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Carcinogenicity

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Description of key information

The available data and available weight of evidence demonstrate that the C10-C12 Aromatic hydrocarbons are highly unlikely to be carcinogenic and are not classifiable as carcinogens.  

Key value for chemical safety assessment

Justification for classification or non-classification

These findings do not warrant the classification of C10-C12 Aromatic hydrocarbons as a carcinogen under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP) or under the Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.

Additional information

The weight of evidence is derived from study records reported for the C10-C12 Aromatics, and read across from the closely related C9 Aromatic solvents and high flash aromatic naphtha. Both the C10-C12 and related C9 Aromatics are not genotoxic and are not classifiable as mutagens based upon the results of reliable in vitro and in vivo studies. In bacterial reverse mutation studies, both the C10-12 and the related C9 Aromatic solvents were not mutagenic in the presence or absence of metabolic activation (See C9 Aromatics IUCLID section 7.6.1 and the same section in this IUCLID). The C10-C12 aromatics were not clastogenic or anuegenic in vivo as evidenced by a negative rat erythrocyte micronucleus study (IUCLID section 7.6.2). This is concordant with the findings that high flash aromatic naphtha is also clearly not mutagenic, clastogenic or aneugenic in mammalian cells in vitro, and in rats in vivo as evidenced by: (a) a negative mammalian gene mutation (HGPRT forward mutation specific locus) assay; (b) negative chromosome aberration tests (Chinese Hamster Ovary Chromosomal Aberration Test, Chinese Hamster Ovary Sister Chromatid Exchange Assay); and (c) an in vivo inhalation exposure bone marrow chromosomal aberration study in rats (C9 Aromatics IUCLID sections 7.6.1 and 7.6.2).

 

The C10-C12 aromatics did not produce pre-neoplastic changes in any tissues during sub-chronic (90 day) repeat dose testing (IUCLID sections 7.5.1 and 7.5.3). Likewise, the closely related C9 aromatic solvents did not produce hyperplastic or pre-neoplastic changes in any tissues in sub-chronic (90 day) and chronic (12 month) repeat-dose studies. No test article-related lesions, including no cancer-relevant lesions, were found in extensive histological examinations of the tissues of rats chronically exposed to C9 aromatic solvents by inhalation for 6 hours per day, 5 days per week for 12 months (C9 Aromatics IUCLID section 7.5.3).   Likewise, no test article-related lesions, including no cancer-relevant lesions, were found in extensive histological examinations of the tissues of rats sub-chronically exposed to C9 Aromatic and C10-C12 Aromatic solvents by inhalation for ≥ 90 days (IUCLID section 7.5.3).  Similarly, subchronic oral dosing with C10-C12 aromatic solvent did not produce pre-neoplastic changes and had a NOAEL of 300 mg/kg bw/day (IUCLID section 7.5.1).

 

Notably, studies on the metabolism of 14C-1,2,4-trimethylbenzene, a prototypical C9 aromatic compound and a close relative of the compounds present in C10-C12 aromatic solvents demonstrated that > 99% of the administered radioactivity was excreted in urine within 24 hours following oral dosing.1 Little or no tissue-bound residual radioactivity was detected in this study, demonstrating that the metabolism of the C9 aromatic molecules, and their close relatives in the C10-C12 Aromatic solvents, do not bioaccumulate and are unlikely to result in the formation of DNA adducts or other associated DNA lesions.

 

1.Huo JZ, Aldous S, Campbell K, Davies N. Distribution and metabolism of 1,2,4-trimethylbenzene (pseudocumene) in the rat. Xenobiotica1989;19:161-170.