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EC number: 209-674-2
CAS number: 590-19-2
no toxicokinetic or metabolism data available for 1,2 -butadiene and
there are also no repeat dosing or reproductive studies available. A
strategy for read-across to close analogues has therefore been developed
to address data gaps for these endpoints. Metabolism to active
metabolites (epoxides) is critical to the toxicology of C4 alkenes and
therefore this has defined the approach taken for read-across.
the closest isomer is 1,3-butadiene. The metabolism of 1,3-butadiene to
its epoxide metabolites (both mono- and di-epoxides) plays a critical
role in defining the susceptibility of a particular species to the
toxicity of 1,3-butadiene after repeat dosing. In
contrast, the presence of adjacent double bonds (allenes) in 1,2
-butadiene is likely to preclude the formation of reactive epoxide
metabolites. Although there are no metabolism data on 1,2 -butadiene,
oxidation of 1,2-butadiene and other allenes by chemical reaction with
ozone caused fragmentation of the molecule and generation of carbonyl
compounds (Kolsaker and Teige 1970). Chemical reaction of other allenes
with per acids has occasionally produced allene oxides but mostly
results in a complex mixture of products (Krause,and Hashmi 2004 ).
Allenes can, in the presence of hydrogen peroxide, form an epoxide
intermediate. This intermediate may either isomerize to form a
cyclopropanone, react with nucleophiles, or form a spirodioxide, which
can further react with nucleophiles (Krause and Hasmi, 2004). However,
the strongly acidic or oxidising conditions required for this reaction
are unlikely to occur in a cellular environment.
species that have a high rate of metabolism of 1,3-butadiene therefore
seem inappropriate to use as read-across for repeat dosing studies
although for endpoints such as acute toxicity, skin/eye irritation and
sensitization this is less important. Mice have a far higher
susceptibility to repeat dose toxicity, carcinogenicity and genotoxicity
than rats due to the greater ability in mice to generate both the
monoepoxide, and in particular the diepoxide, in combination with a
lesser ability to eliminate these epoxides.
the study of Kreiling et
al (1986) the pharmacokinetics of 1,3-butadiene in mice after inhalation
exposure from 10 to 5000 ppm in a closed system were investigated and
compared with that of rats. Linear pharmacokinetics applied in both
species at exposure
concentrations below 1000 ppm, and saturation of metabolism was observed
at concentrations of about 2000 ppm. Metabolic clearance in the lower
concentration range where first order metabolism applies was 7300 mL/h
(rat) and 4500 mlLh (mice). Maximal metabolic elimination rate (Vmax) in
mouse was 400 pmol/h/kg compared with 220 pmol/h/kg in rats. This shows
that 1,3-butadiene is metabolized by mice at higher rates compared to
et al (1994) determined the concentrations of 1,3-butadiene and its mono
and diepoxides in the blood of rats and mice during and after exposure
to inhaled 1,3-butadiene at 62.5, 625 or 1250 ppm for 6h. Steady-state
blood concentrations of 1,3-butadiene were higher in mice than in rats.
Uptake of 1,3-butadiene was saturable at the highest inhaled
concentration in both species. In mice, 1,3-butadiene monoxide
concentrations in blood were up to 8-fold higher than in rats; and mice,
but not rats, had quantifiable levels of the diepoxide in the blood.
These data suggest that the greater sensitivity of mice to
1,3-butadiene-induced toxicity and carcinogenicity compared to rats, may
be partially explained by the increased metabolism resulting in higher
concentrations of the mono and diepoxides.
studies and many others (see review in EU RAR, 2002) therefore indicate
that the mouse is not an appropriate species to use for read-across
studies from 1,3-butadiene to 1,2-butadiene where high levels of active
metabolites are formed with the former and no evidence to indicate that
any would be formed with the latter. The rat however, with its lower
levels of epoxides seems a reasonable species to use as the primary
source of data for read-across studies from 1,3-butadiene to
mono-butene isomers, have also been used to help provide weight of
evidence. These compounds also show species differences in metabolism
but do not form the diepoxide. Rats and mice exposed to isobutene
(2-methylpropene). at concentrations up to 500ppm had maximal metabolic
elimination rates of 340 µmol/kg/h for rats and 560 µmol/kg/h for mice.
The atmospheric concentration at which Vmax/2 was reached was 1200 ppm
for rats and 1800 ppm for mice. The metabolism was saturable in both
species and was blocked by inhibitors of P450 enzymes. The epoxide 1,1
-dimethyloxirane was formed as a primary reactive metabolite of
isobutene in both species (Csanady et al, 1991). 2-Methylpropene has a
strong database for repeat dose toxicity and studies in rats and mice
are therefore used as surrogates for 1,2-butadiene. Other mono-butene
isomers (1- butene and 2-butene) have also been used to provide weight
of evidence for the reproductive toxicity endpoints.
and Teige (1970). Ozonation of allenic hydrocarbons, Acta Chem.
Scandinavica 24, 2101-2108
Hashmi Eds, (2004). Modern Allene chemistry.
(2002). European Union Risk Assessment Report for 1,3-butadiene. Vol.
20. European Chemicals Bureau
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