Tetramethyl orthosilicate

Endpoint summary

Additional information

Data are available for tetramethyl orthosilicate from two reliable in vitro bacterial mutagenicity studies and from a reliable in vivo micronucleus assay. No further data are available, however, information is available for the structural analogue tetraethyl orthosilicate (CAS number 78-10-4) from in vitro cytogenicity and mutagenicity studies in mammalian cells.

Both tetramethyl orthosilicate and tetraethyl orthosilicate hydrolyse to tetrahydroxysilane; the other products of hydrolysis are methanol and ethanol respectively, which are not genotoxic (OECD (2004a), OECD (2004b)). Tetramethyl orthosilicate hydrolyses very rapidly, with a hydrolysis half-life of <3 mins (R4 data, supported by QSAR), tetraethyl orthosilicate hydrolyses rapidly, with a hydrolysis half-life of 6.7 h at pH 7 and at 25°C (measured data). It is considered therefore that read-across from tetraethyl orthosilicate to tetramethyl orthosilicate is scientifically justified. Additional information is given in a supporting report (PFA (2013aa)) attached in Section 13 of the IUCLID 5 dossier. Genetic toxicity data available for the registered substance and other orthosilicates are shown in the Table below. The results of all the available studies are in agreement; none of the substances are genotoxic. For further discussion of read across between orthosilicates see endpoint summary 7.5.

Tetraethyl orthosilicate was chosen as read-across substance as it has the same hydrolysis product as registered substance and neither substance has any functional groups that are associated with genetic toxicity.

Summary of genetic toxicity data for orthosilicates

CAS Number	Chemical Name	Bacterial mutagenicity	In vitromammalian cytogenicity	In vitromammalian mutagenicity	In vivogenotox
681-84-5	Tetramethyl orthosilicate	Negative	-	-	Negative in micronucleus
78-10-4	Tetraethyl orthosilicate	Negative	Negative	Negative	-
682-01-9	Tetrapropyl orthosilicate	Negative	-	-	-

Tetramethyl orthosilicate has been tested for mutagenicity to bacteria in a study which was conducted according to OECD TG 471 and in compliance with GLP (Safepharm, 2001). No evidence of a test substance related increase in the number of revertants was observed with or without metabolic activation in Salmonella typhimurium strains TA98, TA100, TA1535 and TA1537 or Escherichia coli WP2 uvrA in either the range finding or the main experiment using the plate incorporation method. Appropriate positive and solvent controls were included and gave expected results. It is concluded that the test substance is negative for mutagenicity to bacteria under the conditions of the test. The result of the supporting study (Dow Corning Corporation 1987a) is in agreement with the key study. The more reliable study was selected as key.

The analogous substance tetraethyl orthosilicate (CAS number 78-10-4) has been tested in CHO cells in a reliable study according to OECD 473 and in compliance with GLP (BioReliance, 2002). A slight increase in the number of structural chromosome aberrations above the concurrent vehicle controls was observed; this was considered not to be of biological significance as the percentage of aberrant cells in the treated group, 2.5%, was within the historical control range of 0.0% to 6.5% . No increase in numerical chromosome aberrations was observed. It is concluded that the test substance is negative for the induction of chromosome aberrations under the conditions of the test. The original study was considered reliability 1. Read-across to the registered substance is considered scientifically justified and is reliability 2.

The analogous substance, tetraethyl orthosilicate, has been tested for mutagenicity in a reliable study according to a protocol that is similar to OECD TG 476 using Chinese hamster ovary (CHO) cells (Bushy Run Research Centre, 1981). Weak responses (increase in the number of revertants relative to the solvent control ) were obtained at the 1.4 and 1.1 µg/ml concentrations tested without activation. The biological significance of these results was doubtful because the effects were produced at non-consecutive doses and were within the range of variations observed in historical negative control data. It is therefore considered that the test substance is negative for the induction of mutations in mammalian cells under the conditions of this test. The original study and the read-across are considered to be reliability 2.

Tetramethyl orthosilicate was tested in an in vivo rat micronucleus assay according to OECD 474 1987, and in compliance with GLP (Dow Corning Corporation, 1987). The study is considered to be reliability 2. No evidence of a test substance mediated induction of micronuclei was observed following inhalation exposure to the maximum tolerated dose. It was noted that the NCE/PCE ratio was variable due to difficulty in scoring NCEs. It is concluded that the test substance is not genotoxic under the conditions of the test.

Justification for selection of genetic toxicity endpoint
The selected bacterial mutagenicity study was the most reliable study available for the surrogate substance. It was conducted according to an appropriate OECD guideline and in compliance with GLP. The selected mammalian studies were the only available mammalian mutagenicity and cytogenicity studies for the surrogate substance. The cytogenicity study was conducted according to an appropriate OECD guideline; the cytogenicity study was conducted in accordance with a protocol that was similar to an appropriate OECD guideline. Both these studies were conducted in compliance with GLP.

Short description of key information:
In vitro:
Gene mutation (Bacterial reverse mutation assay / Ames test): negative with and without metabolic activation in Salmonella typhimurium strains TA98, TA100, TA1535 and TA1537 and Escherichia coli WP2 uvrA (OECD TG 471) (Safepharm 2001).
Cytogenicity in mammalian cells: read-across from analogous substance tetraethylorthosilicate (CAS number 78-10-4); negative with and without metabolic activation in CHO cells (OECD 473) (BioReliance, 2002).
Mutagenicity in mammalian cells: read-across from analogous substance tetraethylorthosilicate (CAS number 78-10-4); negative with and without metabolic activation in CHO cells (similar to OECD TG 476) (Bushy Run Research Centre, 1981).

In vivo:
Micronucleus assay inhalation study in rat: Negative at maximum tolerated dose (OECD TG 474) (Dow Corning Corporation, 1987).

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

Based on the available in vitro and in vivo genotoxicity data, tetramethyl orthosilicate is not classified for mutagenicity according to Regulation 1272/2008/EC.