3-(dimethoxymethylsilyl)propyl methacrylate

Endpoint summary

Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

Bacterial mutagenicity (Ames test): negative, with or without metabolic activation in Salmonella typhimurium strains TA 1535, TA 98, TA 97a, TA 100 and TA 102 (OECD 471) (Bioservice, 2003f).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (negative)

Genetic toxicity in vivo

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

[Dimethoxy(methyl)silyl]methyl methacrylate has been tested in a valid bacterial reverse mutation assay, according to the OECD TG 471 (1989), and under GLP, using Salmonella typhimurium strains TA 1535, TA 98, TA 97a, TA 100 and TA 102 (Bioservice, 2003).

No increase in the number of revertants was observed in any test strain, with or without metabolic activation. Appropriate positive, negative and solvent controls were added and gave expected results. It is concluded that the test substance is negative for mutagenicity to bacteria under the conditions of the test.

(3-Acryloxypropyl)methyldimethoxysilane has been tested for mutagenicity to bacteria (Shin Etsu, 1990). No evidence of a test-substance related increase in the number of revertants was observed with or without metabolic activation in Salmonella typhimurium strains TA 98, TA 100, TA 1535, TA 1537 or E. coli WP2 uvrA in the initial or the repeat experiments up to 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

There are no available measured data for 3-[Dimethoxy(methyl)silyl]propyl methacrylate (CAS 14513-34-9) for genetic toxicity. Therefore, the Annex requirements are fulfilled by data on structurally analogous substances. This document describes the analogue approach for fulfilling this endpoint by read-across from two source substances, 3-[dimethoxy(methyl)silyl]propyl acrylate (CAS 13732-00-8) and [dimethoxy(methyl)silyl]methyl methacrylate (CAS 121177-93-3), according to the Read-across Assessment Framework (RAAF).

Read-across is proposed in accordance with RAAF Scenario 2: “This scenario covers the analogue approach for which the read-across hypothesis is based on different compounds which have the same type of effect(s). For the REACH information requirement under consideration, the effects obtained in a study conducted with one source substance are used to predict the effects that would be observed in a study with the target substance if it were to be conducted. The same type of effect(s) or absence of effect is predicted. The predicted strength of the effects may be similar or based on a worst case.”

The read-across justification is presented (Table 5.6.4) according to RAAF scenario 2 assessment elements (AE) as outlined in Table B1 of the RAAF1:

Table 1: RAAF scenario 2 assessment elements (AE) as given in Appendix B (Table B1) of the RAAF1

AE A.1	Characterisation of source substance
AE A.2	Link of structural similarity and differences with the proposed Prediction
AE A.3	Reliability and adequacy of the source study
AE 2.1	Compounds the test organism is exposed to
AE 2.2	Common underlying mechanism, qualitative aspects
AE 2.3	Common underlying mechanism, quantitative aspects
AE 2.4	Exposure to other compounds than to those linked to the prediction
AE 2.5	Occurrence of other effects than covered by the hypothesis and Justification
AE A.4	Bias that influences the prediction

1.       AE A.1 Identity and characterisation of the source substance

The first source substance, 3-[dimethoxy(methyl)silyl]propyl acrylate (CAS 13732-00-8), has a silicon atom bound to two methoxy groups, one methyl group and one propyl acrylate group. Its predicted hydrolysis half-lives are 0.2 h at pH 4, 1.6 h at pH 7 and 0.03 h at pH 9 and 25°C.

The half-lives at pH 4, 7 and 9 and 37.5°C, relevant to human exposure, are 0.08 h, 0.6 h, 0.01 h respectively.

The hydrolysis products in this case are 3-[dihydroxy(methyl)silyl]propyl acrylate and methanol.

The source substance has log Kow of 2.9 at 20°C and vapour pressure of 4.1 Pa at 25°C.

The second source substance [dimethoxy(methyl)silyl]methyl methacrylate (CAS 121177-93-3), has a silicon atom bound to two methoxy groups, one methyl group and one methyl methacrylate group. Its predicted hydrolysis half-lives are 1.8 h at pH 7, 0.2 h at pH 4, 0.04 h at pH 9 and 25°C.

The hydrolysis products in this case are [dihydroxy(methyl)silyl]methyl methacrylate and methanol. The source substance has a log Kow of 2.4 at 20°C, vapour pressure of 37 Pa at 25°C and water solubility of 2500 mg/l.

2.       AE A.2 Link of structural similarities and differences with the proposed prediction

The source substance, 3-[dimethoxy(methyl)silyl]propyl acrylate (CAS 13732-00-8), and the target substance, 3-[dimethoxy(methyl)silyl]propyl methacrylate (CAS 14513-34-9), are structurally similar. They are both dimethoxy silanes with one methyl side-chain and one propyl(meth)acrylate. The difference is that the source substance has a propylacrylate side-chain, whereas the target substance has an additional methyl group at the end of the side-chain, making it propylmethacrylate (see Table 1).

These two substances both hydrolyse at a similar rate to a disilanol (1 mole) and methanol (2 moles). The hydrolysis products of these two substances are structurally similar in the same way as the parent substances. They are both disilanols with one methyl side-chain and one propyl(meth)acrylate. The difference is that the source substance has a propylacrylate side-chain, whereas the target substance has an additional methyl group at the end of the side-chain, making it propylmethacrylate (see Table 1).

The source substance, [dimethoxy(methyl)silyl]methyl methacrylate (CAS 121177-93-3), and the target substance, 3-[dimethoxy(methyl)silyl]propyl methacrylate (CAS 14513-34-9), are structurally similar. They are both dimethoxy silanes with one methyl group. The difference is that the source substance has a methyl methacrylate side-chain attached to the silicon atom, while the target substance has a propyl methacrylate side-chain instead.

These two substances both hydrolyse at a similar rate to a disilanol (1 mole) and methanol (2 moles). The hydrolysis products of these two substances are structurally similar in the same way as the parent substances. They are both disilanols with one methyl side-chain. The difference is that the source substance has a methyl methacrylate side-chain, whereas the target substance has propyl methacrylate side-chain (see Table 1).

Table 2: Physico-chemical properties

Property	Target substance	Source substance	Source substance
Substance name	3-[Dimethoxy(methyl)silyl]propyl methacrylate	3-[dimethoxy(methyl)silyl]propyl acrylate	[dimethoxy(methyl)silyl]methyl methacrylate
CAS number	14513-34-9	13732-00-8	121177-93-3
Hydrolysis half-life	1.5 h at pH 7 and 25ºC	1.6 h at pH 7 and 25ºC	1.8 h at pH 7 and 25ºC
Silanol hydrolysis product	3-[dihydroxy(methyl)silyl]propyl methacrylate	3-[dihydroxy(methyl)silyl]propyl acrylate	[dihydroxy(methyl)silyl]methyl methacrylate
Non-Si hydrolysis product	methanol	methanol	methanol
LogKow value	3.4 at 20°C (QSAR)	2.9	2.4 at 20°C (QSAR)
Vapour pressure	1.3 Pa at 25°C (QSAR)	4.1 Pa	37 Pa at 25°C (QSAR)
Water solubility	240 mg/L	Not specified	2500 mg/l

3.       AE A.3 Reliability and adequacy of the source study

3-[Dimethoxy(methyl)silyl]propyl acrylate has been tested for mutagenicity to bacteria. No evidence of a test-substance related increase in the number of revertants was observed with or without metabolic activation in Salmonella typhimurium strains TA 98, TA 100, TA 1535, TA 1537 or E. coli WP2 uvrA in the initial or the repeat experiments up to 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.

[Dimethoxy(methyl)silyl]methyl methacrylate has been tested in a valid bacterial reverse mutation assay, according to the OECD TG 471 (1989), and under GLP, using Salmonella typhimurium strains TA 1535, TA 97a, TA 98, TA 100 and TA 102. No increase in the number of revertants was observed in any test strain, with or without metabolic activation. Appropriate positive, negative and solvent controls were added and gave expected results. It is concluded that the test substance is negative for mutagenicity to bacteria under the conditions of the test.

4.       AE A.4 Bias that influences the prediction

Data on the source substances 3-[dimethoxy(methyl)silyl]propyl acrylate (CAS 13732-00-8) and [dimethoxy(methyl)silyl]methyl methacrylate (CAS 121177-93-3) were read-across to the registered (target) substance 3-[dimethoxy(methyl)silyl]propyl methacrylate (CAS 14513-34-9). The source substances and the target substance have similar chemical structure and physico-chemical properties. All three substances hydrolyse at similar rates, and produce 3-[dihydroxy(methyl)silyl]propyl methacrylate, 3-[dihydroxy(methyl)silyl]propyl acrylate or [dihydroxy(methyl)silyl]methyl methacrylate, as the silicon-containing hydrolysis products. They share a common non-silanol hydrolysis products methanol. Therefore, their toxicological properties are expected to be similar, with similar genotoxic effects. These are the closest structural analogues with available data. All alkoxysilanes with (meth)acrylate side-chains show consistent results for bacterial mutagenicity.

There is an ongoing Comet Assay study for another structural analogue 3-trimethoxysilylpropyl methacrylate (CAS 2530-85-0). Read-across strategy for the registered substance would be reconsidered once results from this ongoing study are available.

5.       AE A.2.1 Compounds the test organism is exposed to

The source substances as well as the target substance hydrolyse rapidly in contact with water. Therefore, the test organism is exposed to both the parent substances and their hydrolysis products, 3-[dihydroxy(methyl)silyl]propyl methacrylate, 3-[dihydroxy(methyl)silyl]propyl acrylate, [dihydroxy(methyl)silyl]methyl methacrylate and methanol.  The source and target substances have been profiled using the OECD QSAR Toolbox v. 4.1. The three substances and their silanol hydrolysis products show similar profiles:  

•       All show an alert for DNA binding by OECD, due to the presence of the (meth)acrylate groups. This is relevant for genetic toxicity

•       They all have no alerts in other profilers relevant for genetic toxicity including DNA alerts for AMES by OASIS v.1.4, DNA alerts for CA and MNT by OASIS v.1.1, in vitro mutagenicity (Ames test) alerts by ISS, Keratinocyte gene expression, Protein binding alerts for Chromosomal aberration by OASIS v.1.2, DNA binding by OASIS v.1.4.

•       Profiles for other toxicological endpoints are also consistent.

Additionally, presence of the O-C-Si-O fragment is detected in [dimethoxy(methyl)silyl]methyl methacrylate (CAS 121177-93-3). This substance is a methylmethacrylate rather than propylmethacrylate, which means that it has an alert for in vivo mutagenicity (Micronucleus) alerts by ISS (H-accepter-path3-H-acceptor). This alert explores the possibility that a chemical interacts with DNA and/or proteins via non-covalent binding, such as DNA intercalation or groove-binding (Snyder et al. 2006). Structures of the type HbondAcc-A-A-HbondAcc are selected, where HbondAcc is any atom that is potentially a hydrogen-bond acceptor and A is any other atom. The substances with a propyl (meth)acrylate side-chain do not show this alert. The presence of this additional alert for one of the source substances makes the read-across conservative.

The non-silanol hydrolysis product methanol has been tested for mutagenicity to bacteria in seven Ames tests. No evidence of a test-substance related increase in the number of revertants was observed in any of these studies. Therefore, methanol was concluded to be negative for mutagenicity to bacteria.

6.       AE A.2.2 and A.2.3 Common underlying mechanism, qualitative and quantitative aspects

No toxicity data are available for the target substance 3-[dimethoxy(methyl)silyl]propyl methacrylate, therefore data are read-across from the structurally analogous substances 3-[dimethoxy(methyl)silyl]propyl acrylate and [dimethoxy(methyl)silyl]methyl methacrylate. These three substances hydrolyse at similar rate to a disilanol (1 mole) and methanol (2 moles). The non-silanol hydrolysis product, methanol, has been shown not to be genotoxic. Moreover, they have similar physico-chemical properties. Thus, all three substances are expected to have similar toxicity profiles.

7.       AE 2.4 Exposure to other compounds than to those linked to the prediction

Neither the target substance, 3-[dimethoxy(methyl)silyl]propyl methacrylate, nor the source substances, 3-[dimethoxy(methyl)silyl]propyl acrylate and [dimethoxy(methyl)silyl]methyl methacrylate, have impurities of toxicological concern.

The test substance in the study with the source substance, 3-[dimethoxy(methyl)silyl]propyl acrylate, has a purity of 100%.

The test substance in the study with the second source substance, [dimethoxy(methyl)silyl]methyl methacrylate, has a purity of 98.6%.

The target substance, 3-[dimethoxy(methyl)silyl]propyl methacrylate (CAS 14513-34-9), has a purity of >98% and no impurities are present at >1%.

8.       AE 2.5 Occurrence of Other Effects than Covered by the Hypothesis and Justification

Not relevant

References:

European Chemicals Agency (ECHA) (2015) Read-across Assessment Framework. Appendix B, Scenario 2.

Snyder, R. D., Ewing, D. and Hendry, L. B. 2006. DNA intercalative potential of marketed drugs testing positive in in vitro cytogenetics assays. Mutat. Res. 609, 47-59.

Justification for classification or non-classification

Based on the read-across available data for 3-[dimethoxy(methyl)silyl]methyl methacrylate, no classification for genetic toxicity is required according to Regulation (EC) No 1272/2008.