Triethoxypropylsilane

Endpoint summary

Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

No measured data are available to assess the genotoxic potential of the registered substance, triethoxypropylsilane, however, reliable data are available for the following structural analogue substances: trimethoxypropylsilane (CAS 1067-25-0), trimethoxymethylsilane (CAS 1185-55-3), and triethoxyoctylsilane (CAS 2943-75-1).

WoE approach CAS 1067-25-0 and CAS 2943-75-1: Gene mutation (Bacterial reverse mutation assay / Ames test): negative with and without metabolic activation in Salmonella typhimurium strains: TA 98, TA, 100, TA 1535, TA 1537 and Escherichia coli strain: WP2 uvrA (according to OECD TG 471).

WoE approach CAS 1185-55-3 and CAS 2943-75-1: Mutagenicity in vitro in mammalian cells: positive with metabolic activation in mouse lymphoma L5178Y cells with the structural analogue substance trimethoxymethylsilane (CAS: 1185-55-3) and negative with and without metabolic activation in mouse lymphoma L5178Y cells with the structural analogue subtance triethoxyoctylsilane (CAS: 2943-75-1) (according to OECD TG 476).

WoE approach CAS 1185-55-3 and CAS 2943-75-1: Cytogenicity in in vitro mammalian cells: positive with metabolic activation in CHO cells with the structural analogue substance trimethoxymethylsilane (CAS 1185-55-3) and negative with and with metabolic activation in CHO cells with the structural analogue substance triethoxyoctylsilane (CAS 2943-75-1) (according to OECD TG 473).

Link to relevant study records

Reference

Reference 1

Endpoint:

in vitro gene mutation study in bacteria

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Remarks:

Summary of available data used for the endpoint assessment of the target substance

Adequacy of study:

key study

Justification for type of information:

Please refer to the attached justification below and the overall justification for grouping of substances attached in IUCLID Section 13.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Species / strain:

E. coli WP2 uvr A

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

no cytotoxicity nor precipitates, but tested up to recommended limit concentrations

Vehicle controls validity:

valid

Untreated negative controls validity:

not examined

True negative controls validity:

not examined

Positive controls validity:

valid

Species / strain:

S. typhimurium TA 1535

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

no cytotoxicity nor precipitates, but tested up to recommended limit concentrations

Remarks:

5000 μg/plate

Vehicle controls validity:

valid

Untreated negative controls validity:

not examined

True negative controls validity:

not examined

Positive controls validity:

valid

Species / strain:

S. typhimurium TA 1537

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

no cytotoxicity nor precipitates, but tested up to recommended limit concentrations

Vehicle controls validity:

valid

Untreated negative controls validity:

not examined

True negative controls validity:

not examined

Positive controls validity:

valid

Species / strain:

S. typhimurium TA 98

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

no cytotoxicity nor precipitates, but tested up to recommended limit concentrations

Vehicle controls validity:

valid

Untreated negative controls validity:

not examined

True negative controls validity:

not examined

Positive controls validity:

valid

Species / strain:

S. typhimurium TA 100

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

no cytotoxicity nor precipitates, but tested up to recommended limit concentrations

Vehicle controls validity:

valid

Untreated negative controls validity:

not examined

True negative controls validity:

not examined

Positive controls validity:

valid

A second source substance was tested in an Ames test with similar results.

Conclusions:

Interpretation of results:
negative with and without metabolic activation

Under test conditions, no mutagenic effect was observed for the source substances trimethoxy(propyl)silane (CAS: 1067-25-0) and triethoxyoctylsilane (CAS: 2943-75-1) in any of the test strains without and with metabolic activation. As explained in the analogue justification, it is considered that the target and the source substances are unlikely to lead to differences in genetic toxicity potential.

Reference 2

Endpoint:

in vitro cytogenicity / chromosome aberration study in mammalian cells

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Remarks:

Summary of available data used for the endpoint assessment of the target substance

Adequacy of study:

key study

Justification for type of information:

Please refer to the attached justification below and the overall justification for grouping of substances attached in IUCLID Section 13.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Species / strain:

Chinese hamster Ovary (CHO)

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

no cytotoxicity nor precipitates, but tested up to recommended limit concentrations

Vehicle controls validity:

valid

Untreated negative controls validity:

valid

True negative controls validity:

not examined

Positive controls validity:

valid

Additional information on results:

A further study on another source substance is available. In a valid study according to OECD 473 and under GLP, trimethoxy(methyl)silane (CAS: 1185-55-3) induced a statistically significant dose related increase in the number of structural aberrations in the presence of activation. It is concluded that trimethoxy(methyl)silane is positive for the induction of chromosome aberrations in the presence of activation under the conditions of the study.

Conclusions:

Interpretation of results: negative without metabolic activation, ambigous with metabolic acitivation

Reliable studies from two source substances are available. Triethoxyoctylsilane (2943-75-1) has been tested in a reliable in vitro cytogenetic assay according to OECD TG 473 and under GLP. The test substance did not induce statistically and biologically significant increases in the chromosomal aberration frequency of CHO (Chinese hamster ovary) cells. It is concluded that triethoxyoctylsilane is negative for the induction of chromosome aberrations (not clastogenic) in vitro under the conditions of the test.
In a valid study according to OECD 473 and under GLP, trimethoxy(methyl)silane (CAS: 1185-55-3) induced a statistically significant dose related increase in the number of structural aberrations in the presence of activation. It is concluded that trimethoxy(methyl)silane is positive for the induction of chromosome aberrations in the presence of activation under the conditions of the study.
In conclusion, the induction of chromosome aberrations with metabolic activation is ambigous whereas without metabolic activation it is found to be negative. As explained in the analogue justification, it is considered that the target and the source substances are unlikely to lead to differences in genetic toxicity potential.

Reference 3

Endpoint:

in vitro gene mutation study in mammalian cells

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Remarks:

Summary of available data used for the endpoint assessment of the target substance

Adequacy of study:

key study

Justification for type of information:

Please refer to the attached justification below and the overall justification for grouping of substances attached in IUCLID Section 13.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Species / strain:

mouse lymphoma L5178Y cells

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

cytotoxicity

Remarks:

with S9: growth inhibition starting at 1 mM (I) and 2.0 mM (II), but not dose-dependent; without S9: concentration related increase starting at 1.0 mM (I) and 0.1 mM (II)

Vehicle controls validity:

valid

Untreated negative controls validity:

not applicable

True negative controls validity:

not examined

Positive controls validity:

valid

Additional information on results:

A further study on another source substance is available.Trimethoxy(methyl)silane (CAS: 1185-55-3) has been tested in a valid study according to OECD 476 and under GLP. A dose-related increase in the mutant frequency was observed in the presence of metabolic activation, and relatively smaller than larger colonies were formed at the two highest concentrations. It is concluded that the substance is positive for mutagenicity to mammalian cells under the conditions of the test.

Conclusions:

Interpretation of results: ambigous

Reliable studies from two source substances are available. In a mutagenicity test, conducted according to OECD guideline 476 and GLP, under the test conditions reported, the source substance triethoxyoctylsilane is considered to be non-mutagnic in the in vitro mammalian cell gene mutation assay (thymidine kinase locus) in mouse lymphoma L5178Y cells. The second source substance trimethoxy(methyl)silane (CAS: 1185-55-3) has been tested in a valid study according to OECD 476 and under GLP. A dose-related increase in the mutant frequency was observed in the presence of metabolic activation, and relatively smaller than larger colonies were formed at the two highest concentrations. It is concluded that the substance is positive for mutagenicity to mammalian cells under the conditions of the test.
In conclusion, mammalian mutagenicity is considered ambigous. As explained in the analogue justification, it is considered that the target and the source substances are unlikely to lead to differences in genetic toxicity potential.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (positive)

Genetic toxicity in vivo

Description of key information

No measured data are available to assess the genotoxic potential of the registered substance, triethoxypropylsilane, however, reliable data are available for the following structural analogue substances: trimethoxymethylsilane (CAS 1185-55-3) and triethoxy(2,4,4-trimethylpentyl)silane (CAS 35435-21-3).

WoE approach CAS 1185-55-3 and CAS 35435-21-3: In vivo: Mouse erythrocyte micronucleus assay (oral gavage): negative (according to OECD TG 474).

Link to relevant study records

Reference

Endpoint:

in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Remarks:

Summary of available data used for the endpoint assessment of the target substance

Adequacy of study:

key study

Justification for type of information:

Please refer to the attached justification below and the overall justification for grouping of substances attached in IUCLID Section 13.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Sex:

male/female

Genotoxicity:

negative

Toxicity:

yes

Remarks:

clinical signs suggesting systemic toxicity observed

Vehicle controls validity:

valid

Negative controls validity:

not applicable

Positive controls validity:

valid

Additional information on results:

A further study on another source substance is available. Triethoxy(2,4,4-trimethylpentyl)silane (CAS: 35435-21-3) has been tested in a reliable in vivo mouse micronucleus assay according to OECD 474 and under GLP. No statistically significant increase in the number of cells with micronuclei was observed after oral administration of the limit dose of 2000 mg/kg bw. Appropriate positive and vehicle controls were included and gave expected results. The PCE / NCE ratio was slightly affected in treated males, indicating that the test item was of low toxicity to the target tissue. It is concluded that the test substance is negative for the induction in micronuclei under the conditions of the test.

Conclusions:

Interpretation of results: negative

Reliable studies from two source substances are available. Trimethoxy(methyl)silane (CAS: 1185-55-3) has been tested in a valid study according to OECD 474 and under GLP. No increase in the indicence of micronucleated PCE was observed resulting from exposure to the test substance by oral gavage up to limit concentrations. It is concluded that the test substance is negative for the induction of micronuclei under the conditions of the test. Clinical signs of toxicity were observed that suggested systemic availability, though no toxicity to target tissue was observed. Triethoxy(2,4,4-trimethylpentyl)silane (CAS: 35435-21-3) has been tested in a reliable in vivo mouse micronucleus assay according to OECD 474 and under GLP. No statistically significant increase in the number of cells with micronuclei was observed after oral administration of the limit dose of 2000 mg/kg bw. Appropriate positive and vehicle controls were included and gave expected results. The PCE / NCE ratio was slightly affected in treated males, indicating that the test item was of low toxicity to the target tissue. It is concluded that the test substance is negative for the induction in micronuclei under the conditions of the test.
In conclusion, mammalian mutagenicity is considered negative. As explained in the analogue justification, it is considered that the target and the source substances are unlikely to lead to differences in genetic toxicity potential.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (negative)

Additional information

Studies were chosen as key when the available study was of relevance and of sufficient quality for classification and labelling and for risk assessment.

No measured data are available to assess the genetic toxicity potential of the registered substance, triethoxypropylsilane. However, an OECD 471 and an OECD 473 with the registered substance are on-going, but the results will not be available for this current dossier update. Therefore as an interim measure, the hazard assessment was performed based on available data for the structural analogue substances, trimethoxy(propyl)silane (CAS: 1067 -25 -0), triethoxyoctylsilane (CAS: 2943-75-1), trimethoxymethylsilane (CAS: 1185-55-3) and triethoxy(2,4,4-trimethylpentyl)silane (CAS: 35435-21-3). In accordance with Regulation (EC) No. 1907/2006 Annex XI, 1.5 “Grouping of substances and read across” and following the Read across assessment framework (RAAF, ECHA 2017) read across from an analogue substance has been applied to support the human health hazard assessment of tritethoxy(propyl)silane. Details on read across justifications can be found in the attached justification in the respective target entry and in the overall justification for grouping of substances attached in IUCLID Section 13.

 

Bacterial mutagenicity in vitro:

Key in vitro bacterial reverse mutation studies are available for the structural analogue substances trimethoxypropylsilane and triethoxyoctylsilane in compliance with GLP and according to OECD TG 471 (Huls AG,1996 and Bioservices, 1998). No increase in the frequency of revertants relative to control was observed with or without metabolic activation at any concentration, in any of the test organisms in both studies with the structural analogue substances. The findings of the initial plate incorporation assays were confirmed in the repeat pre-incubation assays in both studies. It is therefore concluded that both structural analogue substances are negative for mutagenicity to bacteria under the conditions of the tests. This therefore supports the lack of bacterial mutagenicity potential of the registered substance, triethoxypropylsilane.

 

Mammalian Mutagenicity in vitro:

Key in vitro mammalian mutagenicity studies in mouse lymphoma L5178Y cells are availablefor the structural analogue substances trimethoxymethylsilane and triethoxyoctylsilane, respectively, according to OECD 476 and in compliance with GLP. A dose-related increase in the mutant frequency was observed in the presence of metabolic activation, and relatively smaller than larger colonies were formed at the two highest concentrations of trimethoxymethylsilane. It is concluded that trimethoxymethylsilane is positive for mutagenicity to mammalian cells under the conditions of the test (TNO, 2002). With triethoxysilane, no biologically relevant increase in mutation rate was found in mouse lymphoma L5178Y cells with or without metabolic activation in either the initial or the repeat experiment, up to limit and cytotoxic concentrations. The global evaluation factor was not exceeded at any concentration. In addition, colony sizing showed no clastogenic effects in either experiment. It is concluded that triethoxyoctylsilane (CAS: 2943 -75 -1) is negative for mutagenicity to mammalian cells under the conditions of the test (BSL, 2012).

 

Cytogenicity in vitro: 

Key in vitro cytogenicity studies in Chinese hamster ovary (CHO) cells are available for the structural analogue substances trimethoxymethylsilane and triethoxyoctylsilane, respectively, in compliance with GLP and according to OECD TG 474. Trimethoxymethylsilane induced a statistically significant dose related increase in the number of structural aberrations in the presence of metabolic activation. It is concluded that trimethoxymethylsilane is positive for the induction of chromosome aberrations in the presence of metabolic activation under the conditions of the study (Dow, 2004). However, triethoxyoctylsilane did not induce statistically and biologically significant increases in the chromosomal aberration frequency of CHO cells. It is concluded that triethoxyoctylsilane is negative for the induction of chromosome aberrations (not clastogenic) in vitro under the conditions of the test (MA Bioservices 1997).

 

In vivo:

No measured data are available to assess the in vivo cytogenicity potential of the registered substance, triethoxypropylsilane, however reliable data are available for the structural analogue substances, triethoxy(2,4,4-trimethylpentyl)silane (CAS: 35435-21-3) and trimethoxymethylsilane (CAS: 1185-55-3). Since all three parent substances hydrolyse in contact with water to produce silanol hydrolysis products which are structurally related, read-across between the substances is deemed to be appropriate.

 

Key in vivo mouse erythrocyte micronucleus studies are available for the structural analogue substances triethoxy(2,4,4-trimethylpentyl)silane and trimethoxymethylsilane conducted according to OECD TG 474 and in compliance with GLP. No statistically significant increase in the number of cells with micronuclei was observed after oral administration of the limit dose of 2000 mg/kg bw with the structural analogue triethoxy(2,4,4-trimethylpentyl)silane (Bioservice 2001). This lack of clastogenic effect was also confirmed with the other structural analogue substance trimethoxy(methyl)silane. No increase in the incidence of micronucleated PCE resulting from exposure up to the limit concentration of 2000 mg/kg bw was observed. Clinical signs of toxicity were evident that suggested systemic availability, though no toxicity to target tissue was observed (RTC, 2002). The results of both studies are in agreement of the lack of cytogenicity potential and thereby supporting the lack of cytogenicity potential of the registered substance, triethoxypropylsilane.

 

The results of testing in mammalian cells with the structural analogue substance trimethoxymethylsilane showed evidence of genetic toxicity in the presence of metabolic activation. There was evidence for clastogenicity (causing chromosomal aberrations) in the presence of metabolic activation in vitro. An in vivo study did not support this finding, so it is concluded that the in vitro result does not reflect an ability to cause chromosome aberrations in vivo. Clinical signs of toxicity were observed that suggested systemic availability, although it is noted that the test substance did not affect the NCE/PCE ratio. Therefore, with regard to the presented data, the registered substance is assumed to have neither mutagenic nor cytogenic potential.

Justification for classification or non-classification

The available in vitro and in vivo genotoxicity data is reliable and suitable for classification. Based on this data, classification for mutagenicity according to Regulation (EC)1272/2008 is not warranted.