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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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Meets scientific standards, however, results might be influenced by the incubation temperature of 37°C (boiling point 35°C).

Data source

Reference
Reference Type:
publication
Title:
Comparative studies on the metabolism and mutagenicity of vinyl ethers
Author:
Sone T, Isobe M, and Takabatake E
Year:
1989
Bibliographic source:
J Pharmacobio-Dyn. 12: 345-351

Materials and methods

Objective of study:
metabolism
Principles of method if other than guideline:
In-vitro assay for microsomal oxidation of the vinyl moiety of ethyl vinyl ether.
GLP compliance:
not specified

Test material

Constituent 1
Chemical structure
Reference substance name:
Ethyl vinyl ether
EC Number:
203-718-4
EC Name:
Ethyl vinyl ether
Cas Number:
109-92-2
Molecular formula:
C4H8O
IUPAC Name:
ethyl vinyl ether
Details on test material:
Ethyl vinyl ether (EVE) from Tokyo Kasei Kogyo Ltd; reagent grade.
No further details.
Radiolabelling:
no

Test animals

Species:
other: in vitro using microsomes of male Wistar rats
Strain:
Wistar
Sex:
male

Administration / exposure

Route of administration:
other: in vitro
Duration and frequency of treatment / exposure:
Incubation for 20 minutes
Doses / concentrations
Remarks:
Doses / Concentrations:
4% solution
No. of animals per sex per dose / concentration:
in vitro
Details on study design:
In-vitro assay for microsomal oxidation of the vinyl moiety of vinyl ethers.
Assay of microsomal oxidation
0.2 µmol ethyl vinyl ether (or other vinyl ethers, see remarks) dissolved in 20 µL methanol was preincubated with 0.5 mL of the microsomal suspension that was diluted to 0.2-1.6 mg protein/mL at 37°C for 3 minutes. Microsomal suspension: Liver S9 -mix of PCB-pretreated male Wistar rats. The reaction was started by the addition of NADPH-regenerating system in phosphate buffer, pH 7.4. The mixture was incubated at 37°C for 20 minutes.
The enzyme reaction was stopped by the addition of 0.5 M phosphoric acid (1.5 mL) saturated with 2,4-dinitrophenylhydrazine.

Results and discussion

Toxicokinetic / pharmacokinetic studies

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

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
Microsomal oxidation to unstable epoxides.
The oxidation rate of EVE was 2.9 nmol/mg protein/min.

Any other information on results incl. tables

The oxidation rates of aromatic vinylethers (phenyl-,
4-nitrophenyl-, 4-cyanophenyl-, 4-acetophenyl-, and
4-chlorophenyl vinyl ether) and of n-butyl vinylether were
also determined.

The oxidation rates of the aromatic vinylethers ranged
between 8.2 to 11.2 nmol/mg protein/min and were thus much
higher than those of the aliphatic vinyl ethers (n-butyl:
5.1, and ethyl vinylether 2.9 nmol/mg protein/min).

The aliphatic vinyl ethers (n-butyl- and ethyl vinylether)
and 4-chlorophenyl- and phenyl vinyl ether were not
mutagenic in the Ames test, in contrast to the other tested
aromatic vinyl ethers.
Mutagenicity correlated with reported data on the half-life
of the epoxides. Half-lifes of 3.9 minutes and more were
associated with mutagenicity, whereas the epoxide half-life
of the non-mutagenic 4-chlorophenyl- and the phenyl vinyl
ether were 1.3 and 0.6 min, respectively.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): other: oxidation of EVE resulted in unstable epoxides
Microsomal oxidation of EVE resulted in the respective epoxides; the oxidation rate was 2.9 nmol/mg protein/min; the epoxides are unstable.
Executive summary:

In in vitro assays 0.2 µmol ethyl vinyl ether dissolved in 20 µL methanol was preincubated with 0.5 mL of the microsomal suspension

of PCB-pretreated male Wistar rats that was diluted to 0.2-1.6 mg protein/mL at 37°C for 3 minutes. The reaction was started by the addition of NADPH-regenerating system in phosphate buffer, pH 7.4. The mixture was incubated at 37°C for 20 minutes. The enzyme reaction was stopped by the addition of 0.5 M phosphoric acid (1.5 mL) saturated with 2,4-dinitrophenylhydrazine. Microsomal oxidation to unstable epoxides was reported. The oxidation rate of EVE was 2.9 nmol/mg protein/min.

Comment: all category members did not show any mutagenic activity in in vitro and in vivo studies.

Conclusion: Microsomal oxidation of EVE resulted in the respective epoxides; the oxidation rate was 2.9 nmol/mg protein/min; the epoxides are unstable.