Genotoxicity of 4-trifluoromethylaniline in vitro and in vivo: Evaluation of DNA adducts, DNA strand breaks and/or mutations

2115 We evaluated the potential genotoxicity risk of 4-trifluoromethylaniline (TFMA), a material used in the synthesis of pharmaceutical drugs and a known structural component and metabolite of a marketed drug, in various short-term in vitro and in vivo test systems. TFMA increased mutations 5.4- to 14-fold (maximum) over background levels at 1000 or 3000 μg/plate in Salmonella typhimurium strains TA100 and TA1535 and in an E. Coli strain WP2 uvrA pKM101, both with and without S9 activation in a plate incorporation assay. In a pre-incubation assay in TA100, 2.1- to 3.7-fold increases in mutation were seen and DNA adducts were found at 100 to 1000 μg/plate (equivalent to 0.9 to 8.9 mM) both with and without S9 activation. Adducts were measured by the 32 P-postlabeling assay, using nuclease P1 and butanol for enhancement with HPLC and TLC for separation. Both mutagenic and adduct signals were slightly ( 90%) and some minor adducts were seen, which were chromatographically similar in bacteria, hepatocytes, and calf thymus DNA with and without S9. The numbers of adducts per 10 6 nucleotides were in the range 0.01 to 0.2 in bacteria and hepatocytes and 3 to 9 in calf thymus DNA at the concentrations tested. On a per mM basis, the order of adduct response was bacteria