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Members of the butenes category have the potential to be absorbed and widely distributed. Eide et al (1995) reported that rats exposed to 300 ppm (688 mg/m3) of 1-alkenes (from C2-C8, including 1-butene) for 12h per day for 3 days had increased concentrations of the alkenes in blood and tissues, proportional to increasing numbers of carbon atoms. In contrast, levels of haemoglobin and DNA adducts decreased with increasing numbers of carbon atoms. The 1-alkenes were widely distributed within the body with the lowest concentrations in blood and the highest in fat. Concentrations of 1-butene (micromol/kg tissue) were: blood 1.9, liver 0.8, lung 4.9, brain 3.0, kidneys 5.7, fat 70.0. DNA adducts (N-7 alkyl guanine) (adducts/107nucleotides) were: lymphocytes 0.8 and liver 2.1 after exposure to 1-butene. Vaz et al (1998) investigated the rates of oxidation of model olefins (including cis and trans 2-butene) using P450 2B4 and 2E1 mutants. The results support the idea that different electrophilic species support and affect epoxidation. P450 2E1 was the major isoform responsible for epoxidation of 2-butene followed by hydroxylation. Epoxidation of the cis isomer was faster than the trans with the opposite occurring for hydroxylation.

 

More extensive metabolism and distribution studies have been carried out on the butene isomer, 2-methylpropene (isobutene). A higher rate of metabolism in the mouse and saturation of metabolism in rats and mice have been demonstrated in vivo by Csanady et al (1991) and Henderson et al (1993). In the study of Csanady et al (1991), rats and mice were exposed to 2-methylpropene, at concentrations up to 500 ppm (1147 mg/m3), metabolic elimination was first order. The maximal metabolic elimination rates were 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 (2754 mg/m3) for rats and 1800 ppm (4131 mg/m3) for mice. The metabolism was saturable in both species and was blocked by inhibitors of P450 enzymes. In the study of Henderson et al (1993), rats were exposed to 2-methylpropene at concentrations from 40 to 4000 ppm (91.8-9180 mg/m3). Rapid metabolism to oxidised metabolites excreted in the urine occurred and isobutenediol and 2-hydroxyisobutyric acid were identified as metabolites. Blood levels of 2-methylpropene were linearly related to exposure up to 400ppm (918 mg/m3) but were supralinear at 4000 ppm (9180 mg/m3) indicating saturation of metabolism at this higher dose level. Absorption of inhaled 2-methylpropene was about 8% up to 40ppm but decreased at higher concentrations. At 40 ppm, over 90% of absorbed 2 -methylpropene was metabolised but at 4000 ppm, 20% was excreted unchanged, also indicating saturation of metabolism.

Similar findings were reported during a carcinogenicity study on 2-methylpropene (NTP, 1988). The major urinary metabolite of 2-methylpropene (2-hydroxyisobutyric acid: HIBA) was measured in the urine of rats and mice as an indicator of exposure. F344/N rats and B6C3F1 mice were exposed to 2-methylpropene at concentrations of 0, 500, 2,000 or 8,000 ppm, (1147, 4589, 18,359 mg/m3) for 105 weeks. In both species, the amount excreted increased with increasing exposure concentration but when HIBA concentration was normalized to isobutene exposure concentration, the relative amount of HIBA excreted decreased with increasing exposure concentration, implying nonlinear kinetics (NTP, 1988).

 

The in vivo metabolism studies are supported by extensive in vitro metabolism studies. Cornet et al (1991) showed that 2-methylpropene was metabolised to its epoxide 2-methyl-1,2-epoxypropane in a mouse liver in vitro system. The epoxide was rapidly further metabolised by epoxide hydrolase to methyl-1,2-propanediol and by glutathione-S-transferase to the glutathione conjugate. Further studies (Cornet et al, 1995a) using in vitro rat, mouse and human liver systems demonstrated that the lowest rates of biotransformation to the epoxide metabolite were found in human liver, followed by rat then mouse. Quantification of levels of epoxide hydrolase, the major enzyme responsible for the detoxification of the epoxide, in these species revealed that human liver has the highest level followed by rats then mice. In contrast, levels of P450 were lowest in humans. These results demonstrate a clear species difference in the metabolism of 2-methylpropene and suggest that mice and rats are not good models for the metabolism of 2-methylpropene in species where concentrations of the primary epoxide metabolite are likely to be lower than in these rodent species.

 

The biotransformation of 2-methylpropene was also investigated in vitro in rat lung and liver (Cornet et al, 1995b). Biotransformation to the epoxide in rat lung was 50% lower than that in liver indicating that the lung is less exposed to the epoxide than the liver, even though 2-methylpropene is a gaseous compound entering the body through the lungs. The low biotransformation to the epoxide correlates with low levels of mixed function oxidase activity in lung tissue compared with liver.

 

In summary, members of the butenes category are absorbed, widely distributed, metabolised and excreted in rats and mice. Absorption and metabolism is greater in mice than rats although metabolism is saturable in both species. Oxidation by P450 results in the formation of epoxides that are rapidly further metabolised by epoxide hydrolase and glutathione-S-transferase to metabolites that are excreted in urine. Interspecies studies of in vitro metabolism indicates that humans have the lowest capacity for oxidative metabolism of the butenes and the highest for the detoxification pathways.