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Key value for chemical safety assessment

Additional information

All streams within the C4 high 1,3-butadiene category (CAS numbers; 68476-52-8, 68477-42-9, 68955-28-2, 87741-01-3, 92045-23-3) contain at least 0.1% w/w 1,3-butadiene and this substance drives the mutagenicity classification for this category. 1,3-Butadiene is genotoxic in vitro and in vivo in both somatic and germ cells in the mouse but is not genotoxic in vivo in both somatic and germ cells in the rat. The available data on several groups of 1,3-butadiene-exposed workers did not show any association between 1,3-butadiene exposure and increased gene mutations, primarily HPRT mutations. No 1,3-butadiene-related chromosome aberrations have been demonstrated in humans. Mutagenicity data are available on some of the streams in the C4 high 1,3-butadiene category and the results of in vitro and in vivo genotoxicity studies are likely to reflect the proportion of 1,3-butadiene in the stream at the time of testing. Negative, positive and weakly positive results were variously obtained. The other component substances within this category are not genotoxic and have no impact on the classification of the category. The presence of >=0.1% 1,3-butadiene therefore indicates that members of this category are likely to be mutagenic and the category warrants classification of Muta. Cat 2: R46 (May cause heritable genetic effects) under Dir 1999/45/EC and Germ Cell Mutagenicity Cat1B: H340 (May cause genetic defects) under GHS/CLP. CAS numbers 68955-28-2, 87741-01-3 and 92045-23-3 are already classified as Muta 1B:H340 under GHS/CLP.

 

 

Specific data are as follows:

 

 

Non-human information

 

Streams: In vitro, negative results were obtained in a bacterial mutation assay and a mammalian cell transformation assay whilst positive results were obtained in a mammalian cell mutation assay and an unscheduled DNA synthesis assay on butadiene concentrate (CAS number 68955-28-2), although the latter test was only weakly positive (MEHSL 1985, Gulf oil 1983 and 1984). In vivo, micronucleus assays conducted in mice exposed to CAS numbers 68955-28-2 and 68476-52-8 were both positive (Dow 2001a and Gulf Oil 1984b).

1,3-Butadiene: In vitro, positive results were obtained in bacterial mutation assays (Araki et al 1994, and a mammalian cell cytogenetic assay (Asakura et al 2008). In vivo, somatic cell cytogenetic and gene mutation studies in the mouse and dominant lethal studies in the mouse were positive. (Adler et al 1994). Similar studies in the rat were negative.

 

Butane: In vitro, key bacterial mutation assays have been conducted in the presence and absence of metabolic activation. Butane was not mutagenic in this test system (Kirwin and Thomas 1980, NTP, 2005). An in vitro, key, mammalian cell cytogenetic assay has been conducted in the presence and absence of metabolic activation. Butane caused no increases in the frequencies of chromosome aberrations in this assay (Safepharm, 2008). No mammalian in vivo genotoxicity data are available for butane but it was negative in the Sex Linked Recessive Lethal assay in drosophila (NTP, 2005).

 

Isobutane: In vitro, a key bacterial mutation assay has been conducted in the presence and absence of metabolic activation. Isobutane was not mutagenic in this test system (Kirwin and Thomas, 1980). No in vivo genotoxicity data are available for isobutane.

 

Butene isomers (butenes): In vitro bacterial mutation tests on all isomers were negative in the presence and absence of metabolic activation Araki (1994) Safepharm (1992a). 2-Butene has been tested in vitro in a chromosome aberration study (Safepharm 1992b) where it was not clastogenic to rat lymphocytes in vitro in the presence and absence of metabolic activation. This result is also supported by other negative in vitro genetic toxicity studies on 2-methylpropene; a micronucleus assay in human lymphocytes (Jorritsma et al 1995), a mouse lymphoma mutation assay (IRI 1981) and a mammalian cell transformation assay (IRI 1981) were negative. In vivo, a key bone marrow micronucleus assay on 2-methylpropene (Exxon 1990), and a mouse peripheral blood micronucleus test (NTP 1998) were both negative.

 

 

Human information

 

1,3-Butadiene: There are many studies on human in occupational settings. The available data on several groups of 1,3-butadiene-exposed workers, both in 1,3-butadiene monomer production and in the polymerization of 1,3-butadiene, did not show any association between 1,3-butadiene exposure and increased gene mutations, primarily HPRT mutations (Albertini et al, 2001, 2003 & 2007, Wickliffe et al 2009). One group of investigators have shown a relationship in workers exposed to 1,3-butadiene but a different method was used by these investigators to measure the HPRT mutation than in the other studies, and there are questions on whether co-exposures were adequately accounted for. Nevertheless, a recent study from these investigators has shown that reduced exposures to all potential genotoxic agents in these facilities have resulted in negative findings (Wickliffe et al, 2009). No 1,3-butadiene-related chromosome aberrations have been demonstrated in humans (Albertini et al 2001, 2003, 2007).

 

 

There are no data on the genetic toxicity of butane, isobutane and butene isomers in humans.


Short description of key information:
All streams within this category (CAS numbers; 68476-52-8, 68477-42-9, 68955-28-2, 87741-01-3, 92045-23-3) contain at least 0.1% w/w 1,3-butadiene. 1,3-Butadiene is genotoxic in vitro and in vivo in both somatic and germ cells in the mouse but is not genotoxic in vivo in both somatic and germ cells in the rat. The available data on several groups of 1,3-butadiene-exposed workers did not show any association between 1,3-butadiene exposure and increased gene mutations, primarily HPRT mutations. No 1,3-butadiene-related chromosome aberrations have been demonstrated in humans. The proportion of the component substance, 1,3-butadiene, in the stream at the time of testing will therefore affect the results of genotoxicity tests. Both positive and negative results were obtained in in vitro mutagenicity tests on CAS no. 68955-28-2 whilst positive results were obtained in in vivo tests on CAS no. s 68955-28-2 and 68476-52-8. The available data therefore indicates that members of this category may be mutagenic in humans.

Endpoint Conclusion: Adverse effect observed (positive)

Justification for classification or non-classification

Members of the C4 high 1,3-butadiene category contain at least 0.1% w/w 1,3-butadiene and this substance drives classification. In addition streams within the category were mutagenic. There are sufficient data available to conclude that streams within the C4 high 1,3-butadiene category are genotoxic in vitro and in vivo in both somatic and germ cells. Classification of Muta. Cat 2: R46 (May cause heritable genetic effects) under Dir 1999/45/EC and Germ Cell Mutagenicity Cat1B: H340 (May cause genetic defects) under GHS/CLP is therefore warranted. CAS numbers 68955-28-2, 87741-01-3 and 92045-23-3 are already classified as Muta 1B:H340 under GHS/CLP.