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Carcinogenicity

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Description of key information

The substance is regarded as not having a concern for carcinogenic potential on the basis of:

1)    Negative findings in tests for gene mutation / mutagenicity.

2)    Evaluation using Derek Nexus, an accepted (Q)SAR tool designed for the qualitative prediction of the possible toxicity of chemicals, a procedure in accordance with Annex XI of Regulation 1907/2006. In this, TOTM triggered plausible alerts (in mouse and rat only) for carcinogenicity. These alerts were fired due to the potential for the structure to induce peroxisome proliferation in rats and mice, probably by association with phthalate esters. Peroxisome proliferators have been shown to activate one or more nuclear steroid hormone-like receptors (PPARs) which induce increases in the oxidative enzyme activity associated with peroxisome proliferators. The strength of the binding with the PPAR sites is expected to be a factor in determining the potency of peroxisome proliferators. These alerts are regarded as having little relevance in human, as humans appear to be insensitive or unresponsive at doses which caused marked peroxisome proliferation in rats or mice (European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC), 1992. Hepatic peroxisome proliferation. ECETOC Monograph No. 17).

3)    Molecular modelling studies performed by Kambia et al. (Kambia N, Renault N, Dilly S, Farce A, Dine T, Gressier B Luyckk M, Brunet C and Chavatte P. Molecular modelling of phthalates – PPARs interactions. Journal of Enzyme Inhibition and Medicinal Chemistry, 23(5): 611–616, 2008) indicate that TOTM is not able to fit into PPARα and PPARγ binding sites due to its larger size relative to the corresponding phthalate ester, implying that any predicted activity may not actually be able to occur.

4)    A repeat-dose study to investigate the potential hepatotoxicity of TOTM (See Section 7.5.1 - Repeated dose toxicity: 28 day dietary study in rats – BIBRA) showed that TOTM produced the same spectrum of morphological and biochemical changes in the rat liver but with much less potency in its action than those produced by DEHP (the equivalent phthalate ester).

Key value for chemical safety assessment

Additional information

A carcinogenicity study may be required in accordance with REACH Regulation 1907/2006, Annex X, Section 8.9.1 of Column 1, Annex X. It is proposed to waive the need to conduct this study on the basis that:

1)    Negative findings in tests for gene mutation / mutagenicity.

2)    Evaluation using Derek Nexus, an accepted (Q)SAR tool designed for the qualitative prediction of the possible toxicity of chemicals, a procedure in accordance with Annex XI of Regulation 1907/2006. In this, TOTM triggered plausible alerts (in mouse and rat only) for carcinogenicity. These alerts were fired due to the potential for the structure to induce peroxisome proliferation in rats and mice, probably by association with phthalate esters. Peroxisome proliferators have been shown to activate one or more nuclear steroid hormone-like receptors (PPARs) which induce increases in the oxidative enzyme activity associated with peroxisome proliferators. The strength of the binding with the PPAR sites is expected to be a factor in determining the potency of peroxisome proliferators. These alerts are regarded as having little relevance in human, as humans appear to be insensitive or unresponsive at doses which caused marked peroxisome proliferation in rats or mice (European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC), 1992. Hepatic peroxisome proliferation. ECETOC Monograph No. 17).

3)    Molecular modelling studies performed by Kambia et al. (Kambia N, Renault N, Dilly S, Farce A, Dine T, Gressier B Luyckk M, Brunet C and Chavatte P. Molecular modelling of phthalates – PPARs interactions. Journal of Enzyme Inhibition and Medicinal Chemistry, 23(5): 611–616, 2008) indicate that TOTM is not able to fit into PPARα and PPARγ binding sites due to its larger size relative to the corresponding phthalate ester, implying that any predicted activity may not actually be able to occur.

4)    A repeat-dose study to investigate the potential hepatotoxicity of TOTM (See Section 7.5.1 - Repeated dose toxicity: 28 day dietary study in rats – BIBRA) showed that TOTM produced the same spectrum of morphological and biochemical changes in the rat liver but with much less potency in its action than those produced by DEHP (the equivalent phthalate ester).

Justification for classification or non-classification

Non classification is justified on the basis of:

1)    Negative findings in tests for gene mutation / mutagenicity.

2)    Evaluation using Derek Nexus, an accepted (Q)SAR tool designed for the qualitative prediction of the possible toxicity of chemicals, a procedure in accordance with Annex XI of Regulation 1907/2006. In this, TOTM triggered plausible alerts (in mouse and rat only) for carcinogenicity. These alerts were fired due to the potential for the structure to induce peroxisome proliferation in rats and mice, probably by association with phthalate esters. Peroxisome proliferators have been shown to activate one or more nuclear steroid hormone-like receptors (PPARs) which induce increases in the oxidative enzyme activity associated with peroxisome proliferators. The strength of the binding with the PPAR sites is expected to be a factor in determining the potency of peroxisome proliferators. These alerts are regarded as having little relevance in human, as humans appear to be insensitive or unresponsive at doses which caused marked peroxisome proliferation in rats or mice (European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC), 1992. Hepatic peroxisome proliferation. ECETOC Monograph No. 17).

3)    Molecular modelling studies performed by Kambia et al. (Kambia N, Renault N, Dilly S, Farce A, Dine T, Gressier B Luyckk M, Brunet C and Chavatte P. Molecular modelling of phthalates – PPARs interactions. Journal of Enzyme Inhibition and Medicinal Chemistry, 23(5): 611–616, 2008) indicate that TOTM is not able to fit into PPARα and PPARγ binding sites due to its larger size relative to the corresponding phthalate ester, implying that any predicted activity may not actually be able to occur.

4)    A repeat-dose study to investigate the potential hepatotoxicity of TOTM (See Section 7.5.1 - Repeated dose toxicity: 28 day dietary study in rats – BIBRA) showed that TOTM produced the same spectrum of morphological and biochemical changes in the rat liver but with much less potency in its action than those produced by DEHP (the equivalent phthalate ester).