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Chapter 3 STRUCTURE-ACTIVITY RELATIOWSEIPS AMONG TEE CARCINOGENIC AROMATIC AMIDES In cer tain instances, aromatic amines are Conner ted in the host organism to arylhydroxamic acids or arylhydroxylamine derivatives, which are believed to be the ultimate carcinogenic fores of those amine which are carcinogens (Miller and Miller, 1976~. m ese substances induce tumors, usually in tissues distant from their sites of administration (Clayson and Garner, 1976) . rhe tumor site varies with the chemical, species, and strain of test animal used. So far, there is little understanding as to why one aromatic amine attacks one tissue while another amine affects a different one. Irving (1979) discussed species and tissue differences in aromatic amine metabolism as one factor in determining the distribution of induced tumors. Other factors, such as differing tissue and species levels in prereplicative DNA repair, cell proliferation, and hormonal responsiveness, also need to be considered before a comprehensive picture of tumor distribution can be formulated. Besides the ~tructure-activity relationships of the aromatic amines themselves, aromatic aroyl- and acylamides, aromatic hydroxylamines and hydroxamic acids, and aromatic ado, hydrator nitroso, and nitro compounds are also discussed in this chapter. In this discussion, aromatic amines and their derivatives are regarded as carcinogens if they significantly induce cancer in any tissue in any species. 60

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Clayson (1953) suggested that, to be carcinogenic, an aromatic amine had to: o poseese two or three con fidgeted aromatic ring systems {~.g., biptleny} or napbthalene) and o have the amino group substituted in the aromatic ring in the pare position to a conjugated aromatic system. his suggestion has been refined more recently by the clear demonstration that single-ring aromatic amines such as o-toludine may induce cancer (We isburger et al ., 1978 I, although structures of the type suggested by Clayson (1953) represent some of the more potent carcinogens. Another important discovery has been the demonstration of the cons iderable carcinogen ic potency of certa in amino and nitroheterocyclic aromatics, such as the derivatives of S-nitrofuran, nitrothiazole, and nitroimidazole . mese compounds also have considerable importance because of their use in medicines for animals and bumans, to treat parasitic infections. Because these substances; are structurally dissimilar to the simpler aromatic amines, they are discussed separately. The information on which the conclusions in this chapter are based has been reviewed by Miller and Miller (1976), Clayson and Garner (1976), and Weiaburger et al. (1978~. 61

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SUBSTITUENTS ON THE NITROGEN Alkyla t ion Alkylation of the aromatic amino group has been intensively studied only with derivatives of p-dimethylaminoszobenzene. In this particular series, the presence of at least one methyl group on the amino group is held to be essential to hepatocarcinogenicity in rats ; longer alkyl groups depress activity. Detailed examination of the evidence supporting this statement reveals that few nonalkylated derivatives (analogs of p-aminoszobenzene) beve been studied and that the evidence for the essential nature of the methyl group is confined mainly to 4-dimethylaminoszobenzene itself. In specific cases, such as 3-methoxy-4-aminoazobenzene or 4-(o-tolylazo)~-toluidine, the N-methyl group is not essential, and tumors are induced. Painting ~-aminoszobenzene or a range of similar chemicals on rat skin leads to skin tumors (Fare and Orr, 1965; Fare, 19661. There is very limited evidence for the importance of an alkyl group on the nitrogen to the carcinogenic potency of aromatic amines. A methyl group may be essential to the activity of 4-dimethylaminoazobenzene and certain of its analogs in rat hepatocarcinoqenesis. Dimethyl derivatives are metabolically monodemethylated to monomethylaminoszobenzene derivatives and then to the unsubstituted amines. Contrary to earlier evidence, the reverse process, arylamine methylation, is not a major metabolic 62

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pa thway (Scr ibner et al ., 1965 ) . Bigher alkyl groups generally result in chemicals with lower carcinogenicity than do those provided by the free amines. Honoalkylaromatic dines can be converted to the corresponding n$trosaeines in the presence of nitrous acid at an acid pE. Arylation Ablation of the amino group to diarylamines or triarylamines is believed to abolish carcinogenic activity, although the evidence for this conclusion is tenuous. Phenyl-2-naphthylamine has been studied intensively because of its use as a substitute for 2-naphthylamine, a rubber-compounding ingredient. me urine of humans and dog e exposed to this apparently noncarcinogenic cbeeica1 contains low levels of free 2-naphthylamine (Batten and pathway, 1977; Mummer and Tordoir, 1975; ~ . At this time, there is no explanation for this finding--whether the 2-nap~thylamine is liberated within the host or is an artifact of urine collection, or whether there is ~ similar degradation of other dierylamines. The biologic significance of this observation can be judged from the fact that the mount of ur inary 2-naphthylamine found after exposing bumans to 10 as of pbenyl-2-naphthylamine is equivalent to that in the sake of 4-40 cigarette';. Hoff's~ann et al. t1969, found 1 ~.~g of 2-napt~thylamine in the smoke of 40 cigarettes. A`:ylation Acetylation and deacetylation of aromatic amines are coon 63

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metabolic reactions in most species, except dogs, which lack the ability to acetylate these chemicals. Consequently, aromatic Mines and acetamide~ generally possess similar carcinogenic potencies. Higher homologs of the acetyl group do not appear to have been investigated. N-2-fluorenylformamide is less potent than the ace~cyl der ivative (Miller et al., 1962} . Aroyl Der ivatives Aroyl derivatives bave been examined, particularly in the 2-fluorenylamine ser ies . Although N-2-fluorenylbenzamide is inactive, the corresponding N-hydroxy-2-fluorenylbenzamide is carcinogenic. This finding suggests that aroylation blocks N-hydroxylation, the essential activation route for this carcinogen . The benzenesulfonamide der ivatives of 2-fluorenylamine are likewise inactive, but its N-hydroxy derivative is carcinogenic (Gutmann et al., 1967) . N-Hydroxylat ion N-Hydroxylation of aromatic amines or of their amides is generally regarded as the f irst step toward their metabolic activation. If active, aromatic bydroxylamines or hydroxamic acids are more potently carcinogenic than are the non-N-hydroxylated chemical=; however, the demonstration of this increase in potency may require careful selection of a system (Miller et al., 1964) . In specif to instances, the N-hydroxylated compound demonstrates activity, and the parent compound does not. 1-Napb~bylamine, for 64

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example, is not demonstrably carcinogenic if free from the potently carcinogenic 2-isomers bowever, the corresponding H-hydroxy derivative, is carcinogenic (Rado~ki et al., 1971} . Esters of N-HYdroxY Der ivatives Esters of N-Bydroxy derivatives of aromatic amines have been regarded as the ultimate carcinogenic form of the aromatic abides. Some of These derivatives are highly genotoxic, if they can be delivered to the test system and the critical receptors before they interact with other possible targets suab as thiole. The less polar model esters (such as N~acetoxy-2-fluorenylacetemide) are thus more readily shown to be carcinogenic than are the more polar derivatives (such as the sulfate ester of N-bydroxy-2-fluorenylacetamide). Different esters appear to vary in their ability to act as leaving groups in the production of *e arylnitrenium ion. For example, the O-glucuronic acid ester of N-hydroxy-2-fluor enylacetamide does not appear as capable of producing the nitreniue ion as do either the ace toxy or sulfate esters (Irving and Wiseean, 1971) . Azo Compounds and Bydrazo Compounds m eve compounds are reduced in the anaerobic portions of the gastrointestinal tract, or by the tissue enzyme, azoreductese, to compounds, each of which contains an amino group. Severe1 examples of azo compounds, themselves carcinogenic and capable of reduction 65 /

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to carcinogenic aromatic amines have been reported. Bonser et al. 1954 and Weisburger et al. (1978) reported that 1-to-tolyllazo~ 2-napbthol is carcinogenic and may be reduced to o-toluidine, which is also carcinogenic. Me high carcinogenic potency of ~ series of dyes (Direct Black 38, Direct Brown 95, and Direct Blue 6), which are capable of reduction to benzidine, has been reported by the National Cancer Institute (1978~. Aroma t ic C-Ni trove Compounds These compounds are of interest because of their easy conversion to arylhydroxylamines . Certa in C-nitroso compounds are effective nitrosating agents. THE RING SYSTEM AND The POSITION OF THE AROMATIC AMINO GROUP Ring-sub~tituted amino derivatives of most substances containing one, two, three, and possibly four aromatic rings may be carcinogenic. The placement of the amino group is the critical factor . Thus, 2-naphthylamine, 2-acetamidofluorene, 2-anthramine, and 2-phenanthrylacetamide are potent carcinogens; 1-naphthylamine, 3-acetamidofluorene, 9-anthramine, and 9-phenanthrylacetamide are not. The presence of a large conjugated group pare to the amino group appears to enhance carcinogenic activity but is not a requirement for this property, as is clearly demonstrated by the fact that single-r ing aromatic amines and der i~ratives of methylenedianiline are carcinogenic (International Agency for Research on Cancer, 1974a,b,c; Weiaburger et al., 1978} . 66

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The basic ring system for carcinogenic aromatic amines may be entirely carbocyclic {2-naphthylamine, 4-biphenylamine}, any show limited numbers of heteroatoms (3-aminodiphenylene oxide, 4-~ - uinoline-1-oxide), or may be highly beterocyclic {nitridazole, metronidazole}. The heterocyclic chemicals are d~wuseed separately later in this chapter. Ring substituents on the carcinogenic potential of aromatic amines are subd ivided into Analogs of ~-dimethylaminoszobenzene Aromatic amines with single amino groups Analogs of the phenylenediamines Analogs of benzidine. This subdivision is necessary because the various types of carcinogenic aromatic amines appear to be affected differently by substituents. Analogs of P-DimethYlaminoa20benzene Analogs of p-dimethylaminoszobenzene have been extensively studied for their induction of rat liver tumors. were are five different positions available for manosubstitution. The effects of the substituents on carcinogenic activity are presented in Tables 3-1, and 3-2. .67

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Table 3-1 Effect of Substituents on the CarcinogenicaAct~ivity of N,N-DimethYl-p-phenyl2aoaniline- SubstitilPot 2 3 2' a' 4' 2,3' 2,4' 2,6' 3',4' 3''5' 2 "4'. - -CH3 -C2H5 -CF3 -F -C1 -Br -OH -OCH3 -oC2Hs - NO2 -NH2 -SO3H -CO2H + + + - - ~ ~ + + ~ + + + + ~ + _ + + + a From Clayson and Garner, 1976, with permission. b Ear duct, skin, and intestinal tumors, but no hepatomas. c Bladder papillomas; hepatomas possibly induced 68 .

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~s1 In Icy - o - Q. 1 - I= - c] en 1 - D 1 11 o _ _ en o _ ~ ~ . ._ ._ ~1 69

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Aromatic Amines Containing Single Amino Groups mere aromatic amines have a number of similarities that lead to structure-activity relationships. Methyl Substitution. Especially when ortho to the amino group, . methyl substitution appears to entrance activity, as is demonstrated by comparing the carcinogenic potential of 2' ,3-dimethyl-4- aminobiphenyl to 4-aminobiphenyl, or of 3-methyl-2-amino- naphthylamine to 2-naphthylamine. me effect of methyl groups in other positions in the 4-aminobiphenyl system was extensively studied by Walpole and Williams (19587. Methyl groups in both ortho positions, as with 2,6-dimethylaniline (2,6-xylidine), may be deactivating (National Cancer Institute, in press). My. Ortho substitution of a methoxyl group has a varied effect. onus, 3-methoxy.-4-aminobiphenyl and 1-methoxy-2-fluorenylacetamide are just as, or even more, potent than the parent carcinogen in rats, although 3-methoxy-2-fluorenylacetamide was found to be without activity. Similar results were reported for the free amines. Other ~nethoxyl substitutions also make the molecule more carcinogenic as, for example, in the case of ~cresidine as compared.to aniline or 7-methoxy-2-fluorenylacetamide as compared to 2-fluorenylacetamide. Halogen Substitution. This is best illustrated by using floor ine substitut ion to block metabol ic detox if ication of aroma tic amides. Fluorine enhances carcinogenicity, as illustrated by the 70

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appear to possess certain specific structural characteristics, such ~8 o one, two, or three conjugated aromatic ring systems, o an aromatic amino group substituted in the position pare to the conjugated aromatic system, or o groups such as methyl, aethoxyl, or fluorine substituted in specific positions relative to the amino group. Aniline, as the simplest aromatic amine, might be considered the reference chemical for structure~carcinogenic activity relationships in this ser ies. However, although it has induced cancer in rats (National Cancer Institute , 1978q ), but not in mice , it has shown negative results in mutagenicity tests. If norharmc~n is present in Salmonella tests the results are positive (Hagao et al., 1977) . Emus, it may induce splenic hemang iosarcoma and other sarcomas by a ecbanism different from Mat by which other aromatic aaines induce the ir ef feats . Ear example, the methemoglobinemis induced by aniline may stress the spleen, which removes deter is in red blood cells from the circulation, thereby setting up tbe conditions for splenic tumorigenesis. ~C~loroaniline induces similar cancers and, likewise, induce'; high levels of methemoglobinemia (National Cancer Institute, 1979d) . Et~Cr e s id i ne ~ 2-me theory- 5 -me thyla n i l i ne ~ induced bladde r carcinomas and olfactory neuroblastomas in rats and bladder 75

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care inomas and hepa tocellular carcinomas in mice (National Cancer Institute, 1979c) . ~Cresidine produced positive results in microbial mutagenicity tests. There in no reason to doubt that genotoxic factors play a role in inducing these tumors and, as they occur at sites usual for aromatic amines, ~cresidine should be regarded as a potent carcinogen. The ortho methoxyl group is probably responsible for enhancing the activity of thin amine. 2,4-Diaminotoluene (National Cancer Institute, 1978h) induced hepatocellular carcinomas in male and female rats and in female mice. In female rats, mammary adenocarcinomas were induced. The substance is mutagenic in microbial systems. It is a genotoxic carcinogen, and its activity is enhanced by the methyl group ortho to the amino group. Methylene-bisto-chloraniline' is clearly more carcinogenic than is methylenedianiline (Munn, 1967) . It provides an example of the enhancing effects of ortho chloro substitution; ortho methyl substitution also enhances carcinogenicity. Furazolidine is a borderline carcinogen. This is to be expected from its single-ring structure, as activity in the nitro heterocyclic series is highest when two aromatic heterocyclic ring systems exist in the molecule . 76

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REFERENCES Structure-Activi ty Relationsh ips Batten, P.L., and D.E. Hathway. 1977. Dephenylation of N-phenyl-2-naphthylamine in dogs and its possible oncogeni~ implications. Br. J. Cancer 35: 342-346. Bonser , G.M., D.B. Clayson, and J.W. Jull. 1954 . Induction of tumors with 1- (2-tolylazo)-2-naphthol (oil orange TX) . Nature 174: 879-880. Bryan, G. T., ed . 1978 . Carc inogenes is--A Comprehens ive Surrey, Vol. 4. Nitrofurans: Chemistry, Metabolism, Mutagenesis, and Carcinogenesis. Raven Press, New York. 238 pp. Bulay, O., H. Urman, D.B. Clayson, and P. St.ubik. 1977. Carcinogenic effects of nir idazole on rodents infected with Schistosoma mansoni. J. Natl. Cancer Tnst. 59:1625-1630. Clayson, D. B. . 195 3 . A wor k ing hypothes is for the mc~de of carcinogenesis of aromatic amines. Br. J. Cancer 7:460-471. Clayson, D. B., and R.C. Garner . 1976. Carcinogenic aromatic amines and related compounds. Pp. 366-461 in C.E. Searle, ed. Chemical Carcinogens. ACS Monograph 173. American Chemical Society, Washington, D.C. l 77

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Far c, G. 1966. Rat sk in carcinogenesis by topical applications of some azo dyes. Cancer Res. 26: 2406-2408. Farr, G., and J.W. Orr. 1965. The effect of dietary copper on rat carcinogenesis by 3-methoxy dyes. II. Multiple skin tuners by pa int ing wi th 3-methoxy-4 -d imethylaminoa zobenzene . Cancer Res . 25: 1784-1791. Gutmann, H.R., S.B. Galitski, and W.A. Foley. 1967. The conversion of noncarcinogenic aromatic amides to carcinogenic arylhydroxamic acids by synthetic N-hydroxylation. Cancer Res. 27:1443-1455. Hof fman , D., Y. Masuda , and E. L. Wynder . 1969 . a-NaPhthylamine and 6-naphthylamine in cigarette smoke. Nature 221: S54-556. International Agency for Research on Cancer. 1974a. 4,4'-Methylene his (2-chloroaniline) . Pp. 65-71 in IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. Volume 4. International Agency for Research on Cancer, Lyon. International Agency for Research on Cancer. 1974b. 4,4'-Methylene bis (2-methylaniline) . Pp. 73-77 in IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. Volume 4. International Agency for Research on Cancer, Lyon. 78

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International Agency for Research on Cancers 1974c. 4,4'-Methylene dianiline. Pp. 79-85 in TARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. Volume 4. International Agency for Research on Cancer, Lyon. Irving, C.C. 1979. Species and tissue variations in the metabolic activation of aromatic amines. Pp. 211-227 in A.C. Griffin and C.R. Shaw, eds . Carcinogens: Identif ication and Mechanisms of Action. 31st Annual Symposium on Fundamental Cancer Research, H.D. Anderson Hospital and Tumor Institute, Universities of Texas Cancer Center, Houston, 1978. Raven Press, New York. Irving, C.C., and R. Wiseman, Jr. 1971. Studies on the carcinogenicity of the glucuronides of N-hydroxy-2-acetylaminofluorene and N-2-fluorenylhydroxylamine in the rat. Cancer Res. 31:1645-1648. Kummer , R., and W. F. Boudoir . 1975. . Pbenyl-betanaphthylamine (PBNA), another carcinogenic agent? Tijdschr. Soc. Geneeskd. 53:415-419. Miller, E.C., and J.A. Miller. 1976. me Metabolism of chemical carcinogens to reactive electrophiles and their possible mechanisms of action in carcinogenesis. Pp. 737-762 in C.E. Searle, ed. Chemical Carcinogens. ACS Monograph 173. American Chemical Society, Wash ington, D. C . 79

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Miller, E.C., J.A. Miller, and M. Enomoto. 1964. The comparative carcinogenicities of 2-acetylaminofluorene and its N-hydroxy metabolite in mice, hamsters and guinea pigs. Cancer Res. 24: 2018-2031. Miller, E.C., T.L. Fletcher, A. Margreth, and J.A. Miller. 1962. me carcinogenicities of derivatives of fluorene and biphenyl: Fluoro der ivatives as probes for active sites in 2-acetylaminof luorene. Cancer Res . 22:100 2-1014 . Munn, A. 1967. Occupational bladder tumors and carcinogens: Recent developments in Britain. Pp. 187-193 in K.F. Lampe, R.A. Penalver, and A. Soto, eds. Bladder Cancer: A Symposium. Aesculapius Publishing Co., Birmingham. Nagao, M., T. Yahagi, T. Kawachi, T. Sugimura, T. Kosuge, K. Tsuji, K. Wakabayashi, S. Mizusaki, and T. Matsumoto. 1977. Comutagenic action of norharman and harman. Proc.. Jap. Acad. 53~21:95-98. National Cancer Institute. 1978. 13-Week subahronic toxicity studies of Direct Blue 6, Direct Black 38, Direct Brown 95 dyes. ITS Carcinogenesis Technical Report Ser. ies No. 108. DHEW Publication No. (NIH) 18-1358. U.S. Dept. of Health, Education, and Welfare, Public Health Service, National Institutes of Health, Bethesda, Md. 127 pp. 80

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National Cancer Institute. 1978a. Bioassay of 2,4-dinitrotoluene for possible carcinogenicity. CAS No. 121-14-2. ITS Carcinogenesis Technical Repor t Ser. ies No. 54 . DHEW Publication No. (NIH) 78-1360 . U. S. Dept. of Health, Education, and Welfare, Public Health Service, National Institutes of Health, Bethesda, Md. [99] pp National Cancer Institute. 1978b. Bioassay of 4-chloro-o-phenylenediamine for possible carcinogenicity. CAS No. 95-83-0. ITS Carcinogenesis Technical Report Series No. 63. DREW Publication No. (NTH) 78-1313. U.S. Dept. of Health, Education, and Welfare, Public Health Service, National Institutes of Health, Bethesda, Md. ~ 94 ~ pp. National Cancer Institute. 1978c. Bioassay of 5-nitro-o-toluidine for possible carcinogenicity. CAS No. 99-S5-8. ITS Carcinogenesis Technical Report Series No. 107. DHEW Publication No. (NIH) 78-1357 . U. S. Dept. of Health, Education, and Welfare, Public Health Service, National Institutes of Health, Bethesda, Md. [95] pp. National Cancer Institute. 1978d. Bioassay of 4-nitroantbranilic acid for possible carcinogenicity. CAS No. 619-17-0. ITS Carcinogenesis Technical Report Series No. 109. DHEW Publication No. (NIH) 78-1364. U.S. Dept. of Health, Education, and Welfare, Public Health Service, National Institutes of Health, Bethesda, Md. [ 105] pp. 81

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National Cancer Institute. 1978e. Bioassay of 2-chloro-p-phenylenediamine sulfate for possible carcinogenicity. CAS No. 61702-44-1. ITS Carcinogenesis Technical Report Ser ies No. 113. DHEW Publication No. (NIH) 78-1368 . U. S. Dept. of Health, Education, and Welfare, Public Health Service, National Institutes of Health, Bethesda, Md. [87] pp. National Cancer Institute. 1978f. Bioassay of 5-nitro-o-anisidine for possible carcinogenicity. CAS No. 99-59-2. TTS Carcinogenesis Technical Report Ser ies No. 127. DREW Publication No. (NIH) 78-1382. U.S. Dept. of Health, Education, and Welfare, Public Health Service, National Institutes of Health, Bethesda, Md. [117] pp. National Cancer Institute. 1978g. Bioassay of aniline hydrochloride for possible carcinogenicity. CAS No. 142-04-1. TTS Carcinogenesis Technical Report Series No. 130. DHEW Publication No. (NIH) 78-138S. U.S. Dept. of Health, Education, and Welfare, Public Health Service, National Institutes of Health, Bethesda, Md. [96] pp. Nat tonal Cancer Institute. 1978h. Bioassay of 2-5-toluenediamine sulfate for possible carcinogenicity. CAS No. 6369-S9-1. ITS Carcinogenesis Technical Report Series No. 126. DHEW Publication No. (NIH) 78-1381. U.S. Dept. of Health, Education, and Welfare, Public Health Service, National Institutes of Health, Bethesda, Md. [101] PPe 82

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National Cancer Institute. 1979a. Bioassay of 2-nitro-p-phenylenediamine for possible carcinogenicity. CAS No. 5307-14-2 . ITS Carcinogenesis Technical Report Ser ies No. 169 . DHEW Publication No. (NIH} 79-1725 . U. S. Dept. of Health, Education, and Welfare, Public Health Service, National Institutes of Health. Bethesda, Md . f 84 ~ pp. National Cancer Institute. 1979b. Bioassay of 4-nitro-o-phenyldiamine f or pass ible ca rc inogen ic i ty. CAS No . 99 -S6-9 . ITS Ca rc inogenes is Technical Report Series No. 180. DHEW Publication No. (NIH) 79-1736. U.S. Dept. of Health, Education, and Welfare, Public Health Service, National Institutes of Health, Bethesda Md. f 85] pp. National Cancer Institute. 1979c. Bioassay of p-cresidine for possible carcinogenic~ty. CAS No. 120-71-8. ITS Carcinogenesis Technical Report Series No. 142. DHEW Publication No. (NIH) 79-1397. U.S. Dept. of Health, Education, and Welfare, Public Health Service, National Institutes of Health, Bethesda, Md. f 105] pp. National Cancer Institute. 1979d. Bioassay of ~chloraniline for possible carcinogenicity. CAS No. 106-47-8. ITS Carcinogenesis Technical Report Ser. ies No. 189. CHEW Publication No. (NIH) 79-1745 . U.S. Dept. of Health, Education, and Welfare, Public Health Service, National Institutes of Health, Bethesda, Md. [90] pp. 83

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National Cancer Institute. In press. Bioassay of 2,6-dimethylaniline for possible carcinogenicity. National Cancer Institute Carcinogenesis Technical Report Series. U.S Public Health Service, National Institutes of Health, Washington, D.C. Pr ice, J.M., J.E. Morris, and J.J. Lalich. 1966. Evaluation of the carcinogen ic activity of 5-nitrofuran derivatives in the rat. Fed. Proc. Fed. Am. Soc. Exp. Biol. 25:419. (Abstract No. 1297) . Radomski, J.L., E. Brill, W.B. Deichmann, and E.M. Glass. 1971 Carcinogenicity testing of N-hydroxy and other oxidation and decompos ition products of 1- and 2-naphthylamine. Cancer Res 31: 1461-1467. Rustia, M., and P. Shubik 1972. Induction of lung tumors and malignant lymphomas in mice by metronidazole. J. Natl. Cancer. Inst. 48: 721-729. Schribner, J.D., J.A. Miller, and E.C. Miller. 1965. 3 -Me thy lme rcapto-21-me thyl-4-aminoa zobenzene: An a lka l ine-degrada t ion product of a labile protein-bound dye in the livers of rats fed N,N - imethyl-4-aminoazobenzene. Biochem. Biophys. Res. Commun. 20: 560-S65. Stein, R.J., D. Yost, F. Petroliunas, and A. von Escb; 1966. Ca rc inogen ic ac t iv ity of n i trofurans: A h istolog ice 1 evaluat ion. Fed. Proc . Fed . Am. Soc . Exp. Biol. 25:291 (Abstract No. 578 ~ . 84

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Weisburger, E.K., A.B. Russfield, F. Hamburger, J.H. Weisburger, E . Boger, C. G. Van Dongen, and K. C . Chu. 1978. Testing of twenty-one environmental aromatic amines or der ivatives for long-term toxicity for carcinogenicity. J. Environ. Pathol. Toxicol. 2:325-356. 85