(chloromethyl)diethoxymethylsilane

Endpoint summary

Description of key information

Skin irritation/corrosion: not irritating
Eye irritation: not irritating

Key value for chemical safety assessment

Skin irritation / corrosion

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Skin irritation:

In the available weight of evidence study of the read accross substance (Chloromethyl)triethoxysilane CAS RN 15267 -95 -5 (reliability score 1) the test item was tested for its skin irritating properties according to the OECD TG 404 and in compliance with GLP. 3 female New Zealand White rabbits were semiocclusively treated with 0.5 ml of the test material on the shaved dorsal area of the trunk for 4 hours. No irritant effects were noted during the 72 h observation period. No deaths occurred, and no signs of systemic toxicity were reported. Moreover, the body weight was not affected by the treatment. In conclusion, the test material was considered to be not irritating to the rabbits' skin under the conditions of the test.

In a RTECS data entry (reliability score 4) for the test item Silane, chloromethylmethyldiethoxy- CAS RN 2212-10-4 after administration of 20 mg test item for 24 hr onto the rabbit skin a reaction severity as moderate was recorded. No further details are available. As the reliability of the data can not be proved and the scoring system as to which the judgement "moderate" severity has been awarded in a weight of evidence approach the read accross testing has a higher reliability and is therefore used for this endpoint.

Read-across justification

 

There is one measured data available for (Chloromethyl)diethoxymethylsilane (CAS 2212-10-4) for skin irritation/corrosion. However, as the result is sourced from secondary literature (RTECS) only, without access to the original reference for review and no further information is available the reliability of the study is not assignable. This document describes the analogue approach for fulfilling this endpoint by read-across from a source substance (Chloromethyl)triethoxysilane (CAS 15267-95-5), according to the Read-across Assessment Framework (RAAF)[1].

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 source substance, (Chloromethyl)triethoxysilane (CAS 15267-95-5) contains a chloromethyl silane group in addition with an ethoxy moiety. (Chloromethyl)triethoxysilane hydrolyses rapidly to form (chloromethyl)silanetriol (1 moles) and ethanol (3 moles) under conditions relevant in the environment or in vivo, with a half-life of 2.5 h. A half-life value of approximately 2.5 h at 20-25°C and pH 7 was obtained using an accepted validated QSAR method.

At pH 2 (the known pH of the stomach), the calculated hydrolysis rate is approximately 5 seconds.

The source substance has log Kow of 2.5 at 20°C (QSAR), water solubility of 1.1E+03 mg/l at 20°C (QSAR) and vapour pressure of 6.5 Pa at 25°C (QSAR).

 

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

The registration substance, (Chloromethyl)diethoxymethylsilane (CAS 2212-10-4), and the read-across substance, (Chloromethyl)triethoxysilane (CAS 15267-95-5), are structurally similar. (Chloromethyl)triethoxysilane (CAS 15267-95-5) contains a chloromethyl silane group in addition to three ethoxy-groups attached to the Si atom, while in (Chloromethyl)diethoxymethylsilane (CAS 2212-10-4) only two ethoxy-groups are attached to the Si atom of the chloromethyl silane group and the third ethoxy group is substituted by a methyl group.

This structural difference remains in the Si-containing hydrolysis product for the target and source substance. The Si hydrolysis product for the target substance is (chloromethyl)methylsilanediol while the Si hydrolysis product for the source substance is chloromethylsilanetriol.

 

Table 2: Physico-chemical properties

 

Property		Target substance		Source substance
Substance name		(Chloromethyl)diethoxymethylsilane		(Chloromethyl)triethoxysilane
CAS number		2212-10-4		15267-95-5
Hydrolysis half-life at pH 4 and 20 - 25°C		1.1 – 24 min (QSAR)		12 min (QSAR)
Silanol hydrolysis product		(chloromethyl)methylsilanediol		chloromethylsilanetriol
Non-Si hydrolysis product		Ethanol		Ethanol
LogKow Value		1,82 at 25°C (QSAR)		2.5 at 20°C (QSAR)
Vapour pressure		25.2 hPa at 25°C (measured)		6.5 Pa at 25°C (QSAR)
Water solubility		1487 mg/L at 25°C (QSAR)		1.1E+03 mg/l at 20°C (QSAR)

 

 

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

 

In the available weight of evidence study (BSL BioService, 2011) the test item was tested for its skin irritating properties according to the OECD TG 404 and in compliance with GLP. 3 female New Zealand White rabbits were semiocclusively treated with 0.5 ml of the test material on the shaved dorsal area of the trunk for 4 hours. No irritant effects were noted during the 72h observation period. No deaths occurred, and no signs of systemic toxicity were reported. Moreover, the body weight was not affected by the treatment. In conclusion, the test material was considered to be not irritating to the rabbits' skin under the conditions of the test.

 

4. AE A.4 Bias that influences the prediction

 

Data on the source substance (Chloromethyl)triethoxysilane (CAS 15267-95-5) were read-across to the registered (target) substance (Chloromethyl)diethoxymethylsilane (CAS 2212-10-4). The source substance and the target substance have similar chemical structure and physico-chemical properties. Both substances hydrolyse at similar rate to a similar Si-containing hydrolysis product, chloromethylsilanetriol resp. (chloromethyl)methylsilanediol. The non-silanol hydrolysis product is the same, ethanol. Due to that, their toxicological properties are expected to be similar, with similar skin irritation potential. No other data for relevant substances were available. This substance is the closest structural analogue to the target substance available.

 

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

 

Both substances hydrolyse rapidly in contact with water under conditions relevant for oral exposure. Therefore, the test organism is mainly exposed to their hydrolysis products, (chloromethyl)methylsilanediol, resp. chloromethylsilanetriol. The source and target substances have been profiled using the OECD QSAR Toolbox v. 4.1. The two substances and their silanol hydrolysis products show similar profiles for all toxicological endpoints. No alert for skin irritation/corrosion was detected by OECD QSAR Toolbox v.4.1. No classification for skin irritation has been assigned to the substance.

 

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 Chloromethyl)diethoxymethylsilane (CAS 2212-10-4), therefore data are read-across from the structurally analogous substance (Chloromethyl)triethoxysilane (CAS 15267-95-5). Both substances hydrolyse at similar rate to a similar Si-containing hydrolysis product, chloromethylsilanetriol resp. (chloromethyl)methylsilanediol. The non-silanol hydrolysis product, ethanol, is not expected to be relevant for this endpoint. Moreover, they have similar physico-chemical properties. Thus, both substances are expected to have similar toxicity profiles.

 

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

 

The target substance, Chloromethyl)diethoxymethylsilane (CAS 2212-10-4), does not have any impurities of toxicological concern. The source substance, (Chloromethyl)triethoxysilane (CAS 15267-95-5), has a named impurity of approx. 1% is Ethanol (CAS 64-17-5). It is not expected that the ethanol impurity will contribute to the skin irritation potential of the source substance. The test substance in the study with the source substance, (Chloromethyl)triethoxysilane (CAS 15267-95-5), has a purity of 97.2%.

 

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

 

Not relevant.

 

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

Eye irritation:

In the available weight of evidence study of the read accross substance (Chloromethyl)triethoxysilane CAS RN 15267 -95 -5 the test item was investigated for eye irritation according to the OECD TG 405, and in compliance with GLP. The test item was applied by instillation of 0.1 ml into the left eye of each of three young adult New Zealand White rabbits. Scoring of irritation effects was performed approximately 1, 24, 48 and 72 hours post treatment. No abnormal findings were observed in the cornea or for the iris light reflex of any animals at any of the measurement intervals. Slight redness of the conjunctivae was noted in one animal at 1 and 24 hours after treatment. Thereafter, all animals were negative. The mean score was calculated separately for each animal across three scoring times (24, 48, and 72 hours after instillation) for corneal opacity, iris light reflex, redness and chemosis of the conjunctivae, respectively. The individual mean scores for corneal opacity and iris light reflex were 0.0 for all three animals. The individual mean scores for the conjunctivae were 0.0 in two animals and 0.33 in one animal for reddening and all 0.0 for chemosis. No deaths occurred, no signs of systemic toxicity were reported, and the body weight was not affected by the treatment. Hence, the test item was considered to be not irritating to the rabbits' eye under the conditions of the test.

In a RTECS data entry (reliability score 4) for the test item Silane, chloromethylmethyldiethoxy- after administration of 100 mg test item for 24 hr into the rabbit eye a reaction severity as moderate was recorded. No further details are available. As the reliability of the data can not be proved and the scoring system as to which the judgement "moderate" severity has been awarded in a weight of evidence approach the read accross testing has a higher reliability and is therefore used for this endpoint.

Read-across justification

 

There is one measured data available for (Chloromethyl)diethoxymethylsilane (CAS 2212-10-4) for eye irritation. However, as the result is sourced from secondary literature (RTECS) only, without access to the original reference for review and no further information is available the reliability of the study is not assignable. This document describes the analogue approach for fulfilling this endpoint by read-across from a source substance (Chloromethyl)triethoxysilane (CAS 15267-95-5), according to the Read-across Assessment Framework (RAAF)[1].

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 source substance, (Chloromethyl)triethoxysilane (CAS 15267-95-5) contains a chloromethyl silane group in addition with an ethoxy moiety. (Chloromethyl)triethoxysilane hydrolyses rapidly to form (chloromethyl)silanetriol (1 moles) and ethanol (3 moles) under conditions relevant in the environment or in vivo, with a half-life of 2.5 h. A half-life value of approximately 2.5 h at 20-25°C and pH 7 was obtained using an accepted validated QSAR method.

At pH 2 (the known pH of the stomach), the calculated hydrolysis rate is approximately 5 seconds.

The source substance has log Kow of 2.5 at 20°C (QSAR), water solubility of 1.1E+03 mg/l at 20°C (QSAR) and vapour pressure of 6.5 Pa at 25°C (QSAR).

 

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

The registration substance, (Chloromethyl)diethoxymethylsilane (CAS 2212-10-4), and the read-across substance, (Chloromethyl)triethoxysilane (CAS 15267-95-5), are structurally similar. (Chloromethyl)triethoxysilane (CAS 15267-95-5) contains a chloromethyl silane group in addition to three ethoxy-groups attached to the Si atom, while in (Chloromethyl)diethoxymethylsilane (CAS 2212-10-4) only two ethoxy-groups are attached to the Si atom of the chloromethyl silane group and the third ethoxy group is substituted by a methyl group.

This structural difference remains in the Si-containing hydrolysis product for the target and source substance. The Si hydrolysis product for the target substance is (chloromethyl)methylsilanediol while the Si hydrolysis product for the source substance is chloromethylsilanetriol.

 

Table 2: Physico-chemical properties

 

Property		Target substance		Source substance
Substance name		(Chloromethyl)diethoxymethylsilane		(Chloromethyl)triethoxysilane
CAS number		2212-10-4		15267-95-5
Hydrolysis half-life at pH 4 and 20 - 25°C		1.1 – 24 min (QSAR)		12 min (QSAR)
Silanol hydrolysis product		(chloromethyl)methylsilanediol		chloromethylsilanetriol
Non-Si hydrolysis product		Ethanol		Ethanol
LogKow Value		1,82 at 25°C (QSAR)		2.5 at 20°C (QSAR)
Vapour pressure		25.2 hPa at 25°C (measured)		6.5 Pa at 25°C (QSAR)
Water solubility		1487 mg/L at 25°C (QSAR)		1.1E+03 mg/l at 20°C (QSAR)

 

 

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

 

In the available weight of evidence study(Harlan, 2012) the test item was investigated for eye irritation according to the OECD TG 405, and in compliance with GLP. The test item was applied by instillation of 0.1 ml into the left eye of each of three young adult New Zealand White rabbits. Scoring of irritation effects was performed approximately 1, 24, 48 and 72 hours post treatment. No abnormal findings were observed in the cornea or for the iris light reflex of any animals at any of the measurement intervals. Slight redness of the conjunctivae was noted in one animal at 1 and 24 hours after treatment. Thereafter, all animals were negative. The mean score was calculated separately for each animal across three scoring times (24, 48, and 72 hours after instillation) for corneal opacity, iris light reflex, redness and chemosis of the conjunctivae, respectively. The individual mean scores for corneal opacity and iris light reflex were 0.0 for all three animals. The individual mean scores for the conjunctivae were 0.0 in two animals and 0.33 in one animal for reddening and all 0.0 for chemosis. No deaths occurred, no signs of systemic toxicity were reported, and the body weight was not affected by the treatment. Hence, the test item was considered to be not irritating to the rabbits' eye under the conditions of the test.

 

4. AE A.4 Bias that influences the prediction

 

Data on the source substance (Chloromethyl)triethoxysilane (CAS 15267-95-5) were read-across to the registered (target) substance (Chloromethyl)diethoxymethylsilane (CAS 2212-10-4). The source substance and the target substance have similar chemical structure and physico-chemical properties. Both substances hydrolyse at similar rate to a similar Si-containing hydrolysis product, chloromethylsilanetriol resp. (chloromethyl)methylsilanediol. The non-silanol hydrolysis product is the same, ethanol. Due to that, their toxicological properties are expected to be similar, with similar eye irritation potential. No other data for relevant substances were available. This substance is the closest structural analogue to the target substance available.

 

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

 

Both substances hydrolyse rapidly in contact with water under conditions relevant for oral exposure. Therefore, the test organism is mainly exposed to their hydrolysis products, (chloromethyl)methylsilanediol, resp. chloromethylsilanetriol. The source and target substances have been profiled using the OECD QSAR Toolbox v. 4.1. The two substances and their silanol hydrolysis products show similar profiles for all toxicological endpoints. No alert for eye irritation was detected by OECD QSAR Toolbox v.4.1. No classification for eye irritation has been assigned to the substance.

 

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 Chloromethyl)diethoxymethylsilane (CAS 2212-10-4), therefore data are read-across from the structurally analogous substance (Chloromethyl)triethoxysilane (CAS 15267-95-5). Both substances hydrolyse at similar rate to a similar Si-containing hydrolysis product, chloromethylsilanetriol resp. (chloromethyl)methylsilanediol. The non-silanol hydrolysis product, ethanol, is not expected to be relevant for this endpoint. Moreover, they have similar physico-chemical properties. Thus, both substances are expected to have similar toxicity profiles.

 

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

 

The target substance, Chloromethyl)diethoxymethylsilane (CAS 2212-10-4), does not have any impurities of toxicological concern. The source substance, (Chloromethyl)triethoxysilane (CAS 15267-95-5), has a named impurity of approx. 1% is Ethanol (CAS 64-17-5). It is not expected that the ethanol impurity will contribute to the eye irritation potential of the source substance. The test substance in the study with the source substance, (Chloromethyl)triethoxysilane (CAS 15267-95-5), has a purity of 97.3%.

 

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

 

Not relevant.

 

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

Justification for selection of skin irritation / corrosion endpoint:
In a weight of evidence approach the more reliable study with the read accross substance (Chloromethyl)triethoxysilane CAS RN 15267-95-5 was selected for assessment.

Justification for selection of eye irritation endpoint:

In a weight of evidence approach the more reliable study with the read accross substance (Chloromethyl)triethoxysilane CAS RN 15267-95-5 was selected for assessment.

Justification for classification or non-classification

The available weight of evidence data are reliable and suitable for classification. Based on these data classification for skin irritation and eye irritation according to 67/584/EEC and EC/1272/2008 is not warranted.