Characterization of metabolites and disposition of tertiary amyl methyl ether in male F344 rats following inhalation exposure.

Tertiary amyl methyl ether (TAME) is a fuel additive used to reduce carbon monoxide in automobile emissions. Because of the potential for human exposure, this study was conducted to develop methods for the characterization and quantitation of metabolites in expired air and excreta of rats exposed to a mixture of [13C]- and [14C]TAME ([2,3,4-13C]- and [2-14C]2-methoxy-2-methylbutane). The distribution of TAME in rats was determined following inhalation exposure, and TAME-derived metabolites were characterized in expired air and urine. Male rats were exposed for 6 h via nose-only inhalation to 2500 ppm [14C/13C]TAME, and expired air, urine and feces were collected for up to 7 days. Over 95% of the total recovered radioactivity was excreted by 48 h after exposure. Recovered radioactivity was expired as organic volatiles (44%) and 14CO2 (3%) and excreted in urine (51%) and feces (1%). Both TAME and its metabolite tertiary amyl alcohol (TAA) accounted for > or =90% of the radiolabel in expired air 0-8 h following exposure termination. Three major urinary metabolites of TAME were identified: (1) a direct glucuronide conjugate of TAA; (2) a product of oxidation at the methylene carbon of TAA (2,3-dihydroxy-2-methylbutane); (3) a glucuronide conjugate of metabolite 2. Metabolite 1 accounted for most of the TAME-derived metabolites excreted 0-8 h following exposure termination. Further metabolic products of TAA (metabolites 2 and 3) accounted for most of the excreted TAME-derived metabolites at later time points.