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EC number: 203-678-8
CAS number: 109-53-5
A category aproach (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 IUCLID chapter 13). The category members have similar
structure and physico-chemical, environmental, and ecotoxicological
properties or follow a trend with respect to these properties. The
toxicological profiles of all category members are very similar.
The metabolic pattern is expected to
be similar between all category members, as the structural differences
are rather small.
Basic toxicokinetics isobutyl vinyl ether
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 IBVE.
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.
Data on clinical signs in the inhalation
hazard test in rats (BASF, 1974) suggested rapid absorption of IBVE.
Narcosis was observed within 3 minutes of exposure to saturated vapour.
In vivo study with methyl
vinyl ether (MVE, weight of evidence)
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).
In vitro assay with ethyl
vinyl ether (EVE, weight of evidence)
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
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.
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.
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