Registration Dossier

Administrative data

Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information
In vitro: Gene mutation (Bacterial reverse mutation assay / Ames test): read-across from structural analogue [2-(perfluorohexyl)ethyl]dichloro(methyl)silane (CAS 73609-36-6): negative with and without activation in Salmonella typhimurium strains TA 1535, TA 1537, TA 98, TA 100 and TA 102 (OECD TG 471) (LPT 2002).
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (negative)

Additional information

No data are available on the genetic toxicity of the registered substance, so data for the structural analogues [2-(perfluorohexyl)ethyl]dichloro(methyl)silane (CAS 38436-16-7) and [2-(perfluorohexyl)ethyl]triethoxysilane (CAS 51851-37-7) have been used to fulfil the information requirements.

[2-(perfluorohexyl)ethyl]dichloro(methyl)silane has been tested in a reliable study, conducted according to OECD 471 and in compliance with GLP (LPT, 2002). No test-substance related increase in the number of revertants was observed with and without metabolic activation when tested up to cytotoxic concentration in Salmonella typhimurium strains TA 1535, TA 1537, TA 98, TA 100 and TA 102. The result of the initial plate incorporation assay was confirmed in an independent experiment using the pre-incubation method. Appropriate positive and solvent controls were included and gave expected results. It is concluded that the substance is negative for mutagenicity to bacteria under the conditions of the test.

[2-(perfluorohexyl)ethyl]triethoxysilane has been tested for mutagenicity to bacteria, in a study which was conducted according to the OECD Guideline 471, compliant with GLP (Hüls 1997). The range of strains does not comply with the current guideline. No evidence of a test-substance related increase in the number of revertants was observed with or without metabolic activation in the initial plate incorporation assay or the repeat preincubation experiment up to cytotoxic/limit concentrations. Appropriate positive and solvent controls were included and gave the expected results. It is concluded that the test substance is negative for mutagenicity to bacteria under the conditions of the test.

Read-across justification

Non-testing methods including read-across from surrogate substances are able to provide information on genetic toxicity (REACH Guidance part 07a, R.7.7.3). In the case of genetic toxicity the presence or absence of functional groups that are known to be related to genetic toxicity is considered important, as the presence or absence of reactive groups and molecular substructures is associated with mutagenic and carcinogenic properties of chemicals (Benigni and Bossa, 2006). Consideration is therefore given to the structural similarity, particularly presence or absence of structural alerts for genetic toxicity, when selecting surrogate substances for genetic toxicity endpoints. Additional information on read across approach is given in a supporting report (PFA 2013aa) attached in Section 13.

Read-across hypothesis

The hypothesis is that that source (read-across) substances and registration (target) substance have similar systemic toxicological properties because they hydrolyse to similar silanol hydrolysis products, [2-(perfluorohexyl)ethyl]silanetriol and [2-(perfluorohexyl)ethyl]methylsilanediol and the non-silicon products, methanol, ethanol and hydrogen chloride. None of the substances or hydrolysis products have structural alerts for genetic toxicity. Based on publically available information, methanol, ethanol and hydrogen chloride are not known to contribute to toxicity at the relevant dose levels (OECD, 2004a, 2004b and 2002), which is discussed further below.

The predicted hydrolysis half-lives of the registered substance, [2-(perfluorohexyl)ethyl]trimethoxysilane, are 0.4 h at pH 4, 0.4 h at pH 5, 8.8 h at pH 7 and 0.1 h at pH 9, all at 20 - 25°C.The products of hydrolysis are [2-(perfluorohexyl)ethyl]silanetriol and methanol.

The read-across substance, [2-(perfluorohexyl)ethyl]dichloro(methyl)silane, hydrolyses very rapidly, with a hydrolysis half-life of approximately 5 seconds at pH 2 and 25°C, at pH 7 and 37.5°C and at pH 2 and 37.5°C. The products of hydrolysis are [2-(perfluorohexyl)ethyl]methylsilanediol and hydrogen chloride.

The read-across substance, [2-(perfluorohexyl)ethyl]triethoxysilane, hydrolyses more slowly, with a hydrolysis half-lives of approximately 5.2 hours at 37.5ºC and pH 7, and approximately 26 seconds at 37.5ºC and pH 2. The products of hydrolysis are [2-(perfluorohexyl)ethyl]silanetriol and ethanol.

Read-across justification

(a) Structural similarity

[2-(Perfluorohexyl)ethyl]trimethoxysilane and [2-(perfluorohexyl)ethyl]dichloro(methyl)silane are both silanes with highly fluorinated alkyl groups attached to the silicon; the registered substance has three methoxy groups attached to the silicon, the read-across substance has two chlorine groups and one methyl group. Both hydrolyse rapidly to similar silicon-containing hydrolysis products, [2-(perfluorohexyl)ethyl]silanetriol and [2-(perfluorohexyl)ethyl]methylsilanediol. The other hydrolysis products, methanol and hydrogen chloride, are not expected to contribute to genetic toxicity. [2-(perfluorohexyl)ethyl]triethoxysilane also has a fluorinated hexyl(ethyl) group attached to the silicon; it also has three ethoxy groups. It hydrolyses at a slower rate than the other two substances to produce [2-(perfluorohexyl)ethyl]silanetriol and ethanol, which is not expected to contribute to genetic toxicity.

(b) Similar silicon containing hydrolysis products: [2-(perfluorohexyl)ethyl]trimethoxysilane and [2-(perfluorohexyl)ethyl]dichloro(methyl)silane form similar silicon-containing hydrolysis products, [2-(perfluorohexyl)ethyl]silanetriol and [2-(perfluorohexyl)ethyl]methylsilanediol. [2-(perfluorohexyl)ethyl]triethoxysilane forms the same silicon-containing substance, [2-(perfluorohexyl)ethyl]silanetriol, as the registered substance.

(c) Lack of structural alerts: none of the substances or hydrolysis products has structural alerts for genotoxicity (Benigni et al., 2008).

(d) Lack of genetic toxicity of the non-silicon hydrolysis products.

Hydrogen chloride gave negative results in the most reliable of the bacterial mutagenicity studies. Positive results were obtained in mutagenicity and cytogenicity assays using mammalian cells (OECD, 2002; ECHA disseminated dossier for hydrogen chloride). The positive results were associated with decrease in pH, and it is considered that the positive results were likely to have been caused by reduced pH. Positive results caused by high or low pH effects are considered not to be relevant for in vivo situations (ECHA 2012), and testing should be carried out at neutral pH.

Methanol has been tested in vitro in bacterial and mammalian mutagenicity assays and in micronucleus and chromosome aberration assays. The majority of the results were negative (OECD, 2004). In the ECHA disseminated dossier for methanol, the conclusions of all the key in vitro studies and the weight of evidence of the in vivo assays are negative.

Ethanol is negative in Salmonella typhimurium bacterial mutagenicity assays, up to limit concentrations, including an appropriate 5th strain (TA 102). No evidence for cytogenicity was found in chromosome aberration studies using cultured human lymphocytes or Chinese hamster ovary cells. A mammalian mutagenicity assay using L5178Y cells gave negative results with and without metabolic activation. Ethanol did not induce micronuclei in bone marrow of rats, or chromosome aberrations in rats or hamsters. Ethanol was negative in the most reliable rodent dominant lethal assay (OECD, 2004b).

Benigni and Bossa (2006). Current Computer-Aided Drug Design 2, (2), 169-176.

Benigni et al (2008).The Benigni/Bossa rule base for mutagenicity and carcinogenicity JR Scientific report EUR 23241 EN

OECD (2002): SIDS Initial Assessment Report for SIAM 15, Boston, USA, 22-25 October 2002: hydrogen chloride, CAS 7647-01-0.

OECD (2004a): SIDS Initial Assessment Report for SIAM 19, Berlin, Germany, 18-20 October 2004, Methanol, CAS 67-56-1.

OECD (2004b): SIDS Initial Assessment Report for SIAM 19, Berlin, Germany, 19-22 October 2004, Ethanol, CAS 64-17-5.

PFA (2013aa). Peter Fisk Associates, Genotox Analogue Report, PFA.300.004.001

Justification for classification or non-classification

Based on the available in vitro bacterial mutagenicity data for [2-(perfluorohexyl)ethyl]dichloro(methyl)silane and [2-(perfluorohexyl)ethyl]triethoxysilane, [2-(perfluorohexyl)ethyl]trimethoxysilane is not classified for mutagenicity according to Regulation (EC) No 1272/2008.