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As part of the international Pig-a validation trials, we examined the induction of Pig-a mutant reticulocytes and red blood cells (RETCD59- and RBCCD59-, respectively) in peripheral blood of male Sprague Dawley® rats treated with urethane (25, 100 and 250 mg/kg/day) or saline by oral gavage for 29 days. Additional endpoints integrated into this study were: micronucleated reticulocytes (MN-RET) in peripheral blood; chromosome aberrations (CAb) and DNA damage (%tail intensity via the comet assay) in peripheral blood lymphocytes (PBL); micronucleated polychromatic erythrocytes (MN-PCE) in bone marrow; and DNA damage (comet) in various organs at termination (the 29th dose was added for the comet endpoint at sacrifice). Ethyl methanesulfonate (EMS;200 mg/kg/day on Days 3, 4, 13, 14, 15, 27, 28 and 29) was evaluated as the concurrent positive control (PC). All animals survived to termination and none exhibited overt toxicity, but there were significant differences in body weight and body weight gain in the 250-mg/kg/day urethane group, as compared with the saline control animals. Statistically significant, dose-dependent increases were observed for urethane for: RETCD59- and RBCCD59- (on Days 15 and 29); MN-RET (on Days 4,15 and 29); and MN-PCE (on Day 29). The comet assay yielded positive results in PBL (Day 15) and liver (Day 29), but negative results for PBL (Days 4 and 29) and brain, kidney and lung (Day 29). No significant increases in PBL CAb were observed at any sample time. Except for PBL CAb (likely due to excessive cytotoxicity), EMS-induced significant increases in all endpoints/tissues. These results compare favorably with earlier in vivo observations and demonstrate the utility and sensitivity of the Pig-a in vivo gene mutation assay, and its ability to be easily integrated, along with other standard genotoxicity endpoints, into 28-day rodent toxicity studies. [ABSTRACT FROM AUTHOR]

3-Chloro-p-toluidine hydrochloride (CPT-HCl) is an aniline derivative used in the manufacture of the dye palatine fast yellow; it is alsoregistered as a selective, low-volume-use (<45 kg/yr) avicide. Threein vitro mutagenicity tests of CPT-HCl were performed according to methods recommended by the U.S. Environmental Protection Agency (EPA):the Ames/Salmonella assay, the Chinese hamster ovary/hypoxanthine-guaninephosphoribosyl transferase (CHO/HPRT) mammalian cell forward gene mutation assay, and the CHO chromosome aberration assay. CPT-HCl did not display mutagenic activity using the Ames/Salmonella or CHO/HPRT assays. However, CPT-HCl induced statistically significant concentration-dependent, metabolically activated increases in the proportion of aberrant cells and aberrations/cell in cultured CHO cells. Resultsare suggestive of minimal mutagenicity effects associated with exposure to anilines and their derivatives. [ABSTRACT FROM AUTHOR]