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Chapter 8 2,4-DIAMINOTOLUENE NH2 \ H3C of/ \ - NH2 ~ . 2,4-Diaminotoluene (toluene-2,4-diamine; 2,4-DT) is a colorless crystal that melts at 99C. It is soluble in hot water. 2,4-DT synthesis takes place in three steps, beginning with the nitration of toluene in a mixture of nitric and sulfuric acids at 30C to 70C. The resultant mononitrotoluene mixture is then nitrated again in a somewhat stronger acid medium to a mixture of dinitrotoluene isomers, of which the largest fraction is 2,4-dinitrotoluene {75.89~. A number of processes can then be used to produce 2, 4-DT from 2,4-dinitrotoluene. All of these methods involve catalytic hydrogenation, followed by pur if ication, to remove unwanted isomers and byproducts, PRODUCTION Table 8-1 lists the current producers of 2,4-DT, their locations, and (where available) their estimated annual capacities (Chemical Economics Handbook, 1977-1978; Stanford Research Institute International 1979; United States International Trade Commission, 1979~. 198

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TABLE 8-1 Producers of 2,4-DT Company and Plant location Air Products and Chemicals, Inc. Industr ial Gases Div. Middlesex, N . J. Pasadena, Tex. A1 1 fed Chemica 1 Corpora tion Specialty Chemicals Division Moundsville, W. Va. Amer lean Cyanamid Co. Organic Chemicals Division Bound Brook, N. J. BASE Wyandotte Corporation Polymers Group Urethane Division Geismar, La. E. I . du Pont de Nemours & Company, Inc. Elastomer Chemicals Department Deepwater, N. J. Hobay Chemical Corporation Estimated Annual Capacity as of January 1, 1979a mousends of metric tons (owned by Bayer AG, Federal Rep. of Germany} Polyurethane Division Cedar Bayou, Tex. New Martinsville, W. Va. Olin Corporation O1 ins Chemicals Group Ast~tabula, Ohio Brandenburg, Ky. Lake Charles, La. Rochester, N. Y. Rubicon Chemicals Inc. (jointly owned by Uniroyal, Tnc., and Imperial Chemical Industr ies Limited, United Kingdom) Geismar, La. NIP 57a 30 Not 36 25 47 36 11 NOR 36 NIP 15 Estimates of production capacities are based on an assumed 2,4- diaminotoluene capacity of O .8 mete ic tons for each aetr ic ton of eoluene diisocyanate capacity, except for Air Products and Cbemicals, Inc., which does not produce toluene diisocyanate. b Not repor ted . 199

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Total U.S. production of 2,4-DT has declined in recent years (U. S. International Trade Cc~mmisaion, 1976-1978) as shown in Table 8-2 . USES 2,4-DT is used almost exclusively for the production of toluene d i isocyanate . Other V. S. . consumption is estimated to amount to less than 230 metr ic tons annually (Chemical Economics Mandbook, 197 7-197 8 ) . Mixtures of isomers of 2, 4-DT are normally used to produce toluene diisocyanate. The most important mixture contains 80% of the 2 ,4-isomer and 209 of the 2,6-isomer. Eight U.S. companies produced 284, 072 . 4 metr ic tons of the 80/20 toluene di isocyanate mixture in 1978 (International Trade Commission, 1978~. A mixture containing 65% 2 ,4-isomer and 351 2,6-isomer is also used in significant quantities. Only a small quantity of 2,4-DT is isolated for oonver s ion to pure 2, 4 -toluene di i~ocyanate . The Chemical Economics Handbook (1977-1978 ~ estimated the U. S . consumption pattern for toluene diisocyanate in 1978 as Down in Table 8-3. 2, 4-DT can be used to produce (approximately} 60 dyes, which are used to color silk, wool, paper, boat f ibers, cellulosic f ibers, and cotton. The following nine dyes are believed to have been produced from 2,4-DT in the United States during 1978: Basic Brown 4, Basic 200

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Table 8-2 Annual Production of 2, 4-DTa . . Year 1976 1977 1978 Thousands of metr ic tons 105 e 9 lOle 1 63 e3 a Data from U. S. International Trade Commission, 1976-1978. 201

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Table 8-3 U.S. Consumption of Toluene Di-isocyanate in 1978a Use ~ _ Flexible polyurethane foams Polyurethane surface coatings Polyurethane elastomers Other (including rigid polyurethane foam) Total Percent of Total 83% 6 3 8 100% a Data from Chemical Economics Handbook, 1977-1978. 202

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Orange 1, Direct Brown 2, Direct Brown 154, Direct Black 4, Leuco Sulphur Orange 1, Leuco Sulphur Brown 10, Solvent Brown 12, and Sulphur Black (Colour Index, 1975; U.S. International Trade Commission, 1978) . They are used in spirit varnishes and wood stains as indicators, in the manufacture of pigments, and as biolog to s ta ins . 2,4-DT is used as a developer for direct dyes, particularly to obtain black, dark blue, and brown shades, and to obtain navy blue and black colors on leather. It is also used to dye furs and was an ingredient in hair dye formulations until banned in 1971 (International Agency for Research on Cancer, 19781. EXPOSURE More than 99% of the 2,4-DT produced in the United States is used to produce toluene di isocyanate, generally at the site of production. The s ingle exception is the Air Products and Chemicals Plant at Pasadena, Tex., which produces no toluene diisocyanate and conversely, a 45,000 metric ton/year capacity toluene diisocyanate plant at Freeport, Tex. operated by Dow Chemical, which does not produce its own 2,4-DT. Therefore, the main sources from which humans are exposed will be the plants listed in Table 8-1. However there is no information on which to base an analysis of either occupational or general exposures from plant emissions. Because the substance is solid at ambient temperatures, air emissions from 2,4-DT production do not appear to be significant. 203

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However, contamination of wastewater discharges from the plants is a likely route of exposure. The hydrogenation of dinitrotoluene yields 4 mol of water for every mat of 2 ,4-DT produced (600 1 of water per metric ton of 2,4-DT) . This water is separated in a dehydration column at 100C-150C at atmospheric pressure (Milligan and Gilbert, 1978~. Because the vapor pressure of 2,4-DT is 11 mm Hg at 150C and it is soluble in hot water, the separated water is undoubtedly highly contaminated. This wastewater is probably treated before it is discharged. Some 2 ,4-DT could find its way into consumer products as an impurity in dyes. However, such exposure is nearly impossible to quantify. Under the U. S . Food and Drug Administration (FDA) regulation concerning 2,4-DT, (21 CFR 177) is listed under the category of ant ioxidants and ant iozonants . The total of these components is not to exceed S ~ by we ight of rubber product. The U.S. Occupational Safety and Health Administration does not have an occupational standard covering the exposure of workers to 2,4-Dr. 2()4

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ANALYTIC METHODS Jones et al. (1978) reported separations of nondye components in the commercial food color preparation Brown FK. The dye, which is manufactured by the reaction of diazotized sulfanilic acid with a mixture of m-phenylenediamine and 2,4-diaminotoluene, has been shown to consist of six major colored components. High-pressure liquid chromatography (HPLC) and thin-layer chromatography (TLC) procedures were evaluated for their ability to separate a mixture of the six dye components as well as the starting compounds (e.g., 2,4-DT) used in the synthesis. Two different columns and solvent systems were used in the HPLC investigations with a W absorption detector set at 254 nm. One of the systems, which consisted of a column of Partisil 5 loaded with 7% aminopropyl phase, was subjected to a 30-minute linear gradient from acetonitrile-water (2:3) to acetonitrile-water (2:3 containing sodium biphosphate (2 g/1~. Only partial resolution of the components was obtained. The other HPLC system, which consisted of a column of Chromosorb Si 100 loaded with a 21% octadecyl phase subjected to a 17-minute linear gradient from 5% to 40% acetonitrile in water (containing 1.2 and 2.4 g/1 of sodium biphosphate and sodium hypophosphate, respectively} was more successful: all nine components of the mixture were separated with essentially baseline resolution. Unger and Friedman (1979) developed an HPLC procedure to assay 2,6- and 2,4-DT. Their technique was adaptable to biomonitoring and metabolic studies with samples of urine and plasma from rats. A normal-phase silica column was used with a mobile phase consisting 205

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of acetonitrile-water saturated chloroform (8:2) and a 250 nm W absorption detector. The two compounds were resolved as 'sharp peaks in 3 minutes, and from 1 ng to 2 ng of each substance was quantitatede Dichloromethane extraction of urine and plasma "piked with 2,4-DT (10 to 200 ppm), yielded recoveries of about 90% or more. TEC tests were performed by using Inactivated silica gel G plates (layer thickness 0.25 mm) with a solvent system of phenol~ater (4 :1) . The starting materials of the manufacturing process {e . g ., 2 , 4-DT) were detected by spraying with 19 Ehrlich 's reagent in 50% acetic acid. Although the TLC system resolved for the six dye components, it was not suitable for the other compounds since sulfanilic acid was not resolved from one of the dye components. The two aromatic amines (2,6- and 2,4-DT) were not well resolved and ran close to the solvent front. Spectrophotofluor imetry {SPF} was the basis for a method described by Guthrie and Mckinney (1977) to analyze 2,4- and 2,6-DT in flexible polyurethane foams at levels as low as 1 ppm. me amines were extracted wi th methanol, separated by TLC, and assayed by SPF after reaction with Fluram reagent. The SPF assay was accomplished by uniformly spraying the developed and dried TLC plate with an 0.015% solution of Fluram in acetone and measuring the fluorescent spots (NEX = 390, XEm = 500 nm) with a "bin-film chromatographic scanner. The instability of the Fluram derivative required that quantitative measurements be completed within 1 hour. The nonuniform cbaracteristic of foams was determined by assaying sample extracts in duplicate at the 10 to 15 ppm level. Precision, 206

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usually within +10% for a given extract, was +30% for six different samples of tbe same foam. Lepri et al. (1976} investigated the behavior of several coloring agents (including 2,4-DT} used in oxidation-type hair dyes on thin layers of various ion exchangers. Some of the systems provided un ique separations. Examples of such systems are AG 1-X4 (CH3co2-) developed with 0.1 mol acetate buffer in a 4:1 water-methanol mixture; BD-cellulose developed with 0.5 mol acetate buffer solution; Dowex 50-X4 (H+) with O .1 mo1 acetate buffer in a 1:1 mixture of water-methanol; Rexyn 102 (H+) developed with various mixtures of dimethy~formamide-water; and AG 3-X4A developed with 95% ethyl alcohol. Rf values were tabulated for some IS compounds . Two direct gas chromatography {GC) procedures for separation and analysis of isomeric diaminotoluenes were reported in 1968. Willeboordse _ al. (1968} separated mixtures of 2,3-, 3,4-, 2,4-, 2,5-, and 2,6-DT using a mixed partitioning agent of Carbowax 20M and Saponate DS-10 on base-loaded Chromosorb G. followed by Saponate DS-10 on the same solid support. Boufford (1968) separated a mixture of 3,4-, 2,3-, 2,4-, 2,5-, and 2,6-DT on a column of 5% Bentone 34 plus 155 Hyprose SP-80 [octakis(2-hydroxypropyl)-sucrose] on potassium-hydroxide-treated Chromosorb W at 170C. Helium carrier gas and a hydrogen flame ionization detector (FID) were used. The analysis of 2,4-DT was specifically mentioned in several of the procedures described for primary aromatic amines. Additional 207

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discussions in the literature (details unavailable) involve in situ TLC determinations of toluenediamine and methylenedianiline isomers in the products of hydrolytic degradation of polyurethanes (Lesiak and Orl ikowska, 1978 ~ and an ultrasonic method to assay amine ! solutions, including toluenediamine (Bogdanova et al., 1976) 4 208 .

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significantly different for the control and 2, 4--treated groups. Similar results were obtained for the other compounds. Chromosomal Damage in Humans . No data are available on the possible genotoxic effects of 2,4-DT Eer se in humans. However, in a recent epidemiologic study of the potentially genotoxic effects of hair dyes (Kirkland et al., 1978), chromosomal damage was investigated in peripheral-blood lymphocytes of professional hair colorists. The authors found no significant differences in chromosomal damage in cultured per ipheral-blood lymphocytes from 60 professional ha ir colorists as compared with those of 36 control subj ects closely ma tched for age and sex. There was a statistically signif icant excess of chromosomal damage (mainly chromatic breaks ~ in women wi th dyed ha ir when age-matched women were regrouped according to whether their hair was dyed or not. Men (mean age 22 .9 years) with dyed hair had signif icantly less cheomosomal damage than did men (mean age 31.5 years) whose hair was not dyed. Possible confounding factors in these findings are that most tinters wear gloves when applying hair dyes and, even without gloves, percutaneous absorption of ha ir dye constituents may be effectively impeded by the horny surface of the bands and by the lack of sebaceous glands in the palms ; ha ir dye constituents are readily absorbed through the scalp, which contains numerous sebaceous glands; and the lower frequency of chromosomal aberrations in young men with dyed hair (compared with the frequency in slightly older men without dyed hair) is 217

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probably due to an age effect. This preliminary evidence on the genotoxic effects of hair dyes in humans warrants further study in view of the known mutagenicity and carcinogenicity in animals of several hair dye constituents. C NCLUSIONS 2,4-DT is carcinogenic in rats and mice after oral administration; the produces amine produces liver and mammary gland tumors. There is some evidence that it also induces sarcomas at the site of subcutaneous injection in rats. Published data on the carcinogenicity of 2,4-DT after application to mouse skin are not adequate for evaluation. 2,4-DT is a potent mutagen in microbial test systems and causes germ cell mutation in D. melanogaster. The substance may cause chromosome! damage to (chromatic and chromosome gaps and breaks) in humans. It also induces cell transformation in an _ vitro mammalian carcinogenesis test system. However, there are no data, such as case reports or epidemiologic studies, on the carcinogenicity of 2,4-DT in humans. RECOMMENDATIONS There is absolutely no information available on the 218

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mechanism by which 2,4-DT is activated in susceptible species, including rats and mice. However , given the demonstration of carcinogenicity in two species of animals and the data on the genotoxic effects in In vitro systems, it is prudent to assume that humans are under some increased rink from exposure to 2, 4-DT. Recommendations for future research with 2,4-DT include studies of the mechanism by which the chemical is activated in rats, mice and humans, testing for carcinogenicity in additional species to obtain more data on the relationship between metabolism and carcinogenicity, and examination of the in vitro metabolism of 2,4-DT in human tissues to supplement the preliminary observations of Glinsukon et al. {19757. This kind of additional data would make it easier to estimate the extent of risk to humans exposed to 2,4-DT 219 .

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REFERENCES Production, Uses, Exposure Chemical Economics Handbook. 1980. Stanford Research Institute International, Menlo Park, Calif . Code of Federal Regulations. food and additives: Polymers. 1980. Title 21, Part 177. Indirect Office of the Federal Register, National Archives and Records Service, General Services Administration, Washington, D.C. Colour Index. 1971. Third edition, volume 4. m e Society of Dyers and Colourists, Bradford, Yorkshire. International Agency for Research on Cancer. 1978. 2,4-Diaminotoluene. Pp. 83-95 in IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Volume 16. International Agency for Research on Cancer, Lyon. Milligan, B., and K.E. Gilbert. 1978. ~nines, aromatic--Diaminotoluenes. Pp. 321-329 in Kirk-Othmer Encyclopedia of Chemical Technology, Third edition, volume 2. John Wiley & Sons, New York . SRI International. 1979. 1979 Directory of Chemical Producers: United States of America. Stanford Research Institute International, Menlo Park, Calif. 1122 p. 220

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V. S. International Trade Commission. 1977. Synthetic Organic Chemicals . Un ited States Production and Sales, 1976 . USED Publication 833. U.S. Government Printing Office, Washington, D.C. 357 pp. UPS. International Trade Commission. 1978. Synthetic Organic Chemicals. United States Production and Sales, 1977. USTTC Publication 920. U.S. Government Printing Office, Washington, r).c. 417 pp. U. S. International Trade Commission . 1979. Synthetic Organic Chemicals. United States Production and Sales, 1978. USITC Publication 1001. U.S. Government Printing Office, Washington, D.C. 369 pp. 221

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Analytic Methods Bc~danova, T.M., P.V. Mulyanov, N.M. Monabarzh, and M.L. Piroshkova. 1976. Ultrasonic method for analysis of amine solutions. Zavod. Lab. 42:1486-1487. [Chem. Abs. 86:199421s, 1977.] Boufford, C.E. 1968. Determination of isomeric diaminotoluenes by direct gas-liquid chromatography. J. Gas. Chromatogr. 6:438-440. Guthrie, J.L., and R.W. McKinney. 1977. Determination of 2,4- and 2, 6-diaminotoluene in flexible urethane foams. Anal. Chem. 49: 1676-1680 . Jones, A.D., D. Hoar, and S.G. Sellings. 1978. Separation of non-dye components of Brown FK by high-performance liquid chromatography. J. Chromatogr. 166:619-622. Lepri, L., P.G. Desideri, and V. Coas. 1976. Separation and identification of colouring agents in the oxidation-type hair dyes by ion exchange thin-layer chromatography. Ann. Chim. (Rome) 66:451-460. Lesiak, T., and H. Orlikowska. 1978. ~In situ~ determination of toluenediamine and methylenedianiline isomers in the products of hydrolyltic degradation of polyurethanes after separation by thin-layer chromatography. Chem. Anal. (Warsaw) 23:469-475. [Chem. AbS. 89: 216094u, 1978.] 222

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Anger, P.D., and M.A. Friedman. 1979. High-performance liquid chromatography of 2,6- and 2,4-diaminotoluene and its application to the determination of 2,4-diaminotoluene in urine and plasma. J. Chromatogr. 174:379-384. Willeboordse, F., Q. Quick, and E.T. Bishop. 1968. Direct gas chromatographic analysis of i~omeric diaminotoluenes. Anal. Chem. 40:1455-1458. 223

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Health Effects Ames, B.N., H.O. Kammen, and E. Yamasaki. 1975. Hair dye. are mutagenic: ingredients. Identification of a variety of mutagenic Proc. Natl. Acad. Sci. U.S.A. 7~:2423-2427. Aune, T., S.D. Nelson, and E. Dybing. 1979. Mutagenicity and irreversible binding of the hepatocarcinogen 2,4-diaminotoluene. Chem. Biol. Interact. 25:23-33. Blij~even, W.G.H. 1977. Mutagenicity of four hair dyes in Drosophila melanogaster. Mutat. Res. 48:181-186. Burnett, C., B. Lanman, R. Giovacchini, G. Walcott, R. Scala, and H. Keplinger. Oxidation of ha ir dyes. Fahmy, M.J., and O.G. Fahmy. 1975. Long-term toxicity studies on Food Cosmet. Toxicol. 13: 353-357 . 1977. Mutagenicity of hair dye components relative to the carcinogen benzidine in Drosophila melanogaster. Mutat. Res. 56: 31-38. Giles, A.L., Jr., C.W. Chung, and C. Kommineni. 1976. Dermal carcinogenicity study by mouse-skin painting with 2,4-toluenediamine alone or in representative hair dye formulations. J. Toxicol. Environ. Health 1:433-440. 224

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Glinsukon, T., T. Benjamin, P. Granthem, E. Weiaburger, and Poller. 1975. Enzy~na tic N-acetylation of 2,4-toluenediamine by liver cytosole from various species. Xenobiotica 5 (87: 475-483. Gosselin, R.E., H.C. Hodge, R.P. Smith, and M.N. Gleason. 1976. Section II, p. 141 in Clinical Toxicology of Commercial Products: Acute Poisoning. E our th ed. Williams and Wilkins, Baltimore. Grantham, P.H., L. Mohan, T. Ben jamin, P.P. Poller, J.R. Miller, and E.K. Weisburger. 1979. Comparison of the metabolism of 2,4-toluenediamine in rats and mice. J. Environ . Pathol. Toxicol. 3 :149-166. Hossack, D.J.N., and J.C. Richardson. 1977. Examination of the potential mutagenicity of hair dye constituents using the micronucleus test. Exper ientia 33:377-378. International Agency for Research on Cancer. 1978. 2,4-Diaminotoluene. Pp. 83-95 in lARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Volume 16. International Agency for Research on Cancer, Lyon. Ito, N., Y. Hiasa, Y. Konishi, and M. Marugami. 1969. The development of carcinoma in liver of rats treated with m-toluylenediamine and the synergistic and antagonistic effects with other chemicals. Cancer Res. 29 :1137-1145. 225

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Kirkland, D.J., S.D. Lawler, and S. Venitt. 1978. Chromosomal damage and hair dyes. Lancet 2:124-128. National Cancer Institute. 1979. Bioassay of 2,4-Diaminotoluene for Possible Carcinogenicity. CAS No. 95-80-7. ITS Carcinogenesis Technical Report Series No. 162. DHEW Publication No. (NIB) 79-1718. U.S. Dept. of Health, Education, and Welfare, Public Health Service, National Institutes of Health, Bethesda, Md. 122 pp. National Institute for Occupational Safety and Health. 1978. Pp. 1233 in Registry of Toxic Effects of Chemical Substances, 1978, Lewis, R.J., Sr., ed. DHEW (NIOSH) Publication No. 79-100. U.S. Department of Health, Education, and Welfare, Public Health Service, Center for Disease Control, National Institute for Occupational Safety and Health, Cincinnati, Ohio. Ong, T. 1978. Use of the spot, plate and suspension test systems for the detection of the mutagenicity of environmental agents and chemical carcinogens in Neurospora crassa. Mutat. Res. 53:297-308. Pienta, R.J., M.J. Shah, W.B. Lebherz III, and A.W. Andrews. 1977. Correlation of bacterial mutagenicity and hamster cell transformation with tumorigenicity induced by 2,4-toluenediamine. Cancer Lett. 3:45-52. 226

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thneda, M. 1955. Production of rat sarcoma by injections of propylene glycol solution of m-toloylenediamine. Gann. 46: 597-604 . Unger, P.D., A.Je Salerno, W.C. Hess, and M.A. Friedman. 1980 . Tissue distr ibution and excretion of 2, 4- ~ 14C] Toluenediamine in the mouse. J. Box. Environ. Health. 6: 107-114 . venitt, S. 1978. Mutagenicity of hair dyes: Some more evidence and the problems of its interpretation. Mutat. Res. 53: 278-279 . (Abstract No. 214 ~ . Waring, R.H., and A.E. Pheasant. 1976. Some phenolic metabolites of 2, 4-diam~notoluene in the rabbit, rat and guinea-pig . Xenobiotica 6: 257-262. Weisburger , E.K., A.B. Russf ield, F. Hombur'3er , J.H. Weisburger, E. Boger, C.G. Van Dongen, and K.C. Chu. 1978. Testing of twenty-one environmental aromatic amines or der i~ratives for long-term toxicity or carcinogen icity. J. Environ . Pathol . 0~xicol. 2: 3 25-356 . 227