Registration Dossier

Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Remarks:
combined repeated dose and reproduction / developmental screening
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
Remarks:
The restrictions were limited histophatology of toxicity phase animals.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2005
Report Date:
2005

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
yes
Remarks:
Limited histophatology of toxicity phase animals.
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: liquid

Test animals

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 hr): 10-15/hour
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

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
Doses / concentrationsopen allclose all
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.

Examinations

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

Results and discussion

Results of examinations

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.


Effect levels

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

Target system / organ toxicity

Key result
Critical effects observed:
no

Applicant's summary and conclusion

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.