Registration Dossier

Administrative data

Description of key information

In a 28-day repeated dose study, conducted according to an appropriate OECD Test Guideline and in compliance with GLP, a NOEL (no-observed-effect-level) could not be established for the submission substance, Reaction Mass of 3,3-diphenylhexamethyltrisiloxane and 3,3,5,5tetraphenylhexamethyltetrasiloxane, however, no adverse effects were seen in this study and so the NOAEL (no-observed- adverse-effect-level) was considered to be ≥ 1000 mg/kg (RCC, 2004).

In a supporting study, a Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test (oral route), 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, a structural analogue to the submission substance. A NOAEL of ≥1000 mg/kg bw/day was determined (DCC, 2005). This study is included because it is needed for reproductive/developmental read-across.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
23 June 2004 to 06 October 2004
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
Version / remarks:
1995
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
Version / remarks:
1996
Deviations:
no
GLP compliance:
yes (incl. certificate)
Limit test:
no
Specific details on test material used for the study:
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: at room temperature
- Stability under test conditions: stable
- Solubility and stability of the test substance in the solvent/vehicle: The test item was diluted in corn oil.
- Reactivity of the test substance with the solvent/vehicle of the cell culture medium: not applicable

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: The test item was weighed into a tared glass beaker on a suitable precision balance and the vehicle added (weight:volume). The mixtures were prepared using a magnetic stirrer. Homogeneity of the test item in the vehicle was maintained during the daily administration period using a magnetic stirrer.
- Preliminary purification step (if any): none
- Final dilution of a dissolved solid, stock liquid or gel: not applicable
- Final preparation of a solid: not applicable

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: RCC Ltd., Switzerland
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 6 weeks
- Weight at study initiation: males 146 g (mean); females 127 g (mean)
- Fasting period before study: none
- Housing: In groups of five in Makrolon type-4 cages
- Diet (e.g. ad libitum): Pelleted standard rat maintenance diet, ad libitum
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: Under test conditions after health examination. Only animals without any visible signs of illness were used for the study.


DETAILS OF FOOD AND WATER QUALITY: None of the contaminants analysed in the water and diet is considered to have been present at a concentration which would have affected the validity of the results.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3°C
- Humidity (%): 30-70 %
- Air changes (per hour): 10-15 per hours
- Photoperiod (hours dark / hours light): 12/12

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: The test item was weighed into a tared glass beaker on a suitable precision balance and the vehicle added (weight:volume). The mixtures were prepared using a magnetic stirrer. Homogeneity of the test item in the vehicle was maintained during the daily administration period using a magnetic stirrer. The test formulations were prepared weekly.

VEHICLE
- Justification for use and choice of vehicle (if other than water): Based on solubility study.
- Concentration in vehicle: not specified
- Amount of vehicle (if gavage): not specified
- Lot/batch no. (if required): not specified
- Purity: not specified
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Concentration, homogeneity and stability (after 2 hours and 7 days) of the dose formulations were determined in samples taken after experimental start. Concentration and homogeneity of the dose formulations were determined in samples taken during week 3 of the treatment.
Duration of treatment / exposure:
28 days
Frequency of treatment:
Daily
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Dose / conc.:
200 mg/kg bw/day (actual dose received)
Dose / conc.:
600 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:
5 males and 5 females
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: Based upon the results of a non-GLP 5-day dose- range-finding study (RCC Study Number 853872) in which CBI was administered by gavage to 2 rats per group and sex. Animals showed no clinical signs.
- Rationale for animal assignment (if not random): random
- Rationale for selecting satellite groups: no satellite groups
- Post-exposure recovery period in satellite groups: none
- Section schedule rationale (if not random): random
Positive control:
not used
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily for mortality and viability. General cage side observations once prior to administration then twice daily on days 1-3; once daily on days 4-28.
- Cage side observations checked included: mortality, viability and general clinical signs of toxicity

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once before the first test item exposure and once weekly during weeks 1-3 in random order.

BODY WEIGHT: Yes
- Time schedule for examinations: at sacrifice

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / Not specified

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: not specified
- Anaesthetic used for blood collection: Yes (isoflurane) / No / Not specified
- Animals fasted: Yes
- How many animals: all animals
- Parameters checked in table [No.1] were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: not specified
- Animals fasted: Yes
- How many animals: all animals
- Parameters checked in table [No.1] were examined.

URINALYSIS: Yes
- Time schedule for collection of urine: not specified
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Parameters checked in table [No.1] were examined.

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: at week 4
- Dose groups that were examined: All rats
- Battery of functions tested: Hind-forelimb grip strength measurement was performed using a push-pull strain gauge. Locomotor activity was measured quantitatively. Decreased or increased activity was recorded. Activity was measured with an AMS Föhr Medical Instruments GmbH. Activity of the animals was recorded for 10-minute intervals over a period of 60 minutes. These data and the total activity over 60 minutes were reported.


IMMUNOLOGY: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (see table No 2)

HISTOPATHOLOGY: Yes (see table No 2)
Statistics:
The following statistical methods were used to analyse the grip strength, locomotor activity, body weight, organ weights and ratios, as well as:
-The Dunnett-test (many to one t-test) based on a pooled variance estimate was applied if the variables could be assumed to follow a normal distribution for the comparison of the treated groups and the control groups for each sex.
-Fisher's exact-test was applied to the macroscopic findings.
The following statistical methods were used for statistical analysis of clinical laboratory data:
-Quantitative data were analysed by a one-way analysis of variance (ANOVA) when the variances are considered homogeneous according to Bartlett.
Alternatively, if the variances are considered to be heterogenous (psO.05), a non-parametric Kruskal-Wallis test was used. Treated groups were compared
to the control groups using Dunnett's test if the ANOVA was significant at the 5% level and by Dunn's test in the case of a significant Kruskal-Wallis test
(psO.05).
-Ordinal data such as urine sediment were analysed using the KruskaI-Wallis test. If this test was significant (pcontrol group and each of the treatment groups using Dunn's test.
Clinical signs:
no effects observed
Description (incidence and severity):
No test-item related clinical signs.
Mortality:
no mortality observed
Description (incidence):
All animals survived until scheduled necropsy.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
In males at 1000 mg/kg/day body weight gain was decreased at weeks 2 and 3 of the treatment period. In females at 600 and at 1000 mg/kg/day, body weights were lower than those of the controls at week 2. Body weight gain was decreased at 600 and at 1000 mg/kg during weeks 2 and 3. These findings were considered to be test item-related, but were minor and of no toxicological relevance.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No test item-related changes in food consumption.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
There were no changes in haematological data after 4 weeks that could definitively be related to treatment with the test item. All differences recorded were considered to be incidental and in general comparable with those of the controls and within limits of the historical reference data.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
There was a slight to moderate reduction in total bilirubin levels in both sexes in all test item treated groups, a moderate increase in cholesterol levels and moderate to slight increase in phospholipid levels in females in all test item treated groups, a slightly lower GLDH activity in males at 600 and 1000 mg/kg/day and slightly lower K + and Ca++ level in females at 1000 mg/kg/day.

Slightly lower A/G ratios were noted in females at 1000 mg/kg/day, however, as there were no toxicologically relevant effects on the absolute levels of albumin or globulins, this was considered to be fortuitous and not related to treatment with the test item.
Urinalysis findings:
no effects observed
Description (incidence and severity):
No treatment-related changes.
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
Grip Strength at week 4
In males at 600 mg/kg/day, the grip strength was reduced in the forelimb. In females, the grip strength was reduced in the forelimb at 200 mg/kg/day and in the hind limb at 600 and 1000 mg/kg/day. Since these findings were minor and there was no clear dose relationship, they were considered to be incidental and not related to treatment with test item.

Locomotor Activity
In females at 200 mg/kg/day, the locomotor activity was increased at 40 and 50 minutes. At 1000 mg/kg/day, the locomotor activity was increased only at 40 minutes.
Since these findings were minor and there was no clear dose relationship, they were considered to be incidental and not related to treatment with test item.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
In males at 200 and 600 mg/kg/day liver weights were increased. The liver/body weight ratio was increased at all dose levels, whereas the liver/brain weight ratio attained statistical significance only at 600 mg/kg. In females liver weights were increased absolutely and relatively at all dose levels.
Gross pathological findings:
no effects observed
Description (incidence and severity):
No test item-related macroscopic findings were evident at necropsy. All other macroscopic findings recorded were considered to be within the range of normal background lesions, which may be seen in rats of this strain and age.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
In the liver of males and females at 200, 600 and 1000 mg/kg/day, minimal to slight, mostly centrilobular hepatocellular hypertrophy was recorded. Increased incidence and/or severity (ranging from minimal to moderate degrees) of hepatic fatty change (periportal to diffuse) could be observed in male animals at 1000 mg/kg/day and females at 200, 600 and 1000 mg/kg/day. Increased incidence of minimal degree of bile duct proliferation was observed in males at 600 mg/kg/day and in females at 200 and 600 mg/kg/day. In the thyroid gland of most males at 1000 mg/kg/day (4/5) and single males at 200 mg/kg/day (215) and 600 mg/kg/day (1/5), minimal hypertrophic changes of the follicular epithelium could be observed. All other microscopic findings recorded were considered to be within the range of normal background lesions, which may be seen in rats of this strain and age. The observed effects were not considered to be adverse and of toxicological significance.
Histopathological findings: neoplastic:
not examined
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 effect was observed.
Critical effects observed:
no
Conclusions:
In the 28 -day repeated dose study, conducted according to an appropriate OECD Test Guideline and in compliance with GLP, a NOEL (no-observed-effect-level) could not be established for the test substance, however, no adverse effects were seen in this study and so the NOAEL (no-observed- adverse-effect-level) of the test substance was considered to be ≥ 1000 mg/kg.
Endpoint:
short-term repeated dose toxicity: oral
Remarks:
combined repeated dose and reproduction / developmental screening
Type of information:
experimental study
Adequacy of study:
supporting 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
Remarks:
The restrictions were limited histopathology of toxicity phase animals.
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
yes
Remarks:
Limited histopathology of toxicity phase animals.
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 oral 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 of the dose solutions was conducted on the day of the first preparation and prior to the end of dosing.
Duration of treatment / exposure:
Males: 92 days
Females: 91 days
Frequency of treatment:
Daily, 7 days a week
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.

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: once a day for general observations
- Cage side observations included: abnormal muscle movements (tremors, convulsions), abnormal behaviour, posture and resistance to removal.

DETAILED CLINICAL OBSERVATIONS: Yes. 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 and bizarre behaviour were also recorded.
- Time schedule: 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

FOOD CONSUMPTION: Yes
- Time schedule for examinations: at least once a week

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: prior to the administration of the test substance and prior to necropsy
- Dose groups that were examined: toxicity group animals treated with 0, 100, 500, 1000 mL/kg/day

HAEMATOLOGY: Yes
- Time schedule for collection of blood: prior to necropsy
- Anaesthetic used for blood collection: Yes (Isoflurane)
- Animals fasted: Yes
- How many animals: all adult males and toxicity group females
- Parameters checked in table [No. 1] were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: prior to necropsy
- Animals fasted: Yes
- How many animals: all adult males and toxicity group females
- Parameters checked in table [No. 1] were examined.

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: prior to dosing and on week 12 of the study
- Dose groups that were examined: on all males and all toxicity group females
- Battery of functions tested: sensory activity / grip strength / motor activity / other: abnormal muscle movements; abnormal behaviour; evaluation of level of activity

Sacrifice and pathology:
GROSS PATHOLOGY: Yes (Table 2)
HISTOPATHOLOGY: Yes (Table 2)
Other examinations:
Organ weights were examined at necropsy
Statistics:
-SAS version 8.2 was used for all data analysis
-Statistical significance was reported for p-value
-ANOVA test was used to analyse body weight, body weight changes, organ weights, organ to body weight ratios, food consumption data, haematology data, clinical chemistry and prothrombin times
-Shapiro-Wilk test was used to analyse normality
- Levene's test was used to analyse homogeneity of variance
- Kruskal-Wallis test was used when data was not compliant with parametric requirements
-Dunnett's test or Wilcoxon test for pair-wise comparisons of the exposed groups to the control groups]
- Jonckheere-Terpstra test was used to analyse Categorical Functional Observational Battery data
- Cochran-Armitage trend test was used to analyse microscopic findings
- Mixed modeling repeated measures were used to analyse clinical signs data
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY: One female treated with 500 mg/kg/day was found in moribund condition due to cardiac tamponade, and sacrificed on study day 21. One male control animal was found dead on day 65 of unknown reasons. All other animals survived throughout the study period. There were no statistically significant clinical signs.

BODY WEIGHT AND WEIGHT GAIN: There were no statistically significant changes in body weight among exposure groups.

FOOD CONSUMPTION: Increase in food consumption was noted in females treated with high dose during the first half of the study. The findings are not of toxicological significance. There were no differences in the average daily food consumption in the toxicity male group.

OPHTHALMOSCOPIC EXAMINATION: No treatment-related eye lesions were observed in the female and male toxicity groups.

HAEMATOLOGY: There were no treatment-related alterations in haematology. Statistically identified increases for segmented neutrophils in 100 and 1000 mg/kg/day females was noted, as well as a decreased percentage of eosinophils in 500 and 1000 mg/kg/day treatment animals. No dose response pattern was observed in the segmented neutrophils and both neutrophil and eosinophils values were within published normal ranges. No toxicological significance is given to these findings.

CLINICAL CHEMISTRY: There were no treatment-related alterations in clinical chemistry. Statistically identified differences across female and male treatment animals were noted for albumin, total protein and glucose, and for alanine aminotransferase, respectively. However, no dose response pattern and was observed and no toxicological significance was given to these findings.

NEUROBEHAVIOUR: No statistically significant changes in motor activity and functional observation battery.

ORGAN WEIGHTS: There were no statistically significant differences in organ weights among treatment groups. The ratio of thymus to the final body weight in males treated with 500 mg/kg/day for significantly increased, however no treatment-related pattern was observed and no toxicological significance was given to this finding.

GROSS PATHOLOGY: There were no gross morphological changes attributable to the test substance.

HISTOPATHOLOGY: NON-NEOPLASTIC: There were no treatment-related changes in tissues and organs in control and high dose groups.


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
Critical effects observed:
no
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 was >= 1000 mg/kg/day.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

A 28-day oral repeated dose toxicity study was available for the registration substance. In this repeated dose toxicity study (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). The study comprised of five animals per group and sex that were sacrificed after 28 days of treatment. Clinical signs, food consumption and body weights were recorded periodically during the acclimatization and treatment periods. In week 4, a functional observation battery was performed and after 4 weeks, blood and urine samples were collected for clinical laboratory investigations. At the end of the dosing period, all animals were killed, necropsied, examined post mortem and slides of selected tissues were examined histopathologically.

All animals survived until scheduled necropsy. No test item-related clinical sign was evident. No changes were noted in grip strength or locomotor activity. No test item-related changed in food consumption. No effects of toxicological relevance in body weight were noted.

There were no changes in haematological data after 4 weeks that could definitively be related to treatment with the test item. There was a slight to moderate reduction in total bilirubin levels in both sexes in all test item treated groups, a moderate increase in cholesterol levels and moderate to slight increase in phospholipid levels in females in all test item treated groups, a slightly lower GLDH activity in males at 600 and 1000 mg/kg/day and slightly lower potassium and calcium levels in females at 1000 mg/kg/day. No treatment-related changes were noted after 4 weeks.

In males at 200 and 600 mg/kg/day liver weights were increased. The liver/body weight ratio was increased at all dose levels, whereas the liver/brain weight ratio attained statistical significance only at 600 mg/kg. In females, liver weights were increased absolutely and relatively at all dose levels.

In the liver of males and females at 200, 600 and 1000 mg/kg/day, minimal to slight, mostly centrilobular hepatocellular hypertrophy was recorded.

An increased incidence and/or severity (ranging from minimal to moderate) of hepatic fatty change (periportal to diffuse) was observed in male animals at 1000 mg/kg/day and females at 200, 600 and 1000 mg/kg/day. An increased incidence of minimal degree of bile duct proliferation was observed in males at 600 mg/kg/day and in females at 200 and 600 mg/kg/day. In the thyroid gland of most males at 1000 mg/kg/day (4/5) and single males at 200 mg/kg/day (2/5) and 600 mg/kg/day (1/5), minimal hypertrophic changes of the follicular epithelium could be observed.

In this study there were hepatic findings that were considered to be a metabolic adaptation to treatment with the test item. The clinical biochemistry findings reflected this. The thyroid finding was considered to be a secondary finding following hepatic hypertrophy, i.e. due to increased metabolic turnover of thyroid hormones.

Based on these findings, a NOEL (no-observed-effect-level) could not be established, however, no adverse effects were seen in this study and so the NOAEL (no-observed- adverse-effect-level) was considered to be ≥ 1000 mg/kg. The study was conducted according to appropriate OECD Test Guideline and in compliance with GLP.

In a supporting study, 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. 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.

Justification for classification or non-classification

Based on the available data for the submission substance, no classification for systemic organ toxicity following repeated exposure is required according to Regulation (EC) No 1272/2008.