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Administrative data

Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

Gene mutation (Bacterial reverse mutation assay / Ames test): negative with and without metabolic activation in S. typhimurium strains TA 1535, TA 1537, TA 98 and TA 100 and E. coli WP2 uvrA (OECD TG 471) (BioReliance, 2000).

Cytogenicity in mammalian cells: negative with and without metabolic activation in Chinese hamster lung fibroblasts (V79) (OECD TG 473) (ASTA Medica, 1998a).

Mutagenicity in mammalian cells: read-across from Polysulfides, bis[3-(triethoxysilyl)propyl] (CAS 211519-85-6), negative in L5178Y mouse lymphoma cells (OECD TG 476) (Harlan, 2010).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (negative)

Genetic toxicity in vivo

Description of key information

Micronucleus assay study (ip administration) in rat: Negative (OECD TG 474) (ASTA Medica, 1998b).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (negative)

Additional information

Information is available from reliable studies for all the required in vitro endpoints. Where there was more than one result for an endpoint the most reliable study available was chosen as key study. Where there was more than one reliable study, the most recent study was selected. The most reliable bacterial mutagenicity study was conducted using Low purity S2, which is composed of 65-70% S2, 15-20% S3 and 5-10% S1 as impurity, therefore does not have sufficient S2 to meet the Substance Identification Profile, but the other components have similar properties and the supporting studies confirmed that the other constituents did not affect the results. Where reliable studies were not available for the test substances, a study for a multi-component substance including the registration substance was selected. No data are available for mammalian cell gene mutagenicity for the registered substance, however, data are available for the surrogate substance, Polysulfides, bis[3-(triethoxysilyl)propyl] (CAS 211519-85-6). The results of all the studies were in agreement.

Read-across justification

Non-testing methods including read-across from surrogate substances are able to provide information on mutagenic 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 et al., 2008). 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.

Read-across hypothesis

S2, Low purity S2 and Polysulfides, bis[3-(triethoxysilyl)propyl], are closely related substances. S2 includes constituents of Polysulfides, bis[3-(triethoxysilyl)propyl] (S3 and S4), as impurities and Polysulfides, bis[3-(triethoxysilyl)propyl], includes 15-25% S2, with S3 and S4 as the other major constituents. Low purity S2 includes up to 70% S2, with S3 as minor constituent and S1 as impurity. Due to their structural similarity and similar physicochemical properties, the constituents S3 and S4 are considered to be representative of the registered substance.

(a) Structural similarity

The constituents and major impurities of all substances in the analogue have two functional groups in common:

• The triethoxysilane, Si(OEt)3, group (there are two of these per molecule, therefore each molecule has six reactive ethoxy groups).

• The (poly)sulfide, CH2SnCH2 (n = 1-4), group.

Only one of the substances, low purity S2, has n=1, as an impurity at a concentration of 5-10%. None of the substances contain functional groups that are not present in the other substances. Clearly the only difference between the constituents/major impurities is the number of sulfur atoms in the sulfide bridge.

The registration and read-across substances are structurally similar, all contain bis[3-(triethoxysilyl)propyl]- structures with the two (triethoxysilyl)propyl groups linked by di- or polysulfide groups. Details on the composition of the substances is given in Section 1.4 but in summary:

S2 is a monoconstituent substance comprising >80% by weight of disulfide, with approximately 10-20% of the trisulfide as an impurity;

Polysulfides is multiconstituent substance comprising a mixture of di- (S2, 15-25% w/w), tri- (S3, 30-35% w/w) and tetrasulfides (S4, 20-30% w/w).

Low purity S2 comprises 65-70% S2, 15-20% S3 and 5-10% S1 as impurity.

(b) Lack of structural alerts for genetic toxicity

S2, low purity S2 and Polysulfides, bis[3-(triethoxysilyl)propyl], do not include structural alerts for genotoxicity Benigni et al. (2008).

Low purity S2 has been tested a reliable assay conducted according to OECD TG 471 and in compliance with GLP (BioReliance, 2000). The test substance did not cause a positive response in S. typhimurium strains TA 1535, TA 1537, TA 98 and TA 100 and E. coli WP2 uvrA with or without metabolic activation in either the initial or repeat tests using the preincubation method. Appropriate solvent and positive controls were included and gave expected results. The test substance is negative for mutagenicity to bacteria under the conditions of the test. The result was supported by two other studies giving negative results (Hita laboratory, 2000a; TNO, 1996).

S2 has been tested according to OECD 473 and in compliance with GLP. No test substance-induced structural or numerical chromosomal aberrations were observed in Chinese hamster V79 fibroblasts when tested up to cytotoxic concentrations, with and without metabolic activation. The experiment was repeated and the results confirmed. Appropriate solvent and positive controls were included and gave expected results. It is considered that the substance is negative for cytogenicity under the conditions of the test.

This study is supported by studies on Low purity S2 which has been tested in two reliable assays conducted using Chinese hamster lung fibroblasts (V79) (Safepharm, 2002; ASTA Medica). The results of these studies were negative.

The surrogate substance, Polysulfides, bis[3-(triethoxysilyl)propyl], has been tested for mutagenicity in mouse lymphoma L5178Y cells according to OECD TG 176 and in compliance with GLP (Harlan, 2010). No increase in the number of revertants was observed. Appropriate solvent and positive controls were included and gave expected results. It is concluded that the test substance is negative for the mutagenicity in mammalian cells under the conditions of the test.

S2 was tested in an in vivo mouse micronucleus assay conducted to OECD 474 and in compliance with GLP (ASTA Medica, 1998). No evidence of test substance induced increase in micronuclei was observed under the conditions of the test. It should be noted that the PCE/NCE ratio was unchanged in treated animals, so there is no evidence that the test substance reached the target tissue. It is concluded that the test substance is negative for the induction of micronuclei in vivo.

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


Justification for classification or non-classification

Based on the available in vitro and in vivo genotoxicity data, S2 (CAS 56706-10-6) is not classified for mutagenicity according to Regulation 1272/2008/EC.