Tri(isopropoxy)vinylsilane

Endpoint summary

Description of key information

Both key read-across in vitro skin irritation studies for tris(isopropenyloxy)(vinyl)silane (CAS 15332-99-7), conducted according to OECD TG 439, and in compliance with GLP, reported a relative mean tissue viability of > 50 % following 15 min or 60 min exposure to the test item (Bioservice, 2015a & 2015b).

The key read-across in vitro eye irritation study for tris(isopropenyloxy)(vinyl)silane (CAS 15332-99-7), conducted according to OECD TG 437, and in compliance with GLP, reported mean in vitro irritation score of < 3 (1.33) (Bioservice, 2015c).

Key value for chemical safety assessment

Skin irritation / corrosion

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Both key read-across in vitro skin irritation studies for tris(isopropenyloxy)(vinyl)silane (CAS 15332-99-7), conducted according to OECD TG 439, and in compliance with GLP, reported relative mean tissue viability of > 50 % following 15 min or 60 min exposure to the test item (Bioservice, 2015a & 2015b).

A comparison has been made of the predictive powers for organosilicate substance of two reconstituted three-dimensional human skin models, EpiSkin-SM™ and EpiDerm™, in OECD 439 studies. It has been concluded that one of the skin models tends to over predict skin irritation for these substances and the other tends to under predict. Therefore tris(isopropenyloxy)(vinyl)silane has been tested in both EpiSkin and EpiDerm assays. The results of both studies were negative, so it is concluded that the registered substance is not irritating to skin.

Tris(isopropenyloxy)(vinyl)silane has been tested in two reliable in vitro studies for skin irritation conducted according to OECD 439 and in compliance with GLP using EpiSkin-SM tissue (BSL Bioservice, 2015a) and EpiDerm (BSL Bioservice, 2015b). The mean tissue viability of the test-item treated tissues was not reduced relative to the negative controls in either tissue. The positive control produced the expected reduction in viability. It is concluded that the test item is not irritant under the conditions of the tests.

The key read-across in vitro eye irritation study for tris(isopropenyloxy)(vinyl)silane (CAS 15332-99-7), conducted according to OECD TG 437, and in compliance with GLP, reported a mean in vitro irritation score of < 3 (1.33) (Bioservice, 2015c). The in vitro irritation score obtained with the positive control fell within the two standard deviations of the current historical mean and therefore this assay is considered to be valid. It is concluded that the test substance is not irritating to the eye.

Read-across justification

There are no available measured data for tri(isopropoxy)(vinyl)silane (CAS 18023-33-1) for skin and eye irritation. 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 37.5ºC 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 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
LogKow value	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

The key read-across study conducted with tris(isopropenyloxy)(vinyl)silane (CAS 15332-99-7) was conducted according to a protocol similar to OECD test guideline, but not in compliance with GLP. The reported LD₅₀value was greater than 18000 mg/kg bw (TNO, 1983). The following clinical signs were observed after ten male and ten female Wistar rats were dosed with 20 ml/kg bw: sluggishness, ataxia and rough coats. A single male died on the second day. It is concluded that the LD₅₀is >20 ml/kg bw, which is equivalent to approximately 18000 mg/kg, based on a density of 0.9 g/cm³.

4.  AE A.4 Bias that influences the prediction

Tris(isopropenyloxy)(vinyl)silane has been tested in two reliable in vitro studies for skin irritation conducted according to OECD 439 and in compliance with GLP using EpiSkin-SM tissue (BSL Bioservice, 2015a) and EpiDerm (BSL Bioservice, 2015b). The mean tissue viability of the test-item treated tissues was not reduced relative to the negative controls in either tissue. Both studies reported relative mean tissue viability of > 50 % following 15 min or 60 min exposure to the test item (Bioservice, 2015a & 2015b). The positive control produced the expected reduction in viability. It was concluded that the test item is not irritant under the conditions of the tests.

The key in vitro eye irritation study for tris(isopropenyloxy)(vinyl)silane (CAS 15332-99-7), conducted according to OECD TG 437, and in compliance with GLP, reported mean in vitro irritation score of < 3 (1.33) (Bioservice, 2015c). The in vitro irritation score obtained with the positive control fell within the two standard deviations of the current historical mean and therefore this assay is considered to be valid. It was concluded that the test substance is not irritating to the eye.

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 will be predominantly in the keto form, acetone. Vinylsilanetriolhas been profiled using the OECD QSAR Toolbox and 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 only 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.

Justification for classification or non-classification

Based on the available in vitro data, tris(isopropoxy)(vinyl)silane does not require classification for skin or eye irritation according to Regulation (EC) No 1272/2008.