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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:
weight of evidence
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Meets generally accepted scientific standards and is described in sufficient detail.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2006
Report Date:
2006

Materials and methods

Objective of study:
metabolism
Principles of method if other than guideline:
Hydrolysis in gastric acid simulans and in vitro metabolism using rat liver microsomes
GLP compliance:
yes (incl. certificate)
Remarks:
BASF AG, Department Experimental Toxicology and Ecology

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
isobutyl vinyl ether (IBVE)
purity 99.65%.
Test substance No.: 03/0186-4
Batch No.: T110 Partie 25/06
Homogeneous
Stability: 21 July 2007; stability of the test substance under storage conditions over the test period was guaranteed by the sponsor
Radiolabelling:
no

Test animals

Species:
other: in vitro
Strain:
other: not applicable
Sex:
not specified

Administration / exposure

Route of administration:
other: in vitro
Details on exposure:
Exp. 1
Incubation in gastric acid simulans. Simulans: 0.1 M hydrochloric acid. IBVE concentration: 1 mM and 10 mM.
Exp. 2
Incubation with rat liver microsomes microsomes: 0.5 mg microsomal protein/ml incubate. IBVE concentration: 0.5 mM.
Duration and frequency of treatment / exposure:
Exp.1: 4 h
Exp. 2: 2 h
Doses / concentrations
Remarks:
Doses / Concentrations:
Exp.1: 1 or 10 mM
Exp. 2: 0.5 mM
No. of animals per sex per dose:
not applicable
Control animals:
other: not applicable
Details on study design:
Exp. 1
Incubation in gastric acid simulans. Simulans: 0.1 M hydrochloric acid. IBVE concentration: 1 mM and 10 mM. Duration of test: 4 hours. Temperature: 37°C. Sampling intervals: 0, 0.5, 1, 2, and 4 hours after start. Sample preparation: dilution with the same volume of acetone; directly followed by GC-analysis. Experiments were conducted in duplicate.
Exp. 2
Incubation with rat liver microsomes: 0.5 mg microsomal protein/mL incubate. Obtained from Aroclor 1254 induced male Wistar rat liver. Buffer: phosphate buffer, pH 7.4. Cofactor: NADPH-generating system. IBVE concentration: 0.5 mM. Duration of test: 2 hours. Temperature: 37°C. Sampling: at 2 hours after start. Controls: buffer control and heat inactivated microsomes were incubated with IBVE. Positive control substance: testosterone. Sample preparation: dilution with the same volume of acetone followed by centrifugation at 4600 rpm for 10 minutes. The supernatant was subjected to GC-analysis. Experiments were conducted in duplicate.
Details on dosing and sampling:
Analytical method
GC analysis with external calibration. Injector temperature: 200°C. Oven temperature: 45°C. Detection: FID. Calibration curve: prepared from standard solutions generated from IBVE stock solutions diluted with acetone. A buffer control was incubated with 0.5 mM IBVE which served to calculate the recovery from the heat inactivated microsome control incubation. For the microsomal incubation, a one point calibration was used.
Statistics:
The percentage of IBVE recovered from the incubations with heat deactivated (HD) was corrected for the recovery from the buffer control incubations, and the recovery from the active microsome incubation was corrected for the HD incubation recovery.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
no data
Details on distribution in tissues:
no data
Details on excretion:
no data

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
Exp. 1
Stability in gastric acid simulans (0.1 M HCl):
IBVE was not detectable at any time after the addition to 0.1 M Hl at either 1 or 10 mM IBVE. Isobutanol was found immediately after addition and thereafter in the range of 97 to 110 % (1 mM IBVE) or 92-105 % (10 mM IBVE) of the theoretical value.

Exp. 2
Incubations with rat liver microsomes
Recovery of IBVE was 99 % in the buffer control, and 50.8 % with heat deactivated (HD) microsomes. It was calculated from the recovery in the active microsome incubation that, in relation to the HD recovery, 65 % of IBVE was metabolized. Isobutanol was detected in the active incubate, but not in the buffer or HD incubate.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): other: hydrolysis in acid solutions
It was concluded that
(1) IBVE hydrolyzes immediately and completely in hydrochloric acid which was used as gastric acid simulans; isobutanol was detected in the range 92 to 110 % of the theoretical value.
(2) approx. 65 % of IBVE were metabolized in vitro by induced rat liver microsomes within 2 hours under the chosen conditions. Isobutanol was only detected in the active microsome incubations suggesting metabolic degradation of the of the ether bridge of isobutyl vinyl ether.