Registration Dossier

Administrative data

Description of key information

Members of the C4 low 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. There are no specific studies on the streams in this category (CAS Numbers; 91052-98-1, 92045-23-3, 95465-89-7, 95465-90-0 and 95465-91-1) but data on the component substances (butane, isobutane and butene isomers) indicate that members of this 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 in rats or mice for 6 weeks (butane and isobutane) or up to 2 years (butene isomers). Nasal lesions were observed in 2 year rodent studies on 2-methylpropene 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

Mode of Action Analysis / Human Relevance Framework

Additional information

Members of the C4 low butadiene category are flammable gases at room temperature and therefore significant 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. An oral study is, however, available for one of the component substances; 2-methylpropene (see below). The repeat dose inhalational toxicity of streams in this category is expected to be low.

 

There are no specific studies on the streams in this category (CAS Numbers; 91052-98-1, 92045-23-3, 95465-89-7, 95465-90-0 and 95465-91-1) but data are available on the component substances. The repeat dose inhalational toxicity of all these component substances is low and in all cases NOAELs exceed the dose levels which would warrant classification under Dir 1999/45/EC or GHS/CLP.

 

Specific data are as follows:

 

Non-human information

 

Butane: Has been tested at inhalational exposure concentrations up to 9,000 ppm (21394 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 (21394 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 (21394 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: 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). There were no treatment-related effects and the NOAEC was the highest concentration tested.A NOAEC of 9,000 ppm (21394 mg/m3), the highest concentration tested was identified based on the key study of HLS (2010).

 

Butene isomers (butenes): Although oral administration is an unusual and non-relevant route for a gaseous substance, 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

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 low 1,3-butadiene category are flammable gases at room temperature and therefore significant 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 low 1,3-butadiene category have low sub-chronic inhalation toxicity and therefore do not warrant classification under Dir 1999/45/EC or GHS/CLP.