Registration Dossier

Administrative data

Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

Gene mutation (Bacterial reverse mutation assay / Ames test): negative with and without activation in all strains tested (OECD TG 471)

Cytogenicity in mammalian cells: Negative without activation, positive structural, negative numerical with activation (OECD TG 473)

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (positive)

Genetic toxicity in vivo

Description of key information

Micronucleus assay inhalation study in rat: Negative (similar to OECD TG 474)

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (negative)

Additional information

No genotoxicity data are available for the registered substance, hexachlorodisilane. The substance reacts vigorously in contact with water and with solvents recommended in the test guideline. A statement from the testing laboratory regarding the conduct of genetic toxicity experiments with the related substance, decachlorotetrasilane, is attached as supporting information. The registration substance behaves in an identical manner to that described. The genotoxic potential of hexachlorodisilane is therefore assessed on the basis of reliable data for the surrogate substances, trimethoxysilane and trichlorosilane.

The read-across substance trimethoxysilane (CAS 2487-90-3) has been tested for bacterial mutagenicity according to OECD 471 (Microbiological Associates, 1995) and no increase in the number of revertants was observed with or without metabolic activation in either the initial or the repeat assay using Salmonella typhimurium strains TA98, TA100, TA1535, TA1537 and E. coli WP2 uvrA using the preincubation method. It was therefore concluded that trimethoxysilane was negative for mutagenicity to bacteria under the conditions of the study. A second read-across substance trichlorosilane (CAS 10025-78-2) was tested according to a protocol that is similar to OECD 471 and no test substance-related increase in the number of reversions was observed when tested to limit concentrations in Salmonella typhimurium strains TA98, TA100, TA1535, TA1537 or TA1538, with and without metabolic activation, the substance was considered to be non-mutagenic under the conditions of the test (Dow Corning Corporation, 1981).

Trimethoxysilane, when tested in a mammalian cytogenicity study according to OECD 473 (BioReliance, 2007), was found to be positive for the induction of structural, but negative for the induction of numerical, chromosome aberrations in CHO cells with metabolic activation (S9-activated) at the highest dose tested. However, the evidence for the clastogenicity of trimethoxysilane was not confirmed when it was tested in an in vivo micronucleus assay according to a protocol similar to OECD 474 (Dow Corning, 1982). Trimethoxysilane did not induce chromosome breakage or act as a spindle poison in the rodent micronucleus assay even when the animals were exposed to lethal concentrations and was therefore considered to be negative for clastogenicity in Sprague-Dawley rats under the conditions of the test.

No data are available for mutagenicity to mammalian cells. However, as the substance tested was positive in the in vitro cytogenicity assay, in vitro testing for mutagenicity to mammalian cells is not required.

Read-across justification

Non-testing methods including read-across from surrogate substances are able to provide information on mutagenic toxicity (REACH Guidance part 07a, R.7.7.3). In the case of genetic toxicity the presence or absence of functional groups that are known to be related to genetic toxicity is considered important, as the presence or absence of reactive groups and molecular substructures is associated with mutagenic and carcinogenic properties of chemicals (Benigni and Bossa, 2006). Consideration is therefore given to the structural similarity, particularly presence or absence of structural alerts for genetic toxicity, when selecting surrogate substances for genetic toxicity endpoints.

Read-across hypothesis

Trichlorosilane is a close structural analogue of hexachlorodisilane; trichlorosilane has one hydrogen and three chlorine atoms bound to silicon, hexachlorodisilane has two silicon atoms each with three chlorine atoms. Trimethoxysilane is a trialkoxysilane. All three substances hydrolyse in contact with water generating the relevant silanol and then monosilicic acid (which will condense to form amorphous polysilicic acid at concentrations above approximately 100 -150 mg/l). Hydrolysis is likely to occur under the conditions of the studies and also in vivo. The non-silanol products of hydrolysis are methanol and hydrogen chloride, which are not expected to contribute to genetic toxicity, as explained below.

Methanol has been tested in vitro in bacterial and mammalian mutagenicity assays and in micronucleus and chromosome aberration assays. The majority of the results were negative (OECD, 2004). In the ECHA disseminated dossier for methanol, the conclusions of all the key in vitro studies and the weight of evidence of the in vivo assays are negative.

Hydrogen chloride gave negative results in the most reliable of the bacterial mutagenicity studies. Positive results were obtained in mutagenicity and cytogenicity assays using mammalian cells (OECD, 2002; ECHA disseminated dossier for hydrogen chloride). The positive results were associated with decrease in pH, and it is considered that the positive results were likely to have been caused by reduced pH. Positive results caused by high or low pH effects are considered not to be relevant for in vivo situations (ECHA 2012), and testing should be carried out at neutral pH.

Hexachlorodisilane hydrolyses very rapidly with a hydrolysis half-life of approximately 5 seconds at 25°C and pH 4, 7 and 9 (analogue read-across). Trichlorosilane hydrolyses very rapidly, with a hydrolysis half-life < 0.3 minutes at 25°C and pH 4, 7 and 9 (read-across from methyltrichlorosilane) and trimethoxysilane also hydrolyses very rapidly, with a hydrolysis half-life of < 0.3 minutes at pH 4, 7 and 9 and 2°C (measured).

Analogue approach justification

(a) Structural similarity

Trichlorosilane is a close structural analogue of hexachlorodisilane; trichlorosilane has one hydrogen and three chlorine atoms bound to silicon, hexachlorodisilane has two silicon atoms each with three chlorine atoms. Trimethoxysilane is a trialkoxysilane. All three substances hydrolyse in contact with water generating the relevant silanol and then monosilicic acid (which will condense to form amorphous polysilicic acid at concentrations above approximately 100 -150 mg/l).

(b) Structural alerts for genotoxicity

Hexachlorodisilane, trichlorosilane and trimethoxysilane do not include structural alerts for genotoxicity.

(c) Lack of genetic toxicity (other than pH effects) of non-silanol products of hydrolysis.

Trimethoxysilane and trichlorosilane were chosen as read-across substances as they form a similar hydrolysis product as that formed by the registered substance, and none of these substances has any functional groups that are associated with genetic toxicity. The genetic toxicity data available for these and other structural analogue substances are summarised in the table below. Amorphous polysilicic acid is among the substances included in the table, as supporting evidence that production of inorganic silica does not increase the potential for genotoxicity of the registered substance. Additional information is given in a supporting report (PFA, 2013aa) attached in Section 13.

Name

Bacterial Mutagenicity

In Vitro Mammalian Cytogenicity

In Vitro Mammalian Mutagenicity

In Vivo Genotox

10025-78-2

Trichlorosilane

Negative

(Dow Corning Corporation, 1981)

-

-

-

2487-90-3

Trimethoxysilane

Negative

(Microbiological Associates, 1995)

Positive (+MA)

(BioReliance, 2007)

 

Negative in micronucleus

(Dow Corning Corporation, 1982)

998-30-1

Triethoxysilane

 

 

Negative

(Dow Corning Corporation, 1995)

 

681-84-5

Tetramethyl orthosilicate

[tetramethoxysilane]

Negative

Safepharm Laboratories (2001)

-

-

Negative in micronucleus

Dow Corning Corporation (1987)

78-10-4

Tetraethyl orthosilicate

[tetraethoxysilane]

Negative

Hüls AG(1993)

Negative

BioReliance(2002)

Negative

Bushy Run Research Centre(1981)

-

682-01-9

Tetrapropyl orthosilicate

[tetrapropoxysilane]

Negative

LPT(2002)

-

-

-

 N/a

 Synthetic amorphous silica (SAS) [polysilicic acid]

 Negative OECD (2004)

 NegativeOECD (2004)

 Negative OECD (2004)

Negative in chromosome aberration assay

References

Benigni and Bossa (2006). Current Computer-Aided Drug Design 2, (2), 169-176.

BioReliance (2002).In Vitro Mammalian Chromosome Aberration Test. Test article Tetraethyl orthosilicate CAS 87-10-4. Testing laboratory: BioReliance 9630 Medical Center.

BioReliance (2007). In Vitro Mammalian Chromosome Aberration test with Trimethoxysilane (CAS Number 2487-90-3). Testing laboratory: BioReliance 9630 Medical Center Drive, Rockville, Maryland 20850 USA. Owner company: SEHSC. Study number: AB34WR.331. BTL. Report date: 2007-01-17.

Bushy Run Research Centre (1981). Tetraethyl orthosilicate:in vitromutagenesis studies. Testing laboratory: Bushy Run Research Centre 4 Mellon Road Export Pennsylvania 15632 USA. Report no.: 44-68. Owner company: Momentive. Report date: 1981-06-28.

Dow Corning Corporation (1981). Mutagenicity Evaluation of Dow Corning Z-1210 Silane in the Ames bacterial assay. Testing laboratory: Dow Corning Toxicology Department. Report no.: I-0005-0847. Owner company: Dow Corning Corporation. Report date: 1981-04-06.

Dow Corning Corporation, (1982). Evaluation of Trimethoxysilane via acute vapour inhalation in the rodent micronucleus assay. Testing laboratory: Dow Corning toxicology department. Owner company: Dow Corning Corporation. Company study No.: 82-0241-FGM. Report date: 1982-06-29.

Dow Corning (1987). Acute Inhalation Toxicity. Testing laboratory: Dow Corning Corporation, Midland, MI. Report no.: Internal Report No. 1987-I0005-1665.

Dow Corning Corporation (1995). L5178Y/TK+/- Mouse Lymphoma Mutagenesis Assay. Testing laboratory: Dow Corning Corporation Health and Environmental Sciences, Dow Corning Corporation, 2200 West Salzburg Road, Auburn, MI 48611. Report no.: 1995-I0000-39993. Owner company: Dow Corning Corporation. Study number: 151-1193. Report date: 1995-01-05.

Hüls AG (1993a). Determination of mutations caused by DYNASIL A in Salmonella/microsome test based on Ames mutation test under Guideline 84/449/EEC B. 14. Certified translation from German. Testing laboratory: Hüls AG, Testing institute for Biology, building 9015 Postfach 13-20 D-4370 Marl Germany. Report no.: 93-0195-DGM, final report AM-93-3. Report date: 1993-03-26.

LPT(2002). Mutagenicity study of silan TPN in the Salmonella typhimurium reverse mutation assay (in vitro). Testing laboratory: LPT. Report no.: 15425/19/02. Owner company: Wacker. Report date: 2002-09-24.

Microbiological Associates (1995). Y-4398: Salmonella/Escherichia coli Preincubation Mutagenicity Assay with a Confirmatory Assay. Testing laboratory: Microbiological Associates, Inc. Rockwell MD 20850 USA. Owner company: Momentive. Study number: G95AD27.503001. Report date: 1995-04-17.

OECD (2002): SIDS Initial Assessment Report for SIAM 15, Boston, USA, 22-25 October 2002: hydrogen chloride, CAS 7647-01 -0.

OECD SIDS (2004). Soluble Silicates. CAS No. 1344-09-8, 6834-92-0, 10213-79-3, 13517-24-3 and 1312-76-1. SIDS Initial Assessment Report for SIAM 18 Paris, France 20-23 April, 2004.

OECD (2004a): SIDS Initial Assessment Report for SIAM 19, Berlin, Germany, 18-20 October 2004, Methanol, CAS 67-56-1.

Safepharm Laboratories (2001). KBM-04: Reverse mutation assay 'Ames Test' using Salmonella typhimurium and Escherichia coli. Testing laboratory: Safepharm Laboratories Ltd, PO Box No.45, Derby, DE1 2BT, UK. Owner company: Shin Etsu Chemical Co Ltd. Study number: 763/189. Report date: 2001-03-26.


Justification for selection of genetic toxicity endpoint
The studies on the surrogate substances were conducted according to appropriate OECD guidelines and in compliance with GLP.

Justification for classification or non-classification

Based on the available in vitro and in vivo information from the read-across substances trimethoxysilane (CAS number 2487-90-3) and trichlorosilane (CAS 10025-78-2), the registered substance, hexachlorodisilane does not require classification for mutagenicity according to Regulation (EC) No 1272/2008.