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Key value for chemical safety assessment

Additional information

The weight of evidence approach is used to determine the genotoxicity of titanium tetrakis(2-ethylhexanolate). Relevant data from the substance itself but also from the decomposition products, 2-ethylhexanol (2 -EH) and titanium dioxide (TiO2) is assessed. Read-across data from the decomposition products is used for assessment, because the target substance is hydrolytically unstable having the half-life less than 10 minutes (Brekelmans, M. J. C., 2013). Based on the rapid hydrolysis, the intrinsic properties are most likely related to these two decomposition products, 2-EH being the most relevant decomposition product for CSA.

Mutagenicity in bacterial test systems

Titanium tetrakis(2-ethylhexanolate) was tested in a bacterial reverse mutation assay which pre-dates current guideline study (Koops, A., 1977). However, the method is comparable to OECD 471 with one deviation of not using TA 102 bacterial strain. Other salmonella typhimurium strains (TA 1535, TA 1537, TA 1538, TA 98 and TA 100) in concentrations up to 750 µg per plate were tested. The compound was not mutagenic in this assays either in the presence or absence of a liver microsomal system. It did not induce a significant increase over the spontaneous mutation frequency.

The mutagenicity of 2 -ethylhexanol (2 -EH) was tested in bacterial test systems (S. typhimurium TA98, TA100, TA1535, TA1537, TA1538, and E. coli WP2 uvrA) according to OECD TG 471 and TG 472 both with and without metabolic activation in a dose range from 1 to 1000 µg/plate (Shimizu et al., 1985). 2 -EH did not increase the number of revertants in any of the test strains. Growth inhibition was seen at 500 and 1000 µg/plate. The negative and positive controls performed as expected. Therefore, 2 -EH was not mutagenic in bacterial test systems in vitro.

Cytogenicity in mammalian cells

2 -ethylhexanol (2 -EH) was tested in a Chromosome Aberration test according to OECD 473 at concentrations of 0, 50, 108, and 233 µg/ml using Chinese hamster ovary cells (CHO cells) (NTP, 2007). 2-EH did not induce chromosome aberrations in mammalian cells with and without metabolic activation; negative and positive controls performed as expected.

Mutagenicity in mammalian cells

2-EH in the range 0.018, 0.024, 0.032, 0.042, 0.056, 0.075, 0.10, 0.13, 0.18, 0.24 µL/ ml did not increase the mutation frequency in L5178Y mouse lymphoma cells, with or without metabolic activation (Kirby et al., 1983). The growth rate was 10% at the highest dose level. Complete toxicity was seen at 1 µg/ml and above. The study is considered to be valid, though documentation is limited. It was similar to OECD TG 476.

TiO2 is considered a non-mutagenic substance, although evidence of mutagenic activity of titanium or its compounds is scant. However, TiO2 has been shown to be negative when tested using the rec-assay with Bacillus subtilis (Kada et al., 1980).

The results from genotoxicity assays of titanium tetrakis(2 -ethylhexanolate) and 2 -EH are universally negative. In addition, neither of the decomposition products has harmonized classification entries for genotoxicity. Based on the Ames test conducted for the target substance and read-across data from the decomposition products there is enough evidence to conclude that titanium tetrakis(2 -ethylhexanolate) is not genotoxic.


Justification for selection of genetic toxicity endpoint
Conclusion based on the following assays conducted for the degradation product of the target substance: Bacterial reverse mutation assay (Ames test); Mammalian cell gene mutation assay, In vitro mammalian chromosome aberration test

Short description of key information:
In vitro:
Gene mutation (reverse mutation assay/Ames test): negative in all tested bacterial strains with and without metabolic activation (equivalent to OECD TG 471).

Following information is from 2-EH, the degradation product of Titanium tetrakis(2-ethylhexanolate)
Gene mutation (reverse mutation assay/Ames test): negative in all tested bacterial strains with and without metabolic activation (according to OECD TG 471).
Chromosome aberration study in mammalian cells: negative, with and without metabolic activation (according to OECD TG 473).
Gene mutation study in mammalian cells: negative, with and without metabolic activation (according to OECD TG 476).

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

Based on the weight of evidence approach of in vitro genetic toxicity tests from titanium tetrakis(2-ethylhexanolate) and from the degradation products there is no need for classification of the substance for mutagenic effects in accordance with the criteria of CLP Regulation 1272/2008 and the EU directive 67/548/EEC.