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Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

There are no genetic toxicity studies available for Reaction Mass of 2,4,6,8,10-pentamethyl-2,4,6,8,10-

pentavinylcyclopentasiloxane and 2,4,6,8-tetramethyl-2,4,6,8-tetravinyl cyclotetrasiloxane (EC 911-381-6). Therefore, the Annex requirements are fulfilled with data on structurally analogous substances.

Gene mutation (Bacterial reverse mutation assay / Ames test): read-across from octamethylcyclotetrasiloxane D4 (CAS 556-7-2). Negative with and without activation in all strains tested (OECD TG 471 and GLP) (BRRC, 1993a).

Gene mutation (Bacterial reverse mutation assay / Ames test): read-across from decamethylcyclopentasiloxane D5 (CAS 541 -02 -6). Negative with and without activation in all strains tested (OECD TG 471 and GLP) (RCC Cytotest cell research, 2003).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (negative)

Genetic toxicity in vivo

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Bacterial mutagenicity data are available from three reverse mutagenicity studies for octamethylcyclotetrasiloxane D4 (CAS 556-7-2) (BRRC, 1993a; Bayer AG, 1985b; Isquith, 1988a). None of these studies included a strain capable of detecting cross-linking or oxidising mutagens, as required by the current OECD guideline. In view of the lack of genetic toxicity demonstrated in studies on mammalian cells and in two different in vivo assays, and the absence of structural features that indicate that such mutagenicity is likely, testing in an appropriate 5th strain is not considered necessary. In addition, many of the organosilicon substances have been tested in an appropriate 5th strain, and the only organosilicon substance which has given a positive result in a bacterial strain capable of detecting cross-linking or oxidising mutagens contains an epoxy- side-chain (which is a structural feature associated with cross-linking mutagenicity), and this substance was positive in Salmonella typhimurium strains TA 100, TA 1535 as well as in E.coli WP2 uvrA. It is therefore considered that for all the organosilicon substances, whether or not the structure includes structural alerts for genetic toxicity (Benigni et al, 2008), genetic toxicity would be detected in Salmonella typhimurium strains TA 98, TA 100, TA 1535 or 1537.

Decamethylcyclopentasiloxane has been tested according to OECD 471 and in compliance with GLP using Salmonella typhimurium strains TA 1535, TA 1537, TA 98 and TA 100 and Escherichia coli WP2 uvrA (RCC Cytotest cell research, 2003). No test-substance related increase in the number of revertants was detected in the presence or absence of metabolic activation in either the initial plate incorporation assay or the repeat experiment using pre-incubation up to limit concentrations. Appropriate positive, solvent and untreated controls were included and gave expected results. The test substance is therefore considered to be negative for mutagenicity to bacteria under the conditions of the test.

Read-across justification

There are no available measured data for Reaction Mass of 2,4,6,8,10-pentamethyl-2,4,6,8,10-pentavinylcyclopentasiloxane and 2,4,6,8-tetramethyl-2,4,6,8-tetravinyl cyclotetrasiloxane for genetic toxicity. Therefore, the Annex requirements are fulfilled with data on structurally analogous substances. This document describes the analogue approach for fulfilling this endpoint by read-across from two source substances, octamethylcyclotetrasiloxane D4 (CAS 556-67-2) and decamethylcyclopentasiloxane D5 (CAS 541-02-6), 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 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 first source substance, octamethylcyclotetrasiloxane (CAS 556-67-2) D4, is a cyclic siloxane made up of four silicon atoms linked by oxygen atoms, where each silicon atom is fully methyl substituted. Its measured hydrolysis half lives are: 1.8 h at pH 4, 69 - 144 h at pH 7, 0.9 - 1 h at pH 9, and 25°C (OECD 111). At physiological temperature 35ºC and pH 7 (relevant for genetic toxicity testing), the hydrolysis half- life is calculated as 25 hours. The product of hydrolysis is dimethylsilanediol.

The source substance has log Kow of 6.49 at 25.1°C (OECD 123), water solubility of 0.056 mg/l at 23°C and vapour pressure of 132 Pa at 25°C.

The second source substance decamethylcyclopentasiloxane D5 (CAS 541-02-6) is a cyclic siloxane made up of five silicon atoms linked by oxygen atoms. In D5, each silicon atom is fully methyl substituted. Its measured hydrolysis half-lives at 25°C are: 9.3 h at pH 4, 351 h at pH 5.5, 1590 h (66 d) at pH 7, 214 h at pH 8 and 24.8 - 31.6 h at pH 9. The hydrolysis half-life of D5 at 35ºC and pH 7 (relevant for genetic toxicity testing) is 590 hours. The product of hydrolysis is dimethylsilanediol. The source substance has log Kow of 8.02 at 25.3 °C, water solubility of 17 µg/L at 23°C and vapour pressure of 33.2 Pa at 25°C.

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

The registration substance, Reaction Mass of 2,4,6,8,10-pentamethyl-2,4,6,8,10-pentavinylcyclopentasiloxane and 2,4,6,8-tetramethyl-2,4,6,8-tetravinyl cyclotetrasiloxane, has two components, Vi5D5 and Vi4D4. Component 2, Vi4-D4, and the first read-across substance, D4,  are both cyclic siloxanes made up of four silicon atoms linked by oxygen atoms. In D4, each silicon atom is fully methyl substituted, whereas in Vi4-D4 each silicon atom is substituted with one methyl and one vinyl group. Vi4-D4 and D4 have slow hydrolysis rates (63 h at pH 7 and 20-25°C, predicted and 69-144 h at pH 7 and 25°C, respectively) and similar physico-chemical properties: high molecular weight (MW 344.7 and 296.6 respectively), low water solubility (0.0073 – 0.0088 mg/l and 0.056 mg/l, respectively), high log Kow (both 6.5) and high log Koc (both close to 4). D4 and Vi4-D4 are structural analogues with very similar properties.

Similarly, component 1, Vi5-D5, and the second read-across substance, D5, are cyclic siloxanes made up of five silicon atoms linked by oxygen atoms. In D5, each silicon atom is fully methyl substituted, whereas in Vi5-D5 each silicon atom is substituted with one methyl and one vinyl group. Vi5-D5 and D5 have slow hydrolysis rates (1600 h at pH 7 and 20-25°C, predicted and 1590 h at pH 7 and 25°C respectively) and similar physico-chemical properties: high molecular weight (MW 431 and 370.8 respectively), low water solubility (9.1E-06 mg/l and 0.017 mg/l respectively) high log Kow (9.0 and 8.0 respectively) and high log Koc (6 and 5.2 respectively). D5 and Vi5-D5 are structural analogues with very similar properties.  

Table 2: Physico-chemical properties

Property

Target substance

Source substance

Source substance

Substance name

Reaction Mass of 2,4,6,8,10-pentamethyl-2,4,6,8,10-pentavinylcyclopentasiloxane and 2,4,6,8-tetramethyl-2,4,6,8-tetravinyl cyclotetrasiloxane

octamethylcyclotetrasiloxane D4

decamethylcyclopentasiloxane D5

CAS number

Not applicable

556-67-2

541-02-6

Hydrolysis half-life at pH 7

 Component 1 Vi5 -D5 600 h at37.5 ºC 

Component 2 Vi5 -D4 23 h at37.5 ºC

25 h at 35ºC

590 at 35ºC

Silanol hydrolysis product

Methylvinylsilanediol

dimethylsilanediol

dimethylsilanediol

Non-Si hydrolysis product

none

none

none

LogKow value

component 1 Vi5D5: 9 (predicted), component 2 Vi4D4: 6.47 (measured)

6.49 at 25.1°C (OECD 123)

8.02 at 25.3 °C

Vapour pressure

component 1 Vi5D5: 0.6 Pa at 25°C (predicted), component 2 Vi4D4: 93.5 Pa at 25°C

132 Pa at 25°C

33.2 Pa at 25°C

Water solubility

component 1 Vi5D5: 9.1E-06 mg/l (predicted) , component 2 Vi4D4: 0.0073-0.0088 mg/l at 23°C (measured)

0.056 mg/l at 23°C

0.017 mg/l at 23°C

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

Bacterial mutagenicity data are available from three reverse mutagenicity studies for octamethylcyclotetrasiloxane D4 (CAS 556-7-2) (BRRC, 1993a; Bayer AG, 1985b; Isquith, 1988a). None of these studies included a strain capable of detecting cross-linking or oxidising mutagens, as required by the current OECD guideline. In view of the lack of genetic toxicity demonstrated in studies on mammalian cells and in two different in vivo assays, and the absence of structural features that indicate that such mutagenicity is likely, testing in an appropriate 5thstrain is not considered necessary. In addition, many of the organosilicon substances have been tested in an appropriate 5th strain, and the only organosilicon substance which has given a positive result in a bacterial strain capable of detecting cross-linking or oxidising mutagens contains an epoxy- side-chain (which is a structural feature associated with cross-linking mutagenicity), and this substance was positive in Salmonella typhimurium strains TA 100, TA 1535 as well as in E.coli WP2 uvrA. It is therefore considered that for all the organosilicon substances, whether or not the structure includes structural alerts for genetic toxicity (Benigni et al, 2008), genetic toxicity would be detected in Salmonella typhimurium strains TA 98, TA 100, TA 1535 or 1537.

Decamethylcyclopentasiloxane, D5, has been tested according to OECD 471 and in compliance with GLP using Salmonella typhimurium strains TA 1535, TA 1537, TA 98 and TA 100 and Escherichia coli WP2 uvrA (RCC Cytotest cell research, 2003). No test-substance related increase in the number of revertants was detected in the presence or absence of metabolic activation in either the initial plate incorporation assay or the repeat experiment using pre-incubation up to limit concentrations. Appropriate positive, solvent and untreated controls were included and gave expected results. The test substance is therefore considered to be neagative for mutagenicity to bacteria under the conditions of the test.

4.       AE A.4 Bias that influences the prediction

Data on the source substances D4 and D5 were read-across to the registered (target) substance Reaction Mass of 2,4,6,8,10-pentamethyl-2,4,6,8,10-pentavinylcyclopentasiloxane and 2,4,6,8-tetramethyl-2,4,6,8-tetravinyl cyclotetrasiloxane. The source substances and the target substance have similar chemical structure and physico-chemical properties. All three substances hydrolyse at similar rate, and produce similar silicon-containing hydrolysis products, dimethylsilanediol and methylvinylsilanediol. None of them gives a non-silanol hydrolysis product. Therefore, their toxicological properties are expected to be similar, with similar genotoxic potential. No other data for relevant substances were available. These substances are the closest structural analogues to the target substance.

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

The source substances as well as the target substance hydrolyse at similar rate in contact with water under conditions relevant for oral exposure. Therefore, the test organism could possibly be exposed to the parent substance and their hydrolysis products, dimethylsilanediol or methylvinylsilanediol. However, considering that the hydrolysis half-lives for these three substances are very slow it is likely that the parent substance would not undergo hydrolysis and the test organism would be exposed to the parent only.  

There are no data available for the hydrolysis products, dimethylsilanediol and methylvinylsilanediol.

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 Reaction Mass of 2,4,6,8,10-pentamethyl-2,4,6,8,10-pentavinylcyclopentasiloxane and 2,4,6,8-tetramethyl-2,4,6,8-tetravinyl cyclotetrasiloxane, therefore data are read-across from the structurally analogous substances D4 and D5. These three substances hydrolyse at similar rate to a silanol (2 moles). There are no non-silanol hydrolysis products relevant for this endpoint. Moreover, they have similar physico-chemical properties. Thus, all three substances are expected to have similar toxicity profiles.

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

The registration substance, Reaction Mass of 2,4,6,8,10-pentamethyl-2,4,6,8,10-pentavinylcyclopentasiloxane and 2,4,6,8-tetramethyl-2,4,6,8-tetravinyl cyclotetrasiloxane, has two components, Vi5D5 and Vi4D4, with purity greater than 80% for both components.

Neither the target substance nor the source substances have impurities of toxicological concern.

Purity of test substance in the bacterial mutagenicity studies with the source substance, D4, was reported to be >99%.

The test substances in the bacterial mutagenicity study with the second source substance D5, have a purity of >99%.

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

Not relevant.

Justification for classification or non-classification

Based on the available information for

Reaction Mass of 2,4,6,8,10-pentamethyl-2,4,6,8,10-pentavinylcyclopentasiloxane and 2,4,6,8-tetramethyl-2,4,6,8-tetravinyl cyclotetrasiloxane, no classification is required for genetic toxicity based on Regulation (EC) No. 1272/2008.

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