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in the Chemical laboratory Edited by NORMAN V. STEERE, 140 Melbourne Ave., S:E. Minneapolis, Minn. 5 5 4 1 4
CXVI. Occupational Safety and Health Standards
Carcinogens Pursuant to section 6(b) and (c) of the Williams-Steiger Occupational Safety and Health Act of 1970 (29 U.S.C. 655) and Secretary of Labor's Order No. 12-71 (36 FR 8754). Part 1910 of Title 29, Code of Federal Regulations, is hereby amended in the manner set forth below, in order to provide standards dealing with the expasure of employees to certain substances that are known to cause cancer. Background. On May 22, 1972, the Deputy Assistant Secretary of Labor for Occupational Safety and Health requested information from the Director of the National Institute for Occupational Safety and Health (NIOSH) on nine substances alleged to be carcinogens. As part of his ef-
dard serving as a proposal as required by section 6(c)(3) of the Act. Notice of the proceeding was published in the FEDERAL REGISTER an July 16, 1973 (38 FR 18900). On July 27, 1973, a revision of the emergency temporary standard was published a t 38 FR 20074, and an amended notice of rulemaking proceeding was published a t 38 FR 22141, on August 16,1973. The notices invited interested persons to submit, prior to September 5, written mmments, data and arguments concerning the proposals, and also provided for the presentation of oral testimony a t a public hearing scheduled for September 11-14, 1973. Numerous written comments
Occupational Safety and Health Administration. U.S. Department of Labor Solid or liquid mixtures containing 1.0% or mare by weight or volume:
Occupational exposure to fourteen chemicals known to cause cancer is now restricted by Federal regulation effective February 11, 1974. Laboratories using the chemicals are required to post warning signs a t entrances to regulated areas, eontrol access, label containers, maintain an inventory, and incinerate or inactivate wastes. Glove boxes are required for experiments or procedures which could produce aerosols, or laboratory hoods with an average linear face velocity of 150 feet per min and a minimum of 125 feet per min. Air exhausted from the laboratory must he decontaminated. The standards adopted by the Occupational Safety and Health Administration (OSHA) require medical surveillance of employees, indoctrination and training an the nature of carcinogenic hazards in the laboratory, reeord-keeping, and reports of the use of the carcinogens and the number of employees in regulated areas. Release of a carcinogen in an area where employees may be exposed must be reported, with information on the incident resulting in the release. The OSHA Standards have specific provisions far laboratory activities, based on safety guidelines drafted by the Cancer Research Safety Committee of the National Cancer Institute. Any area in which the following chemicals are stored, handled, processed, repackaged or released must comply with the standards: Solid or liquid mixtures containing 0.1% or more by weight or volume:
Chemical Benzidine (and its salts)
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fort to gain the best available scientific data, the Director published on July 6, 1972, a t 37 FR 13285, a request for information concerning 15 substances. The data, arguments, and conclusians received by NIOSH were made available to the Occupational Safety and Health Administration. On January 4, 1973, a petition for an emergency temporary standard from the Oil, Chemical, and Atomic Workers Union (OCAW) and Health Research Group (HRG) was received by the Department of Labor. The petition contained relevant information on the danger of exposure to 10 carcinogens, and suggested regulations to prevent worker exposure to the substances. On February 9, 1973, a notice was published in the FEDERAL REGISTER (38 FR 4037) of the receipt of the petition for issuance of an emergency temporary standard, and information was requested from interested persons on the issues involved. In response to the notice, more than 50 written comments were received. An emergency temporary standard on carcinogens was promulgated an May 3, 1973, a t 38 FR 10929. The standard eoncerned work practices and controls designed to protect employees from exposure to 14 carcinogenic substances. A standard advisory committee on carcinogens was appointed and began its meetings on June 25, 1973. The members of the committee represented employers, employees, Federal and state agencies and professionals. The committee terminated its meetings on August 24, 1973, and submitted to the Assistant Secretary of Labor for Occupational Safety and Health its recommendations for a standard on certain carcinogens on August 27, 1973. The recommendations were published in the FEDERAL REGISTER on September 7, 1973 (38 FR 24375). This rulemakine nraeeedine was eom-
Adopted for Fourteen Carcinogens*
Editor's Note:
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Chemical betaPropiolactone Ethyleneimine 2-Acetylaminofluorene 3.3'-Diehlorobenzidine (and its salts) 4-Dimethvlaminozobenzene
CAS Registgv Number 57578 151564 53963 91941 60117
Laboratories are urged to study the standards and their operations and to take action to comply, for protection of all personnel. Non-compliance can result in exposures and in penalties for violation of the law.
Title 29-Labor CHAPTER XVIIOCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR PART 1910-OCCUPATIONAL SAFETY AND HEALTH STANDARDS
were received and ahout 36 parties testified a t the hearing. The record of the hearing was initially held open until Septemher 28, for additional comments. After the close and certification of the record by the administrative law judge, additional comments mailed on or before September 28 were received. On October 2 the judge reopened the record far the limited purpose of including these additional comments. On October 15, the judge closed the proceeding and forwarded the certified record to the Assistant Secretary of Labor for Occupational Safety and Health for final decision. A final environmental impact statement on the proposed standard on carcinogens was filed with the Council on Environmental Quality on October 2, 1973, and copies were distributed to appropriate agencies. In a letter dated November 2, 1973, the Council pointed out alleged deficiencies in the statement filed. Pursuant to that letter, a supplement to the statement was sent to the Council on November 29, 1973, with a request for a waiver of the full, 30-day review period. By letter dated December 10, 1973, the Council advised that the request had been denied. Notice of the filing of the supplement was published by the Council on December 14, 1973 (38 FR 34488). followine are the maim issues raised The in the record of this proceeding: ~
(1) Selection of carcinogens. Same participants in this proceeding have demanded to know the criteria for the selection of the 14 substances for regulation. As the written submission of Uniroyal Chemical notes, thirteen compounds derive from Appendix A to the 1972 TLV pamphlet published by the American Conference of Government Industrial Hygienists (ACGIH). Alpha-Naphthylamine, which is not in the appendix, has been added because it has frequently been found, in industrial experience and in epidemiologic studies, together with beta-naphthylamine, and because experimental animal studies demonstrate its independent carcinogencity, Dimethylsulfate, which is in the appendix, is not included in the standards because it was concluded after consideration of the relevant literature that the documentation of its carcinogenicity was inadequate. The substances listed by ACGIH (except one) were selected in order to take advantage of the work and judgment of that group. Also, ten of the four-
HRG in their petition. (2) Documentation of coreinogenicity. The National Institute far Occupational Safety and Health (NIOSH), as official scientific advisor to OSHA, submitted to OSHA fourteen hazard review documents; one for each of the substances included in the standards. Each hazard review document contains a summary and evaluation of information and data obtained by NIOSH, including experimental animal and epidemiologic data. All but one of the substances are considered by ACGIH to be carcinogenic in man and/or animals. In promulgating these standards, OSHA has relied extensivelv but not exelusivelv.. on the hazard review documents prepared
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by NIOSH. Some of the substances are recognized as human carcinogens by some employers participating in this proceeding. For instance, although Young Aniline Works apparently takes issue with the studies which demonstrated Benzidine to be a human carcinogen, the Benzidine Task Force of the Synthetic 0rga"ie Chemical Manufacturers Association does not oppose OSHA considering henzidine as carcinogenic to humans. The essence of the NIOSH hazard review documents follows. 2-Aeetylaminofluorene. Experimental animal investigations involving rats, mice, rabbits, dogs, hamsters and fowl have demonstrated the carcinogenicity of 2Acetylaminofluorene (2-AAF). Investigations into the mechanism whereby 2Acetylaminofluorene exerts its earcinogenic effect have demonstrated that the Nhydroxylated metabolite? N-hydroxy-2AAF, was produced in several animal species and was more carcinogenic than the parent compound. The National Cancer Institute (NCI) demonstrated that humans also metaholize this substance to the same carcinogenic metabolite. From these findings, it seems reasonable to conclude that 2-AAF, which has been shown to be carcinogenic in many animal species, is carcinogenic in man. 4-Aminodi~henvl. The ~ o t e n t i a l of 4~minodiphenyl(4-ADP) to'induce bladder cancer in humans has been established in epidemiologic studies conducted by Melick et al. and Koss et al. Deichmann & Radomski considered 4-ADP to possess a relative carcinogenic potential for the dog 6 times greater than that of beta-Naphthylamine, 17 times greater than that of 4Nitrobiphenyl and 27 times greater than that of Benzidine. In addition, the carcinogenicity of CADP has been well-established in the open scientific literature with demonstrated potential for malignant tumor induction in rabbits and mice. The accumulated experimental and epidemiologic evidence have demonstrated 4-Aminatial. Benzidine. Benzidine was demonstrated to be carcinogenic in experimental animal investigations involving rats, dogs, hamsters, and mice. Epidemiologic investigations of worker populations exposed to Benzidine have clearly demonstrated that this substance and its salts are also eareinogenic in humans. The incidence of urinary bladder cancer in workers exposed to Benzidine in these epidemiologic investigations greatly exceeded the incidence of this disease in the general population. 3.3'-Dichlorobenzidine. The determination that 3,3'-Dichlorobenzidine (DCB) is potentially carcinogenic far humans rests on the determination that DCB has been shown to be carcinogenic in controlled animal studies involving rats, mice and hamsters. A clearly defined and statistically significant worker population exposed to DCB only, in either the past or in the present, is difficult to ascertain. Existing worker populations have been either exposed to other listed chemical carcinogens in their past work experience or are presently being exposed to other suspect car(Continued onpageA3241 Volume 51. Number 6. June 1974
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cinogens in addition to DCB. Therefore, the case ibr the human carcinogenicity of DCB must rely on extrapolation to humans of the mast pertinent animal studies of oncogenesis. The studies by the NCI concerning the induction of tumors, significantly including bladder tumors in hamsters, and the studies by Pliss e t al. concerning the induction of tumors in mice and rats present experimental evidence of tumor production in three animal species. Although DCB has been detected in the urine of workers receiving a minimum of exposure, the metabolism of this substance is unclear, although it probably differs from that of other carcinogenic aromatic amines such as Benzidine and betaNaphthylamine. 4-Dimethyldminoozobenzene. Numerous reports concerning carcinogenicity of 4Dimethylaminonzobenzene (DAB) in experimental animals have been published. This substance was demonstrated to he carcinogenic in rats, dogs, neonatal mice and trout. The similarity in metabolism of various aromatic amines in dogs and humans, emphasizes the importance of the finding that DAB has been demonstrated carcinogenic far dogs. alpha-Nophthylamine. The contamination of alphs-Naphthylamine (1-NA) by heta-Naphthylamine (2-NA) a potent carcinogen, and mixed occupational exposures involvine 1-NA and other aromatic amines has confounded the epidemiologic conclusion that 1-NA is carcinogenic in
man. Both 1-NA and 2-NA are readily metabolized ta various derivatives, several of which have a demonstrated carcinogenic potential in experimental animals. The demonstration that a metabolite of 1-NA, N-Hydroxy-I-naphthylamine,possessed a greater carcinogenic potential than the corresponding 2-NA metabolite, N-Hydroxy-2-naphthylamine, emphasizes this consideration. In addition, the extensive epidemiologic study in the dyestuffs industry conducted by Case failed to eliminate an active role for 1-NA as a human bladder carcinogen. betn-Nophthylominr beta-Naphthylamine (2-NA) was demonstrated to induce cancer of the urinary bladder in dogs, rhesus monkeys and hamsters. Tumors were induced in other organs of rats and mice exposed to 2-NA although attempts a t tumor induction in r a b h ~ t swas unsuccessful. Epidemiologic investigations of worker populations exposed to 2-NA clearly demonstrates that this substance is carcinogenic in humans. 4-Nitrobiphenyl. Because of the structural similarity of 4-Aminadiphenyl to 4Nitrobiphenyl and the experimental evidence for in vivo formation of 4-Aminodiphenyl from 4-Nitrobiphenyl, the epidemiologic investigations published by Meliek et al. and by Kass et al. are of special significance. These studies have demonstrated the potential of 4-Aminodiphenyl to induce urinary bladder cancer in humans. The case of the carcinogenicity of 4-Nitrabi~henvl is stronelv s u o ~ o r t e dbv
metabolized, in vim, to CAminodiphenyl (a highly carcinogenic aromatic amine), and the possibility that the cases of human urinary bladder cancer attributed by Melick et al. to 4-Aminodiphenyl only, may have been induced by exposure to 4Nitrobiphenyl as well. N-Nitrosodimethylomine. The cpcinogenicity of N-Nitrosodimethylamine (DMN) far the liver and kidney of the rat has been repeatedly demonstrated in experimental studies. In addition, primary tumors of the lungs have been induced in rats administered oral doses of DMN and inhalation af DMN has produced tumors of the nasal area. Other experimental animal investigations have demonstrated the carcinogenicity of DMN for the mouse, the hamster, the guinea pig, the rabbit and several species of fish. In view of this broad spectrum of carelnogenic activity in experimental animals, DMN must be regarded as potentially carcinogenic far man. beta-Propiolactone. The carcinogenicity of beta-Propidactone (BPL) has been demonstrated in mice by skin application, subcutaneous injection and intraperitoneal injection Malignant tumors have been induced in rats by subcutaneous injection, intratraeheal administration, and intragastric feeding. Skin application to hamsters induced a very high incidence of skin tumors. Although epidemiologic evidence demonstrating BPL to possess a carcinogenic potential for humans is not available, the weight of the experimental animal data indicates that BPL is also a carcinogen in humans. bis(Chloromethy1)ether. Investigations with experimental animals (mice and rats) have demonstrated that bis(ehloromethy])ether (BCME) is a very hazardous carcinogenic substance. Skin application or subcutaneous injection of experimental animals has resulted in malignant lesions a t the site of application or injection and in malignant tumors of the lungs. Of significance was the demonstration that 1 ppm or 0.1 ppm of BCME in air, induced lung cancer in mice or rats. Epidemiologic investigations conducted separately by the National Institute for Occupational Safety and Health and others demonstrated that employee exposure to BCME is extremely hazardous with a high probability of lung cancer. Chloromethyl Methyl ether. The results of investigations with experimental animals exposed to commercial grades of Chloromethyl methyl ether (CMME) have been inconclusive regarding the carcinogenicity of this substance because of contamination by small concentrations of the highly carcinogenic his- derivative-bis(Chloromethyl)ether. However, experimental animal investigations involving chemically purified CMME have demonst.mted that this substance possesses n carcinogenic potential. Epidemiologic investigations reported in 1972 and in 1913 strongly implicated CMME as a human carcinogen, although concomitant exposure to BCME cannot be discounted. 4,4'-Methylene-bisf2-ek10roaniline).The results of experimental animal studies in(Continued o n m g e A328)
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prior demonstration of carcinogenicity in at least two animal studies. volving rats and mice, as reported by three A major question of occupational careidifferent groups of investigators, have nogenesis relates to the extrapolation of clearly demonstrated n rsn~nugrnic POresults of animal experimentation to hutenrlal for 4.4'-.\lvthylcne.bri(2-chlorosnr. mans. The basis of numerous objections to Imc,. The rmrlts ut two ~ndustrialr r ~ ~ d i e r the proposals is that, even assuming the validity of animal experiments, such do involving workers exposed to 4,4'-Methylene-his(2-chloraaniline) were not defininot furnish sufficient evidence that the tive and cannot he relied upon to assess substances involved are carcinogenic to humans. Extrapolation of results obtained the hazards of occupational exposure to this substance, although one of the studies by animal experimentation is alleged to be reported that several exposed workers devitiated by several considerations: (a) veloped hematuria. That certain cancers are specific only to Ethyleneimine. The carcinogenic potensome species; (b) that the conditions of tial of ethyleneimine (EI) has been eonanimal experiments are out of proportion firmed hy a study conducted by Walpole to, and not consistent with, conditions in 1954 involving rats and one sponsored prevailing in industrial exposure; and ( e ) by the National Cancer Institute involving that no cancers have yet been detected in mice. In the first study, animals developed humans exposed to the substances. For injection site sarcomas which the investithose substances whose metabolism is ungators attributed to the direct action of derstood, and is similar in both animals Ethyleneimine, and in the second study 80 and man, the fact that they induce canpercent of the animals developed tumors, cers in animals warrants the expectation including more than ane-half with hepatothat they will induce cancers in men. This mas (which the investigators stated had applies to the substances which cause uri"malignant potentiality") and almost nary bladder cancers in animals acting, not directly, but indirectly through the three-quarters with pulmonary tumors. Although high doses of E I were adminismediation of metabolites formed bath in experimental animals and in exposed tered, the investigators stated there was no wav whether man would be workers. This is also true of those suh- to nredict . more or less susceptible to tumor induestances which apparently require no metation by EI. bolic alteration but attack a particular hiThe ease for the carcinogenicity of EI, ologic system (e.g., respiratory tract, alithen, rests on the extrapolation to humans mentary canal) which is similar in bath of the findings in two separate, controlled animals and humans. The abjections raise the much broader animal studies. This position is compatissue of human exposure to a chemical ible with that of NIOSH concerning the
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which is only known to have caused cancers in experimental animals. It is important to note that some opponents of the regulation of such chemicals do not advocate treating them as if they were harmless with respect to carcinogenic potential. Several employers, for instance insist that such substances must be treated with "care" or "respect," while also insisting that they call for significantly less protection than those substances known to be human carcinogens. We think it improper to afford less protection to workers when exposed to substances found to be carcinogenic only in experimental animals. Once the carcinogenicity of a substance has been demonstrated in animal experiments, the practical regulatory alternatives are to consider them either nan-carcinogenic or carcinogenic to humans, until evidence to the contrary is produced. The first alternative would logically require, not relaxed controls on exposure, but exclusion from regulation. The other alternative logically leads to the treatment of a substance as if it was known to he carcinogenic in man. We agree with the Director of NIOSH, and the report of the Ad Hoc Committee on the Evaluation of Low Levels of Environmental Chemical Carcinogens to the Surgeon General, U.S. Public Health Service, April 22, 1910, that the second alternative is the responsible and correct one. This decision accords with the work practices of some who object to the proposed regulation. For example, although the (Continued onpageA3301
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Pharmaceutical Manufacturers Association argues for the exclusion of research laboratories from the standard, it states as its ground the fact that employees in Pharmaceutical research are taught to work with all chemicals under the assumption that they are dangerous, unless it is specifically known that they are not. (3) The petition, zero tolerance, and permit system. The petition of Oil, Chemical and Atomic Workers Union (OCAW) and Health Research Group (HRG) for an emergency temporary standard on ten substances oroceeds on the assum~tion expuwrc ro .my arnounr c.icarc8tha~ n q e n i r sulrsrmre muat be prrxented. Accordingly. 11 prupwrs a standard ui zero tolerance permitting no exposure whatsoever. This objective would he accomplished by means of a permit system and frequent monitoring and reporting. We agree with the Ad Hoe Committee on the Evaluation of Low Levels of Environmental Chemical Carcinogens that a safe level of human exposure to any of the 14 carcinogens cannot he established by application of present knowledge. But we are not prepared to draw from this state of knowledge the conclusion that such levels do not exist. First, it is the professional opinion of many knowledgeable people that as yet undetermined safe levels of exposure possibly do exist. Also, a conclusion
that safe levels do not exist seems questionable in view of other studies, some in the area of carcinogenicity which demanstrated that below a certain amount of a single or cumulative dosage, no detectable harm is caused, or if harm is caused, the extent of such harm will be of no practicable importance because the latency period orior to manifestation of harmful effects ulll be uf gm-arer duratwn lhsn the normal hiespan ut mnn Swondl) , no powhle CIL pasure to the carcinogens under any circumstances could only he guaranteed by a total ban on the manufacture, use (even for cancer research), and transportation of the substances. As long as the substances are used, exposure to some amounts may occur because of breakdown of equipment or human error. Accordingly, the intent of the standards is to reduce exposure of workers to any of the listed substances to the maximum extent practicable consistent with continued use. Numerous objections have challenged the authority for, and the administrative feasibility of, the permit system proposed on July 16, 1973 (38 FR 18902). It is argued, for instance, that the Act requires the promulgation of general standards, in accordance with the procedures prescribed in section 6 of the Act, while the proposed permits would he tailored to particular users, and would he issued by a different procedure. Another objection argues that a permit system, to be effective, would require authority to stop an operation involving a
carcinogen by administrative action, in contravention of the statutory scheme which contemplates judicial determinations resulting in the cessation of an operation. With regard to feasibility, it is pointed out that a multitude of permits would be required, and that, therefore, the implementation of a permit system would require substantial resources and several years. It has been made clear that there are numerous uses and processes involving carcinogens. It appears, for instance, that there are 8W to 1800 users of 4,4'-methylene his(2-chloroaniline) alone. The investigations and evaluations of thousands of work situations involving a carcinogen, and the completion of the procedures, possibly including hearings, for the granting of the permits, would require many years and the diversion of substantial resources, even if available, from other serious occupational safety and health problems. After considering the administrative and legal aspects of a permit system, as against those of general standards enforced by the use of the current enforcement tools of the Act, the decision has been made not to adopt a permit system. The requirement in the adopted standards for employers to report the uses of carcinogens and the nature of operations involved, together with incidents of releases of carcinogens, will permit significant administrative surveillance. To be continued in the July 1974 issue.
