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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1993
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1993

Materials and methods

Objective of study:
absorption
metabolism
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
The study investigated the metabolism of the individual isomers of 2,3-butanediol (2R,3R-, 2S,3S-, meso-2,3-butanediol and racemic 2,3-butanediol) in perfused livers from fed rats.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
liquid
Specific details on test material used for the study:
- 2R,3R (levo) and 2S,3S (dextro) 2,3-butanediol were obtained from Aldrich Chemical Co.
- Racemic 2,3-butanediol was purchased from Pfaltz and Bauer, Waterbury, CN.
- Meso-2,3-butanediol was obtained from Fluka Chemical Corp., Ronkonkoma, NY.
Radiolabelling:
yes
Remarks:
2H, 14C

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals and environmental conditions:
For liver perfusion experiments:
Male Sprague-Dawley rats (Charles River Laboratories) were fed ad libitum with Purina rat chow. For the series of liver perfusions with unlabelled isomers of butanediol, the rats weighed 210-300 g. For the series of perfusions with radio labelled butanediols, the rats weighed 160-210 g.

Administration / exposure

Route of administration:
other: ex vivo (liver perfusion)
Statistics:
Data were analysed by one-way ANOVA, followed by the Bonferroni test to identify significant differences between groups. Perfusions with labelled 2,3-butanediol were analysed separately from perfusions with unlabelled 2,3-butanediol because of the difference in weights of rats. Significance level was set to p < 0.05.

Results and discussion

Main ADME resultsopen allclose all
Type:
absorption
Results:
Uptake of the 2,3-butanediol isomers decrease in the order: levo > meso > dextro.
Type:
metabolism
Results:
Levo and meso 2,3-butanediol metabolise to acetate, R-3-hydroxybutyrate and CO2, suggesting that 2,3- butanediol is oxidized to acetyl-coA via acetoin.

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Analysis of control liver perfusates from fed rats indicated that any endogenous production of 2,3-butanediol or acetoin was below LOD of the assay (1 µM). In a preliminary perfusion experiment with 20 mM ethanol, neither acetoin nor butane-2,3-diol was produced during the first hour. However, when 5 mM pyruvate was added, acetoin and 2,3-butanediol accumulated up to 15 µM over the second hour. Presence or absence of butane-2,3-diol isomers did not affect the uptake rate of any individual isomer.

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
Differences were observed in the metabolism of individual 2,3-butanediol isomers in perfused rat liver. Interconversion of isomers and oxidation to acetoin was observed with levo and meso, but not with dextro 2,3-butanediol.
In liver perfusions with either levo or meso (radiolabelled) 2,3-butanediol, the substrates were converted to labelled acetate, R-3-hydroxybutyrate and CO2, suggesting that 2,3-butanediol was oxidized to acetyl-CoA via acetoin. Production of radio-labelled CO2, acetate, ketone bodies, acetoin, and other isomers of butane-2,3-diol accounted for approximately one-third of the label uptake.


Applicant's summary and conclusion

Conclusions:
Absorption: Uptake of 2,3-butanediol isomers decrease in the order: levo > meso > dextro.
Metabolism: Levo and meso 2,3-butanediol metabolise to acetate, R-3-hydroxybutyrate and CO2, suggesting that 2,3- butanediol is oxidized to acetyl-coA via acetoin.
Executive summary:

Montgomery et al. 1993 investigated the metabolism of the individual isomers of 2,3 -butanediol (levo (2R,3R), dextro (2S,3S), meso 2,3 -butanediol and racemic 2,3 -butanediol) in perfused livers from fed rats. Differences were observed in the metabolism of individual 2,3-butanediol isomers in perfused rat liver. Interconversion of isomers and oxidation to acetoin was observed with the levo and meso forms, but not with dextro 2,3-butanediol. In liver perfusions with either levo or meso (radio-labelled) 2,3-butanediol, the substrates were converted to labelled acetate, R-3-hydroxybutyrate and CO2, suggesting that 2,3-butanediol was oxidized to acetyl-CoA via acetoin.