1,3,5-trimethyl-1,1,3,5,5-pentaphenyltrisiloxane

Endpoint summary

Description of key information

In the key skin sensitisation study, conducted according to OECD 406, and in compliance with GLP, the read-across test material, 1,3,3,5-tetramethyl-1,1,5,5-tetraphenyltrisiloxane (CAS 3982-82-9), was reported to be not sensitising to the skin of any of the test animals (DCC, 2000).

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:

2000-03-30 to 2000-05-08

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 406 (Skin Sensitisation)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

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: Not stated
- Age at study initiation: 5-8 weeks
- Weight at study initiation: 445-518 g
- Housing: Animals were housed in groups of five in suspended metal cages with wire mesh floors.
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: 12 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17.5 to 22.5
- Humidity (%): 31-52
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Route:

intradermal

Vehicle:

other: Alembicol D

Concentration / amount:

25 and 50 % (v/v) in Alembicol D

No.:

#1

Route:

epicutaneous, occlusive

Vehicle:

other: Alembicol D

Concentration / amount:

25 and 50 % (v/v) in Alembicol D

No. of animals per dose:

Forty male guinea-pigs

Details on study design:

RANGE FINDING TESTS: The animals for the preliminary investigations w ere clipped and shaved the day prior to dosing and the animals for the topical irritancy investigations were re-shaved on the day of dosing. The procedure employed for these investigations were as follows: Intradermal injections - A range of concentrations of the test substance in Alembicol D were injected intradermally (0.I-ml/site) into the clipped left flank of two guinea pigs (per level tested) using a 1 ml plastic syringe and 26 G needle. The resulting dermal responses w ere assessed approximately 24, 48 and 72 hours later.
Topical application - Patches of Whatman No. 3 paper (20 mm x 20 mm) were saturated (volume approximately 0.2ml) with a range of concentrations of the test substance in Alembicol D and applied to the clipped and shaved flanks of each of four guinea-pigs. The patches w ere covered by a strip of "Blenderm" and firmly secured by "Elastoplast" wound round the trunk and fixed with 'sleek impervious plastic adhesive tape. The dressings were removed after an exposure period of approximately 24 hours and the reaction sites were assessed for erythema and oedema. Further examination of the sites was carried out approximately 24 and 48 hours after removal of the dressings.
Based on the results of the preliminary investigations the following concentrations of compound were selected:
Induction intradermal injection - l% vlv in Alembicol D. This was the highest concentation that caused slight irritation but did not adversely affect the animals.
lnduction topical application - as supplied. The test material applied topically as supplied by the Sponsor produced mild to moderate irritation but did not adversely affect the animals.
Topical challenge - 50 and 25% vlv in Alembicol D. From preliminary investigations 50 v/v in Alembicol D was the highest concentration not giving rise to irritating effects


MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: Two (intradermal injection and topical application)
-Test groups: FCA, TS in FCA (50:50 mixture), TS in Alembicol D
- Exposure period: Topical application left for 48 hours, 1 week after intradermal injections.
- Control group: Treated similarly to test animals with the exception that the test substance was omitted. Since there was no vehicle used, the negative control animals received a dry patch. Positive controls received 10% v/v hexyl cinnamic aldehyde (in Alembicol D for the injections) instead of the test substance.
- Site: Scapular region
- Concentrations: Unchanged test substance


B. CHALLENGE EXPOSURE:
- No. of exposures: One
- Day(s) of challenge: Two weeks after the topical induction application.
- Exposure period: Patches were sealed for 24 hours.
- Test groups: 0.2 ml TS in 50% v/v Alembicol D (anterior site), TS in 25% v/v Alembicol D (middle site), Alembicol D only (posterior site).
- Control group: Positive control: HCA in 50% v/v Alembicol and Alembicol only.
- Site: Left flank
- Evaluation (hr after challenge): Observations for clinical effects were conducted on days 1, 7 and 21 after challenge. Challenge sites were evaluated 24 and 48 hours after removal of patches.

Challenge controls:

Negative controls: 0.2 ml of 50 % test material v/v in Alembicol D was applied to the anterior site, 25 % test material v/v in Alembicol D was applied to the middle site and Alembicol D to the posterior site.
Positive controls: Undiluted HCA was applied to the anterior site, 50 % v/v HCA in Alembicol D to the middle site and the vehicle Alembicol D to the posterior site.

Positive control substance(s):

yes

Remarks:

hexyl cinnamic aldehyde

Positive control results:

Intradermal injections: Slight to well defined erythema was observed in positive control animals following topical application with neat hexyl cinnamic aldehyde.
Challenge: All five positive control animals produced evidence of skin sensitisation.

Reading:

1st reading

Hours after challenge:

24

Group:

negative control

Dose level:

25 %, 50 % v/v test material in Alembicol D, and Alembicol D alone

No. with + reactions:

0

Total no. in group:

10

Remarks on result:

no indication of skin sensitisation

Reading:

2nd reading

Hours after challenge:

48

Group:

negative control

Dose level:

25 %, 50 % v/v test material in Alembicol D, and Alembicol D alone

No. with + reactions:

0

Total no. in group:

10

Remarks on result:

no indication of skin sensitisation

Reading:

1st reading

Hours after challenge:

24

Group:

test chemical

Dose level:

25 and 50% v/v in Alembicol D

No. with + reactions:

0

Total no. in group:

20

Remarks on result:

no indication of skin sensitisation

Reading:

2nd reading

Hours after challenge:

48

Group:

test chemical

Dose level:

25 and 50% v/v in Alembicol D

No. with + reactions:

0

Total no. in group:

20

Remarks on result:

no indication of skin sensitisation

Reading:

1st reading

Hours after challenge:

24

Group:

positive control

Dose level:

HCA undiluted, 50 % v/v HCA in Alembicol D, and Alembicol D alone

No. with + reactions:

4

Total no. in group:

5

Remarks on result:

positive indication of skin sensitisation

Reading:

2nd reading

Hours after challenge:

48

Group:

positive control

Dose level:

HCA undiluted, 50 % v/v HCA in Alembicol D, and Alembicol D alone

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:

In the skin sensitisation study, conducted according to OECD 406, and in compliance with GLP, the test material, 1,3,3,5-tetramethyl-1,1,5,5-tetraphenyltrisiloxane, was reported to be not sensitising to the skin of any of the test animals.

Executive summary:

Based on the results of a preliminary study and in compliance with the guideline, an intradermal injection of Dow Corning 704 Diffusion Pump Fluid and 1% v/v in Alembicol D, followed by a topical application of Dow Corning 704 Diffusion Pump Fluid (as supplied) and then a challenge application of Dow Corning 704 Diffusion Pump Fluid, 50 % and 25% v/v in Alembicol D, were administered to guinea-pigs to determine the skin sensitising potential of Dow Corning 704 Diffusion Pump Fluid. Twenty test and ten control guinea-pigs were used in the main study, and five vehicle control and five positive control animals were used in the positive control study. In this study Dow Corning 704 Diffusion Pump Fluid did not produce evidence of skin sensitisation in any of the test animals. All animals in the positive control group produced evidence of skin sensitisation following treatment with hexyl cinnamic aldehyde.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

In the key skin sensitisation study, conducted according to OECD 406, and in compliance with GLP, the read-across test material, 1,3,3,5-tetramethyl-1,1,5,5-tetraphenyltrisiloxane (CAS 3982-82-9), was reported to be not sensitising to the skin of any of the test animals (DCC, 2000).

At induction, 3 intradermal injections of Freund's Complete Adjuvant diluted in water, 1 % (v/v) of test material in Alembicol D, or 1 % (v/v) test material in a 50: 50 mixture of Freund's Complete Adjuvant and Alembicol D, were made intracutaneously to the scapular region of 20 test guinea pigs (day 1). One week later, 0.4 mL of undiluted test substance was applied epicutaneously to the same area for 48 hours, kept in contact with the skin under impermeable plastic adhesive tape.

At challange (two weeks after topical induction application), 0.2 mL of 25 % and 50 % test material in Alembicol D were applied topically to the left flank of each test animal, kept in contact with the skin for 24 hours under impermeable dressing. Dermal recations were evaluated at 24 and 48 hours after removal of the test material. Changes in body weight were recorded on day 1 and the last day of the observation period. At the end of the study period, all the animals were sacrificed and necropsy was performed.

No mortality occurred during the observation period. Expected body weight gain was observed in all the animals. No dermal reactions (erythema or oedema) were noted in any of the test animals at 24 and 48 hours after challenge exposute.

Appropriate negative and positive controls were used and gave expected results.

Read-across justification

There are no available measured data for 1,3,5 -trimethyl-1,1,3,5,5-pentaphenyltrisiloxane (CAS 3390-61-2) for skin sensitisation. This section describes the analogue approach for fulfilling this endpoint by read-across from a source substances, 1,3,3,5 -tetramethyl-1,1,5,5 –tetraphenyltrisiloxane (CAS 3982-82-9) 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

1,3,3,5 -Tetramethyl-1,1,5,5 –tetraphenyltrisiloxane (CAS 3982-82-9) is a linear siloxane with three silicon atoms, connected by two oxygen atoms, in which the Si-O bonds are susceptible to hydrolysis. The terminal silicon atoms are substituted with one methyl and two phenyl groups. Two methyl groups are attached to the middle silicon atom.

The source substance 1,3,3,5 -tetramethyl-1,1,5,5 –tetraphenyltrisiloxane (CAS 3982-82-9) has predicted hydrolysis half-lives of  >5.09 h at pH 5, >329 h (13.7 d) at pH 7, >9.76 h at pH 9  and 25°C. The stated half-life is for removal of parent. Complete reaction to the ultimate end products will take longer. At pH 5 (the pH of skin, 5), the hydrolysis rate is greater than 5.9 hours. The products of hydrolysis are methyl(diphenyl)silanol and dimethylsilanediol. As the substance is highly insoluble in water and hydrolysis is not considered to be relevant.

The source substance has log Kow of 9 at 20-25°C (QSAR), water solubility of 5.9E-09 mg/l at 20-25°C (QSAR) and vapour pressure of 0.00000052 Pa at 25°C (QSAR).

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

Both 1,3,5-trimethyl-1,1,3,5,5-pentaphenyltrisiloxane (CAS 3390-61-2) and 1,3,3,5 -tetramethyl-1,1,5,5 –tetraphenyltrisiloxane (CAS 3982-82-9) are linear siloxanes with three silicon atoms, connected by two oxygen atoms, in which the Si-O bonds are susceptible to hydrolysis. The terminal silicon atoms are substituted with one methyl and two phenyl groups in both the registered substance, 1,3,5-trimethyl-1,1,3,5,5-pentaphenyltrisiloxane (CAS 3390-61-2) and the read-across substance, 1,3,3,5 -tetramethyl-1,1,5,5 –tetraphenyltrisiloxane (CAS 3982-82-9). One methyl and one phenyl groups are attached to the middle silicon atom in the registered substance, 1,3,5-trimethyl-1,1,3,5,5-pentaphenyltrisiloxane (CAS 3390-61-2), and two methyl groups in the read-across substance, 1,3,3,5 -tetramethyl-1,1,5,5 –tetraphenyltrisiloxane (CAS 3982-82-9).

Both substances hydrolyse to two silicon-containing hydrolysis products. The ultimate products of hydrolysis for the registered substance, 1,3,5-trimethyl-1,1,3,5,5-pentaphenyltrisiloxane (CAS 3390-61-2), and the read-across substance, 1,3,3,5 -tetramethyl-1,1,5,5 –tetraphenyltrisiloxane (CAS 3982-82-9), are two molecules of methyl(diphenyl)silanol and one molecule of phenylmethylsilanediol, and two molecules of methyl(diphenyl)silanol and one molecule of dimethylsilanediol, respectively.  

Table 2: Physico-chemical properties

	Target (registration substance)	Source (read-across substance)
CAS number	3390-61-2	3982-82-9
EC number	222-222-9	223-620-5
Chemical Name	1,3,5-trimethyl-1,1,3,5,5-pentaphenyltrisiloxane	1,3,3,5 -tetramethyl-1,1,5,5 –tetraphenyltrisiloxane
Molecular weight  (gmol^-1)	546.89	484.82
log Kow(parent)	9 at 20°C (QSAR)	9 at 20-25°C (QSAR)
Water solubility (parent)	0 mg/L at 20-25°C (QSAR)	5.9E-09 mg/l at 20-25°C (QSAR)
Vapour pressure (parent)	0.000000013 Pa at 25°C (QSAR)	0.00000052 Pa at 25°C (QSAR)
Hydrolysis at pH 5, 20-25°C	>5.09 h (QSAR)	>5.09 h (QSAR)

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

In the key skin sensitisation study, conducted according to OECD 406, and in compliance with GLP, the read-across test material, 1,3,3,5-tetramethyl-1,1,5,5-tetraphenyltrisiloxane (CAS 3982-82-9), was reported to be not sensitising to the skin of any of the test animals (DCC, 2000).

At induction, 3 intradermal injections of Freund's Complete Adjuvant diluted in water, 1 % (v/v) of test material in Alembicol D, or 1 % (v/v) test material in a 50: 50 mixture of Freund's Complete Adjuvant and Alembicol D, were made intracutaneously to the scapular region of 20 test guinea pigs (day 1). One week later, 0.4 mL of undiluted test substance was applied epicutaneously to the same area for 48 hours, kept in contact with the skin under impermeable plastic adhesive tape.

At challange (two weeks after topical induction application), 0.2 mL of 25 % and 50 % test material in Alembicol D were applied topically to the left flank of each test animal, kept in contact with the skin for 24 hours under impermeable dressing. Dermal reactions were evaluated at 24 and 48 hours after removal of the test material. Changes in body weight were recorded on day 1 and the last day of the observation period. At the end of the study period, all the animals were sacrificed and necropsy was performed.

No mortality occurred during the observation period. Expected body weight gain was observed in all the animals. No dermal reactions (erythema or oedema) were noted in any of the test animals at 24 and 48 hours after challenge exposure.

Appropriate negative and positive controls were used and gave expected results.

4.       AE A.4 Bias that influences the prediction

Data on the source substance 1,3,3,5 -tetramethyl-1,1,5,5 –tetraphenyltrisiloxane (CAS 3982-82-9) were read-across to the registered (target) substance 1,3,5 -trimethyl-1,1,3,5,5-pentaphenyltrisiloxane (CAS 3390-61-2). The source substances and the target substance have similar chemical structure and physico-chemical properties. both substances hydrolyse at similar rate. Both substances hydrolyse to two silicon-containing hydrolysis products. The ultimate products of hydrolysis for the registered substance, 1,3,5-trimethyl-1,1,3,5,5-pentaphenyltrisiloxane (CAS 3390-61-2), and the read-across substance, 1,3,3,5 -tetramethyl-1,1,5,5 –tetraphenyltrisiloxane (CAS 3982-82-9), are two molecules of methyl(diphenyl)silanol and one molecule of phenylmethylsilanediol, and two molecules of methyl(diphenyl)silanol and one molecule of dimethylsilanediol, respectively.

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

The source substance as well as the target substance are highly insoluble in water and hydrolysis is not considered to be relevant. Therefore, the test organism is expected to be exposed mainly to the parent substances. However, this read-across justification considers possible exposure to the hydrolysis products too.  

Data on irritation potential of diphenylsilanediol (CAS 947-42-2) and trimethylsilanol (CAS 1066-40-2), which have phenyl/methyl and silanol/silanediol groups are also available. These are the most closely related data to skin sensitisation for the hydrolysis products. The substances, diphenylsilanediol (CAS 947-42-2) and trimethylsilanol (CAS 1066-40-2), were reported to be not irritating to the skin or eyes of rabbits. Thus, it is concluded that phenyl/methyl and silanol/silanediol groups have no irritating potential to skin and the same effect will be observed in the target and source substances.

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 1,3,5-trimethyl-1,1,3,5,5-pentaphenyltrisiloxane (CAS 3390-61-2), therefore data are read-across from the structurally analogous substance 1,3,3,5 -tetramethyl-1,1,5,5 –tetraphenyltrisiloxane (CAS 3982-82-9). Both substances hydrolyse at similar rates to two molecules of methyl(diphenyl)silanol and one molecule of phenylmethylsilanediol, and two molecules of methyl(diphenyl)silanol and one molecule of dimethylsilanediol, respectively.

The phenyl/methyl and silanol/silanediol groups are not expected to have any sensitising potential. 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, 1,3,5-trimethyl-1,1,3,5,5-pentaphenyltrisiloxane (CAS 3390-61-2), nor the source substance, 1,3,3,5 -tetramethyl-1,1,5,5 –tetraphenyltrisiloxane (CAS 3982-82-9), have impurities of toxicological concern.

The test substance in the study with the source substance, 1,3,3,5 -tetramethyl-1,1,5,5 –tetraphenyltrisiloxane (CAS 3982-82-9), has been identified as pure.  According to the substance composition, however, the substance has purity of > 80% with polyphenyl-siloxane impurities present at >1%. No other impurities have been identified to be present at concentration higher than > 0.1%.

The target substance, 1,3,5-trimethyl-1,1,3,5,5-pentaphenyltrisiloxane (CAS 3390-61-2), has a purity of >95% and no impurities are present at >1%. Phenyl-siloxane impurities have been identified.

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

Not relevant.

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

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Based on the available data for the read-across substance 1,3,3,5-tetramethyl-1,1,5,5-tetraphenyltrisiloxane (CAS 3982-82-9), no classification for the registered substance, 1,3,5-trimethyl-1,1,3,5,5-pentaphenyltrisiloxane (CAS 3390 -61 -2) for skin sensitisation is proposed according to Regulation (EC) No. 1272/2008.