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Description of key information

There are no skin sensitisation data available for the registered substance. However, reliable data are available for a structural analogue. The key skin sensitisation study was read-across from 1,1,1,3,5,5,5 -heptamethyl-3 -[(trimethylsilyl)oxy]trisiloxane. The test material was found not to be sensitising in a test conducted according to a Japanese protocol equivalent to current OECD Guideline but not in compliance with GLP (Haruna 2001).

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records
Reference
Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
17 May 2001 - 23 July 2001
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
Study was not conducted in compliance with GLP.
Qualifier:
according to guideline
Guideline:
other: Guidance on Safety Assessment of New Cosmetics (Japan Cosmetic Industry Association, technical materials No.92, 1991)
GLP compliance:
no
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
An LLNA study was not performed because there is an existing reliable study for skin sensitisation using the Guinea Pig Maximisation test method. Furthermore, the LLNA test method is not considered to be suitable for substances that contain silicon. Please refer to the attached document for further details.
Species:
guinea pig
Strain:
Dunkin-Hartley
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Ichikawaya Co., Ltd.
- Age at study initiation: 5-6 weeks
- Weight at study initiation: 350-408g
- Housing: Animals were housed individuallyor in twos in aluminium cages
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 2 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3
- Humidity (%): 55 +/-15
- Air changes (per hr): minimum 10
- Photoperiod (hrs dark / hrs light): 12/12
Route:
intradermal
Vehicle:
olive oil
Concentration / amount:
Induction with test substance: 50% (intradermal)
Re-induction: 50% (topical)
Challenge: 50% or 90% (topical, occluded)
Control animals induction: olive oil
Control animals challenge: 50% or 90% test substance
Positive controls: 0.1% and 1% DNCB solution or non-induced animals 8-% ethanol

No.:
#1
Route:
epicutaneous, occlusive
Vehicle:
olive oil
Concentration / amount:
Induction with test substance: 50% (intradermal)
Re-induction: 50% (topical)
Challenge: 50% or 90% (topical, occluded)
Control animals induction: olive oil
Control animals challenge: 50% or 90% test substance
Positive controls: 0.1% and 1% DNCB solution or non-induced animals 8-% ethanol

No. of animals per dose:
Test (induced animals): 10
Control (non-induced animals): 5
Positive control: 5
Details on study design:
INDUCTION
The day of the first induction was designated as day 0. Six injection points were set in two lines of 3 per row. 0.05mL of the test material was administered intradermally to each injection point, as follows, each injection in duplicate.

The test group was administered 1. Distilled water FCA-emulsion, 2. 50% test substance solution, 3. 50% test substance-FCA emulsion.
The positive control group was administered 1. Distilled water-FCA emulsion, 2. 0.1% DNCB-FCA emulsion, 3. 0.1% DNCB-FCA emulsion
The control group was administered 1. Distilled water-FCA emulsion, 2.Olive oil, 3. Olive oil - FCA emulsion
The positive control (non-induction group) was administered 1. Distilled water - FCA emulsion, 2. 80% ethanol solution, 3. Ethanol - FCA emulsion

On day 6, the induction site was clipped wth an electric hair clipper and 0.1 mL 10% SLS ointment was applied openly for all groups, except positive substance induction group.

On day 7, the SLS ointment was removed with luke warm water. 0.2 mL of 50% test substance solution, 1% DNCB solution, olive oil and 80% ethanol solution was administered to test group, positive control group, test non-induction group and positive control non-induction group skin, respectively. The applied material was spread on a patch, which was attached with adhesive elastic bandage and surgical tape and occluded for 48 hours.

CHALLENGE

On day 23, the challenge site on the flank of animals was clipped of hair. The test substance induction and non-induction groups were applied 50% or 90% test substance on challenge site (10 or 5 animals/each concentration). For positive substance induction and non-induction groups , a 0.1 mL of 0.1% DNCB solution was applied to the challenge site. The materials were spread on a patch, and held in place with adhesive elastic bandage and surgical tape and occluded for 24 hours.

At 24 and 48 hours after patch removal (day 25 and 26), the challenge sites were observed for all groups and skin sensitization potential evaluated for test and positive substances.
Challenge controls:
5 Male guinea pigs served as challenge controls. They were administered olive oil at induction, and challenged with 50% or 90% test substance to parallel treatment of the test group.
Positive control substance(s):
yes
Remarks:
2,4-dinitrochlorobenzene
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
50%
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
50%
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
other: test, non-induction
Dose level:
50%
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
other: test, non-induction
Dose level:
50%
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
90%
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
90%
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
other: test, non-induction
Dose level:
90%
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
other: test, non-induction
Dose level:
90%
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
no indication of skin sensitisation
Reading:
other: 1st/2nd reading
Hours after challenge:
24
Group:
positive control
Dose level:
0.1% DNCB
No. with + reactions:
5
Total no. in group:
5
Remarks on result:
positive indication of skin sensitisation
Interpretation of results:
GHS criteria not met
Conclusions:
The test material was found not to be sensitizing to skin in this guinea-pig Maximization test, conducted according to a protocol equivalent to OECD Guideline but not in compliance with GLP.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

The application of a 50% or 90% solution of test material to guinea pig skin at challenge dose was found not to be sensitizing to skin in the Guinea-Pig Maximization Test (GMPT), conducted according to a Japanese protocol equivalent to OECD Guideline but not in compliance with GLP (Haruna 2001). There were no clinical signs in any of the test animals, and appropriate positive and negative controls were in place.

Read-across justification

There are no available measured data for 1,1,1,5,5,5-hexamethyl-3,3-bis[(trimethylsilyl)oxy]trisiloxane (CAS 3555-47-3) for skin sensitisation. This document describes the analogue approach for fulfilling this endpoint by read-across from a source substance 1,1,1,3,5,5,5-heptamethyl-3-[(trimethylsilyl)oxy]trisiloxane (CAS 17928-28-8), 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 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, 1,1,1,3,5,5,5-heptamethyl-3-[(trimethylsilyl)oxy]trisiloxane (CAS 17928-28-8), is a tertiary branched methylated siloxane structure of four Si atoms. The longest siloxane chain consists of three silicon atoms and two oxygen atoms, with a Si-O branch on the central silicon atom in the chain. The silicon atoms are fully substituted by methyl groups. Hydrolysis half-life values of 3.6 h at pH 4, 630 h at pH 7, 5.3 h at pH 9 and 20-25°C were obtained using an accepted calculation method.  

At pH 5.5 (the known pH of the skin), he hydrolysis half-life is expected to be between the values for pH 4 (3.6 h) and pH 7 (630 h). The products of hydrolysis are trimethylsilanol (3 moles) and methylsilanetriol (1 moles).

The source substance has log Kow of 8.2 at 20°C (QSAR), water solubility of 0.00189 mg/l at 23°C (QSAR) and vapour pressure of 210 Pa at 25°C (OECD 104).

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

The registration substance, 1,1,1,5,5,5-hexamethyl-3,3-bis[(trimethylsilyl)oxy]trisiloxane (CAS 3555-47-3), and the read-across substance, 1,1,1,3,5,5,5-heptamethyl-3-[(trimethylsilyl)oxy]trisiloxane (CAS 17928-28-8), are structurally similar and are members of an analogue group of linear and branched siloxanes.

1,1,1,3,5,5,5-Heptamethyl-3-[(trimethylsilyl)oxy]trisiloxane (CAS 17928-28-8)  a is a tertiary branched methylated siloxane structure of four Si atoms, while 1,1,1,5,5,5-hexamethyl-3,3-bis[(trimethylsilyl)oxy]trisiloxane (CAS 3555-47-3) is a quaternary branched methylated siloxane structure of five Si atoms. In both substances the longest siloxane chain consists of three silicon atoms and two oxygen atoms. The source substance has a Si-O branch on the central silicon atom in the chain, while the target substance has two Si-O branches on the central silicon atom in the chain. The silicon atoms are fully substituted by methyl groups.

The source and target substances share a common hydrolysis product, trimethylsilanol. (Poly)silicic acid is the other hydrolysis product for the target substance and methylsilanetriol for the source substance. These two substances both hydrolyse in similar rate to 4 moles or 3 moles of trimethylsilanol.

Table 2: Physico-chemical properties

Property

Target substance

Source substance

Substance name

1,1,1,5,5,5-hexamethyl-3,3-bis[(trimethylsilyl)oxy]trisiloxane

1,1,1,3,5,5,5-heptamethyl-3-[(trimethylsilyl)oxy]trisiloxane

CAS number

3555-47-3

17928-28-8

Hydrolysis half-life at pH 5.5

>1.9 < 74 h

>3.6 h < 630 h

Silanol hydrolysis product

trimethylsilanol

trimethylsilanol

Non-Si hydrolysis product

(poly)silicic acid

methylsilanetriol

LogKow value

9 at 20°C (QSAR)

8.2 at 20°C (QSAR)

Vapour pressure

15 Pa at 25°C (measured)

210 Pa at 25°C (OECD 104)

Water solubility

0.1507 µg/l at 20-25°C (measured)

0.00189 mg/l at 23°C (QSAR)

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

The application of a 50% or 90% solution of test material to guinea pig skin at challenge dose was found not to be sensitizing to skin in the Guinea-Pig Maximization Test (GMPT), conducted according to a protocol equivalent to OECD Guideline but not in compliance with GLP (Haruna 2001). There were no clinical signs in any of the test animals, and appropriate positive and negative controls were in place.

4.       AE A.4 Bias that influences the prediction

Data on the source substance 1,1,1,3,5,5,5-heptamethyl-3-[(trimethylsilyl)oxy]trisiloxane (CAS 17928-28-8) were read-across to the registered (target) substance 1,1,1,5,5,5-hexamethyl-3,3-bis[(trimethylsilyl)oxy]trisiloxane (CAS 3555-47-3). The source substance and the target substance have similar chemical structure and physico-chemical properties. Both substances hydrolyse at similar rate to the same Si-containing hydrolysis product, trimethylsilanol. However, the other hydrolysis products are different, (poly)silicic acid and methylsilanetriol for the target and source substance, respectively. Despite that, their toxicological properties are expected to be similar, with similar acute toxicity. No other data for relevant substances were available. These substances are the closest structural analogues to the target substance; other siloxanes show consistent results (PFA, 2013u).

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

Both substances hydrolyse at similar rates to the same Si-containing hydrolysis product. Therefore, the test organism is might be exposed to both the parent substance or hydrolysis products, trimethylsilanol, (poly)silicic acid and methylsilanetriol.  The source and target substances have been profiled using the OECD QSAR Toolbox v. 4.1. The three substances and their silanol hydrolysis products show similar profiles for all toxicological endpoints. No alert for acute toxicity was detected by OECD QSAR Toolbox v.4.1.  

The sensitisation potential of (poly)silicic acid is well established. No classification for sensitisation has been assigned to the substance.

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 1,1,1,5,5,5-hexamethyl-3,3-bis[(trimethylsilyl)oxy]trisiloxane (CAS 3555-47-3), therefore data are read-across from the structurally analogous substance 1,1,1,3,5,5,5-heptamethyl-3-[(trimethylsilyl)oxy]trisiloxane (CAS 17928-28-8). These substances hydrolyse at similar rate to 4 moles or 3 moles of trimethylsilanol. The other hydrolysis product, (poly)silicic acid and methylsilanetriol, is not expected to be relevant for this endpoint. 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

The target substance, 1,1,1,5,5,5-hexamethyl-3,3-bis[(trimethylsilyl)oxy]trisiloxane (CAS 3555-47-3), has a named impurity at 5-20%: 1,1,1,5,5,5-Hexamethyl-3-[(trimethylsilyl)oxy]-3-trisiloxanyl tris(trimethylsilyl) orthosilicate (CAS 18602-90-9 and synonym of Q2M6 or M6Q2). No toxicological data are available for M6Q2 however based on the weight of evidence for linear and branched siloxanes acute toxicity is not expected (PFA, 2013u). The source substance, 1,1,1,3,5,5,5-heptamethyl-3-[(trimethylsilyl)oxy]trisiloxane (CAS 17928-28-8), does not have any impurities of toxicological concern.

The test substance in the study with the source substance, 1,1,1,3,5,5,5-heptamethyl-3-[(trimethylsilyl)oxy]trisiloxane (CAS 17928-28-8), has a purity of 99.9%.

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.

PFA (2013u). Peter Fisk Associates, Mammalian toxicity of linear and branched siloxanes Analogue Report, PFA.300.002.008


Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

Based on the available read-across information on 1,1,1,5,5,5-hexamethyl-3,3-bis[(trimethylsilyl)oxy]trisiloxane, no classification is necessary in accordance with Regulation (EC) No 1272/2008.