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Basic toxicokinetics

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basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Test procedures were in accordance with generally accepted scientific standards and described in sufficient detail. No GLP data was provided.

Data source

Reference Type:
Pharmacokinetics of 2-butanol and its metabolites in the rat
Dietz FK, Rodriguez-Giaxola M, Traiger GJ, Stella VJ, Himmelstein KJ
Bibliographic source:
Journal of pharmacokinetics and biopharmaceutics 9: 553-576

Materials and methods

Objective of study:
Principles of method if other than guideline:
Development of a pharmacokinetic model.
GLP compliance:
not specified

Test material

Constituent 1
Chemical structure
Reference substance name:
EC Number:
EC Name:
Cas Number:
Molecular formula:
Constituent 2
Reference substance name:
2-Butanone (Methyl ethyl ketone; MEK)
2-Butanone (Methyl ethyl ketone; MEK)
Constituent 3
Reference substance name:
3-Hydroxy-2-Butanone (3H-2B)
3-Hydroxy-2-Butanone (3H-2B)
Constituent 4
Reference substance name:
2,3-Butanediol (2,3-BD)
2,3-Butanediol (2,3-BD)
Test material form:
other: aqueous solution
Details on test material:
2-butanol and 2-butanone were obtained from Matheson Coleman and Bell, Norwood, Ohio. 3H-2B and 2,3-BD were obtained from Aldrich Chemical
Co., Milwaukee, Wise.

Test animals

Details on test animals or test system and environmental conditions:
Male Sprague-Dawley rats weighing 200-280 g were used throughout the study. Animals were maintained on an ad libitum diet of commercial chow and water in a temperature-controlled room with a 12 hr light-dark cycle.

Administration / exposure

Route of administration:
oral: unspecified
not specified
Details on exposure:
2-butanol (2.2 ml/kg or 1776 mg/kg as a 22% aqueous solution), 2-butanone (2.1 ml/kg or 1690 mg/kg as a 21% aqueous solution) 2,3-BD (0.68 ml/kg or 676 mg/kg as a 6.8% aqueous solution) were administered orally to animals which had been fasted overnight. Intravenous injections of 400 and 800 mg/kg of 3H-2B (as a 85% aqueous solution) and 2,3-BD (as a 60% aqueous solution) were administered via the dorsal vein of the penis to rats under light ether anesthesia.
Duration and frequency of treatment / exposure:
Single dose (oral or i.v.)
Doses / concentrations
Doses / Concentrations:
2-butanol: 2.2 ml/kg or 1776 mg/kg as a 22% aqueous solution (oral).
2-butanone: 2.1ml/kg or 1690 mg/kg as a 21% aqueous solution (oral).
2,3-BD : 0.68 ml/kg or 676 mg/kg as a 6.8 % aqueous solution (oral or i.v.).
3H-2B: 400 or 800 mg/kg as a 60% aqueous solution (i.v.)
No. of animals per sex per dose / concentration:
Not stated
Control animals:
not specified
Details on study design:
Male rats were given oral doses of 2-butanol, 2-butanone, 2,3-BD (or i.v.), or 3H-2B (i.v.) and serial blood samples were collected for up to 30 hours following treatment.
Details on dosing and sampling:
Blood concentrations of 2-butanone, 2-butanol, 3-hydroxy-2-butanone and 2,3-butanediol were determined by gas chromatography. Serial blood samples were collected from the tail vein at selected times after the administration of 2-butanone or 2,3-butanediol. Prior to deproteinization with ZnSO4 and Ba(OH)2, an aliquot of a stock internal standard solution was added to each blood sample. The identification of unknown compounds was carried out by comparison of their gas chromatographic retention times with those of authentic samples deproteinized and injected under identical conditions. Blood concentrations were estimated by the peak ratios of the unknowns to their internal standards. A Varian model 1400 gas chromatograph equipped with a flame ionization detector was used.
Student's t-test was used for statistical evaluation of differences between two means. In the pharmacokinetic model, the differential equations were solved numerically by a Hammings Predictor-Correction method with a Runge-Kutta starter.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Toxicokinetic parametersopen allclose all
Toxicokinetic parameters:
AUC: 3254 +/- 258 mg hr/l (2-butanol), 9868 +/- 566 mg hr/l (2-butanone), 443 +/- 93 mg hr/l (3H2B) and 3167 +/- 503 mg hr/l (23BD)
Toxicokinetic parameters:
Cmax: 0.59 mg/ml (2-butanol)
Toxicokinetic parameters:
Tmax: 2 hours (2-butanol)

Metabolite characterisation studies

Metabolites identified:
Details on metabolites:
Metabolites identified with oral exposure to 2-butanol were - 2-butanone, 3H-2B and 2,3-BD.
Metabolites identified with oral exposure to 2-butanone were - 2-butanol, 3H-2B and 2,3-BD.

Any other information on results incl. tables

Blood concentrations of 2-butanol and its metabolites 2-butanone, 3H-2B, and 2,3-BD were measured. Peak blood concentrations of 2-butanol (0.59 mg/ml) were observed within 2 hours of exposure. Blood levels declined to less than 0.05 mg/ml at 16 hours. As the blood 2-butanol concentration fell, the metabolite concentrations of 2-butanone, 3H-2B, and 2,3-BD concentrations rose to maximums at 8, 12, and 18hr, respectively. The peak concentration of 2-butanone was 0.78 mg/ml, while that of 2,3-BD was 0.21 mg/ml. 3H-2B reached a peak concentration of 0.04 mg/ml. Total AUC values for 2-butanol, 2-butanone, 3H-2B, and 2,3-BD were 3254 ± 258, 9868 ± 566, 443 ± 93, and 3167 ± 503 mg-hr/l, respectively.

Following an oral dose of 2-butanone, blood concentrations of 2-butanone and its metabolites 2-butanol, 3H-2B, and 2,3-BD were measured. Blood MEK concentrations of 0.95 mg/ml peaked at 4 hours and declined to less than 0.07 mg/ml at 18 hours. As the 2-butanone concentration fell, the end metabolite 2,3-BD rose to a maximum concentration of 0.26 mg/ml at 18 hours. Peak concentrations of 2-butanol and 3H-2B were 0.033 and 0.027 mg/ml, respectively. These were detected at 6 and 8 hr after the 2-butanone administration. Total AUC values for 2-butanone, 2-butanol, 3H-2B, and 2,3-BD were 10,899 ± 824, 414 ± 38, 382 ± 38, and 3863 ± 238 mg-hr/l, respectively.

Applicant's summary and conclusion

Interpretation of results (migrated information): no bioaccumulation potential based on study results 2-butanol and 2-butanone were rapidly eliminated in the blood within 16 and 20 hours after oral exposure, respectively.
In the development of the pharmacokinetic model, the authors confirmed that a limited amount of 2-butanol could be recovered as glucuronide in the urine. Most of the alcohol appears to undergo oxidation via alcohol dehydrogenase to its corresponding ketone, 2-butanone. The results showed a limited amount of the ketone undergoes a backward reduction to its parent alcohol, 2-butanol. 3H-2B and 2,3-BD are found to be common metabolites of 2-butanol and 2-butanone. The model was able to simulate blood concentrations and elimination of all 4 compounds after oral administration of 2-butanol, and the results after i.v. of 3H-2B and 2,3-BD. AUC analysis suggested that the quantities of 3H-2B and 2,3-BD formed from oral doses of 2-butanol and 2-butanone are comparable. The results supported the estimation in that no significant difference in the AUC of 2-butanone was observed after dosing with either 1776 mg/kg of 2-butanol or 1690 mg/kg of 2-butanone (10,899 ± 824 vs. 9868 ± 566 mg-hr /liter, respectively).
Executive summary:

Pharmacokinetic disposition of 2 -butanol and 2 -butanone are identical following oral exposure. Both substances are rapidly absorbed following exposure (as shown by rapid increase in blood concentrations following dosing) and rapidly eliminated in the blood. Both substances are also metabolized to identical substances with similar AUC values.