3-[3,3,3-trimethyl-1,1-bis[(trimethylsilyl)oxy]disiloxanyl]propyl methacrylate

Endpoint summary

Description of key information

The key in vivo skin sensitisation study was read-across from (1,1,3,3-tetramethyldisiloxane-1,3-diyl)dipropane-1,3-diyl dimethacrylate (CAS 18547-93-8). In the key in vivo skin sensitisation study, conducted according to an appropriate OECD test guideline and in compliance with GLP, the test material (1,1,3,3-tetramethyldisiloxane-1,3-diyl)dipropane -1,3-diyl dimethacrylate was concluded to be not sensitising to skin (Eurofins, 2017).

Key value for chemical safety assessment

Skin sensitisation

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

The key skin sensitisation study, conducted according to OECD TG 406, and in compliance with GLP, reports the test substance, (1,1,3,3-tetramethyldisiloxane-1,3-diyl)dipropane-1,3-diyl dimethacrylate, (CAS 18547-93-8) to be not sensitising to guinea pig skin (Eurofins, 2017).

 

At induction, 3 epicutaneous occlusive applications of 100% test material were performed to the flanks of 20 test guinea pigs. The same procedure was repeated 3 times for 3 consecutive weeks. The dressing patch was held in contact with the skin for 6 hours. Dermal reactions were examined after each application.

 

At challenge (two weeks after last topical induction application), 0.5 mL of 25 % test material in acetone were applied topically to the right flank of each test animal, kept in contact with the skin for 6 hours under occlusive dressing. Dermal reactions were evaluated at 24 and 48 hours after removal of the test material. Changes in body weight were recorded prior to administration and at the end of the observation period. All animals were observed for signs of toxicity at least once daily during the test period.

There was no evidence of sensitisation as the percentage of sensitised animals was 5%. All animals of both groups survived throughout the test period. No signs of toxicity were recorded. The body weight development of all animals was within the range of variation for this strain.

Read-across justification

There are no available measured data for 3-[tris(trimethylsiloxy)silyl]propylmethacrylate (CAS 17096-07-0) for skin sensitisation. Therefore, the Annex requirements are fulfilled by read-across. This document describes the analogue approach for fulfilling this endpoint by read-across from a source substance, (1,1,3,3-tetramethyldisiloxane-1,3-diyl)dipropane-1,3-diyl dimethacrylate (CAS 18547-93-8) 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 RAAF1

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, (1,1,3,3-tetramethyldisiloxane-1,3-diyl)dipropane-1,3-diyl dimethacrylate (CAS 18547-93-8), is a disiloxane with two methyl groups and a propylmethacrylate group attached to each silicon atom. The predicted hydrolysis half-lives for the siloxane group are approximately 1 h at pH 4, 1 h at pH 5, 63 h at pH 7 and 0.8 h at pH 9 and 20-25°C. The low water solubility and high log K_ow may mean that hydrolysis in vivo is slower than this.

At pH of skin, 5.5, the hydrolysis rate is expected to be >1 h and <63 h. The product of hydrolysis is 3-[hydroxy(dimethyl)silyl]propyl methacrylate (2 moles).

The source substance has log K_ow of 8.1 at 20°C (QSAR), water solubility of 1.5E-03 mg/L at 20°C (QSAR) and vapour pressure of 0.005 Pa at 25°C (QSAR).

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

The registration and the read-across substance, (1,1,3,3-tetramethyldisiloxane-1,3-diyl)dipropane-1,3-diyl dimethacrylate (CAS 18547-93-8), are structurally similar and are members of an analogue group of organosilicon substances containing a methacrylate group. Both substances are siloxanes with one or more propyl methacrylate side-chains bound to silicon atoms.

The target substance is a trisiloxane with a propyl methacrylate group at the central silicon and three methyl groups on each of the other silicons. The source substance is a disiloxane with one propylmethacrylate group and two methyl groups bound to each silicon. The key differences in the structure are that:

1. The target substance is a trisiloxane and the source substance is a disiloxane.

2. The target substance contains one propylmethacrylate group and the source substance contains two propylmethacrylate groups.

The methacrylate group is associated with the potential for skin sensitisation (see Section 6); whereas alkoxysiloxanes without reactive functional groups do not show sensitisation (PFA, 2015t, Peter Fisk Associates, Analogue report - mammalian toxicity of alkyl alkoxysilanes, PFA.404.002.002). This property does not depend on the siloxane chain length. Therefore, the presence of the propylmethacrylate side-chain is the key structural feature for read-across. The presence of two of these groups in the source substance makes the read-across worst-case.

The source and target substances have similar physicochemical properties (very low water solubility), very high log K_ow and low vapour pressure. They hydrolyse with similar predicted rates. The low water solubility and high log K_ow may mean that the hydrolysis in vivo is slower than predicted.

There are two silanol hydrolysis products for the registered substance, 3-(trihydroxysilyl)propyl methacrylate (1 mole) and trimethylsilanol (3 moles), and one for the read-across substance, 3-[hydroxy(dimethyl)silyl]propyl methacrylate (2 moles). Neither substance produces a non-silanol hydrolysis product.

The target and source substances both hydrolyse to give a silanol with a propylmethacrylate side-chain. This is 3-(trihydroxysilyl)propyl methacrylate (1 mole) for the target substance and 3-[hydroxy(dimethyl)silyl]propyl methacrylate (2 moles) for the source substance. These two hydrolysis products are structural analogues. 3-(trihydroxysilyl)propyl methacrylate has three hydroxyl (silanol) groups and a propyl methacrylate group attached to the silicon atom, while 3-[hydroxy(dimethyl)silyl]propyl methacrylate has one hydroxyl (silanol), two methyl and one propyl methacrylate groups attached to the silicon atom. The difference is that two of the hydroxyl groups in the hydrolysis product of the target substance are replaced by methyl groups in the hydrolysis product of the source substance. There is also a second hydrolysis product for the target substance: trimethylsilanol. This substance is found to be not sensitising based on weight-of-evidence from reliable studies with other alkoxysilanes and silanols (PFA, 2015t, Peter Fisk Associates, Analogue report - mammalian toxicity of alkyl alkoxysilanes, PFA.404.002.002).

Table 2: Physico-chemical properties of the source and target substances

Property		Target substance		Source substance
Substance name		3-[3,3,3-Trimethyl-1,1-bis[(trimethylsilyl)oxy]disiloxanyl]propyl methacrylate		(1,1,3,3-Tetramethyldisiloxane-1,3-diyl)dipropane-1,3-diyl dimethacrylate
CAS number		17096-07-0		18547-93-8
Hydrolysis half-life at pH 5and 25ºC		2 hour (QSAR)		1 hour (QSAR)
Silanol hydrolysis product		3-(Trihydroxysilyl)propyl methacrylate (1 mole) and trimethylsilanol (3 moles)		3-[Hydroxy(dimethyl)silyl] propyl methacrylate (2 moles)
Non-Si hydrolysis product		Not applicable		Not applicable
LogKow value		9.0 at 20°C (QSAR)		8.1 at 20°C (QSAR)
Vapour pressure		0.11 Pa at 20°C (OECD 104)		0.005 Pa at 25°C (QSAR)
Water solubility		5.8E-05 mg/L at 20°C (QSAR)		1.5E-03 mg/L at 20°C (QSAR)

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

In the in vivo skin sensitisation study, conducted according to an appropriate OECD test guideline and in compliance with GLP, the test material (1,1,3,3-tetramethyldisiloxane-1,3-diyl)dipropane-1,3-diyl dimethacrylate, (CAS 18547-93-8) (was concluded to be not sensitising to skin (Eurofins, 2017). The study was assigned a Reliability of 1.

At induction, 3 epicutaneous occlusive applications of 100% test material were performed to the flanks of 20 test guinea pigs. The same procedure was repeated 3 times for 3 consecutive weeks. The dressing patch was held in contact with the skin for 6 hours. Dermal reactions were examined after each application.

At challenge (two weeks after last topical induction application), 0.5 mL of 25 % test material in acetone were applied topically to the right flank of each test animal, kept in contact with the skin for 6 hours under occlusive dressing. Dermal reactions were evaluated at 24 and 48 hours after removal of the test material. Changes in body weight were recorded prior to administration and at the end of the observation period. All animals were observed for signs of toxicity at least once daily during the test period.

There was no evidence of sensitisation as the percentage of sensitised animals was 5%. All animals of both groups survived throughout the test period. No signs of toxicity were recorded. The body weight development of all animals was within the range of variation for this strain.

4. AE A.4 Bias that influences the prediction

Data on the source substance (1,1,3,3-tetramethyldisiloxane-1,3-diyl)dipropane-1,3-diyl dimethacrylate (CAS 18547-93-8) were read-across to the registered (target) substance 3-[3,3,3-trimethyl-1,1-bis[(trimethylsilyl)oxy]disiloxanyl]propyl methacrylate (CAS 17096-07-0).

The source substance, (1,1,3,3-tetramethyldisiloxane-1,3-diyl)dipropane-1,3-diyl dimethacrylate, and the target substance have similar chemical structure and physico-chemical properties. These two substances hydrolyse at similar rates to produce the structurally similar hydrolysis products, 3-[hydroxy(dimethyl)silyl]propyl methacrylate and 3-(trihydroxysilyl)propyl methacrylate. Therefore, their toxicological properties are expected to be similar, with similar skin sensitisation effects. This substance is the closest structural analogue to the target substance that has skin sensitisation data. Another structural analogue is 3-trimethoxysilylpropyl methacrylate (CAS 2530-85-0), which has low reliability data for skin sensitisation with equivocal results due to response in the negative control. There is also a local lymph node assay (LLNA) for CAS 2530-85-0 available which reported the test item to be not sensitising. The study report is not yet finalised, therefore it is not included in the dossier at this stage. Reconsideration of the skin sensitisation endpoint for all organosilicon substances containing methacrylate groups will be undertaken based on the outcome of this study.

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

The source substance, (1,1,3,3-tetramethyldisiloxane-1,3-diyl)dipropane-1,3-diyl dimethacrylate (CAS 18547-93-8), as well as the target substance can hydrolyse in contact with water. Therefore, the test organism may be exposed to both the parent substances and their hydrolysis products, 3-(trihydroxysilyl)propyl methacrylate and trimethylsilanol or 3-[hydroxy(dimethyl)silyl]propyl methacrylate.  

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

No toxicity data are available for the target substance 3-[3,3,3 -trimethyl-1,1-bis[(trimethylsilyl)oxy]disiloxanyl]propyl methacrylate (CAS 17096-07-0), therefore, data are read-across from the structurally analogous substance (1,1,3,3-tetramethyldisiloxane-1,3-diyl)dipropane-1,3-diyl dimethacrylate (CAS 18547-93-8).

The target substance and the source substance, (1,1,3,3-tetramethyldisiloxane-1,3-diyl)dipropane-1,3-diyl dimethacrylate (CAS 18547-93-8) are structurally similar. Both are siloxanes containing one or two propylmethacrylate side-chains. They have similar physico-chemical properties. Both hydrolyse at similar rates to form a trisilanol or silanol with a propylmethacrylate side-chain. There are no non-silanol hydrolysis products for either substance. The second hydrolysis product of the target substance is trimethylsilanol (CAS 1066-40-6), which is found to be non-sensitisting.  Thus, both substances are expected to have similar toxicity profiles.

The source and target substance have been profiled using the OECD QSAR Toolbox v. 4.1. The two substances and the propyl-methacrylate containing silanol hydrolysis products show consistent profiles for all toxicological endpoints. They all show alerts for skin sensitisation due to the methacrylate group. Currently, the available evidence indicates that skin sensitisation is not observed for organosilicon compounds containing an alkylmethacrylate side-chain. However, 3-trimethoxysilylpropyl methacrylate (CAS 2530-85-0) has low reliability data for skin sensitisation with equivocal results due to response in the negative control. There is also a local lymph node assay (LLNA) for CAS 2530-85-0 available which reported the test item to be not sensitising. The study report is not yet finalised, therefore it is not included to the dossier at this stage. Reconsideration of skin sensitisation endpoint for all organosilicon substances containing methacrylate groups will be undertaken based on the outcome of this study.

The trimethylsilanol hydrolysis product does not show alerts for skin-sensitisation.

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

Neither the target substance, 3-[3,3,3-trimethyl-1,1-bis[(trimethylsilyl)oxy]disiloxanyl]propyl methacrylate (CAS 17096-07-0), nor the source substances, (1,1,3,3-tetramethyldisiloxane-1,3-diyl)dipropane-1,3-diyl dimethacrylate (CAS 18547-93-8) have impurities of toxicological concern.

The test substance in the study with the source substance, (1,1,3,3-tetramethyldisiloxane-1,3-diyl)dipropane-1,3-diyl dimethacrylate (CAS 18547-93-8), has a purity of 97.6%.

The target substance, 3-[3,3,3-Trimethyl-1,1-bis[(trimethylsilyl)oxy]disiloxanyl]propyl methacrylate (CAS 17096-07-0), 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.

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Based on the available data for (1,1,3,3-tetramethyldisiloxane-1,3-diyl)dipropane-1,3-diyl dimethacrylate, no classification of the target substance is required for skin sensitisation according to Regulation (EC) No. 1272/2008.