Evaluation of Propanil and Its N-Oxidized Derivatives for Genotoxicity in the Salmonella 3 typhimurium Reversion, Chinese Hamster Ovary/Hypoxanthine Guanine Phosphoribosyl Transferase, and Rat Hepatocyte/DNA Repair Assays.MCMILLAN, D. C, SHADDOCK, J. G., HEFLICH, R. H., CASCIANO, D. A. AND HINSON, J. A. 1988. Fundam. Appl. Toxicol. 11, 429-4 439. Since the herbicide propanil (3,4-dichloropropionanilide) is an aromatic amide and many 7 other aromatic amides are genotoxic via A'-hydroxy (7V-OH) metabolites, JV-oxidized derivatives of propanil and 3,4-dichloroaniline were synthesized and tested for genotoxicity. Propanil, 3,4-dichloroaniline, and their N-OH derivatives were not mutagenic in the Salmonella typhimurium reversion assay using tester strains TA97, TA98, TA100, and TA104, in both the presence and absence of exogenous metabolic activation (S9). In addition, the test compounds were not muta 3 genic in the Chinese hamster ovary/hypoxanthine guanine phosphoribosyl transferase (CHO/ HGPRT) assay, in both the presence and absence of S9. 3,3',4,4'-Tetrachloroazobenzene (TCAB) and its azoxy derivative (TCAOB), which are synthetic contaminants and/or degradation products of propanil, were also inactive in the S. typhimurium reversion and CHO/HGPRT assays (±S9). Unscheduled DNA synthesis (UDS) assays weie performed to determine if propa nil derivatives were able to induce DNA damage in primary rat hepatocytes. Although TCAB 3 was the only derivative tested which induced an elevation in DNA repair, the extent was not statistically significant. Hepatocyte toxicity, as measured by the release of lactate dehydrogenase 24 hr after exposure, was induced by all the test compounds in a concentration-dependent man. Incubations of N-OH-3,4-dichloroaniline with DNA in vitro resulted in only a low level of binding that was not affected by pH. This observation may partially explain the lack of mutagenicity observed in genotoxicity assays with propanil derivatives.
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