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Chapter 7 4, 4 ' ~METHYLENE-BIS (2~CHIORakNILTNE) H2 N 53CH2gNH2. C1 C1 4, 4 '-Mett~ylene-bis (2-chloroaniline), commonly referred to as MOCA (a req istered trade name), is a nearly odorless, crystalline solid that is yellow to tan in color (du Pont, 1977~. Its molecular weight is 267, its specif ic gravity (solid) is 1.44, its melting point is 110°C, and its solubility (t by weight) at 24°C is as follows: tr ichloroethylene, 4 . 2; toluene, 7. 5; ethoxyethylacetate, 34.4; mesityloxide, 43.0; methylethylketone, 51.0; tetrahydrofuran, 55 . 5; dimethylformamide, 61. 7; and dimethylsulfoxide, 75.0 . Its vapor pressure ranges from 1.3 x 10 5 mm Hg at 60°C to 5.4 x 10 S mm Hg at 120° C . MOCA is also known by the following synomyms, acronyms, and trade names: diamino-3-chlorophenylmethane, bisamine, di- (4-amino-3-chlorophenyl~methane, 4,4 '-diamino-3,3 '-dichlorodiphenylmethane, 3, 3 ' -d ichloro-4 -4 ' -d iaminod iphenyln~ethane, me thylene-bi s {o-chloroan i l ine ), E:,~ ' -methylene-bi~ (o-ct~ loroan i l ine ), DAC PM, MBOCA, MCA, Curaline M, Curene 442, and Cyanaset. 168

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PRODUCTION The sole U. S . producer of MOCA is Anderson De~relopn~ent Company in Adr fan , MiCh . (Stanford Research Institute International, 1979 ), but production has presumably been halted as a result of current litigation (see below) . du Pont had produced MOCA at its ~epwater, N.J. plant until 1978, when the company decided to phase out production (Chemical Week, 1978) . Because of the proprietary nature of the data , actual production levels are not reported, and estimates of annual MOCA production have varied substantially since 1974 (Table 7-1~. As indicated, estimated annual production rates have been as low as 500 kg to more than 4,500 kg. Because estimated annual consumption levels are much higher than these figures, it is likely that production levels are closer to 2 to 3 million kilograms. Some unknown quantity of MOCA is probably imported. USES MOCA is applied principally as a curing agent for polyurethanes and epoxy resins which are then used in the manufacture of specialized products, particularly integral-skin polyurethane semirigid foam (used for crash padding) and solid urethane rubber molding such as gear blanks and industrial tires (National Institute for Occupational Safety and Health, 19787. MOCA is added to vary the hardness, flexibility, and impact strength of these products. file most recent information on MOCA consumption indicates that more than 99% is used to manufacture polyure thanes . 169

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TABLE 7-1 Estimateda Production of MOCA, 1972-1978 Year 197 2 1974 1975 1976 1977 1978 Estimated Gross Production (Thousands of Kg ) 3,300 approx. 0.5 1+ 4.5 2,000-2 ,700b 4.5 Data Source Bell, 1973 U . S . Interna t iona 1 Trade Commiss ion, 19 7 5 U.S. International Trade Commission, 1976 U. S. International Trade Commission, 1977 Chemical and Engineering News, 1978 U.S. International Trade Commision, 1979 a Actual rates are not reported because of company con f identiality. b U. S. . consumption . 170

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Polyuretbanes cured with MOCA have been used in hundred. of applications (International Agency for Research on Cancer, 1974) . Military applications include ball seals on nuclear submariner, positioning strips in Poseidon missiles, and in encapsulation of electric components. In the automotive industry, they have been used in dashboard padding and in numerous small parse. Other reported uses include shoe soles; rolls for postage stamp machines; cutting bars in plywood manufacture; rolls and belt drives on ca'Qeres, computers, and reproducing equipment; and wheels and pulleys for escalators and elevators. Although systems to produce polyurethane elastomers without MOCA have been developed in recent years, many manufacturers continue to use MOCA-based methods because of the superior performance of the resulting products (Ulrich, 1978~. EXPOSURE me great potential for the distribution of aromatic amides throughout the environment as a consequence of the ir production has recently been documented (Williams, 1979~. Beginning in 1970, a small chemical plant began producing MOCHA in the southeastern Michigan town of Adrian. Between 1971 and 1978, production ranged from 184 ,137 kg to 580,684 kg per year Merger, 1979) . Initially, wastes from the plant were discharged into the Raisin River, which serves as a water source for some downstream communities. After 1973, the wastes were channeled into a lagoon before they entered Adrian ' s wastewater treatment system. In the winter of 1978-1979, 171

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continuing problems at the treatment facility prompted a closer examination of the materials coming from this lagoon and the plant. Local residents had long been disturbed by odors and dust that periodically permeated the area. Consequently, when the state recognized that MOCA was one of several products of this plant, numerous samples were analyzed. The results of these studies disclosed that nearly 18 km2 is contaminated with MOCA including approximately one-half of the town of approximately 20,000 inhabitants. m e compound appears to have been spread by every possible mechanism. Airborne particulates were the probable source of the material (up to 400 ppm) that collected in the eavetroughs of adj acent houses (Michigan De pa rtment of Natural Resources, 1979~. Mechanical tracking from the plant was suggested by the high levels of MOCA along the road that led from the facility. Surface soil samples from public roads as far as 1.6 km from the plant contained up to 2 ppm MOCA; those adjacent to the plant, up to 590 ppm; garden and yard samples from the local residences contained, up to 55 ppm; and house dust from vacuum cleaners, up to 18 ppm (Michigan Department of Natural Resources, 1979~. According to Parris et al. (1980) and Walkington (1979), transport aria water was evident from the MOCA content of sludge from the settl ing lagoon (1, 600 ppm), the wastewater treatment plant (18 ppm) ,and the Raisin River {10 ppm). Secondary transport of the compound also is believed to have occurred as a consequence of the agricultural use of the sludge frown the wastewater treatment plant. 172

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Evidence that humans }cave been exposed is provided by analyzing urine for MOCA. There are no Methods for analyzing urine for its metabolites. In experiments with rats, only a small quantity (usually less than 0.3~) of MOCA was excreted unchanged (Rommineni _ al. 19787. thus, the actual exposure is far greater than is implied by the concentration detected in the urine. Since essentially nothing is known about the metabolic disposition of MOCA in animals or humans, it is difficult to estimate exposure from urine analyses. Furthermore, it is likely that there is significant excretion of MOCA in bile. Available MOCA metabolism data indicate that the substance behaves as a polymorphic substrate for the acetyl CoA-dependent N-acetyltransferase of both rabbit and human liver (Glowinski et al., 1978~. The genetically determined levels of this enzyme may, in fact, determine the rapidity with which MOCA is excreted and/or converted to the reactive species involved in the carcinogenic process. From previous knowledge of aromatic amine metabolism in vivo, it is also expected that MOCA metabolites would be excreted relatively rapidly. Thus far, only the 5-hydroxy derivative has been reported as a urinary metabolite from an observation made in a study of dogs, a species incapable of N-acetylation (Barnes, 1964 ~ . The paucity of knowledge about MOCA metabolism complicates attempts to evaluate exposure by analyses of ur inary excretion. In spite of these complications, however, three categories of individuals were shown to have been exposed: the workers, their families ~ including spouses and children of all ages), and preschool children (ages 2 to 5 years) tiering in the area of the plant 173

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(Williams, 19791. It is believed that the families were contaminated by workers carrying MOCA home on their clothing since direct contamination of clothing was de~on';trated. me preschool children were presumed to have been emoted while playing in MOCA-contaminated soil; older neighborhood children did not have detectable levels of MOCA {i.e., ~ 0.3 ppt'} in urine. The workers were found to have up to 59 ppm MOCA in their urine; the members of the workers' families had urine MOCA levels of up to 15 ppb; ne ighborhood chi ldren had up to 2 ppb. The detection of MOCA in the urine of the workers' families was not dependent on the location of residence. It is not known whether plant materials grown in the gardens of the a rea represent a source of human exposure . Experiments to resolve this question are in progress. Heasurments suggest that the level of MOCA in the soil has declined little if any since the summer of 1979. Analyses of urine specimens from workers at several facilities that used the product from Adrian and other sources demonstrated that some individuals exore ted up to 0.7 ppm MOCA (Barger and Saftlas, 1979~. These observations; confirm findings of earlier studies (Hosein and Van Roosmalen, 19781. Environmental samples obtained from sites that had not been exposed to MOCA for more than 4 years still contained detectable levels of the amine (Schleusener, personal communication, 1980~. As far as is known, the Adrian plant has been the only MOCA production site in the United States for several years. Since current litigation has presumably halted 174

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production in Adrian, MOCA is now believed to be available to American users only from foreign sources. Conceivably, the use of MOCA-containing products could be a hazard. It is possible, for example, that hydrolysis of MOCA-containing polyurethanes could release very low levels free MOCA, or unreacted MOCA might be leached from plastic under certain conditions (Henning, 1974). Occupational exposures to MOCA are of concern, as indicated by recent federal actions. In 1969, the Food and Drug Administration disallowed the use of MOCA as a component of certain food-contact articles (Federal Register, 1969) . The National Institute for Occupational Safety and Health (NIOSH) recommended a standard of 3.0 ~g/m3 in breathing zone a ir determined as a time-we ighted average . me Occupational Safety and Health Administration (OSHA) is expected to set a standard for MOCA in 1980. me American Conference of Governmental Industrial Hygienists {ACG]H) has adopted a threshold limit value, time-weighted average concentration of 0.02 ppm for MOCA (American Conference of Governmental Industrial Hygienists, 19791. A national NIOSH survey (1978) indicated that in the early 1970's approximately 55,000 U.S. workers could have been exposed to MOCA. The ma jor ity of these workers were employed in small- to medium-sized establ ishments . Concentrations in the workplace were sampled in one study in Italy. As indicated in Table 7-2, concentrations ranged from 0.04 to 4.5 mg/m3--much higher than the proposed OSHA standard. It is not possible to judge the similarity between Italian and U.S. production conditions. 175

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Table 7-2 Sampled Concentrations of MOCA in the Workplace at One Facility in Italya MOCA Duration Concentration Sample Location (minutes) mg/m3) Near the blend ing reactor 180 0 .0400 where MOCA is mixed manu- ally Near another reactor 180 0.110 where MOCA is mixed automatically Above the oven in wh ich the 140 O . 283 container of MOCA is rehea ted Near the oven in which the 140 0.041 con ta iner of MOCA is rehea ted Above the exhaust of the 140 4.5 MOCA blending reactors a Source: Abstracted from Traina et al., 1978. 176

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ANALYTIC ME: THODS In additon to the general procedures already described for primary aromatic amines, most of the analytic methods for MOCK have focused on the analysis of air or urine by using gas chromatography (GC) or high-pressure liquid chromatography IMPLY procedures. Sawicki (1975) sampled air by drawing it through a tube of Gas-ch rom S . Sect ions of the tube pack ing were then extracted with 0.5 ml of acetone and analyzed by direct injection into ~ gas chromatograph equipped with a 30-cm long, 2.3 mm (internal diameter) stainless steel column packed with 10% Dexsil 300 GO coated on 80/90 mesh Anak rom ABS. The investigator used helium as the carrier gas and a flame ionization detector. An in Section of 1 p 1 of the acetone extract permitted the detection of 2 ng of MOCA or approximately 2 ~g/m3 for a 500-1 air sample. In field trials, no impurity was encountered that caused interference with the retention time of MOCA. Isomers of chloroaniline commonly associated with MOCA were completely resolved and did not interfere. The solvent effect was pronounced in that the MOCA peak appeared on the tailing edge of the acetone peak. It was therefore necessary to restrict injection volumes to 2 pi or less. At about the same time, Yasuda (1975) reported a method essentially identical to that of Sawicki, except that a 0 . 33 m long , 0 .04 cm ~ internal diameter ~ stainless steel column packed with the 10% Detail 300 GO was used. Sensitivities of both methods were identical. 177

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Van Roosmalen et al. (1979) reported a procedure to determine trace leve Is of MOCA in ur ine . We samples were partially cleaned up by solvent extraction, followed by thin-layer chromatography {TLC} on plates of silica gel G. The MOCA was then extracted from the TLC plate, converted to its trifluoroacetyl derivative, and analyzed by GC. The gas chromatograph was equipped with a 1.8 m long, 0.32 cm (internal diameter) glass column packed with 3% OV-1 on Gas Chrom Q and a flame ionization detector (FID}. A detection limit of ~ ~g/1 was claimed. After the investigators prepared the trifluoroacetyl derivative which is highly electron-capturing, they chose to use the FID and did not mention the possibility of using the more sensitive and specific electron capture-gas chromatograph system. The only HPLC procedure found in the literature for MOCA was reported in 1979 by Rappaport and Morales (1979} for determining airborne exposure of humans to MOCA. A personal sampler consisted of a filter to remove the. particulate HOCA, followed by a bed of silica gel to remove the vapors. We compound was extracted from the sampler stages with methanol, and a 10 pi alic~uot was in jected into an HPLC instrument equipped with a reverse-phase system and a 254 nm W detector. Quantitation of 3 ng of MOCA corresponded to 0.15 ~g/sample. Precision levels were 9.2% and 14% for 1.5 and 0.15 fig samples, respectively. 178

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MOCA was also tested in a pre incubation mc~dif ication of the Salmonella/raicrosome test in the National Institute of Environmental Health Sciences (NIEHS) Environmental Mutagenesis Test Development Program. S-9 from Aroclor 1254 induced male rat and Syrian hamster liver was used with |strains TA 98, TA 100, TA 1535, and TA 1537. MOCHA was mutagenic for strains TA 98 and TA 100 with S-9; hamster S-9 produced a higher response than rat S-9 in the TA 100 ultra in, and the responses in TA 98 were equivalent (K. Mortlenans, personal communication) . TeratogenicitY No data were available to evaluate the potential teratogenicity or reproduct ive tax ici ty of MOCA . CONCLUSIONS MOCA is a mutagen for Salmonella, requiring liver S-9 for its activity. Results in press show it is also active in bacterial repair tests, phage induction tests, E. cold mutagenesis, Drosophila, and cell transformation _ vivo. Mixed results were observed with yeast, chromosomal effects in cultured cells. and the micronucleus test In vivo. A more complete evaluation awaits publication of the IPESTTC study. Studies in test animals have demonstrated conclusively that MOCA is a carcinogen. This activity is to be expected from its structure, which is similar to that of other aromatic amines that 187

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induce tumors in humans as well as in animals. Although the paucity of epidemiologic evidence does not permit an evaluation of the carcinogenic effects of MOCA, it is reasonable to assume that, given a sufficiently high exposure, it may also be carcinogenic in burns. RECOMMENDATIONS The MOCA-exposed population in and around Adr fan, Mich . and ind ividua Is exposed as a consequence of the use of COCA should be studied further to learn whether or not the compound is carcinogenic in humans. This goal requires three types of effort. The f irst is to explore the metabolic disposition of MOCA so that methods for evaluating exposure to it can be developed. The second phase is to apply these methods, including an evaluation of necropsy specimens from any member of this population who dies during the course of investigation. Such studies would help better def ine the potential for risk to individuals, as well as aid in monitoring the effects of the cleanup efforts. The final step is the prospective surveillance of this population to determine whether exposure to MOCA increases their tendency to develop cancer. - 188

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REE1 ~ NCES Production, Uses, Exposure American Conference of Governmental Industrial Hygienists. 1979. TLVa: Threshold Limit Values for Chemical Substances and Physical Agents in the Workroom Environment with Intended Changes for 1979. American Conference of Governmental InduS trial Hygienists, Cincinnati, Ohio. 94 pp. Barnes, J.R. 1964. Toxicity study on VOCAL --4, 4 'methylene-bis (2-chloroaniline). Study No. MR-652-2, Sep. 10. DuPont Haskell Laboratory, Wilmington, De1. Bell, D. R. September 28, 1973. Final Environmental Impact Statement Proposed Regulation (Administrative Action), Handling of Cer ta in Carcinogens. Washington, D.C. Chemical & Eng ineer ing News. manufacture. 56 (36) :7. Occupational Safety and Health Administration, 1978. Du Pont to halt MOCA curative Chemical Week. 1978. Du Pont phasing out MOca production. 123(10):13. E. I . du Pont de Nemours & Co. 1977. 'MBOCA' and LD~813: Diamine curing agents for isocyanate-containing polymers. Pub. No. AP-710. 1. Federal Register. 1969. 34 (230~: 19073. Tuesday, December 2, 1969. 189

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Glowinski, I.B., H.E. Radtke, and W.W. Weber. 1978. Genetic variation in N-acetylation of carcinogenic arylamines by human and rabbit liver. Mol. Pharmacol. 14:940-949. Harger, J.R.E. 1979. Toxic Substance Control Commission, State of Michigan. Additional information concerning corene, memo to P.S. Cole, October 10, 1979 (curene production) . Harger, J.R.E., and A.F. Saftlas. 1979. Toxic Substance Control Commission. Analysis of 4,4 '-methylene-b~s- (2-chloroaniline) user data, memo to P. S. Cole. December 19,1979 . Henning, H. F. 1974 . Prec autions in the use of methylene-bis-`,-chlor-~a`,iline (MBOCA). Ann. Occup. Bye. 17: 137-14 2 . Hose in , H. R., and P . B. Vail Roosmalen . 1978. Acute exposure to methylene-bis -ort:ho- chioroaniline (MOCA) . Am. Ind. Hyg. Assoc. J. 39:496-497. International Agency for Research on Cancer. 1974. 4,4'-llethylene bis (2-chloroaniline). Pp. 65-11 in IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Han. Volume 4. International Agency for Research on Cancer, Lyon. 190

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Kommineni, C., D.H. Groth, I.J. Frockt, R.W. Voelker , and R.P. Stano~rick . 1979. Determination of the tumor igenic potential of methylene-bis-orthochloroaniline. J. Environ. Pathol. Toxicol. 2 (5 ): 149-171. Michigan Depar tments of Natural Resources . 1979. Curene Contamination in Adrian, Sugary of Investigations 1-9. Michigan Depar tment of Natural Resources, Air Quality Division, Lansing, Michigan . National Institute for Occupational Safety and Health. 1978. Special Hazard Review wi th Control Recommendations for 4 ,4 '-Methylene-bis (2-chloroaniline) . DREW {NIOSH} Publication No. 78-188. Available from National Technical Information Service, Springfield, Va., as PB-297 822. U.S. Dept. of Health, Education, and Welfare, Publ ic Health Service, Center for Disease Control, Cincinnati, Ohio. 67 pp. Parris, G.E., G.W. Diachenko, R.C. Entz, J.A. Poppiti, P. Lombardo, T.K. Rohrer, and J.L. Hesse. 1980. Waterborne methylene bis (2-chloroaniline ~ and 2-chloroaniline contamination around Adr fan, Michigan. Bull. Environ. Contam. Toxicol . 24: 497-503. Schleusener, P.L. 1980. Letter to C. M. King with enclosures. Michigan Department of Natural Resources. April 28, 1980. 191

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SRI International. 1979. 1979 Directory of Chemical Producers: Un ited States of Amer ice . Stanford Research Institute International, Menlo Park, Calif . 1122 pp. Traina, G., C. Sala, F. Beretta, and G. Cortona. 1978. Determinazone dell ' inquinamento ambrentale da MBOCA in una fabbrica di elastomer) polivretanici. Med. Liav. 69:530-536 Ulrich, H. 1978. Polyurethane. Modern Plastics 55 (10A) :88, 90, 96 -97 . U. S. International Trade Commission. 1976. Synthetic Organic Chemicals. United States Production and Sales, 1975. USIIC Publication 804. U.S. Government Printing Office, Washington, D.C. 246 pp. U. S. . Interna tional Trade Commission . 1977. Synthetic Organic Chemicals. United States Production and Sales, 1976. USING Publication 833. U.S. Government Printing Office, Washington, D.C. 357 pp. U. S. International Trade Commission. 1979. Synthetic Organic Chemicals . Un ited States Production and Sales, 1978. USITC Publication 1001. U.S. Government Printing Office, Washington, D.C. 369 pp. lg2

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U. S. International Trade Commission, 1975. Syn the t ic Organ ic Chemicals. United States Production and Sales, 1974 . USITC Production 176. tJ.S. Government Printing Office, Washington, D.C. 256 pp. Walk ington, T. 1979. Michigan Department of Natural Resources, meeting with the city (Adrian) on April 23, 1979, Adrian-AndersOn Development Co. File, May 7, 1979. Williams, D.E. 1979. Curene 442 test results, Tables 1-9, October 5, 1979. Division of Environmental Epidemiology, Michigan Department of Public Health, Lansing, Michigan. 193

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Analytic Methods Rappaport, S.M., and R. Morales. 1979. method for 4 ,4 '-methylenebis (2-chloroaniline) . 51: 19-23 . Air sampling and analytical Anal. Chem. Sawicki, E. 1975. 3, 3 '-Dichloro-4 ,4 '-diaminodiphenylmethane (HOCA) in a ir: Analyt ical method . Health Lab . Sc i . 12: 415-418 . Van Roosmalen, P.B., A.L. Klein, and I. Drum~nond. 1979. An improved method for determination of 4,4'-methylene his- (2-chloroaniline) (MOCA) in urine. 40: 66-69 . Yasuda, S.K. 1975. Am. Ind. Hyg. Assoc. J. Determination of 3, 3 '-dichloro-4, 4 '- diaminadiphenylmethane in air. J. Chroma tog r . 104: 283-290. 194

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Health Ef feats Anderson, D., and J.A. Styles. bacter ial mutation test. Barnes, J. R. 1964. 1978. Appendix II. me Br . J. Cancer 37: 924-930 . HA Toxicity study on FOCAL 4, 4 'methylene-b~s- (2-chloroaniline, . Study No. MR-652-2, Sept. 10 . DuPont Haskell Laboratory, Wilmington, De1. Glowinski, I.B., H. E. Radtke, and W.W. Weber. 1978. Genetic var. iation in N-acetylation of carcinogen ic arylamines by human and rabbit liver. Mol. Pharmacol. 14: 940-949. Ho, T., A.A. Hardigree, F.W. Larimer, C.E. Nix, T.K. Rao, S.C. Tipton, and J. L. Epler . 1979 . Compara tive mutagen ic i ty study of potentially carcinogenic industrial compounds. Environ. Mutagen. 1 :167-168 (Abstract No. Ea-10) . Hosein, H.R., and P.B. Van Roosmalen. 1978 . Summary repor t: Acute exposure to methylene-bis-o-chloroaniline {MOCA). Am. Ind. Hyg. Assoc. J. 39 :496-497. Kommineni, C., D.H. Groth, I.J. Frockt, R.W. Voelker, and R.P. Stanovick. 1979. Determination of the tu'Dorigenic potential of methylene-bis~or thochloroaniline. J. Environ. Pathol. Toxicol . 2 (5 ): 149-171 . 195

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Linch, A.L., C.B. O'Conner, J.R. Barnes, A.S. Killian, Jr., and W.E. Neeld , Jr . 19 71 . Methylene-bis-ortho~chloroan iline (MOCA ): Evaluation of hazards and expo';ure control. Am. Ind. Hyg. AsSoc. J. 32: 802-819. Mastromatteo, E. 1965. Recent occupational experiences in Ontario. J . Occup. Med . 7: 50 2 - 511 . McCann , J., E. Choi , E. Yamasaki, and B.N. Ames. of carcinogens 1975. Detection mutagens in the Salmonella/microsome te~t: Assay of 300 chemicals. Proc. Natl. Acad. Sci. U.S.A. 72: 5135-5139. Russfield, A.B., F. Homburger, E. Boger, C.G. Van Dongen, E.K. Weisburger, and J.H. Weisburger. 1975. The carcinogenic effect of 4,4 '-methylene-bis- {2-chloroaniline} in mice and rats. Tox icol . Appl ~ Pharmacol . 31: 4 7-54 . Stula, E.F., H. Sherman, J.A. Zapp, Jr., and J.W. Clayton, Jr. 1975. Experimental neoplasia in rats from oral administration of 3,3 '-dichlorobenzidine, 4,4 '-methylene-bi'; {2-chloroaniline), and 4,4 '-methylene-bis (2-methylaniline) . 31: 159-176. 196 Toxicol. Appl. Pharmacol.

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Stula, E.~., J.R. Barnes, H. Sherman, C.F. Reinhardt, and J.A Zapp, Jr. 1977. Urinary bladder tumors in dogs from 4, 4 '-me thylene-b is (2-chloroan il. ine ~ (MOCA ~ . J. Environ . Pathol. Tuxicol. 1:31-50. Takemura, N., and H. Shimizu. 1978. Mutagenicity of some . aromatic amino- and nitro~ompounds. Stat. Res. 54: 256-257 (Abstract No. 35 ~ . 197