Registration Dossier

Administrative data

Description of key information

Members of the butenes category are flammable gases at room temperature and therefore the requirement for data on oral and dermal repeat dose toxicity is waived in accordance with REACH Annex XI. Members of the butenes category have low sub-chronic toxicity. Inhalation exposure is the most relevant route. No significant exposure-related toxicological effects or target organ toxicity have been observed in inhalation studies of up to 2 years in rats or mice. Nasal lesions were observed in 2 year rodent studies at the highest concentration and the NOAEC of 2000 ppm (4589 mg/m3) in rats is based on the lack of effect at this concentration.

Key value for chemical safety assessment

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEC
4 589 mg/m³

Additional information

Members of the butenes category are flammable gases at room temperature and therefore significant exposure via the dermal or oral routes is unlikely. In accordance with Section 2 of REACH Annex XI, studies on oral and dermal repeat dose toxicity do not need to be conducted as they are technically not feasible. An oral study is, however, available for 2-methylpropene (Hazleton 1986). Although oral administration is an unusual and non-relevant route for a gaseous substance, the analytical results indicated that the gas remained dissolved in the corn oil vehicle and the target concentration (148.6mg/kg) was achieved. No toxicologically significant changes were observed in rats that received dose levels up to 148.6 mg/kg/day (the maximum achievable concentration by this route) when 2-methylpropene was administered orally to rats over 28 days. A NOAEL of 148.6 mg/kg/day was established (Hazleton 1986).

 

Repeat dosing studies via inhalation exposure are available for but-1-ene, 2-butene and 2-methylpropene. All studies have shown minimal systemic or target organ toxicity. Exposure of rats to but-1-ene at concentrations of 500, 2000, 8000 ppm (1147, 4589, 18,359 mg/m3) did not induce systemic toxicity in males or females exposed for a minimum of 28 days or in pregnant female rats exposed for 14 days pre-mating, through mating and gestation to day 19. No treatment-related effects on body weight, clinical chemistry, organ weights or histopathology were found. Neurotoxicity screening also showed no effects on motor activity or functional observation battery. A NOAEC of 8000 ppm (18,359 mg/m3) (the highest dose level) was established (Huntingdon, 2003). 

 

 Exposure of rats to 2-butene at target concentrations of 2500 or 5000 ppm (5737 or 11,474 mg/m3) did not induce significant systemic toxicity in males and females exposed for 28 days, or in pregnant female rats exposed for 14 days pre-mating, through mating and gestation to day 19 (TNO 1992b). Mean absolute organ weights and relative weights were comparable in all groups. No abnormal, treatment-related macroscopic changes (all groups) or pathological changes (only determined in control and 5000 ppm groups) were observed. The only treatment-related changes were some small decreases in body weights and body weight gains in both sexes at both dose levels and decreased food consumption at 5000 ppm during the first week (premating). Although the authors (TNO 1992b) interpreted the NOAEC as 2500 ppm based on these findings, a reanalysis by RIVM (2007) concluded that as these effects were not dose-related and not consistently present during the study the NOAEC for 2-butene should be 5000 ppm (11,474 mg/m3) (RIVM 2007 and ammended SIDS report 2007).

 

2-Methylpropene also caused no toxicologically significant changes when rats were exposed to 250, 1000 or 8000ppm (573, 2294 or 18,359 mg/m3) for 13 weeks. The only clinical change was an elevation in ketone bodies detected in urine at 1000 ppm and 8000 ppm (males), the toxicological significance of this is unknown. The NOAEC was 8000 ppm (18,359 mg/m3) the highest concentration level tested (Hazleton 1982). Similar results were obtained in 14 week inhalation studies conducted by the NTP (NTP, 1998). F344/N rats and B6C3F1 mice were exposed to 2-methylpropene at concentrations of 0, 500, 1,000, 2,000, 4,000, or 8,000 ppm, (1147, 2294, 4589, 9179, 18,359 mg/m3) for 14 weeks. There were no significant exposure-related toxicologic effects in either species at any dose level. Increased kidney weights in mice; and increased liver and kidney weights and minimal hypertrophy of goblet cells lining the nasopharyngeal ducts in rats, were considered to be non-toxic adaptive responses. The NOAEL for both studies was 8000 ppm (18,359 mg/m3) the highest concentration level tested.

 

Carcinogenicity studies on 2-methylpropene were also conducted by the NTP. 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 (NTP, 1998). The non-neoplastic findings from these studies were confined to effects on nasal tissues. In mice, hyaline degeneration of the olfactory and respiratory epithelium was increased in both sexes. The severities of hyaline degeneration increased with increasing exposure concentration. However, this was considered by the NTP to be a nonspecific adaptive response that had no adverse effect on affected animals. The NOAEC for toxicity in mice was therefore 8000ppm (18,359 mg/m3). Similar findings were observed in rats although the lesions were more severe. An additional finding in rats was that hypertrophy of goblet cells lining the nasopharyngeal duct was marginally increased with 100% incidence in males at 8000 ppm. The NOAEC for toxicity in the rat study was therefore 2000 ppm (4589 mg/m3), lower than that in mice (OECD SIDS Report for Isobutylene, 2003).

There are no repeat dose toxicity data in humans.

In conclusion, all members of the butenes category showed low sub-chronic and chronic toxicity up to concentrations of 2000 ppm (4589 mg/m3). Effects were confined to mild adaptive responses in the nose.

Justification for classification or non-classification

Members of the butenes category are flammable gases at room temperature and therefore dermal and oral exposure are unlikely. An oral study conducted at the maximum achievable concentration (148.6 mg/kg/day) showed no adverse effects. As oral exposure is not relevant for humans, this study is not considered relevant for classification purposes.  Inhalational exposure is the only relevant route and members of the butenes category have low sub-chronic inhalational toxicity and therefore do not warrant classification under Dir 67/548/EEC or GHS/CLP.