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There are 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.

 

Structurally, 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.

Animal 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.

 

In 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 rats.

 

Himmelstein 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.

 

These 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 1,2-butadiene.

 

The 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.

 

References

Kolsaker and Teige (1970). Ozonation of allenic hydrocarbons, Acta Chem. Scandinavica 24, 2101-2108

 

Krause,and Hashmi Eds, (2004). Modern Allene chemistry. ISBN-13:978-3-527-30671-8-Wiley-WCH, Weinheim 

 

EU RAR (2002). European Union Risk Assessment Report for 1,3-butadiene. Vol. 20. European Chemicals Bureau (http://ecb.jrc.ec.europa.eu/DOCUMENTS/Existing-Chemicals/RISK_ASSESSMENT/REPORT/butadienereport019.pdf)