Rat liver microsomal metabolism of 2-fluoro-, 2-chloro- and 2-bromo-4-methylaniline was investigated using h.p.l.c. Metabolites identified include products from side-chain C-hydroxylation (benzyl alcohols and benzaldehydes) and N-hydroxylation (hydroxylamines and nitroso derivatives). Aromatic ring hydroxylation was not a major reaction pathway. 2. A new type of microsomal metabolite was detected which was identified as a secondary amine, i.e. a halogenated N-(4'-aminobenzyl)-4-methylaniline. 3. In addition to these products azoxy, azo and hydrazo derivatives were formed. 4. Benzyl alcohols and halogenated N-(4'-aminobenzyl)-4-methylanilines were the major microsomal metabolites for all three 2-halogenated 4-methylanilines. 5. Quantification of the metabolite patterns demonstrated an influence of the type of halogen substituent on the rate of microsomal metabolism. The rate of side-chain C-hydroxylation increases in the order 2-fluoro-4-methylaniline < 2-chloro-4-methylaniline < 2-bromo-4-methylaniline. 6. The rate of N-hydroxylation increases from 2-bromo-4-methylaniline < 2-fluoro-4-methylaniline < 2-chloro-4-methylaniline. That 2-chloro-4-methylaniline is N-hydroxylated to a larger extent is in accordance with its greater mutagenicity, twice that of 2-bromo-4-methylaniline.
