Registration Dossier

Administrative data

Description of key information

Five in vivo skin sensitisation studies in guinea pigs conducted according to the Buehler and Guinea Pig Maximisation Test protocols form a weight of evidence for the skin sensitising potential of trimethoxy(vinyl)silane. Three Guinea Pig Maximisation Tests and one Buehler test gave clear negative results (WIL, 1999; Huls, 1994; WIL, 1996 and WIL 2000). A second Buehler test gave a positive result (Huls, 1993).


Three trimethoxy(vinyl)silane manufacturers have provided statements which confirm that there have been no cases of skin sensitisation amongst workers during more than 40 years of manufacture (see Section 7.10.4) (Wacker, 2017; Momentive, 2017; Evonik Degussa, 2017).


Key value for chemical safety assessment

Skin sensitisation

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

There are five existing in vivo skin sensitisation studies in guinea pigs conducted according to the Buehler and Guinea Pig Maximisation Test protocols that form a weight of evidence for the skin sensitising potential of trimethoxy(vinyl)silane.

Three Guinea Pig Maximisation Tests and one Buehler test gave clear negative results (WIL, 1999; Huls, 1994; WIL, 1996 and WIL 2000). A second Buehler test gave a positive result (Huls, 1993).

The most recent test conducted for skin sensitising potential of trimethoxy(vinyl)silane found the test material not sensitising in a Guinea Pig Maximisation Test, was conducted according to current OECD guideline and in compliance with GLP (WIL 2000). The reported sensitisation incidence index for the test group was 0% (0/20) following challenge. The study concluded that the test material is not a skin sensitiser in the guinea pig.

A second reliable Guinea Pig Maximisation Test with the registered substance (Huls, 1994) showed irritant reactions evident at induction; however, no skin reactions were present at challenge and the study concluded the test material not to be a sensitiser under the conditions of the test.

In the third reliable Guinea Pig Maximisation Test with the hydrolysis product of trimethoxy(vinyl)silane, vinylsilanetriol (WIL, 1996) the sensitization incidence index for the test group was calculated to be 5% (1/20) following challenge with 10% test material in acetone. There were no sensitization reactions in the test group following rechallenge with 10% test material. The sensitization incidence index for the test group was 0%. Vehicle control sites on the test group animals treated with 100% acetone displayed no evidence of sensitization at challenge. The study concluded the test substance to be a non-sensitiser. Due to the rapid hydrolysis of trimethoxyvinylsilane (half-life less than 0.1 hour at physiological pH) testing of the hydrolysis product is considered representative of the skin sensitisation potential of trimethoxy(vinyl)silane.

In a reliable Buehler test (WIL, 1999) which was conducted according to current guideline and in compliance with GLP, at the first challenge, 1/20 animals showed a reaction in response to the test material. However, at rechallenge, no reactions were evident. The test material was concluded to be non-sensitising under the conditions of the study.

In a second reliable Buehler Test (Huls, 1993) the registered substance (but not controls) showed irritant reactions evident at induction, and positive skin reactions were present at challenge in 13/20 test animals and 0/10 control animals. The study concluded the test material to be a sensitiser under the conditions of the test.

The weight of evidence from five in vivo skin sensitisation studies in guinea pigs according to the Buehler and the maximisation test protocol suggests that trimethoxy(vinyl)silane should not be classified as skin sensitiser. This is due to the consistent absence of a skin sensitisation potential of trimethoxy(vinyl)silane in four animal studies: three GPMTs and one Buehler assay; versus a positive finding in a single Buehler test.

In addition to the in vivo experimental animal data, three producers of trimethoxy(vinyl)silane have provided statements which confirm that there have been no cases of skin sensitisation amongst workers during more than 40 years of manufacture (Wacker, 2017; Momentive, 2017, Evonik Degussa, 2017).

These data included internal information from: relevant plants, number of employees, exposure description; medical surveillance, regular health checks (especially concerning skin status) already performed on employees of the relevant plants, information from the Network of Departments of Dermatology for the surveillance and scientific evaluation of contact allergies, information from Employer's liability insurance association (BG Bau), information from customer and a comprehensive literature search there have been no cases of skin sensitisation during more than 20 years of production, handling and use of trimethoxy(vinyl)silane.

There is therefore no evidence that this substance causes skin sensitisation under relevant exposures in workers.

Additional testing to further confirm the negative conclusion is not required as there are already four reliable in vivo tests showing negative results compared with one positive result. When comparing outcomes from a Buehler test with those of the GPMT, the intradermal induction step increases the GPMT’s effectiveness in triggering a sensitisation response and makes, along with the longer induction patch application (48 hrs in the GPMT vs 6 hrs in the Buehler assay), the GPMT is more sensitive compared to the Buehler test. This is scientifically widely recognised and the reason why the regulatory community prefers the GPMT over the Buehler test for skin sensitisation hazard identification purposes. This added sensitivity gives extra weight to the negative findings in the three GPMTs.

There is also a question regarding the reliability of the LLNA for silicon-based substances, which means that conducting such a study will not add weight to the database for a positive or negative outcome and therefore will not make any contribution to the protection of human health. The current accepted and preferred method for skin sensitisation testing according to the REACH legislation (EC no 1907/2006) and CLP Regulation (EC No 1272/2008) is the murine local lymph node assay (LLNA). A validated test method, OECD TG 429 (OECD 2010) is available for the LLNA. The guideline acknowledges the limits of the LLNA, and states that there are instances where ‘test substance classes or substances containing functional groups shown to act as potential confounders’ make the use of guinea pig tests more appropriate. It is concluded that the LLNA is not applicable where the properties of the test material cause interference in the accuracy of the LLNA (OECD 2010). The statement in the OECD TG 429 is given with reference to the findings of Basketter et al. (2009a), who demonstrated false positives in silicone based substances which had previously been demonstrated to be non-sensitisers in the guinea pig maximisation test (GPMT). The importance of available evidence from guinea pig results, consideration of chemical reactivity, epidermal bioavailability and clinical and experimental human data are emphasised as central to reaching appropriate regulatory decisions for substances which have been shown to fall outside the specificity of the LLNA (Basketter et al., 2009b). The non-applicability of the LLNA for silicone based substances has also been demonstrated by Petry et al. (2012). The sensitisation potential of polyfunctional silicone materials was tested in a comparative study investigating the GPMT and the LLNA assays, which found the five tested substances to be negative in the GPMT whereas they were concluded to be weak to moderate skin sensitisers in the LLNA (Petry et al., 2012).

References:

 

Basketter D, Ball N, Cagen S, Carillo JC, Certa H, Eigler D, Garcia C, Esch H, Graham C, Haux C, Kreiling R, Mehling A (2009a). Application of weight of evidence approach to assessing discordant sensitisation datasets: implication for REACH. Reg. Toxicol. Pharmacol.,55, 90-96.

 

Basketter D, McFadden JF, Gerberick F, Cockshott A, Kimber I (2009b) Nothing is perfect, not even the local lymph node assay: a commentary and the implications for REACH.Contact Dermatitis, 60, 65-69.

OECD (2010). OECD Guidelines for the Testing of Chemicals, Section 4. Health Effects, Test No. 429: Skin Sensitisation. Publication date: 23 July 2010

 

Petry, T., Bosch, A., Coste, X., Dupuis, V., Eigler, D., Germain, P. (2012). An assessment of the skin sensitisation hazard of a group of polyfunctional silicones using a weight of evidence approach. Regulatory Toxicology and Pharmacology, 64, 305-314.

 

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

The weight of evidence from five in vivo skin sensitisation studies in guinea pigs conducted according to the Buehler and Guinea Pig Maximisation Test protocols, together with over 20 years of occupational medical data, literature search results and data from an insurance association, suggests that trimethoxy(vinyl)silane does not require classification according to Regulation (EC) 1272/2008.