Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

No Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test was available for the submission substance; therefore, data were read-across from a structural analogue.

In a Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test, performed according to OECD TG 422, and in compliance with GLP, no biologically significant, treatment-related effects on reproduction were reported in rats for 1,3,5-trimethyl-1,1,3,5,5-pentaphenyltrisiloxane by oral gavage at 100, 500, 1000 mg/kg bw/day. A NOAEL of ≥1000 mg/kg bw/day was derived (DCC, 2005).

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2004-09-14 to 2005-02-21
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
yes
Remarks:
There is a discrepancy about treatment duration of females between executive summary and treatment regime paragraph. Also, the pups were killed on postnatal day 4.
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories Inc., United States
- Age at study initiation: 7 weeks
- Weight at study initiation:
Females: 189.8 to 237.2 g
Males: 285.5 to 357.1 g
- Fasting period before study: none
- Housing: individually housed individually in suspended wire-mesh cages during quarantine and throughout the course of the study.
- Diet: Certified rodent diet, ad libitum
- Water: Municipal water, ad libitum
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°F): 64-79°F
- Humidity (%): 30-70 %
- Air changes (per hour): 10-15/hour
- Photoperiod (hours dark / hours light): 12/12
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Dosing solutions were prepared twice during the course of the study. Corn oil was the chosen vehicle. The test substance was weighed then enough vehicle was added to obtain the correct volume.

VEHICLE
- Justification for use and choice of vehicle (if other than water): Corn oil was the chosen vehicle in the 14-day range-finding study.
- Concentration in vehicle: no data
- Amount of vehicle (if gavage): no data
- Lot/batch no. (if required): 1st preparation 122K0131; 2nd preparation 103K0107
- Purity: As provided by the manufacturer
Details on mating procedure:
- M/F ratio per cage: A 1:1 mating ratio was used.
- Length of cohabitation: The female animals were housed continuously with the same male until evidence of mating occurred.
- Proof of pregnancy: presence of a vaginal plug and/or sperm in vaginal smear referred to as day 0 of pregnancy
- After successful mating each pregnant female was caged: individually
- Any other deviations from standard protocol: no
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Dosing solutions analysis were analysed by CG/FID to verify concentration, stability and homogeneity of the test substance in the vehicle. Prior to the experiment, a high dose solution was prepared and stability testing was performed on days 0, 14, 35 and 50. Following the second preparation of dose solutions, homogeneity analysis of the low and high dose solutions was conducted on day 0 and stability analysis of the low dose solution was conducted on days 0 and 50. Concentration verification was of the dose solutions was conducted on the day of the first preparation and prior to the end of dosing.
Duration of treatment / exposure:
Both males and females were treated with the test substance for 2 weeks prior to mating period and continued through the mating period. Males were treated for 92 days and females were treated up to and including postpartum day 3 according to treatment regime paragraph in the study report or up to gestation day 19 according to the execute summary in the study report.
Frequency of treatment:
Daily, 7 days a week
Details on study schedule:
- parental animals not mated until 2 weeks after selection.
- Age at mating of the mated animals in the study: 9 weeks
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Dose / conc.:
500 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
10 males and 10 females per dose
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: Dose levels were determined based on the results of a 14-day range-finding study. Doses were administered at a volume of 2 mL/kg of body weighed. The administered volumes were based on the weekly scheduled body weights.

Positive control:
Not used
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: prior to start of treatment and on week 12 of the treatment period.
- Cage side observations included: abnormal muscle movements (tremors, convulsions), abnormal behaviour, posture and resistance to removal.

DETAILED CLINICAL OBSERVATIONS: Yes. The general health conditions of the animals were recorded. Detailed physical examinations included changes in skin, fur, eyes, mucous membranes, occurrence of secretions and excretions, and autonomic activity. Changes in gait, posture, and response to handling as well as the presence of clonic or tonic movements, stereotypes, bizarre behaviour were also recorded.
- Time schedule: once a day for general observations; detailed observations were performed before the first dose and once a week thereafter

BODY WEIGHT: Yes
- Time schedule for examinations: on the first day of dosing, then once a week and on the day of necropsy. During gestation the females were weighed on gestation days 0, 7, 14 and 20, within 24 hours after parturition, and day 4 postpartum.

OTHER:
FOOD CONSUMPTION: Yes
- Time schedule for examination: Individual food consumption for male animals was recorded on the first day of dosing, weekly thereafter until the day of necropsy with an exception of the two week mating period. Female animals' food consumption was recorded on days 1, 8, 15, and on gestation days 0, 7, 14 and 20, and on day 4 postpartum.
Oestrous cyclicity (parental animals):
Not examined.
Sperm parameters (parental animals):
Parameters examined in adult control and high dose males: testis weight, epididymis weight
Litter observations:
STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: no

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring: number and sex of pups, stillbirths, live births, presence of gross anomalies, weight gain

GROSS EXAMINATION OF DEAD PUPS: yes, for external abnormalities only
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals were sacrificed at the end of the treatment period.
- Maternal animals: All surviving female animals were euthanized on postpartum day 4. The females that did not deliver were euthanized on gestation day 25 or 26.

GROSS NECROPSY
- Gross necropsy consisted of examination of the external surface and all orifices of the body, the cranial, thoracic and abdominal cavities and their contents in male animals. For pregnant females, the number of corpora lutea and the number of implantation sites were recorded. For 8 females with positive evidence of mating that failed to produce litter, the uteri were stained to enable counting of possible reabsorbed implant sites.

HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated in Table [No.1] were prepared for microscopic examination and weighed, respectively.
Postmortem examinations (offspring):
SACRIFICE
- The F1 offspring were sacrificed at 4 days of age.
- These animals were subjected to postmortem macroscopic examinations only.
GROSS NECROPSY
- Gross necropsy consisted of external examinations.

HISTOPATHOLOGY / ORGAN WEIGTHS
No pup tissues were collected.
Statistics:
ANCOVA (Analysis of Covariance): used for analysis of reproductive parameters
ANOVA: used for analysis of litter size
Reproductive indices:
The evaluated reproductive indices were: mean gestation length, mean number of implantation sites, mean number of corpora lutea, mean mating and fertility indices
Offspring viability indices:
The evaluated offspring viability indices were: mean litter size, mean live litter size, mean litter weight, mean ration live births/ litter size
Clinical signs:
no effects observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
no effects observed
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS): No clinical signs or mortality were noted among male and female animals.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS): No statistically significant differences among male exposure groups were noted. The female reproductive groups showed statistically significant differences in body weights for gestation week 2. The observed changes were not considered toxicologically significant. There were no statistically significant changes in the average daily food consumption.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS): There were no treatment-related effects apparent for any of the reproductive endpoints. Three females in 0 and 500 mg/kg/day groups had positive evidence of mating and were non-pregnant. One female in 100 mg/kg/day had positive evidence on mating and was non-pregnant. One female in 1000 mg/kg/day group was found with one past term foetus at necropsy.

ORGAN WEIGHTS (PARENTAL ANIMALS): There were no statistically significant changes in organ weights in male animals.

GROSS PATHOLOGY (PARENTAL ANIMALS): There were no gross morphological changes noted in test animals.

HISTOPATHOLOGY (PARENTAL ANIMALS): There were no histopathological changes noted in male animals (male animals examined only).

Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects observed
Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
not examined
VIABILITY (OFFSPRING): No test-substance induced effect was observed.

CLINICAL SIGNS (OFFSPRING): No test-substance induced effect was observed.

BODY WEIGHT (OFFSPRING): No test-substance induced effect was observed.

GROSS PATHOLOGY (OFFSPRING): No test-substance induced effect was observed.


Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects observed
Key result
Reproductive effects observed:
no

Table 1: Mean reproductive parameters for reproductive group female rats

 

 

Litter

Initial

Final

 

 

 

Days gestation

Male pups

Female pups

Males/females

Total pups

Day 4 viable pups

Viable/ total

Litter weight (g)

Average pup weight (g)

Litter weight (g)

Average pup weight (g)

Total implants

Corpora lutea

Group 1

 Control

Mean

22

8.4

7.9

1.1

16.3

15.4

0.9

108.9

6.7

160.5

10.5

17.0

22.6

N

7A

7

7

7

7

7

7

7

7

7

7

7

7

Group 2

200 mg/kg bw/day 

Mean

21.9

7.0

8.1

0.9

15.1

14.7

1.0

95.6

6.3

150.2

10.3

16.6

21.3

N

9A

9

9

9

9

9

9

9

 

9

9

9

9

Group 3

 500 mg/kg bw/day

Mean

21.7

6.1

9.6

0.7

15.7

15.3

1.0

99.9

6.4

152.7

10.0

16.4

18.0

N

7A

7

7

7

7

7

7

7

7

7

7

7

7

Group 4

 1000 mg/kg bw/day

Mean

21.8

6.9

8.8

0.9

15.7

15.1

1.0

98.9

6.3

147.2

9.8

16.6

20.9

N

9B

9

9

9

9

9

9

9

9

9

9

9

9

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A: data of non-pregnant females with positive evidence of mating not included in calculations

B: data of female that failed to deliver not included in calculations

Table 2: Summary of reproductive performance for reproductive group female rats

 

Group 1 (control)

Group 2 (200 mg/kg bw/day)

Group 3 (500 mg/kg bw/day)

Group 4 (1000 mg/kg bw/day)

Females on study

10

10

10

10

Females that died during study

0

0

0

0

Females euthanized in extremis

0

0

0

0

Females allowed to deliver

10

10

10

10

Nongravid

3

1

3

0

Gravid

7

9

7

10

Females with evidence of copulation

10

10

10

10

Number which delivered

7

9

7

9

Number which did not deliver

3

1

3

1

Females with no evidence of copulation

0

0

0

0

Number which delivered

0

0

0

0

Number which did not deliver

0

0

0

0

Conclusions:
In a Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test in rats for 1,3,5-trimethyl-1,1,3,5,5-pentaphenyltrisiloxane, the reported NOAEL value for P and F1 was >= 1000 mg/kg/day.
Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Species:
rat
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

No Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test was available for the submission substance; therefore, data were read-across from a structural analogue.

In a Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test, performed according to OECD TG 422 with acceptable restrictions, and in compliance with GLP, no biologically significant, treatment-related effects on reproduction were reported in rats for 1,3,5-trimethyl-1,1,3,5,5-pentaphenyltrisiloxane by oral gavage at 100, 500, 1000 mg/kg bw/day. A NOAEL of ≥1000 mg/kg bw/day was derived for parental animals and offspring (DCC, 2005).

Following daily oral administration of 100, 500, 1000 mg/kg bw/day of test substance in corn oil to 10 male and 10 female rats, no test substance-related mortality or clinical signs of toxicity occurred in parental animals or pups. There was no test substance-related effect on reproductive performance of parental animals. No macroscopic abnormalities were noted in any of the test animals or pups at necropsy. No changes were evident in any of the treated males at histopathological examinations.

Both males and females were treated with the test substance for 2 weeks prior to mating period and continued through the mating period. Males were treated for 92 days and females were treated up to and including postpartum day 3 according to treatment regime paragraph in the study report or up to gestation day 19 according to the execute summary in the study report. Offsprings were observed until postpartum day 4. Necropsy was performed to all the test animals and pups at the end of the study period. A negative control group was included and gave the expected results.

Read-across justification

There are no available measured data for Reaction Mass of 3,3-diphenylhexamethyltrisiloxane; 3,3,5,5-tetraphenylhexamethyltetrasiloxane and 3-trimethylsiloxy-3,5,5-triphenylhexamethyltetrasiloxane (CAS 352230-22-9) for reproductive and developmental toxicity. Therefore, the Annex requirements are fulfilled by data on structurally analogous substances. The analogue approach for fulfilling this endpoint by read-across from one source substance, 1,3,5-trimethyl-1,1,3,5,5-pentaphenyltrisiloxane (CAS 3390-61-2), according to the Read-across Assessment Framework (RAAF) is discussed.

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 5.9.3) according to RAAF scenario 2 assessment elements (AE) as outlined in Table B1 of the RAAF:

Table 5.9.3. RAAF scenario 2 assessment elements (AE) as given in Appendix B (Table B1) of the RAAF

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, 1,3,5-trimethyl-1,1,3,5,5-pentaphenyltrisiloxane (CAS 3390-61-2), is a linear trisiloxane with phenyl and methyl groups bound to silicon. The substance is highly insoluble in water.  Therefore, hydrolysis half-lives and hydrolysis products are not relevant for this endpoint as hydrolysis is expected to be very slow.

The source substance has a log Kow of 9 at 20°C (QSAR), vapour pressure of 1.3E-08 Pa at 25°C (QSAR) and water solubility of 9.0E-11 mg/L at 20°C (QSAR).

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

Reaction Mass of 3,3-diphenylhexamethyltrisiloxane and 3,3,5,5-tetraphenylhexamethyltetrasiloxane is a multi-constituent substance containing two main constituents 3,3-diphenylhexamethyltrisiloxane (55-70%) and 3,3,5,5-tetraphenylhexamethyltetrasiloxane (15-25%).

The read-across substance, 1,3,5-trimethyl-1,1,3,5,5-pentaphenyltrisiloxane (CAS 3390-61-2), is structurally similar to the main constituent of the submission substance because they are both linear trisiloxanes with phenyl and methyl groups bound to silicon. The difference is that read-across substance has 5 phenyl groups and 3 methyl groups and the main constituent of the submission substance has 2 phenyl groups and 6 methyl groups. The second constituent of the submission substance is also a structural analogue of the read-across substance but has a longer siloxane chain (4 silicon atoms instead of 3, with 4 phenyl groups and 6 methyl groups).

Both the source and the target substances have consistent physicochemical properties. They have very high log Kow, very low water solubility, very low vapour pressure and slow hydrolysis.

Table 5.9.4. Physicochemical properties of the target and source substances

Property

Target substance

Source substance

Substance name

Reaction Mass of 3,3-diphenylhexamethyltrisiloxane; 3,3,5,5-tetraphenylhexamethyltetrasiloxane; 3-trimethylsiloxy-3,5,5-triphenylhexamethyltetrasiloxane

1,3,5-Trimethyl-1,1,3,5,5-pentaphenyltrisiloxane

CAS number

352230-22-9

3390-61-2

Hydrolysis half-life at pH 7

>200 h for Constituent 1

>630 h for Constituent 2

> 200 h

Log Kow value

9.0 at 20°C for Constituent 1 and Constituent 2 of the submission substance

9.0 at 20°C (QSAR)

Vapour pressure

0.068 Pa at 25°C (whole substance) (OECD 104)

3.6E-03 Pa at 25°C (QSAR, Constituent 1)

1.3E-07 Pa at 25°C (QSAR, Constituent 2)

1.3E-08 Pa at 25°C (QSAR)

Water solubility

<0.5234 mg/L at 20°C (whole substance) (OECD 105)

Constituent 1: 2.8E-05 mg/L at 20°C (QSAR)

Constituent 2: 1.5E-10 mg/L at 20°C (QSAR)

9.0E-11 mg/L at 20°C (QSAR)

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

In a Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test, performed according to OECD TG 422 with acceptable restrictions, and in compliance with GLP, no biologically significant, treatment-related effects were reported in rats given 1,3,5-trimethyl-1,1,3,5,5-pentaphenyltrisiloxane, by oral gavage at 100, 500, 1000 mg/kg bw/day. A NOAEL of >1000 mg/kg bw/day was derived (DCC, 2005).

Following daily oral administration of 100, 500, 1000 mg/kg bw/day test substance in corn oil to 10 male and 10 female rats for 90 days, no test substance-related mortality or clinical signs of toxicity occurred during the study period. No macroscopic abnormalities in organs and tissues were noted at pathological and histopathological examinations in any of the test animals. No changes were reported at haematology and clinical chemistry examinations. A negative control group was included and treated with 0 mg/kg bw/day test substance in corn oil. On day 65 one control animal was found dead due to unknown reasons. The rest of the control animals gave the expected results.

4.       AE A.4 Bias that influences the prediction

Data on the source substance 1,3,5-trimethyl-1,1,3,5,5-pentaphenyltrisiloxane (CAS 3390-61-2) were read-across to the registered (target) substance (CAS 352230-22-9). The source substance and the target substance have similar chemical structure and physicochemical properties. Both hydrolyse very slowly, and it is considered that the test organism would be exposed to the parent substances. Their toxicological properties are expected to be similar, with similar target organ toxicity, reproductive and developmental toxicity. 1,3,5-Trimethyl-1,1,3,5,5-pentaphenyltrisiloxane (CAS 3390-61-2) is the closest structural analogue with available data.

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

The source substance as well as the target substance hydrolyse very slowly in contact with water. Therefore, their hydrolysis products are not considered to be relevant as the test organism would mainly be exposed to the parent substances. The source and target substance have consistent toxicological properties and none of the substances has been identified to be of any toxicological concern.

6.       AE A.2.2 and A.2.3 Common underlying mechanism, qualitative and quantitative aspects

Acute and sub-acute toxicity data via oral route are available for the target substance. Following a single oral gavage administration of 2000 mg/kg bw test substance in corn oil to female rats, no mortality was observed in any of the test animals during the 14-day study period. Slightly ruffled fur was noted in two animals at 1-hour reading and persisted up to 3-hour reading in one animal. The body weight of the animals was within the range commonly recorded for this strain and age. No macroscopic findings were recorded at necropsy. The reported LD50 value was greater than 2000 mg/kg bw.

A sub-acute repeated dose toxicity study via oral route was available for the registration substance (RCC, 2004f). The test substance was administered daily by oral gavage to SPF-bred Wistar rats of both sexes at dose levels of 200, 600 and 1000 mg/kg body weight for a period of 28 days. A control group received the vehicle, corn oil, at the same dose volume (5 ml/kg body weight). All animals survived until scheduled necropsy. No test item-related clinical signs, body weight changes, neurobehavioral changes, or food consumption changes were noted in any of the test animals. There were hepatic findings that were considered to be a metabolic adaptation to treatment with the test item. The clinical biochemistry findings reflected this. Moreover, there was a thyroid finding that was considered to be a secondary finding following hepatic hypertrophy, i.e. due to increased metabolic turnover of thyroid hormones. Based on these findings, no adverse effects were seen in this study and the NOAEL (no-observed- adverse-effect-level) was considered to be greater than 1000 mg/kg.

No reproductive or developmental toxicity data are available for the registered substance. Therefore, data are read-across from the structurally analogous substance 1,3,5-trimethyl-1,1,3,5,5-pentaphenyltrisiloxane (CAS 3390-61-2). Both substances have consistent physicochemical properties. They have very high log Kow, very low water solubility, very low vapour pressure and slow hydrolysis. Hydrolysis products are different but considering the long hydrolysis half-lives and high log Kow the test organisms would be exposed to the parent substances. The hydrolysis products are all di- and trisilanols with phenyl and methyl substituents.

Moreover, there were no adverse effects in the Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test for the source substance. These findings were in line with the reported results for the subacute oral toxicity study for the registered substance.  

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

Neither the target substance, Reaction Mass of 3,3-diphenylhexamethyltrisiloxane and 3,3,5,5-tetraphenylhexamethyltetrasiloxane, nor the source substance, 1,3,5-trimethyl-1,1,3,5,5-pentaphenyltrisiloxane, have impurities of toxicological concern.

The test substance in the study with the source substance, 1,3,5-trimethyl-1,1,3,5,5-pentaphenyltrisiloxane, has an analytical purity of 99.7%.

The target substance, Reaction Mass of 3,3-diphenylhexamethyltrisiloxane and 3,3,5,5-tetraphenylhexamethyltetrasiloxane

(CAS 352230-22-9) is a multi-constituent substance containing two main constituents, 3,3-diphenylhexamethyltrisiloxane present at concentration of 55-70% and 3,3,5,5-tetraphenylhexamethyltetrasiloxane at concentration of 15-25%. The impurities are linear and branched siloxanes with 4-7 silicon atoms and phenyl/methyl substituents. These are structural analogues of the main constituents and share the same physicochemical properties (very high log Kow, very low water solubility, very low vapour pressure, slow hydrolysis).

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

Not relevant

Effects on developmental toxicity

Description of key information

No Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test was available for the submission substance; therefore, data were read-across from a structural analogue.

In the key Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test, performed according to OECD TG 422 with acceptable restrictions, and in compliance with GLP, no biologically significant, treatment-related developmental toxicity was reported in rats for 1,3,5-trimethyl-1,1,3,5,5-pentaphenyltrisiloxane by oral gavage at 100, 500, 1000 mg/kg bw/day. A NOAEL of ≥1000 mg/kg bw/day for maternal and developmental toxicity was derived (DCC, 2005).

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2004-09-14 to 2005-02-21
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Qualifier:
according to
Guideline:
other: OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
yes
Remarks:
There is a discrepancy about treatment duration of females between executive summary and treatment regime paragraph. Also, the pups were killed on postnatal day 4.
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories Inc., United States
- Age at study initiation: 7 weeks
- Weight at study initiation:
Females: 189.8 to 237.2 g
Males: 285.5 to 357.1 g
- Fasting period before study: none
- Housing: individually housed individually in suspended wire-mesh cages during quarantine and throughout the course of the study.
- Diet: Certified rodent diet, ad libitum
- Water: Municipal water, ad libitum
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°F): 64-79°F
- Humidity (%): 30-70 %
- Air changes (per hour): 10-15/hour
- Photoperiod (hours dark / hours light): 12/12
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Dosing solutions were prepared twice during the course of the study. Corn oil was the chosen vehicle. The test substance was weighed then enough vehicle was added to obtain the correct volume.

VEHICLE
- Justification for use and choice of vehicle (if other than water): Corn oil was the chosen vehicle in the 14-day range-finding study.
- Concentration in vehicle: no data
- Amount of vehicle (if gavage): no data
- Lot/batch no. (if required): 1st preparation 122K0131; 2nd preparation 103K0107
- Purity: As provided by the manufacturer
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Dosing solutions analysis were analysed by CG/FID to verify concentration, stability and homogeneity of the test substance in the vehicle. Prior to the experiment, a high dose solution was prepared and stability testing was performed on days 0, 14, 35 and 50. Following the second preparation of dose solutions, homogeneity analysis of the low and high dose solutions was conducted on day 0 and stability analysis of the low dose solution was conducted on days 0 and 50. Concentration verification was of the dose solutions was conducted on the day of the first preparation and prior to the end of dosing.
Details on mating procedure:
- M/F ratio per cage: A 1:1 mating ratio was used.
- Length of cohabitation: The female animals were housed continuously with the same male until evidence of mating occurred.
- Proof of pregnancy: presence of a vaginal plug and/or sperm in vaginal smear referred to as day 0 of pregnancy
- After successful mating each pregnant female was caged: individually
- Any other deviations from standard protocol: no
Duration of treatment / exposure:
Both males and females were treated with the test substance for 2 weeks prior to mating period and continued through the mating period. Males were treated for 92 days and females were treated up to and including postpartum day 3 according to treatment regime paragraph in the study report or up to gestation day 19 according to the execute summary in the study report.
Frequency of treatment:
Daily, 7 days a week
Duration of test:
Males: 92 days
Females: treated up to and including postpartum day 3 according to treatment regime paragraph in the study report or up to gestation day 19 according to the execute summary in the study report.
No. of animals per sex per dose:
10 males and 10 females per dose
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: Dose levels were determined based on the results of a 14-day range-finding study. Doses were administered at a volume of 2 mL/kg of body weighed. The administered volumes were based on the weekly scheduled body weights.

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Prior to the start of treatment and during the 12th week of the study
- Cage side observations included: abnormal muscle movements, abnormal behaviour, posture and resistance to removal

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: General clinical observations were made once a day throughout the treatment period. All animals received detailed physical observations once before the start of the treatment and weekly thereafter.

BODY WEIGHT: Yes
- Time schedule for examinations: Individual body weights were determined prior to the treatment, on the first day of dosing, then weekly and on the day of necropsy. During gestation females were weighed on gestation days 0, 7, 14 and 20, within 24 hours after parturition, and on day 4 postpartum.

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # Females were euthanized on postpartum day 4. Mated females that did not deliver were euthanized on gestation days 25 or 26.
- Organs examined: For pregnant females, the number of corpora lutea and the number of implantation sites were recorded. For the females that failed to produce litter the uteri were examined to determine possible reabsorbed implant sites.

OTHER:
FOOD CONSUMPTION: Yes
- Time schedule for examination: Individual male animals' food consumption was recorded on the first day of dosing, weekly thereafter until the day of necropsy with an exception of the two week mating period. Female animals' food consumption was recorded on days 1, 8, 15, and on gestation days 0, 7, 14 and 20, and on day 4 postpartum.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of resorptions: Yes
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: No
- Skeletal examinations: No
- Head examinations: Yes
Statistics:
- ANCOVA was used to analyse Reproductive Parameters.
- ANOVA was used to analyse litter size.
Indices:
The evaluated indices were: mean litter size, mean live litter size, mean litter weight, mean ratio live births/litter size
Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
No treatment-related toxic effect was noted in female animals.
Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: No adverse effects observed
Key result
Abnormalities:
no effects observed
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No treatment-related toxic effect was noted in pups.
Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects observed
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
no

Table 1: Mean reproductive parameters for reproductive group female rats

 

 

Litter

Initial

Final

 

 

 

Days gestation

Male pups

Female pups

Males/females

Total pups

Day 4 viable pups

Viable/ total

Litter weight (g)

Average pup weight (g)

Litter weight (g)

Average pup weight (g)

Total implants

Corpora lutea

Group 1

 

Mean

22

8.4

7.9

1.1

16.3

15.4

0.9

108.9

6.7

160.5

10.5

17.0

22.6

N

7A

7

7

7

7

7

7

7

7

7

7

7

7

Group 2

 

Mean

21.9

7.0

8.1

0.9

15.1

14.7

1.0

95.6

6.3

150.2

10.3

16.6

21.3

N

9A

9

9

9

9

9

9

9

 

9

9

9

9

Group 3

 

Mean

21.7

6.1

9.6

0.7

15.7

15.3

1.0

99.9

6.4

152.7

10.0

16.4

18.0

N

7A

7

7

7

7

7

7

7

7

7

7

7

7

Group 4

 

Mean

21.8

6.9

8.8

0.9

15.7

15.1

1.0

98.9

6.3

147.2

9.8

16.6

20.9

N

9B

9

9

9

9

9

9

9

9

9

9

9

9

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A: data of non-pregnant females with positive evidence of mating not included in calculations

B: data of female that failed to deliver not included in calculations

Table 2: Summary of reproductive performance for reproductive group female rats

 

Group 1 (control)

Group 2 (200 mg/kg bw/day)

Group 3 (500 mg/kg bw/day)

Group 4 (1000 mg/kg bw/day)

Females on study

10

10

10

10

Females that died during study

0

0

0

0

Females euthanized in extremis

0

0

0

0

Females allowed to deliver

10

10

10

10

Nongravid

3

1

3

0

Gravid

7

9

7

10

Females with evidence of copulation

10

10

10

10

Number which delivered

7

9

7

9

Number which did not deliver

3

1

3

1

Females with no evidence of copulation

0

0

0

0

Number which delivered

0

0

0

0

Number which did not deliver

0

0

0

0

Conclusions:
In a Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test in rats for 1,3,5-trimethyl-1,1,3,5,5-pentaphenyltrisiloxane , the reported NOAEL value for maternal and developmental toxicity was >= 1000 mg/kg/day.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Species:
rat
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

No Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test was available for the submission substance; therefore, data were read-across from a structural analogue.

In a Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test, performed according to OECD TG 422 with acceptable restrictions, and in compliance with GLP, no biologically significant, treatment-related maternal or developmental toxicity was reported in rats given 1,3,5-trimethyl-1,1,3,5,5-pentaphenyltrisiloxane by oral gavage at 100, 500, 1000 mg/kg bw/day. A NOAEL of ≥1000 mg/kg bw/day for maternal and developmental toxicity was derived (DCC, 2005).

All 10 female animals were treated with the test substance for 2 weeks prior to mating period, throughout the mating period, and up to and including postpartum day 3 according to treatment regime paragraph in the study report or up to gestation day 19 according to the execute summary in the study report. Pups were observed until postpartum day 4. No abnormalities were noted in any of the test females during examination of ovaries and uterine content. No abnormalities were evident in any of the pups during external examinations. Negative control group was included and gave the expected results.

Read-across justification

There are no available measured data for Reaction Mass of 3,3-diphenylhexamethyltrisiloxane and 3,3,5,5-tetraphenylhexamethyltetrasiloxane (CAS 352230-22-9) for reproductive and developmental toxicity. Therefore, the Annex requirements are fulfilled by data on structurally analogous substances. The analogue approach for fulfilling this endpoint by read-across from one source substance, 1,3,5-trimethyl-1,1,3,5,5-pentaphenyltrisiloxane (CAS 3390-61-2), according to the Read-across Assessment Framework (RAAF) is discussed.

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 5.9.5) according to RAAF scenario 2 assessment elements (AE) as outlined in Table B1 of the RAAF:

Table 5.9.3. RAAF scenario 2 assessment elements (AE) as given in Appendix B (Table B1) of the RAAF

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, 1,3,5-trimethyl-1,1,3,5,5-pentaphenyltrisiloxane (CAS 3390-61-2), is a linear trisiloxane with phenyl and methyl groups bound to silicon. The substance is highly insoluble in water.  Therefore, hydrolysis half-lives and hydrolysis products are not relevant for this endpoint as hydrolysis is expected to be very slow.

The source substance has a log Kow of 9 at 20°C (QSAR), vapour pressure of 1.3E-08 Pa at 25°C (QSAR) and water solubility of 9.0E-11 mg/L at 20°C (QSAR).

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

Reaction Mass of 3,3-diphenylhexamethyltrisiloxane and 3,3,5,5-tetraphenylhexamethyltetrasiloxane is a multi-constituent substance containing two main constituents 3,3-diphenylhexamethyltrisiloxane (55-70%) and 3,3,5,5-tetraphenylhexamethyltetrasiloxane (15-25%).

The read-across substance, 1,3,5-trimethyl-1,1,3,5,5-pentaphenyltrisiloxane (CAS 3390-61-2), is structurally similar to the main constituent of the submission substance because they are both linear trisiloxanes with phenyl and methyl groups bound to silicon. The difference is that read-across substance has 5 phenyl groups and 3 methyl groups and the main constituent of the submission substance has 2 phenyl groups and 6 methyl groups. The second constituent of the submission substance is also a structural analogue of the read-across substance but has a longer siloxane chain (4 silicon atoms instead of 3, with 4 phenyl groups and 6 methyl groups).

Both the source and the target substances have consistent physicochemical properties. They have very high log Kow, very low water solubility, very low vapour pressure and slow hydrolysis. Hydrolysis products are different but considering the long hydrolysis half-lives and high log Kow the test organisms would be exposed to the parent substances.

Table 5.9.4. Physicochemical properties of the target and source substances

Property

Target substance

Source substance

Substance name

Reaction Mass of 3,3-diphenylhexamethyltrisiloxane; 3,3,5,5-tetraphenylhexamethyltetrasiloxane; 3-trimethylsiloxy-3,5,5-triphenylhexamethyltetrasiloxane

1,3,5-Trimethyl-1,1,3,5,5-pentaphenyltrisiloxane

CAS number

352230-22-9

3390-61-2

Hydrolysis half-life at pH 7

>200 h for Constituent 1

>630 h for Constituent 2

> 200 h

log Kow value

9.0 at 20°C for Constituent 1 and Constituent 2 of the submission substance

9.0 at 20°C (QSAR)

Vapour pressure

0.068 Pa at 25°C (whole substance) (OECD 104) 

3.6E-03 Pa at 25°C (QSAR, Constituent 1)

1.3E-07 Pa at 25°C (QSAR, Constituent 2)

1.3E-08 Pa at 25°C (QSAR)

Water solubility

  <0.5234 mg/L at 20°C (whole substance) (OECD 105) 

Constituent 1: 2.8E-05 mg/L at 20°C (QSAR)

Constituent 2: 1.5E-10 mg/L at 20°C (QSAR)

9.0E-11 mg/L at 20°C (QSAR)

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

In a Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test, performed according to OECD TG 422 with acceptable restrictions, and in compliance with GLP, no biologically significant, treatment-related effects were reported in rats for 1,3,5-trimethyl-1,1,3,5,5-pentaphenyltrisiloxane, by oral gavage at 100, 500, 1000 mg/kg bw/day. A NOAEL of >1000 mg/kg bw/day was derived (DCC, 2005).

Following daily oral administration of 100, 500, 1000 mg/kg bw/day test substance in corn oil to 10 male and 10 female rats for 90 days, no test substance-related mortality or clinical signs of toxicity occurred during the study period. No macroscopic abnormalities in organs and tissues were noted at pathological and histopathological examinations in any of the test animals. No changes were reported at haematology and clinical chemistry examinations. Negative control group was included and treated with 0 mg/kg bw/day test substance in corn oil. On day 65 one control animal was found dead due to unknown reasons. The rest of the control animals gave the expected results.

4. AE A.4 Bias that influences the prediction

Data on the source substance 1,3,5-trimethyl-1,1,3,5,5-pentaphenyltrisiloxane (CAS 3390-61-2) were read-across to the registered (target) substance Reaction Mass of 3,3-diphenylhexamethyltrisiloxane and 3,3,5,5-tetraphenylhexamethyltetrasiloxane (CAS 352230-22-9). The source substance and the target substance have similar chemical structure and physicochemical properties. Both hydrolyse very slowly, and it is considered that the test organism would be exposed to the parent substances. Their toxicological properties are expected to be similar, with similar target organ toxicity, reproductive and developmental toxicity. 1,3,5-Trimethyl-1,1,3,5,5-pentaphenyltrisiloxane (CAS 3390-61-2) is the closest structural analogue with available data.

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

The source substance as well as the target substance hydrolyse very slowly in contact with water. Therefore, their hydrolysis products are not considered to be relevant as the test organism would mainly be exposed to the parent substances. The source and target substance have consistent toxicological properties and none of the substances has been identified to be of any toxicological concern.

6. AE A.2.2 and A.2.3 Common underlying mechanism, qualitative and quantitative aspects

Acute and sub-acute toxicity data via oral route are available for the target substance. Following a single oral gavage administration of 2000 mg/kg bw test substance in corn oil to female rats, no mortality was observed in any of the test animals during the 14-day study period. Slightly ruffled fur was noted in two animals at 1-hour reading and persisted up to 3-hour reading in one animal. The body weight of the animals was within the range commonly recorded for this strain and age. No macroscopic findings were recorded at necropsy. The reported LD50 value was greater than 2000 mg/kg bw.

A sub-acute repeated dose toxicity study via oral route was available for the registration substance (RCC, 2004f). The test substance was administered daily by oral gavage to SPF-bred Wistar rats of both sexes at dose levels of 200, 600 and 1000 mg/kg body weight for a period of 28 days. A control group received the vehicle, corn oil, at the same dose volume (5 ml/kg body weight). All animals survived until scheduled necropsy. No test item-related clinical signs, body weight changes, neurobehavioral changes, or food consumption changes were noted in any of the test animals. There were hepatic findings that were considered to be a metabolic adaptation to treatment with the test item. The clinical biochemistry findings reflected this. Moreover, there was a thyroid finding that was considered to be a secondary finding following hepatic hypertrophy, i.e. due to increased metabolic turnover of thyroid hormones. Based on these findings, no adverse effects were seen in this study and the NOAEL (no-observed- adverse-effect-level) was considered to be greater than 1000 mg/kg.

No reproductive or developmental toxicity data are available for the registered substance. Therefore, data are read-across from the structurally analogous substance 1,3,5-trimethyl-1,1,3,5,5-pentaphenyltrisiloxane (CAS 3390-61-2). Both substances have consistent physicochemical properties. They have very high log Kow, very low water solubility, very low vapour pressure and slow hydrolysis. Hydrolysis products are different but considering the long hydrolysis half-lives and high log Kow the test organisms would be exposed to the parent substances. The hydrolysis products are all di- and trisilanols with phenyl and methyl substituents.

Moreover, there were no adverse effects in the Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test for the source substance. These findings were in line with the reported results for the subacute oral toxicity study for the registered substance.

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

Neither the target substance, Reaction Mass of 3,3-diphenylhexamethyltrisiloxane and 3,3,5,5-tetraphenylhexamethyltetrasiloxane, nor the source substance, 1,3,5-trimethyl-1,1,3,5,5-pentaphenyltrisiloxane, have impurities of toxicological concern.

The test/source substance in the study, 1,3,5-trimethyl-1,1,3,5,5-pentaphenyltrisiloxane has an analytical purity of 99.7%.

The target substance, Reaction Mass of 3,3-diphenylhexamethyltrisiloxane and 3,3,5,5-tetraphenylhexamethyltetrasiloxane (CAS 352230-22-9) is a multi-constituent substance containing two main constituents, 3,3-diphenylhexamethyltrisiloxane present at concentration of 55-70% and 3,3,5,5-tetraphenylhexamethyltetrasiloxane at concentration of 15-25%. The impurities are linear and branched siloxanes with 4-7 silicon atoms and phenyl/methyl substituents. These are structural analogues of the main constituents and share the same physicochemical properties (very high log Kow, very low water solubility, very low vapour pressure, slow hydrolysis).

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 data for the read-across substance, no classification is required for reproductive or developmental toxicity according to Regulation (EC) No. 1272/2008.