2,6‐Dichloro‐p‐phenylenediamine: Comparative disposition in male and female rats and mice

Publisher Website
Google Scholar
Abstract
2,6‐Dichloro‐p‐phenylenediamine (DPA) was recently reported to induce hepatocellu‐lar adenomas and carcinomas in male and female B6C3F1 mice but not in F344 rats. The present investigation of comparative disposition in both sexes of each species was designed to detect species‐related variations in DPA disposition that might explain variations in toxicity. Mouse tissues retained higher concentrations of radioactivity at the early time points (15 min and 2 h) than the corresponding rat tissues but were readily cleared at later time points. Elimination of DPA‐derived radioactivity by each species was primarily in urine (56–63% of an intravenous dose of 600 μmol/kg body weight) and secondarily in feces (23–31%). Metabolites were qualitatively similar, but varied quantitatively with species. Rats excreted three major and eight minor metabolites in urine, while mice excreted one major and nine minor metabolites. The major metabolite present in mouse urine (61–78% of radioactivity) was approximately twofold higher than the corresponding major metabolite in rat urine. Efforts to detect covalent binding of DPA and/or metabolites with hepatic DNA indicated no detectable binding in either species. The present study indicates that quantitative variations in disposition and metabolism exist between the two species but does not identify a likely source of species variation in susceptibility to DPA toxicity.