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Administrative data

Description of key information

The key read-across skin sensitisation study for tris(isopropenyloxy)(vinyl)silane (CAS 15332-99-7),conducted according to an appropriate OECD TG 406, and in compliance with GLP, reported the test item to be not sensitising to skin (Bioservice, 2015d).

Key value for chemical safety assessment

Skin sensitisation

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

The key read-across skin sensitisation study for tris(isopropenyloxy)(vinyl)silane (CAS 15332-99-7), conducted according to an appropriate OECD TG 406, and in compliance with GLP, reported the test item to be not sensitising to skin (Bioservice, 2015d).

Tris(isopropenyloxy)(vinyl)silane has been tested in a Buehler study. None of the animals challenged for 6 hours to the test item or the negative control showed any evidence of sensitisation at either 24 or 48 hours after removing the patch (BSL Bioservice 2015d).

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 silicon 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). In addition, research conducted by Petry et al. (2017) shows that in vitro skin sensitisation tests with validated OECD test guidelines are not suitable for aminofunctional silicone substances as they only have limited predictability for this type of substance.

Read-across justification

There are no available measured data for tri(isopropoxy)(vinyl)silane (CAS 18023-33-1) for sensitisation. Therefore, the Annex requirements are not fulfilled. This document describes the analogue approach for fulfilling this endpoint by read-across from the source substance, tris(isopropenyloxy)(vinyl)silane (CAS 15332-99-7),according to the Read-across Assessment Framework (RAAF)[1].

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 5.6.4) 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, tris(isopropenyloxy)(vinyl)silane (CAS 15332-99-7), has one vinyl functional silane with three isopropenyloxy groups. Its hydrolysis half-lives were estimated to be 0.3 h at pH 4, 0.4 h at pH 5, 6.6 h at pH 7 and 0.1 h at pH 9 and 20-25°C. These values are indicative of the upper limit for the hydrolysis half-lives of the submission substance because:

- The carbon-carbon double bond in the isopropenyloxy side-chain could weaken the Si-O bond electronically

- In addition, the carbon atom of the isopropenyloxy side-chain is sterically less hindering compared to isopropyloxy group.

Both of these effects are expected to speed up the hydrolysis rates of the source substance. 

Therefore, the result is reliable, sufficient to justify that the hydrolysis half-lives of the substance is <12 hours and are used for assessment purposes.

As the hydrolysis reaction may be acid or base-catalysed, the rate of reaction is expected to be slowest at around pH 7 and increase as the pH is raised or lowered. The calculated half-life of the substance at pH 2 and 20-25°C is therefore ≤0.003 h (approximately ≤11 seconds). Reaction rate increases with temperature therefore hydrolysis will be faster at physiologically relevant temperatures compared to standard laboratory conditions. Thus, for tris(isopropenyloxy)(vinyl)silane the hydrolysis half-life at 37.5°C and pH 7 (relevant for lungs and blood) is approximately ≤2.4 hours. At 37.5°C and pH 2 (relevant for conditions in the stomach following oral exposure), the half-life is approximately ≤4 seconds. However, it is not appropriate or necessary to attempt to predict accurately when the half-life is less than 5-10 seconds. As a worst-case it can therefore be considered that the half-life of the substance at pH 2 and 37.5°C is approximately 5 seconds. The hydrolysis products in this case are vinylsilanetriol andpropen-2-ol/acetone.

The hydrolysis of [tris(isopropenyloxy)(vinyl)silane] produces vinylsilanetriol and 3 molecules of propen-2-ol. Propen-2-ol is an enol type structure, which is in equilibrium with its keto tautomer, propanone (commonly called acetone). The equilibrium heavily favours the keto form at room temperature. Therefore, the hydrolysis products of [tris(isopropenyloxy)(vinyl)silane] are acetone (3 moles) and vinylsilanetriol (1 mole).

The source substance has LogKow of 3.8 at 20°C and vapour pressure of 5.3 Pa at 25°C.

 

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

The target and source substance have similar physico-chemical properties as well as hydrolysis rates (Table 2). The target substance tri(isopropoxy)(vinyl)silane (CAS 18023-33-1), has a vinyl functional silane with three isopropoxy groups, while the source substance tris(isopropenyloxy)(vinyl)silane (CAS 15332-99-7) has one vinyl functional silane with three isopropenylox groups. The hydrolysis half-lives for both substances have been predicted using a validated QSAR estimation method. Hydrolysis half-lives are estimated to be 0.3 h at pH 4, 0.4 h at pH 5, 6.6 h at pH 7 and 0.1 h at pH 9 and 20-25°C. These values are indicative of the upper limit for the hydrolysis half-lives of the source substance because:

- The carbon-carbon double bond in the isopropenyloxy side-chain could weaken the Si-O bond electronically

- In addition, the carbon atom of the isopropenyloxy side-chain is sterically less hindering compared to isopropyloxy group.

 Both of these effects are expected to speed up the hydrolysis rates of the source substance.

Therefore, the result is considered to be reliable, sufficient to justify that the hydrolysis half-lives of both substances is <12 hours and are used for assessment purposes.

The calculated half-life of both substances at pH 2 and 20-25°C is therefore ≤0.003 h (approximately ≤11 seconds). Thus, for tri(isopropoxy)(vinyl)silane and tris(isopropenyloxy)(vinyl)silane the hydrolysis half-life at 37.5ºC and pH 7 (relevant for lungs and blood) is approximately ≤2.4 hours. At 37.5ºC and pH 2 (relevant for conditions in the stomach following oral exposure), the half-life is approximately ≤4 seconds. However, it is not appropriate or necessary to attempt to predict accurately when the half-life is less than 5-10 seconds. As a worst-case it can therefore be considered that the half-life of the substances at pH 2 and 37.5°C is approximately 5 seconds.

The silicon-containing hydrolysis product for both the target and source substance is vinylsilanetriol. The non-Si hydrolysis products are isopropanol and acetone, respectively.

Reaction rate increases with temperature therefore hydrolysis will be faster at physiologically relevant temperatures compared to standard laboratory conditions.

As the hydrolysis reaction may be acid or base-catalysed, the rate of reaction is expected to be slowest at around pH 7 and increase as the pH is raised or lowered.

Table 2:Physico-chemical properties

Property

Target substance

Source substance

Substance name

tri(isopropoxy)(vinyl)silane

tris(isopropenyloxy)(vinyl)silane

CAS number

18023-33-1

15332-99-7

Hydrolysis half-life

0.4 h at pH 5

≤0.4 h at pH 5

Silanol hydrolysis product

vinylsilanetriol

vinylsilanetriol

Non-Si hydrolysis product

isopropanol

acetone

Log Kowvalue

3.8 at 20°C (QSAR)

3.8 at 20°C (QSAR)

Vapour pressure

64 Pa at 25°C (QSAR)

5.3 Pa at 25°C (QSAR)

 

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

Tris(isopropenyloxy)(vinyl)silane (CAS 15332-99-7) has been tested in a guinea-pig maximisation (Buehler) study, which was conducted according to an appropriate OECD TG 406, and in compliance with GLP. None of the animals challenged for 6 hours to the test item or the negative control showed any evidence of sensitisation at either 24 or 48 hours after removing the patch. The test item was reported to be not sensitising to skin (Bioservice, 2015d).

 

4.  AE A.4 Bias that influences the prediction

Data on the source substance tris(isopropenyloxy)(vinyl)silane (CAS 15332-99-7) were read-across to the registered (target) substance tri(isopropoxy)(vinyl)silane (CAS 18023-33-1). The source substance and the target substance have similar chemical structure and physico-chemical properties. Both substances hydrolyse at the same rate, and produce vinylsilanetriol as the silicon-containing hydrolysis product. The non-silanol hydrolysis products are similar, therefore their toxicological properties are expected to be similar, with similar skin sensitisation effects. No other data for relevant substances were available.

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

The source substance as well as the target substance hydrolyse very rapidly in contact with water. Therefore, the test organism is mainly exposed to their hydrolysis products,vinylsilanetriol and isopropanol or vinylsilanetriol and propen-2-ol which exist predominantly in the keto form, acetone. Vinylsilanetriolhas been profiled using the OECD QSAR Toolboxand it does not contain any structural alerts for toxicity. 

The toxicity of isopropanol has been evaluated in rats and mice by repeated inhalation and oral exposures. The only adverse effects - in addition to clinical signs - identified from these studies were to the kidney and included accumulation of hyaline (protein) droplets in kidney proximal tubule cells (males only, subchronic exposure) and an exacerbation of chronic progressive nephropathy, a spontaneous disease of unknown etiology common in aged rats (males and females, chronic exposure). In the mouse, minimal to mild effects to the kidney including renal tubular proteinosis and tubular dilation were observed following chronic exposure. Generally, these effects were only noted at high doses (> 500 ppm).

Data show that high concentrations of acetone are required to cause death of animals via inhalation route. Acetone is not classified for acute oral, dermal or inhalation toxicity. No studies were located regarding death of animals after intermediate- or chronic-duration inhalation exposure to acetone. The only effect on the respiratory system observed in humans exposed to acetone vapours is irritation of the nose, throat, trachea, and lungs. The irritating properties of acetone in humans have been noted both in workers who were exposed to acetone occupationally and in volunteers under controlled laboratory conditions. Exposure of animals to much higher concentrations of acetone than those reported in humans has resulted in respiratory effects. The irritancy potential of acetone has been investigated in a number of studies. Published data indicates that the substance is irritating to eyes but not skin. Acetone has also been shown not to have any skin sensitisation or target organ toxicity properties. Moreover, acetone does not have any genotoxic potential. There is no indication of adverse reproductive effects in absence of generalized toxicity. Indications of developmental toxicity in mice and rats (reduction of foetal weights, increase of late resorptions) were only observed at exposure concentrations that induced significant maternal toxicity. Therefore, acetone is not considered to have adverse effects on reproduction or development.

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 tri(isopropoxy)(vinyl)silane (CAS 18023-33-1), therefore data are read-across from the structurally analogous substance tris(isopropenyloxy)(vinyl)silane (CAS 15332-99-7). Both substances hydrolyse at the same rate, and produce vinylsilanetriol as the silicon-containing hydrolysis product. The non-silanol hydrolysis products are similar, isopropanol for the target substance andpropen-2-ol/acetone for the source substance, and they have similar toxicity profiles.Following hydrolysis both the target and source substances produce one mole of vinylsilanetriol and one mole of isopropanol orpropen-2-ol/acetone, respectively. Moreover, they have similar physico-chemical properties. Thus, both substances are expected to have similar toxicity profiles.

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

Neither the target substance, tri(isopropoxy)(vinyl)silane (CAS 18023-33-1), nor the source substance, tris(isopropenyloxy)(vinyl)silane (CAS 15332-99-7), have impurities of toxicological concern.

8.  AE 2.5 Occurrence of Other Effects than Covered by the Hypothesis and Justification

Not relevant

 


[1]European Chemicals Agency (ECHA) (2015) Read-across Assessment Framework. Appendix B, Scenario 2.

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.

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.

Petry, T., Bosch, A., Coste, X., Eigler, D., Germain, P., Seidel, S. and Jean, P. A. (2017). Evaluation of in vitro assays for the assessment of the skin sensitization hazard of functional polysiloxanes and silanes (Regulatory Toxicology and Pharmacology, 84, 64-76)


Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

Based on the available studies on skin sensitisation, tris(isopropoxy)(vinyl)silane does not require classification according to Regulation (EC) No 1272/2008.