifi be subject to fibrous particulates, the Commissioner may potsibiy implicate asbestos in the review. 1 has decided to await clarification of the development cf these malignant tumors 5. One comment suggested tint the degree of other types of contamination of soft tissues, namely, sarcomas. proposed requirement that "no csbestcs- and the possible health effects of such 11. One commcntcr presented data containing filter may be used unless it is other particulates prior to developing demonstrating that membrane filtration not possible to manufacture a drug wi:h- applicable regulations. A call for scien was capable of removal of all asbestos out the use of such a filter" be replaced tific information in this regard will be particles from his asbestos-filtered prod by "when an asbestos-containing filter published in the Tzozn-u, Register in the uct (beer) as measured by electron mi is utilized, a suitabie after-fiiter must future. croscopy. However, even though the con also be utilized to retain fibers." 8. One comment objected to the re tainer for this product was subjected to 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 ihe possibility of del eterious effects, ar.d although an after- filter will substantially reduce the num ber of these fibers in toe product, it can not be assumed that it will remove ell of this material. Kence, the Commissioner has determined that the best me.'ns to eliminate asbestos contamination from parenteral crugs 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 an7 product the manufacturing process of which is re quired to te changed. However, he re iterates that the use cf an asbestos filter Trill be permissible crJy upon a demon stration by the manufacturer that the replacement of an asbestos filter by a ncn-fiber-relMsing filter or the utiliza tion of a final or after-filter is non-fiberrcleasing adversely affects the quality, safety, and cllectiver.ess of the product. 6. One comment objected to the state ment in the proposal that the use of asbestos filters in parenteral dru: manu facturing is prehinited "unless it is not possitle to manufacture that drug or drug ingredient without the use of such n filter," claiming that the lack c: 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 dr -ircil product quality rr.d effectiveness without quirement of proof cf reduction of asbes tos fibers by the use cf subsequent nonasbestcs-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. Tiiis and one ether com ment claimed that the National Institute lor Occupational Safety and Health (14IOSH) 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 Feed and Drug Administration and other government agencies are pres ently attempting to develop reproducible, practical ar.d useful methodologies for these analyses, and amendments to these regulations will be promulgated upon the satisfactory completion of tiiis research. The Commissioner has decided that un til these studies are completed, the evi dence for reduction of aabestos-form fiber content need not be obtained if adequate downstream filtration is ac complished. Thus, toe requirement of proof of reduction of asbestos fiber con tent is emitted and the use of a nonfiber-rclcasing filter of 0.2:1 micron maximum rare size is added to tiiis regu lation (0.1? micron maximum, if the manufacturing conditions so dictate). 9. One comment claimed that it is inappropriate to control all types of asbestos fierrs uniformly, as asbestos filters are compered primarily of chrycoUJe which is k-ss hazardous to human health than rur.phiboies. The Commissioner concludes that this differential in hazard has not been es tablished for parcntcrally administered a final rinse by municipal water, the packaged product contained a significant number of asbestos fibers. Similarly, the Fcor' and Drug Administration has found asbestos particles in parenteral drugs produced by manufacturers who do not use asbestos filters m 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 nonfiber-releasing filters equivalent to these required for post-asbeste?-filter filtration to remove inherent'-nber'eontamination. 12. The Environmental Impact Anal ysis Report (EIAR) and other relevant materials have teen reviewed and it has been determined that the proposed use will not have a significant environmental impact. Copies of Che EIAR are available in the office of the Assistant Commis sioner for Public Affairs, Rm. 15E-43, or the office of the Hearing Clerk, Rm. 4-65, Toed and Drug Administration, 5600 Timers Lane, Rockville, MD 20352. 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-renterxi Preparations, Pyrorens," In Remington's Pharmaceutical Sciences, 14th cd,, Chapter 82, p. 1542. 1070. 2. Mascn. T. J.. P. W. McKay and R. TV. Miller. "Arbestos-Lllie Fibers in Duluth Water Supply: Relation to Cancer Mortality," "Juv.-.ul of the American Medical A-aocla- tlun." '23U023. M ly 20. 1374. 3. Comment from Asbestos Research Coun cil. March l, 1074. 4. Cunningham, II. IS. and n. Pontefract: (a) "Asbestos Fibers in Beverages and Drinking Water," Nature" IM2:3J2~333, the use of acUctos-coutaining filters asbestos. Studies by Reeves et al. (Ref. 1071. > FEDERAL REGISTER, VOl. 40, NO, 51--FRIOAY, MARCH 14, 1975 j "1 RULES AND REGULATIONS llSoi) ,t>) "Bympeshssn cp Industrial Chemicals A Food Coatainiaanla." "Journal of the AtoocLiUoa of OUicla.1 Analytical C_emUis." A6:97t5-P31. 137J. t. ponWrac'. R,, and H. M. Cunningham. "Teaetratisr. of .\hb:sios tbrou.cn the DigvstlT Tract cf Eat*," "Nature." 263:352-353, 1973. 6. Davis. J. M. G.. Institute of Occupational products unless it is not possible to man ufacture that drug product or component without the use of ouch a filter. Filtra tion. ca needed, shall be through a nonfiber-relt.using filter. For the purposes of this regulation a non-f.ber-releasiag filter is defined as a nonr-cbcstos. r.cnglass fiber filter which, after any appro (Sera. 501. 302. 731. 52 StAt. 104>-105t. 12SS-1056. os amended; (21 UB.C. 351. 352. 371)) Dated: February 28,1975. A. M. Schmidt. Cormnisiioncr 0/ Food and Drugs. [FP. Doc.75--6733 riled 3-13-75;3:45 nm] Xtdlclce Edinburgh. Scotland, unpublished priate presentment such ca washing'or , report. 1. Eonarr. O. M.. and D. D. Clayton, "Fced- 1=5 of Blue Aib-stcs to Rats." 1007 Annual Report. British Empire Cancer Campaign for Research, p. 242. 8. "Report of the Advisory Committee on Asbestos Cancers to the Director of the In ternational Agency for Research on Cancer." flushing, will not continue to release . fibers into thj 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 o: a liber-releasing filter is required, an additional non-fiber-reieas- "British Journal of Industrial Medicine," 30:163-125.10*3. ' 9. jCelnfeld. M.. J. Messlte. and M. H. Zski. "Mortality Experiences Among Talc Work ers: A follow-up Scudy." "Journal cf Oc cupational Medicine." 16:345-319. 1971. 10. Nicholson. tv. H.. C. J. Mapglare and I. J. Se!L-:oT% "Asbestos Contamination of Rorenteral Drugs," "Science," 177:171-173, lng filter of maximum pore size of 0.22 microns (0.45 microns if'the manuiac- i luring conditions so dictate) shall sub- . r^2 iifQzi tq reduce trie cciatcut 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- , 1973. 11. Schmahl. D.. "Carcerogene Wirklp.g con Asbest bet Implantation von Ratten." "Zoitsehrlft fur Krebsforscbung." 63:561-567, 1353. 12. Roe. F. K. C.. R. L. Carter. M. A. Walters nd J. S. Harrington. "The Pathological ef fects of Subcutaneous Injections of Asbestos fiber'-releasing filter is permissible only . upon submission of proof to the appro priate bureau of the rood and Drug Ad ministration that use.of a non-fiber-re- leasing filter will, or is likely to. j compromise the safety or electiveness of j the drug. j Piters In Mice: Migration of Piters to EubsnesotheUal Tissues and Induction of Meso theliomas," "International Journal of Cancer ."2:633-623.1957. 13. itacazawa. K.. M. S. C. Blrbeck, R. L. Carter and F. J. C. Roe. "Migration of As bestos Fibers lrom Subcutaneous Injection Sites In Mice." "British Journal of Cancer," 24:9G-106.1970. (3) Substitution for a fiber-releasing filter shall be achieved on or before Sep- i tember 14, 19TG. If such substitution is not achieved on or before March 14, | 1976, the manufacturer of the drug prod- ! uct for parenteral injection who requires I the additional C months to develop new manufacturing procedures so as to utl- | 14. "Symposium on Occupational Exposure to Fibrous Glass." sponsored by National In stitute for Occupational Safety and Health. University of Maryland. June 26-27, 1574. 15. Stanton. Mearl F.. "Fiber Carcinogene sis: Is Asbestos the Only Hazard?" "Journal of the National Cancer Institute," 62:633 (1974). lize nor.-fiber-reieasing filters in place of [ fiber-releasing filters shall submit i monthly reports to the appropriate bu- I reau of the Food and Drug Administra- . tion indicating progress in substituting i the new filters. Such a substitution shall be shown to have been eflected without 16. "Occupational Exposure to Asbestos." Criteria document. UG. Public Health Serv ice, National Institute for Occupational Gaiety and Health. Chapter VTT1. pg. 6. 1373. 17. Reeves. A. J.. H. E. Puro. R. G. Smith loss of the safety or effectiveness of the drug. 2. By revising ! 133.9 to read as follows: V. .Ot. K'tllO td V*. sod A J. Verwa'.d. "Experimental Asbestos Carcinogenesis." "Environmental Research," 4:496-511.1971. 133.9 Product containers and tlicir components. Therefore, pursuant to provisions of the Federal Food. Dfug. and Cosmetic Act (secs. SOI. 503. 701, 52 Stat. 10491051, 1055-1C50, as amended; 21 U.S.C. 351, 352, 371) ar.d under the authority delegated to the Commissioner (21 CFR 2.120), Part 133 is amended as follows: 1. By amending $ 133.8 by adding new paragraph <J). to read as follows: 133.8 Production and control proce dures. a Suitable specifications, test methods, cleaning procedures, and when indicated, sterilisation procedures shall be used to assure that containers, closures, and ether component parts of drug packages are suitable for their intended use. Con tainers for parenteral drugs, drug prod ucts er drug components shall be cleansed with water which has been fil tered through a non-fiber-releasing filter equivalent to that indicated in 3 133.8(j) (2). Product containers and their com ponents shall not be reactive, additive, 75 .. CJ) Use of asbestos-containing or other fiber-releasing filters: (1) Filters used In the manufacture, processing or pack aging of components of drag products for parenteral Injection in humans shall or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug of its components beyond the official or established requirements and shall provide adequate protection against not release fibers into such products. No external factors that can cause deterio asbestos-containing or other fiber-re ration or contamination of the drug. leasing filter may be used In the manu Effective date. This order shall be ef- , facture. processing or packaging of such Icciivc April 14, 1975. * FEDERAL REGISTER, VOL 40, NO. 51--FRIDAY, MARCH 14, 1975 l CHRYSOTILE ASBESTOS IN PLASTICS John L. Myers "CAL I OR I A" ASBESTOS UNION CARBIDE CORPORATION MINING AND METALS DIVISION NIAGARA FALLS, NEW YORK Presented on May 14, 1974 at the 32nd Annual Technical Conference of the Society of Plastics Engineers in San Francisco. INTRODUCTI ON Asbestos has received a great deal of attention and publicity in recent years, especially after it was designated a "target health hazard" by OSHA and a "hazardous air pollutant" by the EPA. Many of the articles on asbestos by the press have been emotionally oriented or distorted and in some cases stories have been sensationalized, based on obvious misinterpretation of facts. The use of half-truths or unsubstantiated statements has led to general confusion and the unfair castigation of asbestos and products containing asbestos. The purpose of this paper is to put the matter of asbestos use and asbestos hazards in a logical and practical perspective. In this paper the different types of asbestos and their m3ny uses are discussed along with government regulations controlling the use of asbestos. The health hazards associated with asbestos, both occupational and environmental, and some industrial experience with air sampling and dust control measures are also covered. WHAT IS ASBESTOS? Asbestos is a commerical or generic term used to describe six naturally-occurring "asbestiform" minerals that are fibrous, hydrated metal silicates. The six varieties are divided into two classes, serpentine and amphibole, based on their crystal structure. Chrysotile is the only member of the serpentine class while the amphiboles include crocidolite, amosite, anthophylIite, tremolite and actinolite. Chrysotile is by far the most used variety and accounts for over 95% of U.S. consumption, as noted in Table I. Crocidolite, also known as blue asbestos, is imported from South Africa. Because of its high mechanical strength and good resistance to acids and alkalis, it is used to reinforce a limited variety of plastics where its pronounced color is not objectionable. Amosite, also imported from South Africa, is used primarily in thermal insulation. Although there are some deposits of anthophylIite in the U.S., most of it is imported from Finland. It is used primarily as a filler for polypropylene and in insulating materials. A comparison of the four varieties of asbestos which are of commercial importance is presented in Table II. It should be noted that there are significant differences between chrysotile and the amphiboles with regard to chemical composition and certain physical properties. WHERE IS ASBESTOS USED AMD WHY? Asbestos has served mankind for over 100 years in a broad variety of applications. The general areas in which asbestos is used in the United States are shown in Table III. Based on information from asbestos producers and consumption surveys, it is estimated that the plastics industry uses about 1/5 of the 800,000 tons consumed annually, which makes it the largest single user of asbestos fiber. The largest uses of asbestos by the plastics industry are in vinyl/asbestos floor tile and in phenolic molding compounds. It is also used in other plastics such as polypropylene, polyester, nylon, melamine, epoxy, silicones and vinyls. Asbestos provides According to the 33-member Advisory Committee on Asbestos Cancers of the International Agency for Research on Cancer (a division of the World Health Organization): "There is evidence of an association of mesothelial tumours with air pollution in the neighbourhood of crocidolite mines and of factories using mixtures of asbestos fibre types. The evidence relates to conditions many years ago. There is evidence of no excess risk of mesotheliomas from asbestos air pollution which has existed in the neighbourhood of chcysotile and amosite mines. There are reported differences on incidence of mesothelioma between urban and rural areas, the causes of which hove not been established. There is no evidence of a risk to the general public at present." (5) The same body quoted above has also concluded that there is at present no evidence of lung damage by asbestos to the general public; and such evidence as there is does not indicate any risk of cancer resulting from asbestos fibers present in water, beverages, food or in the fluids used for the administration of drugs. While there seems to be general agreement that the public is not in any present danger from asbestos, it is also recognized that excessive, long-term occupational exposure car, cause serious health problems. Also, if man-made emissions are not controlled, then environmental contamination could approach harmful levels. During the past two years, significant legislation has been enacted by the Federal Government to reduce and control occupational exposure to asbestos fibers and to minimize fiber emissions to the environment. Additional standards or regulations have been proposed or enacted by many state and local governments. SUMMARY OF OSHA REGULATIONS The WiI Iiams-Steiger Occupational Safety and Health Act of 1970 became effective on April 23, 1971, with the following Congressional purpose: "to assure so far as possible every working man and woman in the Nation safe and healthful working conditions and to preserve our human resources." The Act established the Occupational Safety and Health Administration (OSHA) within the Department of Labor, which has responsibility for administration and enforcement. Research and related functions are handled by the Department of Health, Education and Welfare (HEW) through the National Institute of Occupational Safety and Health (NI03H). Five million employers and 60 million of the nation's 80 million workers are covered by OSHA. Specifically excluded from coverage are government employees and operations which are protected under other Federal health and safety laws. In a news release issued January 4, 1972, OSHA announced a Target Health Hazards Program aimed at improving health factors associated wifh working conditions. The following five substances were designated to be the focus of initial and concerted efforts by OSHA and NIOSH: Asbestos, Cotton Dust, Silica, Lead and Carbon Monoxide. At the present time new standards have been established only for asbestos; although, of the 8,000 toxic substances on the exposes. On Mar on j>i , i a ; I , o^uks , >_ .-w.s^: i ; , . .. and mercury, was identified as a ''hazardous air pollutant" by the Administrator of the EPA. National Emission Standards fcr asbestos were then published by the EPA in the Federal register, Vol. 38, No. 65 - Friday, April 6, 1973. Although no numerical emission standards were established, operating criteria are prescribed to prevent or limit asbestos emissions to the outside air from asbestos mills, roadways, certain manufacturing operations, building demolition, and the spray-on application of materials used to insulate or fireproof equipment and machinery. The law further requires that spray-on materials used to - insulate or fireproof buildings, structures, pipes, and conduits shall contain less than \% asbestos on a dry weight basis. This should significantly reduce emissions to which the general public may be exposed, especially in large urban areas. "...the Administrator (of the EPA) has determined that, in order to provide an ample margin of safety to protect the public health from asbestos, it is necessary to control emissions from major m3n-made sources of asbestos emissions into the atmosphere, but that it is not necessary to prohibit all emissions. In this determination, the Administrator has relied on the National Academy of Sciences' report on asbestos, which concludes: 'Asbestos is too important in our technology and economy for its essential use to be stopped. But, because of the known serious effects of uncontrolled inhalation of asbestos minerals in industry and uncertainty as to the shape and character of the dose-response curve in man, it would be highly imprudent to permit additional contamination of the public environment with asbestos. Continued use at minimal risk to the public requires that the major sources of man-made asbestos emission into the atmosphere be defined and controlled."' (7) WHAT IS INDUSTRY DOING? The Asbestos Information Association/Morth America reports that, during the past 30 years, the asbestos industry has spent millions of dollars to improve mining, milling, and manufacturing methods (3). The establishment of safer working conditions has been a prime target and this work continues unabated and in close association with government agencies and independent medical researchers (9). The ultimate goals of the asbestos industry are: ----- Reduction of work-area dust to minimum levels. ----- Protection of workers from asbestos-related diseases. -- Maintenance of environmental emissions at levels low enough to preclude public endangerment. AIR SAMPLING In order to comply with 05HA Standards and to determine the need for dust control measures, air monitoring should be conducted in areas where asbestos is regularly handled or used. OSHA Standards require that "all determinations of airborne concentrations of asbestos fibers shall be made by the membrane filter method at 400-45QX (magnification) (4 millimeter objective) with phase contrast illumination." (10) The equipment for collecting air samples costs less than $400 and is readily available. A phase "this prooucT serves c ta i r porTior c* Trie a ;> ;j e o * w ~ _ Pellets not only reduce dust during conventional handling but they are also available in bulk hopper cars and can be transferred and used in totally enclosed systems. Barring leaks in the system, dust in work areas is virtually eliminated. Used in bulk, asbestos pellets also reduce shipping costs, eliminate warehouse storage and handling, facilitate automation, reduce clean-up, and eliminate bag handling and disposal. The pellets contain no binder and are friable enough to be dispersed in dry form or in aqueous or resinous systems with conventional high- shear grinding equipment (13). Several types of special packaging are currently available and suppliers consider customer requests for unusual requirements. The floor tile industry can obtain asbestos in plastic bags which can be added directly to the compounding operation. Asbestos in bleached paper bags assembled with water-soluble glue and printed with water-dispersible ink can be added directly to paper-making furnishes or acoustical ceiling tile formulations. Water-proof bags are available to permit slurrying of the asbestos in the bag. Wider use of shrink-filming is being offered to reduce dust during bag handling, transportation and storage. Although "wetted" asbestos is not generally available, most suppliers are working with customers to provide "dustless" products. When justified by market demand, asbestos can be treated with water, mineral spirits, glycol or other materials compatible with the application or system. CONCLUSION Asbestos is one of industry's many raw materials which involves a potential hazard when not used with reasonable respect and care. Although all forms of asbestos are recognized as hazardous to health when inhaled excessively, there is growing evidence that crocidolite and amosite are more hazardous than chrysotile. Fortunately the plastics industry uses primarily chrysotile asbestos and in most products the fibers are locked-in to prevent airborne contamination. Although asbestos dust levels are generally lower than expected, industry continues to expend large amounts of time and money to further improve the quality of the workplace. Although the general public is not currently in danger, occupational controls are required to prevent future environmental contamination. Chrysotile asbestos is an important and necessary raw material, vital to the nation's safety and economy; and, with proper control, it can be used safely and in compliance with government regulations. Medical, scientific, government, and industrial personnel must continue to work closely together to establish reasonable exposure limits, provide safe work areas, and eliminate any possibility of public endangerment. TABLE I APPARENT U.S. CONSUMPTION QP ASBESTOS, TONS* (? of Total Shown In Parentheses) Year 1967 1968 1969 1970 1971 1972 Tota 1 720583 817363 784321 728131 758571 808554 Chrysotile 686044(95) 775711(95) 749708(96) 695770(96) 729272(96) 791020(98) AmosIte 12558(1.7) 20467(2.5) 14618(1.9) 14261(2.0) 14580(1.9) 7!25(p.9) CroeldolIte 14917(2.1) 13965(1.7) 10558(1.3) 8936(1.2) 6953(0.9) 5374(0.7) Information based on import and production data from United States Bureau of Mines Minerals Yearbooks. TABLE II COMPARATIVE DATA FOR ASBESTOS MINERALS FORMULA CHRYSOTI LE 3Mg0-2S!02*2H20 CROC IDOLITE Na20' Fe23* 8SI02-H20 AMOSITE l.5MgO-5.5FeO* 8Si02*H20 ANTHOPHYLLITE 7MgO* esi02' H20 COMPOSITION,? SI02 MgO FeO Fe203 AI2O3 HpO CaO NapO CaO+NajO 37-44 39-44 0-6 0-5 0-2 12-15 0-5 - 49-53 0-3 13-20 17-20 2-5 - 4-8 49-53 1-7 34-44 - 2-9 2-5 m 0-3 56-58 28-34 3-12 - 0-2 1-6 m CRYSTALS COLOR TEXTURE FLEXIBILITY HARDNESS, Mohs FIBER DIA., X TENSILE, Mpsi SURFACE CHS. RES. TO AC 10 RES. TO ALK. Fine Fibers Gray/Green Soft/Silky Very Good 2.5-4 180-300 800 PosItive Poor Good Brittle Fibers Blue Harsh Good 4 600-900 600 Negative Good Good Prismatic Crystals Gray/Brown Harsh Good 5.5-6 600-900 200 Negative Good Fair Prismatic Crystals Gray Harsh Poor 5.5-6 600-900 <4 Negative Very Good Good Source: Modern Plastics Encyclopedia!1972-3), and Encyclopedia of Chemical Technology, Volume 2, p. 1360948). z(0 UI UI u >a J < 10 < > a ui i- u S UJ Ul DC rs- *?** 2m ^ CM T > CL < -U < u SLL < 2 i- X H3 O U 3d Zs s? ** (/> Si i | < 25th " w S =2 <-, 5 o CvS is at o" 2r1 .X eo * CY >C 2 x* ooO* EoOmUI i3! *|= ss c f CSS Ox *%x O_*ftu7Mx 11 " IsblraO E uii g'O <jo- <* CD A. 9P O 0. oP O CL UrCI 0O.. ^xuO0. Sta > DCO og^ oO.. >0.' 2 f/i < Cfl O < IA J in 'i" O Z n2c <L g8 SC r U^ uw(9_CDI 10 D<0 2 < 6 ui a3 5 > UJ 3 a < 2 x a a_ 5 r > | 2 JS 3e ~. o 0. 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