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Description of key information

Skin Sensitization (OECD 406, WoE), guinea pig: not sensitizing (RA from CAS 2031-67-6)

Skin Sensitization (OECD 406, WoE), guinea pig: sensitizing (RA from CAS 1185-55-3)

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records
Reference
Endpoint:
skin sensitisation: in vivo (non-LLNA)
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:
weight of evidence
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:
read-across source
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Reading:
1st reading
Hours after challenge:
24
Group:
test group
Dose level:
50% both induction and challenge
No. with + reactions:
0
Total no. in group:
20
Remarks on result:
other: CAS 1185-55-3, Toxikon, 2013
Reading:
2nd reading
Hours after challenge:
48
Group:
test group
Dose level:
50% both induction and challenge
No. with + reactions:
0
Total no. in group:
20
Remarks on result:
other: CAS 1185-55-3, Toxikon, 2013
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
50%
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
other: CAS 1185-55-3, Toxikon, 2013
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
50%
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
other: CAS 1185-55-3, Toxikon, 2013
Reading:
1st reading
Hours after challenge:
24
Group:
positive control
Dose level:
0.1%
No. with + reactions:
5
Total no. in group:
5
Remarks on result:
other: CAS 1185-55-3, Toxikon, 2013
Reading:
2nd reading
Hours after challenge:
48
Group:
positive control
Dose level:
0.1%
No. with + reactions:
5
Total no. in group:
5
Remarks on result:
other: CAS 1185-55-3, Toxikon, 2013

A second study for skin sensitisation found the structural analogue substance CAS 1185 -55 -3 is sensitising in a study conducted according to an OECD 406 and in compliance with GLP (Harlan 2009). The results of the study are deemed equivocal as a result of methodological problems; the irritation potential reported is inconsistent between experiments and the negative control animals were seen to have positive skin reactions. The study is assigned reliability 3 on the basis that the methodological issues reduce its reliability.

It is also noted that the the study by Toxikon (2013) with CAS 1185 -55 -3 which found the test material not sensitising, used a higher concentration of test material (50% at induction and challenge doses), than the study by Harlan (2009) which concluded the test material to be a sensitiser. This adds to the weight of evidence that the result by Toxikon (2013) is more accurate representation of the true sensitisation potential of the registered substance.

In a key guinea pig maximisation study for CAS 2031-67-6 conducted in compliance with GLP and according to OECD TG 406, triethoxy(methyl)silane was found to be a non-sensitiser.

Interpretation of results:
other: CLP/EU GHS criteria are not met, no classification required according to Regulations (EC) No 1272/2008.
Conclusions:
Reliable studies from two source substance are availabe to evaluate the skin sensitisation potential. Both source substances are shown to be not skin sensitising.
As explained in the analogue justification, it is considered that the target and the source substances are unlikely to lead to differences in skin sensitisation potential.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

No data on skin sensitisation is avaiable for diethoxy(dimethyl)silane (CAS 78 -62 -6).Therefore, the risk assessment was performed based on the available data from the source substance trimethoxy(methyl)silane (CAS 1185 -55 -3) and triethoxy(methyl)silane (2031 -67 -6). 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 analogue substances has been applied to support the human health hazard assessment of diethoxy(methyl)silane (CAS 78 -62 -6).

For assessment of skin sensitisation properties of Diethoxy(dimethyl)silane (CAS 78-62-6) a weight of evidence approach was applied using the structural analogues Triethoxy(methyl)silane (CAS 2031-67-6) and Trimethoxy(methyl)silane (CAS 1185-55-3).

 

Two recent studies for CAS 1185-55-3 conducted according to the appropriate OECD guideline were available for review for skin sensitisation (Harlan 2009, Toxikon 2013). Methodological problems were evident in the study by Harlan (2009). The weight of evidence from the skin sensitisation study by Toxikon (2013) and Wacker (2017) support the conclusion of the registered substance not being a sensitiser.

 

The study by Toxikon (2013) was conducted according to an appropriate OECD test guideline, with acceptable restrictions. The restriction was that the starting concentration selected for induction was not the highest to cause mild-to-moderate skin irritation as required by OECD test guideline 406. The highest, non-irritating concentration used in the preliminary test (test article and PEG at 50% dilution) was selected for use in the induction and challenge phases. No positive skin reactions were seen in any of the test animals, and appropriate responses were evident in all the control animals. The study concluded that the test material was not sensitising to guinea pig skin.

 

A second study for skin sensitisation found the test material sensitising in a study conducted according to an OECD 406 and in compliance with GLP (Harlan 2009). The results of the study are deemed equivocal as a result of methodological problems; the irritation potential reported is inconsistent between experiments and the negative control animals were seen to have positive skin reactions. The study is assigned reliability 3 on the basis that the methodological issues reduce its reliability.

 

The details of the study by Harlan (2009) are summarised as follows; trimethoxy(methyl)silane at 25% in PEG 300 was found non-irritating in two prescreen experiments as well as in the second control group. Skin reactions were observed in the test and control group in the first challenge when treated at 25% in PEG 300. At second challenge, local skin reactions were observed in test animals when the test substance was applied at the concentration of 25% in PEG 300 but not at the item concentration of 15% in PEG 300. The presence of skin reactions of grade 1 in 30% and 20% of the test animals after 24 and 48h respectively in the second challenge and absence of any evidence of irritation in the second control group support the conclusion that the skin reactions in the test animals are indicative of sensitization. The equivocal first challenge data followed by positive re-challenge data, lead the study authors to the overall conclusion that the test material is sensitising. However, the reviewer considers the result ambiguous due to the methodological issues in the study.

 

It is also noted that the the study by Toxikon (2013) which found the test material not sensitising, used a higher concentration of test material (50% at induction and challenge doses), than the study by Harlan (2009) whch concluded the test material to be a sensitiser. This adds to the weight of evidence that the result by Toxikon (2013) is more accurate representation of the true sensitisation potential of the registered substance.

 

In addition to the in vivo experimental animal data, two producers of trimethoxy(methyl)silane have provided statements which confirm that there have been no cases of skin sensitisation amongst workers during more than 20 years of manufacture.

 

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 customers 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(methyl)silane.

 

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

 

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 potection 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 2002) 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 2002). 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).

 

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.

 

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.

In a key guinea pig maximisation study for CAS 2031-67-6 conducted in compliance with GLP and according to OECD TG 406, triethoxy(methyl)silane was found to be a non-sensitiser. A group of ten male and ten female guinea pigs was dosed with multiple intradermal injections on day 0 following a topical application on day 7 in order to investigate sensitisation potential of triethoxy(methyl)silane. The topical induction consisted of a 48 hour occluded dermal exposure to 0.5 ml of the test substance in a 50% (v/v) solution in sterile codex liquid paraffin. Eleven days after topical induction, challenge dosing for detection of sensitisation was performed. For challenge dosing, an essentially non-irritating concentration (10% (v/v)) of the test material was applied under occlusion for 24 hours. Although macroscopic examination showed grade 1 erythema/oedema in 3 females 48 h after challenge subsequent histopathological examinations did not reveal any lesion of delayed hypersensitivity in those animals. Including these 3 females the sensitisation index was calculated to be 15% for the test group following rechallenge. Appropriate positive and negative controls gave expected results (Hazleton, 1992c).

In the absence of any chemical structural features indicative of sensitising potential for the submission substance and the number of negative results in tests with the other members of this group, it is concluded in a weight of evidence approach that substances of this group are not sensitising. Therefore the read-across to trimethoxy(methyl)silane and triethoxy(methyl)silane is appropriate.

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

The available data on skin sensitisation of the structural analogue substances, trimethoxy(methyl)silane (CAS 1185 -55 -3) and triethoxy(methyl)silane (CAS 2031-67-6), do not meet the criteria for classification according to Regulation (EC) 1272/2008 or EU Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification of the registered substance.