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Toxicological information

Carcinogenicity

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Description of key information

No data are available for the intermediate but data are available for the major and minor components. Of these, 1,3-butadiene has been shown to be carcinogenic and because it is present at a concentration greater than 0.1%, mandatory classification for carcinogenicity will be required.

Key value for chemical safety assessment

Justification for classification or non-classification

No data are available for the intermediate but data are available for the major and minor components which show most are not carcinogenic.

 

However, the intermediate contains the minor component 1,3-butadiene at ≥0.1% and therefore is considered to be carcinogenic. A mandatory classification of: "May cause cancer" Carcinogenic Cat 1, R45 according to Dir 1999/45/EC and Cat 1A, H350 under Reg (EC) 1272/2008 is required.

Additional information

There are no specific carcinogenicity data for the intermediate. However, there are substantial data on the carcinogenicity of a number of specific components present. Of these, 1,3-butadiene has been shown to be carcinogenic.

 

ASTDR reviewed n-hexane in 1999 and report the material has not been tested for carcinogenicity in animals, nor has it been categorised for its potential for carcinogenicity by the International Agency for Research on cancer (IARC), the National Toxicology Program (NTP) or the EPA (ASTDR, 1999). As stated previously, n-hexane is not mutagenic, nor does it contain structural alerts associated with carcinogenicity.

 

There are no lifetime animal studies available on cyclohexane. However, it is a simple aliphatic chemical and neither cyclohexane nor its metabolites carry alerts for genotoxic activity. It has been shown to be non-genotoxic both in vitro and in vivo. These observations indicate that cyclohexane is not expected to be a genotoxic carcinogen. This conclusion is concordant with that in the EU RAR (2004). 

 

In a chronic gavage investigation, male and female rats and mice were administered 4-vinylcyclohexene in corn oil for 103 weeks at doses of 200 and 400 mg/kg (NTP, 1986). In rats, poor survival reduced the sensitivity of the study for detecting the possible carcinogenic effects of 4-vinylcyclohexene and the NTP concluded the study was an inadequate assessment of carcinogenicity. Gavage (oral) administration of 4-vinylcyclohexene to mice was associated with the occurrence of neoplastic lesions in ovary, lung, haematopoietic system and adrenal gland. This study was considered an inadequate study of carcinogenicity in male mice because of extensive and early mortality at the high dose. In females, 4-vinylcyclohexene significantly increased the incidence of several types of uncommon ovarian tumours in both dose groups. The incidence of adrenal gland tumours was also increased in females; however it was unclear if this was a direct effect of 4-vinylcyclohexene or secondary altered ovarian function. Overall, NTP concluded that the occurrence of ovarian tumours provided clear evidence of potential carcinogenicity of 4-vinylcyclohexene in the mouse. No NOAELs were identified but the LOAEL in female mice was 200 mg/kg.  

 

Based on carcinogenicity studies in rats and mice and lack of evidence of carcinogenicity in humans toluene is considered not to be carcinogenic (NTP (1990); Huff J (2003); Gibson and Hardisty (1983)). According to the EU RAR (2003), “the only useful epidemiological cancer study which has been found does not show an excess of tumours in toluene-exposed workers". Toluene has also been evaluated by IARC in 1989 and 1999 and considered to be not classifiable as to carcinogenicity to humans.

 

 

Minor components with classification for carcinogenicity

 

1,3-Butadiene

(Classification: EU -Toxic T, Carcinogen Cat 1 R45; GHS/CLP - Category 1A, H350): In experimental animals, there is a marked species difference in carcinogenicity (EU RAR 2002). In the mouse, 1,3-butadiene is a potent multi-organ carcinogen. Tumours develop after short durations of exposure, at low exposure concentrations and the carcinogenic response includes rare types of tumours (NTP 1993). In the rat, fewer tumour types, mostly benign, develop at exposure concentrations of 100 to1000-times higher (Owen et al 1987). In humans a positive association was demonstrated between workplace exposure to butadiene for men employed in the styrene-butadiene rubber industry and lymphohaematopoietic cancer (leukemia) (Sathiakumar et al 2005, Graff et al 2005, Delzell et al 2006, Cheng et al 2007, Sielken et al 2006, 2007 & 2008).

 

Complex materials and intermediates are considered to be carcinogens if they contain ≥0.1% 1,3-butadiene.

 

Additional References

ATSDR (1999). Toxicological Profile for n-Hexane.U.S. Department of Health and Human Services Public Health Service Agency for Toxic Substances and Disease Registry.http://www.atsdr.cdc.gov/toxprofiles/tp113. html

EU (2002). European Union Risk Assessment Report: 1,3-butadiene. http://ecb.jrc.ec.europa.eu/DOCUMENTS/Existing-Chemicals/RISK_ASSESSMENT/REPORT/butadienereport019.pdf

EU RAR (2003). European Union Risk Assessment Report for Toluene. EC Joint Research Centre http: //ecb. jrc. ec. europa. eu/DOCUMENTS/Existing- Chemicals/RISK_ASSESSMENT/REPORT/toluenereport032. Pdf 

EU RAR (2004). European Union Risk Assessment Report: Cyclohexane. EC Joint Research Centrehttp://ecb.jrc.ec.europa.eu/DOCUMENTS/Existing-Chemicals/RISK_ASSESSMENT/SUMMARY/cyclohexanesum031.pdf