Genotoxicity of aniline derivatives in various short-term tests

Abstract

SummaryVarious substituted aniline derivatives were tested for genotoxicity in several short-term tests in order to examine the hypothesis that a Substitution at both ortho positions (2,6-disubstitution) could prevent genotoxicity due to steric hindrance of an enzymatic activation to electrophilic intermediates. In the Salmonellajmicrosome assay, 2,6-dialkylsubstituted anilines and 2,4,6-trimethylaniline (2,4,6-TMA) were weakly mutagenic in strain TA100 when 20% S9 mixwas used, although effects were small compared to those of 2,4-dimethylaniline and 2,4,5-trimethylaniline (2,4,5-TMA). In Drosophila me/anogaster, however, 2,4,6-TMA and 2,4,6-trichloroaniline (TCA) were mutagenic in the wing spottestat 2-3 times lower doses than 2,4,5-TMA. In the 6-thioguanine resistance test in cultured fibroblasts, 2,4,6-TMA was again mutagenic at lower doses than 2,4,5-TMA. Two methylene-bis-aniline derivatives were also tested with the above methods: 4,4'-methylene-bis-(2-chloroaniline) (MOCA) was moderately genotoxic in al1 3 test systems whereas 4,4'-methylene-bis-(2-ethyl-6-methylaniline) (MMEA) showed no genotoxicity at all. DNA binding sturlies in rats, however, revealed that both MOCA and MMEA produced DNA adducts in the liver at Ievels typically found for moderately strong genotoxic carcinogens. These results indicate that the predictive value of the in vitro test systems and particularly the Salmonellajmicrosome assay is inadequate to detect genotoxicity in aromatic amines. Genotoxicity seems to be a general property of aniline derivatives and does not seem to be greatly influenced by substitution at both ortho positions.Ortho,ortho-dialkylated anilines, in general, are reported to be non-genotoxic (Zimmer et al., 1980;Mulholland et al., 1983). The hypothesis was that a substitution at both ortho positions could prevent genotoxicity due to steric hindrance of the enzymatic oxidation of the aromatic amino group.

Nasal Cytotoxic and Carcinogenic Activities of Systemically Distributed Organic Chemicals

“…2,4,6-trimethylaniline produced mouse liver DNA strand breaks in the single cell gel electrophoresis assay (Przybojewska, 1999), but was not mutagenic and TOXICOLOGIC PATHOLOGY evidence for its carcinogenic activity was considered not evaluable by IARC (International Agency for Research on Cancer, 1982a). A structural analog, 2,4,5-trimethylaniline, has limited evidence for carcinogenicity in rodents, and was weakly mutagenic to Salmonella with bioactivation (Kugler-Steigmeier et al, 1989). In contrast to the weak mutagenicity in bacteria, 2,4,5-trimethylaniline was quite mutagenic in the Drosophila wing spot assay and to cultured fibroblasts (Kugler-Steigmeier et al, 1989).…”

“…A structural analog, 2,4,5-trimethylaniline, has limited evidence for carcinogenicity in rodents, and was weakly mutagenic to Salmonella with bioactivation (Kugler-Steigmeier et al, 1989). In contrast to the weak mutagenicity in bacteria, 2,4,5-trimethylaniline was quite mutagenic in the Drosophila wing spot assay and to cultured fibroblasts (Kugler-Steigmeier et al, 1989). o-Anisidine (2-methoxyaniline), which lacks the 5-methyl group of pcresidine, was carcinogenic in rodents and positive for bacterial mutagenicity (International Agency for Research on Cancer, 1982c), although negative for DNA adduct formation (Ashby et al, 1994).…”

Quantification of haemoglobin binding of 4,4′-methylenebis(2-chloroaniline)(MOCA) in rats

“…Most recently, Kugler-Steigmeier (1988, male Sprague-Dawley rats), Cheever et al (1988, male Sprague-Dawley rats) Segerb~ick et al (1989, the rat strain is not specified) and Silk et al (1989, male Wistar rats) also described the binding of MOCA to DNA of lung, liver and kidney. Kugler-Steigmeier et al (1989) determined CBI values of 23+7, 55___20 and 4 for DNA of liver, lung and kidney, respectively. The CBIs in the present paper are higher but the hierarchy of the CBI values for the different organs is the same.…”

4,4’-Methylenebis(2-chloroaniline) (MBOCA) May Be Highly Toxic and a Carcinogen Based on an Experimental Study with Mice

“…It was recently proposed that chemical carcinogenesis may involve the formation of chemical adducts in DNA through covalent binding based on the finding that MBOCA produces DNA adducts in rat liver at levels characteristic of genotoxic carcinogens [28]. The plasma 8-OHdG levels were measured to determine whether MBOCA causes oxidative stress.…”