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General Remarks

A category approach (OECD SIDS 2006) is available for vinyl ethers: methyl vinyl ether (MVE; CAS 107-25-5), ethyl vinyl ether (EVE, CAS 109-92-2), and isobutyl vinyl ether (IBVE, CAS 109-53-5) (see chapter 13).

The category members have similar structure and physico-chemical, environmental, and ecotoxicological properties or follow a trend with respect to these properties.

In vivo study with MVE

The saturable inhalation uptake of MVE in male F344 rats was measured during 3 h exposure in a 31-liter battery jar chambers (100, 300, 1000, 3000 ppm [240, 720, 2400, 7200 mg/m³] for 180 min; whole body exposure). Data were transformed by modified Eadie-Hofstee plots to calculate the kinetic parameters. The concentration at which the uptake proceeds at half maximal velocity was Km = 462 ppm; the maximal gas uptake was Vmax= 176 ppm/kg bw/hour, i.e. 12.9 mg/kg bw/hour (Andersen et al., 1980).

Basic toxicokinetics IBVE (weight of evidence)

In in vitro studies (BASF 2006) the test substance IBVE was incubated for up to 4 h in gastric acid simulans (0.1 M hydrochloric acid; IBVE concentration: 1 mM and 10 mM; 37°C; sampling intervals: 0, 0.5, 1, 2, and 4 hours after start) or in a second experiment with rat liver microsomes (0.5 mg microsomal protein/ml incubate; IBVE concentration 0.5 mM, 37°C, sampling 2 hours after start). 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 ether bridge of isobutyl vinyl ether.

In an earlier in vitro study it was shown that the hydrolysis in body fluids is pH dependent (BASF 1994). IBVE hydrolyzed completely within minutes to acetaldehyde and isobutanol when it was incubated with simulated gastric fluid at a pH of 1.5. Hydrolysis was only approximately 20 % in simulated saliva at pH about 9 at all sampling intervals from 0 through 4 hours after the incubation was started, and approximately 40 % after 1, 2, and 4 hours of incubation with intestinal fluid at pH 7.5. In all simulants, remarkable concentrations of acetaldehyde were found even when no or minor hydrolysis occurred, which, according to the study authors, may be due to the production of acetaldehyde during the derivatization step prior to the analysis.

In vitro assay with EVE (weight of evidence)

In in vitro assays (Sone et al., 1989) 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.

Conclusion

There is evidence for rapid absorption after inhalation concerning all category members. In vitro studies with EVE suggested that vinyl ethers may undergo microsomal oxidation to unstable epoxides, however, no mutagenic activity was found. Experiments with IBVE have shown that this vinyl ether 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. In further experiments approx. 65 % of IBVE were metabolized in vitro by induced rat liver microsomes within 2 hours under the chosen conditions. Only isobutanol was detected in the active microsome incubations. These data suggested metabolic degradation of the ether bridge of vinyl ethers.