Reaction mass of 1,1,1,5,5,5-hexamethyl-3-phenyl-3-((trimethylsilyl)oxy)trisiloxane and 1,1,1,7,7,7-hexamethyl-3,5-diphenyl-3,5-bis[(trimethylsilyl)oxy]tetrasiloxane and 1,1,1,9,9,9-hexamethyl-3,5,7-triphenyl-3,5,7-tris((trimethylsilyl)oxy)pentasiloxane

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1994

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1995

Report date:

1995

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

Deviations:

yes

Remarks:

no neurobehavioural tests included

GLP compliance:

yes (incl. QA statement)

Limit test:

yes

Test material

Test material information

Constituent 1

Test animals

Species:

rat

Strain:

other: Fischer 344N

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Raleigh, NC
- Age at study initiation: approx. 7 weeks
- Weight at study initiation: Males 77-93 g Females 75-103 g on arrival
- Fasting period before study: no
- Housing: individually in stainless steel wire mesh cages
- Diet: Purina Rodent Chow 5002 Meal ad libitum except prior to necropsy
- Water: Reverse osmosis purified from local supply ad libitum
- Acclimation period: 12 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-25
- Humidity (%): 23-61
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: To: 07 December 1993 to 09 March 1994

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:
Twice weekly

VEHICLE
- Concentration in vehicle: 0, 5, 30, 90, 200 mg/mL
- Amount of vehicle: 5mL/kg
- Lot/batch no.: Sigma Chemical Co. 42H0864 and 43H0315

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Samples of the dosing formulations (approximately 20 or 40 ml each), including undiluted vehicle, used during treatment weeks l-2, 2-3, 6-7 and
l0-l I were taken for concentration analysis

Duration of treatment / exposure:

91 or 92 days

Frequency of treatment:

Once daily

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

25 mg/kg bw/day (actual dose received)

Doses / concentrations 2

Dose / conc.:

150 mg/kg bw/day (actual dose received)

Doses / concentrations 3

Dose / conc.:

450 mg/kg bw/day (actual dose received)

Doses / concentrations 4

Dose / conc.:

1 000 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

yes, sham-exposed

Details on study design:

Not stated

Positive control:

No

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: once or twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION: Yes
- Time schedule: weekly
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/animal/week: Yes

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: pre-treatment and Week 12
- Dose groups that were examined: All

HAEMATOLOGY: Yes
- Time schedule for collection of blood: day 92 or 93
- Anaesthetic used for blood collection: Yes (sodium pentobarbital)
- Animals fasted: Yes / No / No data
- How many animals: All
- Parameters in table 1 were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: day 92 or 93
- Animals fasted: Yes
- How many animals: All
- Parameters in table 2 were examined.

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

ORGAN WEIGHTS: Yes (see table 3)
GROSS PATHOLOGY: Yes (see table 4)
HISTOPATHOLOGY: Yes (see table 4)

Statistics:

Data was analysed by analysis of variance (ANOVA) followed by Duncan's multiple range comparison test.

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):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

Absolute and relative liver weights showed statistically significant increase in all treated groups, however, no underlying histopathology noted to support the organ weight change.

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Effect levels

Key result

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

other: No effects attributable to treatment at doses up to 1000 mg/kg/day

Target system / organ toxicity

Critical effects observed:

no

Applicant's summary and conclusion

Conclusions:

In a 90-day repeated oral gavage study conducted to OECD Test Guideline 408 and to GLP (reliability score 1), no changes attributable to treatment at doses up to 1000 mg/kg bw/day (the highest dose tested) silsesquioxanes, phenyl, were observed in rats.