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Administrative data

Description of key information

Members of the C4 high 1,3-butadiene 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. Data after inhalational exposure are available on one of the streams in this category (All CAS numbers are; 68476-52-8, 68477-42-9, 68955-28-2, 87741-01-3, 92045-23-3) and on the component substances (1,3-butadiene, butane, isobutane and butene isomers) and indicate that the sub-chronic toxicity of this category is low. Inhalation exposure is the most relevant route. No significant exposure-related toxicological effects or target organ toxicity have been observed in rats or mice in inhalation studies ranging from 7 weeks to 2 years on CAS no. 68476-52-82, butane, isobutane and 2-methylpropene. Nasal lesions were observed in 2 year studies on 2-methylpropene at the highest concentration in male rats. 1,3-Butadiene had low repeat dose toxicity in humans and rats (the most appropriate test species). The mouse was the most sensitive species where the target organs are bone marrow, ovary and testis. Species differences in metabolism are believed to be responsible for the species specific toxicity with humans being more similar to rats The NOAEL of 1000 ppm (2212 mg/m3) was identified from the key study on 1,3-butadiene in rats.

Key value for chemical safety assessment

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEC
2 212 mg/m³

Additional information

Members of the C4 high 1,3-butadiene category are flammable gases at room temperature and therefore exposure via the dermal or oral routes is unlikely. The requirement for data on oral and dermal repeat dose toxicity is waived in accordance with REACH Annex XI, although data on oral toxicity is available for one of the component substances.

 

The repeat dose inhalational toxicity of streams in this category (CAS numbers; 68476-52-8, 68477-42-9, 68955-28-2, 87741-01-3, 92045-23-3) is expected to be low. Data are available on one of the streams and on the component substances. In all cases the repeat dose toxicity is low and in non-human studies NOAELs exceed the dose levels which would warrant classification under Dir 1999/45/EC or GHS/CLP. Limited human data also support this conclusion.

 

Specific data are as follows:

 

Non-human information

 

Streams: Repeated inhalation exposure of C4 Crude Butadiene (CAS no. 68476-52-8), to rats at up to 20 mg/L (20,000 mg/m3) for 37 days produced no evidence of any adverse effects on clinical observations, organ weights, gross or histopathological assessment of organs, neurobehavioural activity, clinical chemistry or haematology endpoints. Based on these data, the NOAEC was 20,000 mg/m3, the highest concentration tested (Dow 2001).

 

1,3-Butadiene: Marked species differences in repeat dose toxicity studies via inhalation exposure are seen with mice being the most sensitive species. It has low toxicity in the rat, with minimal effects seen after exposure to 8000 ppm (17,702 mg/m3) for 2 years (Owen et al, 1987). No chronic non-neoplastic effects were seen in humans, although data are limited. The mouse is the most sensitive species where the target organs are bone marrow, ovary and testis but NOAELs for repeat dose toxicity in the chronic studies have not been established due to neoplasia-related toxicity (NTP, 1993). Species differences in metabolism are believed to be responsible for the species specific toxicity with humans being more similar to rats (EU RAR, 2002). The NOAEC for repeat dose toxicity is 1000 ppm (2212 mg/m3) as defined by studies in rats (Owen et al, 1987).

 

 Butane: Has been tested at inhalational exposure concentrations up to 9,000 ppm (21,394 mg/m3) in rats for up to 6 weeks. No toxicologically significant effects occurred in a 6 week study with n-butane (HLS 2008). There was no systemic toxicity (i. e., no affect on survival, haematological or clinical chemistry parameters, food consumption, body weight, organ weight, and histopathology) or neurological effects (as measured by clinical observations, functional observational battery, and motor activity). A 90 day inhalation study on a 50:50 wt% mixture of n-butane: n-pentane was conducted in rats exposed at up to 4500 ppm daily for 13 weeks, with an interim kill after 28 days (Aranyi 1986). Decreases in body weights of both sexes were observed by test weeks 3 and 4, with males, but not females, recovering towards the end of the exposure period. There were no other treatment-related effects and the NOAEC was the highest concentration tested. A NOAEC of 9,000 ppm (21,394 mg/m3), the highest concentration tested was identified based on the key study of HLS (2008).

 

Isobutane: Has been tested at inhalational exposure concentrations up to 9,000 ppm (21,394 mg/m3) in rats for up to 6 weeks. No toxicologically significant effects occurred in a 6 week study with isobutane (HLS 2010). There was no systemic toxicity (i. e., no affect on survival, haematological or clinical chemistry parameters, food consumption, body weight, organ weight, and histopathology) or neurological effects (as measured by clinical observations, functional observational battery, and motor activity). A 90 day inhalation study on a 50:50 wt% mixture of isobutane: isopentane was conducted in rats exposed at up to 4500 ppm daily for 13 weeks, with an interim kill after 28 days (Aranyi 1986). There were no treatment-related effects and the NOAEC was the highest concentration tested. A NOAEC of 9,000 ppm (21,394 mg/m3), the highest concentration tested was identified based on the key study of HLS (2010).

 

Butene isomers (butenes): No toxicologically significant effects occurred when 2-methylpropene was administered orally to rats at 148.6 mg/kg for 28 days (Hazleton 1986b). No significant exposure-related toxicological effects or target organ toxicity have been observed in 6 week inhalation studies on 1-butene and 2-butene in rats at concentrations up to 8000 ppm (18,359 mg/m3) (TNO 1992, Huntingdon 2003). Carcinogenicity studies on 2-methylpropene were conducted by the NTP. Rats and mice were exposed to 2-methylpropene at concentrations of up to 8,000 ppm, (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).

 

 

Human information

 

1,3-Butadiene: No chronic non-neoplastic effects have been seen in humans, although data is limited (EU RAR 2002).Long-term exposure of humans to 1,3-butadiene may result in an increased risk of lymphohaematopoietic cancer (see Section on Carcinogenicity). Studies of the causes of mortality of workers exposed to 1,3-butadiene have shown no increases in mortality due to lung cancer, cardiovascular disease and digestive system cancer indicating that 1,3-butadiene has no chronic effects on these organ systems in humans (Delzell et al 2006). A more recent study (Tsai et al, 2003) also showed no evidence of adverse haematological findings associated with exposure to 1,3-butadiene when workers from 2 plants were compared with a non-1,3-butadiene exposed group.

 

Isobutane: Repetitive exposures of human volunteers at 500 ppm (1189 mg/m3) up to 8 hours/day, five days/week for 2 weeks were without any measurable untoward physiological effects (Stewart et al 1977, 1978)

 

Butane and butene isomers (butenes): There are no data on repeat dose toxicity in humans.

Justification for classification or non-classification

Members of the C4 high 1,3-butadiene category are flammable gases at room temperature and therefore dermal and oral exposure is unlikely. An oral study conducted on the component substance 2-methylpropene 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 there are sufficient data available on component substances to conclude that streams within the C4 high 1,3-butadiene category have low sub-chronic inhalation toxicity and therefore do not warrant classification under Dir 1999/45/EC or GHS/CLP.