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Toxicological information

Exposure related observations in humans: other data

Administrative data

Endpoint:
exposure-related observations in humans: other data
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study used a single subject and a single dose level.

Data source

Reference
Reference Type:
publication
Title:
Biotransformation of [12C]-and [2-13C]-Labeled Methyl tert-Butyl Ether, Ethyl tert-Butyl Ether, and tert-Butyl Alcohol in Rats: Identification of Metabolites in Urine by [13C] Nuclear Magnetic Resonance and Gas Chromatography/Mass Spectrometry
Author:
Bernauer U, Amberg A, Scheutzow D and Dekant W
Year:
1998
Bibliographic source:
Chem Res Toxicol 1998, 11, 651-658

Materials and methods

Type of study / information:
Study was designed to compare metabolites formed and excreted in urine in humans following oral administration of tertiary butyl alcohol with the results observed in a study with Fischer 344 rats.
Endpoint addressed:
basic toxicokinetics
Test guideline
Qualifier:
no guideline available
GLP compliance:
no
Remarks:
GLP compliance is not relevant to studies conducted with human subjects.

Test material

Constituent 1
Chemical structure
Reference substance name:
2-methylpropan-2-ol
EC Number:
200-889-7
EC Name:
2-methylpropan-2-ol
Cas Number:
75-65-0
Molecular formula:
C4H10O
IUPAC Name:
2-methylpropan-2-ol
Constituent 2
Reference substance name:
tertiary butyl alcohol
IUPAC Name:
tertiary butyl alcohol
Details on test material:
Preparation of radiolabeled tertiary butyl alcohol: An ethereal solution of CH3J was slowly added to Mg turnings covered by diethyl ether and iodine was added to initiate the Grignard reaction. The mixture was stirred at flux, an ethereal solution of [2-13C]-acetone was added, and the mixture was kept at flux for 2 h. After cooling, hydrolysis was performed by adding ice-cold, saturated NH4Cl solution. The aqueous layer was extracted 5 times with diethyl ether; ethereal layers were combined and dried over Na2CO3. The solvent was evaporated and the residue was distilled to yield [2-13C]-tertiary butyl alcohol (42% yield, 97% GC/FID purity). The structure of the reaction product was confirmed by GC/MS and [1H] and [13C] NMR.

Method

Ethical approval:
other: The human experiment was approved by the institutional review board of the University of Würzburg.
Details on study design:
The study was designed to compare the metabolites obtained in human urine following administration of a single oral dose of radiolabelled tertiary butyl alcohol with those observed in a study in which the test material was administered by the oral route to male Fischer 344 rats.
Exposure assessment:
measured
Details on exposure:
[13C]-Tertiary butyl alcohol was administered by the oral route in a gel capsule at a single dose of 5 mg/kg bw to one human male volunteer.

Results and discussion

Results:
Following oral administration of 5 mg/kg bw [13C]-tertiary butyl alcohol to a single male subject, 2-methyl-1,2-propandiol and 2-hydroxyisobutyrate were the major metabolites identified in urine by [13C] NMR analysis. Unconjugated tertiary butyl alcohol and tertiary butyl alcohol glucuronide were also identified as minor metabolites; traces of the presumed tertiary butyl alcohol sulfate were also present.

Any other information on results incl. tables

The purpose of this study was to compare the metabolic urinary profile of a human male administered [13C]-tertiary butyl alcohol by the oral route with that observed in male Fischer 344 rats. Based on a comparison of NMR spectra, the metabolic profile in both species was qualitatively similar. Conjugation of tertiary butyl alcohol with glucuronic acid resulted in urinary excretion of the glucuronide conjugate in both species. There was also indirect evidence for formation of a sulfate conjugate of tertiary butyl alcohol. Intensities of the [13C] signal in the NMR spectra of rat urine suggest this is a major pathway of tertiary butyl alcohol biotransformation in the rat. The authors suggested that low recovery of the presumed tertiary butyl alcohol sulfate in human urine was based on a low affinity of human sulfotransferase-(s) for tertiary butyl alcohol. The presence of 2-methyl-1,2-propanediol and 2-hydroxyisobutyrate in urine of both species suggests further oxidative metabolism of tertiary butyl alcohol. The likely pathway for the formation of these metabolites involves oxidation of tertiary butyl alcohol by cytochromes P450 to give 2-methyl-1,2-propanediol which is further oxidized to 2-hydroxyisobutyrate. [13C]-Acetone was also reported as a minor metabolite in male rats while no acetone was identified in male human urine.

Applicant's summary and conclusion

Conclusions:
The study showed that, in vivo, tertiary butyl alcohol is metabolized in humans to 2-methyl-1,2-propandiol, 2-hydroxyisobutyrate, unconjugated tertiary butyl alcohol, tertiary butyl alcohol glucuronide, and tertiary butyl alcohol sulfate. Since the study was designed to investigate only the urinary metabolic excretion profile and relative levels (major vs. minor) of urinary metabolites following oral administration of tertiary butyl alcohol and did not include mass-balance data, no conclusion can be made on the potential for bioaccumulation.
Executive summary:

In a metabolism study designed to compare the urinary metabolic profile of rats and a human administered a single dose of tertiary butyl alcohol by the oral route, a single male human volunteer received 5 mg/kg bw [13C]-tertiary butyl alcohol in a gelatin capsule. There was a qualitatively similar metabolic profile in both rats and the single human. The major metabolites identified in the urine of both species were 2-methyl-1,2-propanediol and 2-hydroxyisobutyrate. Unconjugated tertiary butyl alcohol and tertiary butyl alcohol glucuronide were present as minor metabolites. Differences were also observed. In the rat, the presumed tertiary butyl alcohol sulfate was present as a major metabolite while in the single human, only traces of the sulfate were present. [13C]-Acetone was also reported as a minor metabolite in rats while no acetone was reported in human urine.