[3-(2,3-epoxypropoxy)propyl]dimethoxymethylsilane

Endpoint summary

Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

There are no genetic toxicity studies available for [3-(2,3-epoxypropoxy)propyl]dimethoxy(methyl)silane (CAS 65799-47-5).

Gene mutation (Bacterial reverse mutation assay / Ames test)

[3-(2,3-Epoxypropoxy)propyl]trimethoxysilane: positive with and without activation in TA97 and TA100 cells (similar to OECD TG 471) (Microtest Research Ltd., 1988).

[3-(2,3-Epoxypropoxy)propyl]diethoxy(methyl)silane: positive with and without activation in TA 100, TA 1535 and WP2 uvrA cells (similar to OECD TG 471) (BioReliance, 2000).

In vitro cytogenicity

[3-(2,3-Epoxypropoxy)propyl]diethoxy(methyl)silane: positive with and without metabolic activation in cultured human lymphocytes (OECD 473) GLP (SafePharm 2004c).

Mutagenicity in mammalian cells

[3-(2,3-Epoxypropoxy)propyl]trimethoxysilane: positive with and without metabolic activation in mouse lymphoma L5178Ycells (similar to OECD TG 476) (Litton Bionetics, 1983).

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (positive)

Genetic toxicity in vivo

Description of key information

In vivo micronucleus assay: [3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane was negative in mice (oral administration by gavage) (OECD 474) (Shin-Etsu, 2009).

Mammalian alkaline comet assay in rat (oral gavage): Ambiguous result. Negative result for cells of glandular stomach and liver with [3-(2,3 -epoxypropoxy)propyl]diethoxy(methyl)silane. The mean tail intensity of cells from the duodenum at the highest dose tested was above the historic control limit and was statistically significant compared to the concurrent negative control. Toxicity: no abnormalities were observed at necropsy and there were no histological alterations detected in any tissue (OECD TG 489) (BSL Bioservice, 2019).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (negative)

Additional information

Data are read across from bacterial and mammalian mutagenicity studies for [3-(2,3-epoxypropoxy)propyl]trimethoxysilane (2530-83-8) and from bacterial and in vitro cytogenicity studies for [3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane (2897-60-1).

The key study for bacterial mutagenicity for [3-(2,3-epoxypropoxy)propyl]trimethoxysilane (2530-83-8) is from a valid study conducted according to a protocol that is similar to OECD TG 471 and under GLP (Microtest Research Ltd., 1988). The test substance produced a five-fold increase in revertants in Salmonella typhimurium TA 100, and a two-fold increase in TA 97 with and without metabolic activation. The test substance is considered mutagenic in Salmonella typhimurium strains TA97 and TA100 both in the absence and presence of metabolic activation under the conditions of the test.

The key study for bacterial mutagenicity for [3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane (2897-60-1) is from a valid bacterial reverse mutation assay conducted according to OECD TG 471 and under GLP, using Salmonella typhimurium TA98, TA100, TA1535 and TA1537 and Escherichia coli WP2uvrA (BioReliance, 2000). There was a positive, dose related increase in the number of revertant colonies in TA 100, TA 1535 and WP2 uvrA, with and without metabolic activation. The test substance is mutagenic in these tester strains. Appropriate positive and solvent controls were added and gave expected results. It is concluded that the test substance is positive for mutagenicity to bacteria under the conditions of the test.

The key study for in vitro cytogenicity for [3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane (2897-60-1) is from a study conducted according to OECD 473, and in compliance with GLP (SafePharm 2004c). The test material induced a statistically significant dose-related increase in the frequency of cultured human blood lymphocytes with chromosome aberrations in the absence and the presence of metabolic activation. Appropriate positive and solvent controls were used and gave the expected results. The test material was therefore considered to be clastogenic to human lymphocytes in vitro.

The key study for mammalian mutagenicity for [3-(2,3-epoxypropoxy)propyl]trimethoxysilane (2530-83-8) is from a valid study conducted according to a protocol similar to OECD TG 476 and under GLP (Litton Bionetics, 1983). The substance induced mutations in mouse lymphoma L1578Y TK cells, both with and without metabolic activation, in a dose dependent manner. It is considered that the test substance is positive for the induction of mutations in mammalian cells under the conditions of this test.

The key study for in vivo cytogenicity for  [3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane: [3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane (2897-60-1) is from a study conducted according to OECD 474, and in compliance with GLP (Shin-Etsu, 2009). No evidence for a test substance induced increase in the incidence of micronucleated polychromatic erythrocytes in mice bone marrow was observed when tested up to the limit concentration. No clinical signs of toxicity were observed following oral administration of 500, 1000 and 2000 mg/kg of test material to mice. Appropriate positive and vehicle controls were included and gave the expected results. It is concluded that the test substance does not cause damage to chromosomes 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. However, the available information on the toxicokinetics suggests that the registered substance will hydrolyse very rapidly in the acidic milieu of the stomach (hydrolysis half-life at 37.5°C and pH 2 is 5 seconds). The hydrolysis product, [3-(2,3-epoxypropoxy) propyl]methylsilanediol is water soluble (1.0E+06 mg/l) and has a favourable molecular weight (192.28) for absorption so systemic exposure is likely. Although the parent substance has a molecular weight which is not favourable for uptake (248.4) it is water soluble (1200 mg/l), so some systemic exposure is possible if unhydrolysed parent compound is left in the stomach. It is therefore concluded based on the result of the study that the test substance is negative for the induction of micronuclei under the conditions of the test.

The read-across substance [3-(2,3 -epoxypropoxy)propyl]diethoxy(methyl)silane (CAS 2897-60-1) has been tested in an in vivo mammalian alkaline comet assay conducted according to OECD TG 489 and in compliance with GLP (BSL Bioservice, 2019). The undiluted test substance was administered orally by gavage at doses of 400, 1000 and 2000 mg/kg bw for two consecutive days. A negative control, physiological saline, was administered according to the same schedule, and a positive control was administered orally 4 hours before sacrifice. The positive control item, ethyl methanesulphonate, induced a statistically significant increase in DNA damage for all evaluated organs, as shown by an increase in mean tail intensity relative to the negative control. The test item did not result in any significant positive signal in the liver and glandular stomach. However, increased comet formation was detected in duodenum cells only after application of the highest tested limit-dose of 2000 mg/kg bw. Neither a dose-response relationship nor any significant signal outside the historical control interval at the lower doses was detected. Duodenum samples were preserved for histopathological analysis; no abnormalities were observed at necropsy and there were no histological alterations detected in any tissue.

Justification for classification or non-classification

The available information for the substance indicates that, based on read-across data, [3-(2,3-epoxypropoxy)propyl]dimethoxy(methyl)silane is mutagenic to bacteria and mammalian cells and causes an increase in chromosome aberrations in vitro. Data from an in vivo micronucleus assay with the surrogate substance, [3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane, indicate that the clastogenic effects observed in vitro are not observed in vivo.

The result of an in vivo mammalian alkaline comet assay with the read-across substance was ambiguous, with increased comet formation at highest dose observed in cells of duodenum but not in cells of the glandular stomach or liver. Consideration of potential for germ cell mutagenicity. The ambiguous result from the comet assay has been considered. Although effects suggesting DNA damage were observed in cells of the duodenum, there is no evidence of DNA damage to cells of the liver, therefore the comet assay does not support classification for germ cell mutagenicity.

Implications for site of contact mutagenicity: the evidence of DNA damage to cells of the duodenum at a level slightly above the historical control suggests that the substance might be a site-of-contact mutagen. Under CLP, only germ cell mutagens are classified.

Based on the available information, [3-(2,3-epoxypropoxy)propyl]dimethoxy(methyl)silane does not require classification for germ cell mutagenicity according to Regulation (EC) No 1272/2008.