The biotransformation of the fuel oxygenates
methyl tert-butyl ether (
MTBE) and
ethyl tert-butyl ether (
ETBE) was studied in rats after inhalation exposure; the biotransformation of the initial metabolite of these
ethers,
tert-butyl alcohol, was studied after oral gavage. To study
ether metabolism, rats were exposed for 6 h to initial concentrations of 2000 ppm of
MTBE or
ETBE, respectively [2-13C]
MTBE and [2-13C]
ETBE. Urine was collected for 48 h after the end of the exposure, and urinary metabolites were identified by 13C NMR (13C-labeled ethers) and gas chromatography/mass spectrometry (GC/MS) (12C- and 13C-labeled
ethers). To study
tert-butyl alcohol metabolism, rats were dosed either with
tert-butyl alcohol at natural
carbon isotope ratio or with 13C-enriched
tert-butyl alcohol (250 mg/kg of
body weight), urine was collected, and metabolites were identified by NMR and GC/MS.
tert-Butyl alcohol was identified as a minor product of the biotransformation of
MTBE and
ETBE. In addition, small amounts of a
tert-butyl alcohol conjugate, likely a
glucuronide, were present in the urine of the treated animals. Moreover, the mass spectra obtained indicate the presence of small amounts of [13C]
acetone in the urine of [13C]
MTBE and [13C]
ETBE-treated rats. 2-Methyl-1,2-propanediol,
2-hydroxyisobutyrate, and another unidentified conjugate of
tert-butyl alcohol, most probably a
sulfate, were major urinary metabolites of
MTBE and
ETBE as judged by the intensities of the NMR signals. In [13C]-
tert-butyl alcohol-dosed rats, [13C]
acetone,
tert-butyl alcohol, and its
glucuronide represented minor metabolites; as with the
ethers, 2-methyl-1,2-propanediol,
2-hydroxyisobutyrate, and the presumed
tert-butyl alcohol sulfate were the major metabolites present. In one human individual given 5 mg/kg [13C]-
tert-butyl alcohol orally, 2-methyl-1,2-propanediol and
2-hydroxyisobutyrate were major metabolites in urine detected by 13C NMR analysis. Unconjugated
tert-butyl alcohol and
tert-butyl alcohol glucuronide were present as minor metabolites, and traces of the presumed
tert-butyl alcohol sulfate were also present. Our results suggest that
tert-butyl alcohol formed from
MTBE and
ETBE is intensively metabolized by further oxidation reactions. Studies to elucidate mechanisms of toxicity for these
ethers to the kidney need to consider potential toxicities induced by these metabolites.