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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
Objective of study:
absorption
metabolism
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
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
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.
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.
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.
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.
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.


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.

Endpoint:
basic toxicokinetics in vivo
Remarks:
in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1996
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Objective of study:
absorption
distribution
excretion
metabolism
toxicokinetics
Qualifier:
no guideline followed
Principles of method if other than guideline:
The study investigated the detoxification route for acetaldehyde: metabolism of diacetyl, acetoin, and 2,3-butanediol in liver homogenate and perfused liver of rats. Therefore, the metabolism of diacetyl (2,3-butanedione), acetoin (3-hydroxy-2-butanone) and 2,3-butanediol, which are metabolites of acetaldehyde, was quantitatively investigated using rat liver homogenate, in vivo experiments and liver perfusion (ex vivo).
GLP compliance:
no
Specific details on test material used for the study:
Diacetyl (2,3-butanedione), acetoin (3-hydroxy-2-butanone) and 2,3-butanediol (standard grade) were purchased from Wako Pure Chemicals.
Radiolabelling:
no
Species:
rat
Strain:
Wistar
Details on species / strain selection:
Wistar strain albino rats
Sex:
male
Details on test animals and environmental conditions:
Rats weighing from 200 to 220 g were purchased from Charles River Japan (Yokohama) and fed on standard rat cake MF (Oriental Yeast, Tokyo) for 7 days before use.
Route of administration:
oral: drinking water
Vehicle:
physiological saline
Details on exposure:
Diacetyl, acetoin, or 2,3-butanediol was dissolved in physiological saline to a final concentration of 1 M.
Duration and frequency of treatment / exposure:
1 hour
Dose / conc.:
5 other: mmol per kg body weight
No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle
Details on study design:
Three different experiment were run:
1. Experiment: Activities of Diacetyl- or Acetoin-Reducing Enzymes in Rat Tissues (liver, kidney, brain)
2. Experiment: Metabolic Experiments on Diacetyl, Acetoin, and 2,3-Butanediol in Rat Liver Homogenates
3. Experiment: In Vivo Metabolic Experiments on Diacetyl, Acetoin, and 2,3-Butanediol
Type:
absorption
Results:
ingestion through the gastrointestinal system
Type:
distribution
Results:
in kidney, liver and brain tissue
Type:
metabolism
Results:
mainly in liver by enzyme activity
Type:
excretion
Results:
conjugation of 2,3-butanediol with uridine diphosphate glucuronide, followed by excretion into urine.
Type:
other: bioaccumulation
Results:
in kidney, liver and mainly brain tissue; total amount of 3% of the administered dose
Details on distribution in tissues:
All compounds (including 2,3-butanediol) were found in liver, kidney and brain after 1 hour of oral administration (in vivo experiments). The total amount of accumulated 2,3-butanediol was 3% of the administered dose. 2,3-Butanediol mainly accumulated in brain tissue.

Accumulation of 2,3-butanediol was thought to be caused by low levels of diacetyl- and acetoin-reducing activity in brain, in combination with the permeability of brain to acetoin and 2,3-butanediol and their affinity for brain tissue.
Key result
Test no.:
#1
Transfer type:
blood/brain barrier
Observation:
distinct transfer
Key result
Test no.:
#2
Transfer type:
secretion via gastric mucosa
Observation:
slight transfer
Key result
Test no.:
#3
Transfer type:
blood/placenta barrier
Observation:
not determined
Details on excretion:
2,3-butanediol is conjugated with uridine diphosphate glucuronide, followed by excretion into urine.
Key result
Test no.:
#1
Toxicokinetic parameters:
Cmax: 780 nmol/mL
Remarks:
measured in perfused liver (ex vivo)
Key result
Test no.:
#2
Toxicokinetic parameters:
Tmax: 40 min
Remarks:
measured in perfused liver (ex vivo)
Metabolites identified:
yes
Details on metabolites:
Enzymatic metabolisms of 2,3-butanediol mainly occurs in the liver (measured in vivo). In very small amounts, 2,3-butanediol metabolises acetoin reversibly (measured in liver homogenate): after addition of 10 nmol 2,3-butanediol to liver homogenate, 9.80±0.28 nmol 2,3-butanediol and 0.16±0.05 nmol acetoin was found. Diacetyl was not detected.
Conclusions:
Absorption: Ingestion through the gastrointestinal system.
Distribution: 2,3-butanediol was found in liver, kidney and brain tissue, the total amount being to 3% of the administered dose. 2,3-butanediol was mainly accumulated in brain tissue.
Metabolism: 2,3-butanediol is mainly metabolised in the liver by enzymatic activity (pyruvate --> acetoin --> 2,3-butanediol).
Excretion: Conjugation of 2,3-butanediol with uridine diphosphate glucuronide, followed by excretion into urine.
Toxicokinetic: Cmax: 780 nmol/mL; Tmax: 40 min
Executive summary:

Otsuka et al. 1996 investigated the detoxification route for acetaldehyde: metabolism of diacetyl, acetoin, and 2,3-butanediol in liver homogenate and perfused liver of rats. Therefore, the metabolism of diacetyl (2,3-butanedione), acetoin (3-hydroxy-2-butanone) and 2,3-butanediol, which are metabolites of acetaldehyde, was quantitatively investigated using rat liver homogenate, in vivo experiments and liver perfusion (ex vivo). The study investigated the distribution of 2,3 -butanediol in rats using a dose of 5 mmol per kg body weight (male rats, n=5). The dose was administered by oral route (drinking water). Rats were euthanized after one hour of exposure.

After one hour of exposure, 2,3 -butanediol was distributed to liver, kidney and brain tissue, the total amount being to 3% of the administered dose. 2,3-butanediol was mainly accumulated in brain tissue. 2,3-butanediol was mainly metabolised in the liver by enzymatic activity (pyruvate --> acetoin --> 2,3-butanediol) and excreted by conjugation of 2,3-butanediol with uridine diphosphate glucuronide, followed by excretion into urine. Toxicokinetic parameters were Cmax: 780 nmol/mL and Tmax: 40 min.

Endpoint:
basic toxicokinetics in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1981
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Objective of study:
other: Pharmacokinetics
Qualifier:
no guideline followed
Principles of method if other than guideline:
The present report develops a hybrid approach, which accounts for a combination of both types of pharmacokinetic models. A pharmacokinetic model was developed to describe the biotransformation of 2-butanol (2-OL) and its metabolites (2-butanone, 3-hydroxy-2-butanone, and 2,3-butanediol) using in vivo experimental blood concentrations.
GLP compliance:
no
Specific details on test material used for the study:
- butane-2,3-diol (2,3-BD)
- obtained from Aldrich Chemical Co., Milwaukee, Wise
Radiolabelling:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals and environmental conditions:
Male Sprague-Dawley rats weighing 200-280 g were used in the study. Animals were maintained on an ad libitum diet of commercial chow and water in a temperature-controlled room with a 12 hour light-dark cycle.
Route of administration:
intravenous
Vehicle:
water
Duration and frequency of treatment / exposure:
Elimination / clearance rate: Single exposure of two concentrations monitored over 12 hours.
Metabolism: Single exposure of one concentration monitored over 16 hours.
Dose / conc.:
400 ppm (nominal)
Remarks:
mg/kg / elimination experiment
Dose / conc.:
800 ppm (nominal)
Remarks:
mg/kg / elimination experiment
Dose / conc.:
676 mg/kg diet
Remarks:
metabolism experiment
No. of animals per sex per dose:
five
Control animals:
yes
Details on study design:
Elimination experiment: Specimen were exposed i.v. to 400 and 800 mg/kg 2,3-BD (as a 60% aqueous solution).
Metabolism experiment: Specimen were exposed orally to 676 mg/kg 2,3-BD.
Details on dosing and sampling:
Blood samples were analysed with gas chromatography.
Statistics:
A Student's t-test was used for statistical evaluation of differences between two means.
Type:
excretion
Results:
elimination / blood clearance rate
Type:
metabolism
Results:
metabolites
Details on excretion:
Elimination: Elimination of 2,3-BD follows monoexponential of first-order kinetics. A slight absorption phase was seen after 2,3-BD administration. The apparent overall elimination rate constant (Ke), half-life (t1/2), and volume of distribution (Vd) for the 400 mg/kg dose are not statistically different from 800 mg/kg dose. Average Ke, t1/2, and Vd values for both doses of 2,3-butandiol were 0.201 hr -1, 3.45 hr, and 737 ml/kg, respectively. The total area und the curve (AUC) 2,3-BD value for the 400 mg/kg dose is 50% of that calculated when the dose of 2,3-BD is doubled to 800 mg/kg. These results indicate that the clearance of 2,3-BD is dose independent over the range of administered doses.

Unpublished data from the author's laboratory indicated that the urinary excretion of 2,3-BD in the rat accounts for 15.2 % as unchanged test item following a 800 mg/kg 2,3-BD i.v. dose, while only 9% of a 400 mg/kg i.v. dose was recovered unchanged.
Key result
Toxicokinetic parameters:
half-life 1st: 3.45 hours
Toxicokinetic parameters:
other: clearance rate
Remarks:
0.201 1/h
Toxicokinetic parameters:
Cmax: 8.5 mg/ml
Remarks:
dose 800 mg/kg
Toxicokinetic parameters:
Cmax: 4.5 mg/ml
Remarks:
dose 400 mg/kg
Toxicokinetic parameters:
Tmax: 1 hour
Metabolites identified:
yes
Details on metabolites:
Metabolism: A quantitative study of 2,3-BD biotransformation was carried out to determine if the substance underwent any significant in vivo conversion to acetoin or diacetyl. 2,3-BD was rapidly absorbed with a peak concentration of 0.72 mg/ml 1 hr after administration. Thereafter, 2,3-BD blood concentration declines to a value of 0.04 mg/ml after 16 hr. Acetoin was the only detectable metabolite of 2,3-BD found in the blood, with a peak concentration of 0.01 mg/ml detected 1 hr after 2,3-BD dosing. No diacetyl was detected.
Conclusions:
Elimination half-life of butane-2,3-diol was 3.45 hours in blood of rats i.v. exposed to 400 mg/kg or 800 mg/kd.
Measured metabolites of butane-2,3-diol was acetoin in blood of rats orally exposed to 676 mg/kg.
Executive summary:

The present report develops a hybrid approach, which accounts for a combination of both types of pharmacokinetic models. A pharmacokinetic model was developed to describe the biotransformation of 2-butanol (2-OL) and its metabolites (2-butanone, 3-hydroxy-2-butanone, and 2,3-butanediol) using in vivo experimental blood concentrations.

Male Sprague-Dawley rats weighing 200-280 g were used in the study. Animals were maintained on an ad libitum diet of commercial chow and water in a temperature-controlled room with a 12 hour light-dark cycle. Specimen were exposed i.v. to 400 and 800 mg/kg 2,3 -BD (as a 60% aqueous solution) in the elimination experiment (n=5) by a single exposure over 12 hours. Specimen were exposed orally to 676 mg/kg 2,3 -BD in the metabolism experiment by a single exposure over 16 hours.

Results elimination experiment: Elimination of 2,3-BD follows monoexponential first-order kinetics. A slight absorption phase was seen after 2,3-BD administration. The apparent overall elimination rate constant (Ke), half-life (t1/2), and volume of distribution (Vd) for the 400 mg/kg dose are not statistically different from 800 mg/kg dose. Average Ke, t1/2, and Vd values for both doses of 2,3-butandiol were 0.201 hr^-1, 3.45 hr, and 737 ml/kg, respectively. The total area und the curve (AUC) for 2,3-BD at 400 mg/kg dose was 50% of the AUC at 800 mg/kg. These results indicate that the clearance of 2,3-BD is dose independent over the range of administered doses. Unpublished data from the author's laboratory indicated that the urinary excretion of 2,3-BD in the rat accounts for 15.2 % as unchanged test item following a 800 mg/kg 2,3-BD i.v. dose, while only 9 % of a 400 mg/kg i.v. dose was recovered unchanged.

Results metabolism experiment: A quantitative study of 2,3-BD biotransformation was carried out to determine if the substance underwent any significant in vivo conversion to acetoin or diacetyl. 2,3-BD was rapidly absorbed with a peak concentration of 0.72 mg/ml one houre after administration. Thereafter, 2,3-BD blood concentration declines to a value of 0.04 mg/ml after 16 hr. Acetoin was the only detectable metabolite of 2,3-BD found in the blood, with a peak concentration of 0.01 mg/ml detected one hour after 2,3-BD dosing. No diacetyl was detected.

Description of key information

Absorption: Ingestion through the gastrointestinal system.

Distribution: 2,3-butanediol was found in liver, kidney and brain tissue, the total amount being to 3% of the administered dose. 2,3-butanediol was mainly accumulated in brain tissue.

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 in the liver.

Excretion: Conjugation of 2,3-butanediol with uridine diphosphate glucuronide, followed by excretion into urine.

Toxicokinetic: Tmax: 40 min - 1 hour; half-life: 3.45 hr (independent of dose).

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

Otsuka et al. 1996 investigated the detoxification route for acetaldehyde: metabolism of diacetyl, acetoin, and 2,3-butanediol in liver homogenate and perfused liver of rats. Therefore, the metabolism of diacetyl (2,3-butanedione), acetoin (3-hydroxy-2-butanone) and 2,3-butanediol, which are metabolites of acetaldehyde, was quantitatively investigated using rat liver homogenate, in vivo experiments and liver perfusion (ex vivo). The study investigated the distribution of 2,3-butanediol in rats using a dose of 5 mmol per kg body weight. The dose was administered by oral route (drinking water). Rats were euthanized after one hour of exposure.

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.

After one hour of exposure, 2,3-butanediol was distributed to liver, kidney and brain tissue, the total amount being to 3% of the administered dose. 2,3-butanediol was mainly accumulated in brain tissue. 2,3-butanediol was mainly metabolised in the liver by enzymatic activity (pyruvate --> acetoin --> 2,3-butanediol) and excreted by conjugation of 2,3-butanediol with uridine diphosphate glucuronide, followed by excretion into urine. Toxicokinetic parameters were Cmax: 780 nmol/mL and Tmax: 40 min.

Dietz et al. 1981 investigated the pharmacokinetics of 2 -butanol and its metabolites (inter alia butane-2.3 -diol) in the rat. Elimination of 2,3-BD follows monoexponential of first-order kinetics. A slight absorption phase was seen after 2,3-BD administration. The apparent overall elimination rate constant (Ke), half-life (t1/2), and volume of distribution (Vd) for the 400 mg/kg dose were not statistically different from 800 mg/kg dose. Average Ke, t1/2, and Vd values for both doses of butane-2,3-diol were 0.201 hr-1, 3.45 hr and 737 mL/kg, respectively. The total area under the curve (AUC) of butane-2,3-diol for the 400 mg/kg dose was 50% of the 800 mg/kg dose. These results indicate that the clearance of butane-2,3-diol is dose independent over the range of administered doses. Unpublished data from the author's laboratory indicated that the urinary excretion of butane-2,3-diol in the rat accounts for 15.2 % as unchanged test item at 800 mg/kg butane-2,3-diol i.v. dose, while only 9 % test item was recovered unchanged at 400 mg/kg i.v. dose.

A quantitative study of butane-2,3-diol biotransformation was carried out to determine if the substance underwent any significant in vivo conversion to acetoin or diacetyl. Butane-2,3-diol was rapidly absorbed with a peak concentration of 0.72 mg/mL one hour after administration. Thereafter, butane-2,3-diol blood concentration declined to 0.04 mg/ml after 16 hours. Acetoin was the only detectable metabolite of butane-2,3-diol found in the blood, with a peak concentration of 0.01 mg/ml detected one hour after butane-2,3-diol administration. No diacetyl was detected.

Metabolism/ Metabolites: Human Metabolome Database (HMDB)*

2,3-Butanediol fermentation is typical for Enterobacter species or microbes found in the gut. In humans, 2,3-butanediol is oxidized to acetyl-CoA via acetoin. 2,3-Butanediol is the excretory product of metabolism of acetoin. *(http://www.hmdb.ca/metabolites/HMDB0003156 - accessed 26.06.2018)