Dichloro(3-chloropropyl)methylsilane

Endpoint summary

Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

Gene mutation (Bacterial reverse mutation assay / Ames test): positive without metabolic activation in strain TA 1535; negative with metabolic activation in strain TA 1535; negative with and without activation in all other strains tested (OECD TG 471)
Mutagenicity in mammalian cells: negative in L5178Y mouse lymphoma cells (OECD TG 476)
Cytogenicity in mammalian cells: negative in Chinese Hamster Ovary cells (OECD TG 473)

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (negative)

Genetic toxicity in vivo

Description of key information

Read-across from analogous substance (3-chloropropyl)diethoxymethylsilane (CAS 13501-76-3): negative in mammalian micronucleus assay (intraperitoneal administration) (EU method B 12 (Hüls 1996a; rel 1).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (negative)

Additional information

Two in vitro bacterial mutagenicity studies are available for the test substance. In the key study (Hüls AG, 1996b), a positive result was obtained in a single strain without metabolic activation. The result was both dose-dependent and reproduced in the repeat study with pre-incubation. In all other strains tested, both with and without metabolic activation, there was no increase in the number of revertant colonies. No cytotoxicity was observed in any of the S. typhimurium strains tested (TA 1535, TA 1537, TA 98 and TA 100) up to the maximum concentration of 5000 µg/plate. The study was conducted according to an appropriate guideline with restrictions and in compliance with GLP. The restriction is that only four bacterial strains were tested and fifth strain for detecting mutagenicity via cross-linking was not used. Negative results were also obtained with all strains tested, S. typhimurium TA 1535, TA 1537, TA 98, TA 100 and TA 102 both with and without activation, in a supporting study, where cytotoxicity was observed at the maximum concentration of 100 µg/plate (LPT, 2002). The study was conducted according to an appropriate OECD guideline and in compliance with GLP. Despite observing negative result in the more recent study (LPT, 2002), a conservative approach was followed and the older study with restrictions that reports positive result was selected as key (Huls, 1996).

In vitro cytogenicity and mutagenicity studies in mammalian cells are also available ( Hüls AG, 1997a and 1997b, respectively). Both of these studies gave negative results and the test substance was judged to be non-genotoxic in mammalian cells. It is considered that the positive result obtained in the key bacterial mutagenicity study, (Hüls AG, 1996), does not indicate a hazard to mammals, as no mutagenicity was observed in the more recent bacterial study (LPT, 2002) or in mammalian cells (Hüls AG, 1997b).

No in vivo data are available for dichloro(3-chloropropyl)methylsilane (CAS 7787-93-1), however, reliable in vivo micronucleus data are available for the related substance, (3 -chloropropyl)diethoxymethylsilane (CAS 13501-76-3). (3-Chloropropyl)diethoxymethylsilane and dichloro(3-chloropropyl)methylsilane  share a common hydrolysis product, (3-chloropropyl)methylsilanediol. The other products of hydrolysis are ethanol and hydrochloric acid respectively. Dichloro(3-chloropropyl)methylsilane (CAS 7787-93-1) has a hydrolysis half-life of <1 min at pH 4, 7 and 9 and 25°C (read-across), that for (3-chloropropyl)diethoxymethylsilane is slower (estimated to be around 20-10 hours). As hydrolysis is likely to occur during testing and following ingestion, and the other products of hydrolysis, hydrogen chloride and ethanol are not genotoxic (OECD (2002), OECD 2004)), it is considered that read-across between these substances is appropriate. Additional information is given in a supporting report (PFA (2013aa)) attached in Section 13 of the IUCLID dossier. The result of the micronucleus study was negative, supporting the conclusion reached from the in vitro data.

Read-across justification

There are no available measured data for dichloro(3-chloropropyl)methylsilane (CAS 7787-93-1) for in vivo genetic toxicity. Therefore, the Annex requirements are fulfilled by data on a structurally analogous substance. This document describes the analogue approach for fulfilling this endpoint by read-across from a source substance, (3-chloropropyl)diethoxymethylsilane (CAS 13501-76-3), 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 1) 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 RAAF

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, (3-chloropropyl)diethoxymethylsilane (CAS 13501-76-3), is an alkoxysilane with  a silicon atom bound to two ethoxy groups, one methyl group and one chloropropyl group. Its predicted hydrolysis half-lives are estimated to be 9.5 hours at pH 7 and 20 -25°C.

The hydrolysis products are (3-chloropropyl)methylsilanediol and ethanol.

The source substance has log Kow of 4.2, water solubility of 36 mg/l and vapour pressure of 6.8 Pa at 25°C.

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

The source substance, (3-chloropropyl)diethoxymethylsilane (CAS 13501-76-3), and the target substance, dichloro(3-chloropropyl)methylsilane (CAS 7787-93-1), are structurally similar. They are both organosilicon compounds with one silicon atom bound to a chloropropyl group, a methyl group and two hydrolysable groups. The difference is that the hydrolysable groups in the source substance are both ethoxy, whereas in the target substance they are both chloro. In general, organosilicon compounds show no evidence of genetic toxicity unless a functional group in the side chain is associated with genetic toxicity. Therefore, the hypothesis is that any genetic toxicity would be associated with the chloropropyl group.

(3-Chloropropyl)diethoxymethylsilane (CAS 13501-76-3) and dichloro(3-chloropropyl)methylsilane (CAS 7787-93-1) share a common hydrolysis product, (3-chloropropyl)methylsilanediol. The other products of hydrolysis are ethanol and hydrogen chloride respectively. Dichloro(3-chloropropyl)methylsilane (CAS 7787-93-1) has a hydrolysis half-life of 5 seconds at pH 7 and 25°C (read-across), that for (3-chloropropyl)diethoxymethylsilane is slower (estimated to be around 10 hours at pH 7 and 20-25°C), however hydrolysis is expected to occur during testing. At physiologically relevant conditions i.e. pH7 and 37.5°C the rate of hydrolysis would be faster, and the estimated hydrolysis half-life of the source substance is 3.5 hours. In an in vivo mammalian micronucleus test samples from the animals are usually collected at 24 and 48 hours following administration. Therefore, this would be enough time for hydrolysis to take place and the test organism would be exposed predominantly to the hydrolysis products.

Table 2: Physico-chemical properties

Property		Target substance		Source substance
Substance name		dichloro(3-chloropropyl)methylsilane		(3-chloropropyl)diethoxymethylsilane
CAS number		7787-93-1		13501-76-3
Hydrolysis half-life at20 -25°C and pH 7		5 seconds (Read-across)		9.5 hours (QSAR)
Hydrolysis half-life at37.5°C and pH 7		5 seconds (Estimate)		3.5 hours (Estimate)
Silanol hydrolysis product		(3-chloropropyl)methylsilanediol		(3-chloropropyl)methylsilanediol
Non-Si hydrolysis product		Hydrogen chloride		ethanol
LogKow value (parent)		Not relevant		4.2 (QSAR)
LogKow value (Si-hydrolysis product)		0.8 at 20°C (QSAR)		0.8 at 20°C (QSAR)
Vapour pressure (parent)		83 Pa at 25°C (QSAR)		6.8 Pa at 25°C (QSAR)
Vapour pressure (Si-hydrolysis product)		0.021 Pa at 25°C (QSAR)		0.021 Pa at 25°C(QSAR)
Water solubility (parent)		Not relevant		36 mg/l (QSAR)
Water solubility (Si-hydrolysis product)		60 000 mg/l at 20°C (QSAR)		60 000 mg/l at 20°C (QSAR)

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

(3-Chloropropyl)diethoxymethylsilane was tested in an in vivo mouse micronucleus assay to EU Method B.12 (Mutagenicity - In Vivo Mammalian Erythrocyte Micronucleus Test) and in compliance with GLP.  No evidence for test substance mediated induction of micronuclei was observed.  It is noted that the PCE / NCE ratio was reduced in the test substance-treated animals indicating the test substance had reached the target tissue. It is concluded that the test substance is not genotoxic under the conditions of the test.

4. AE A.4 Bias that influences the prediction

Data on the source substance (3-chloropropyl)diethoxymethylsilane (CAS 13501-76-3) were read-across to the registered (target) substance dichloro(3-chloropropyl)methylsilane (CAS 7787-93-1). The source substance and the target substance have similar chemical structure and physico-chemical properties. Both substances hydrolyse to produce the same silanol hydrolysis product (3-chloropropyl)methylsilanediol. The non-silanol hydrolysis products are ethanol and hydrogen chloride respectively. Therefore, their toxicological properties are expected to be similar, with similar genotoxic effects. This is the closest structural analogues with available data. Moreover, the target substance would undergo rapid hydrolysis during in vivo testing producing hydrogen chloride which would cause corrosive local effects in the test animals. Therefore, testing the target substance is inappropriate.  

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

The source substance as well as the target substance hydrolyse in contact with water. Therefore, the test organism is expected to be exposed to their hydrolysis products, (3-chloropropyl)methylsilanediol and ethanol or hydrogen chloride respectively. For the source substance, exposure to the parent substance, (3-chloropropyl)diethoxymethylsilane, is also likely.

The non-silanol hydrolysis products hydrogen chloride and ethanol, are not genotoxic (OECD (2002), OECD 2004)).

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

The hypothesis is that the toxicology of the source and target substances is driven by the presence of the chloropropyl group. The hypothesis is supported by the results of profiling using the OECD QSAR Toolbox.  The profiles of the two substances are consistent. In particular, both the substances have alerts for mutagenicity and genotoxic carcinogenicity, which are related to the chloroalkyl group. The profiles for the hydrolysis products are consistent with each other and those of the parent substances.

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

Neither the target substance, dichloro(3-chloropropyl)methylsilane (CAS 7787-93-1), nor the source substance, (3-chloropropyl)diethoxymethylsilane (CAS 13501-76-3), have impurities of toxicological concern.

The test substance in the study with the source substance, (3-chloropropyl)diethoxymethylsilane (CAS 13501-76-3), has a purity of 99.1%.

The target substance, dichloro(3-chloropropyl)methylsilane (CAS 7787-93-1), 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

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

Justification for classification or non-classification

Based on the available in vitro and in vivo genotoxicity data, dichloro(3-chloropropyl)methylsilane is not classified for mutagenicity according to Regulation 1272/2008/EC.