Dimethylbis(octadecyloxy)silane

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1998-12-09 to 1999-01-13

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1999

Report date:

1999

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Version / remarks:

1995

Deviations:

no

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Dimethylbis(octadecyloxy)silane

EC Number:

249-385-9

EC Name:

Dimethylbis(octadecyloxy)silane

Cas Number:

29043-70-7

Molecular formula:

C38H80O2Si

IUPAC Name:

dimethylbis(octadecyloxy)silane

Test material form:

other: solid

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: RCC Ltd, Switzerland
- Age at study initiation: 6 weeks
- Weight at study initiation: males: 135 - 155 g; females: 109-127 g
- Fasting period before study: the animals were fasted for 18 hours before blood sampling, but water was available, ad libitum.
- Housing: in groups of 5 in Makrolon type-4 cages with wire mesh tops and softwood bedding
- Diet: pelleted standard rat maintenance diet, ad libitum
- Water: tap water, ad libitum
- Acclimation period:

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3 °C
- Humidity (%): 40- 70 %
- Air changes (per hr): 10-15 air changes/ hours
- 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:
Test article formulations were prepared once a week. The test article was weighed and ground in a mortar. The test article was transferred in a beaker and the vehicle was added. The mixtures were prepared using an ultrasonic water bath and mixed with magnetic stirrer. The test article formulations were stored at room temperature. Homogeneity of the formulations was maintained using a magnetic stirrer.

VEHICLE
- Justification for use and choice of vehicle (if other than water): no information
- Lot/batch no. (if required): 8001-30-7

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Concentration, homogeneity and stability of dose formulations were determined in samples taken during acclimatization and on day 1. Concentration and homogeneity of the dose formulations were determined in samples taken on week 4 of the treatment. The analyses were performed by RCC ltd. according to a GC method.

Duration of treatment / exposure:

28 days

Frequency of treatment:

daily, 7 days a week

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

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

Doses / concentrations 2

Dose / conc.:

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

Doses / concentrations 3

Dose / conc.:

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

No. of animals per sex per dose:

5 males and 5 females per dose

Control animals:

yes, concurrent no treatment

Details on study design:

- Dose selection rationale: a non-GLP 5-day dose-range finding study was performed, in which the test material was administered orally to 2 rats per group and sex. The highest dose administered with no signs of toxicity was 1000 mg/kg bw/day.

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: once before commencement of administration, then twice daily on days 1-3, thereafter once daily on days 4-28.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once before commencement of administration, then once weekly.

BODY WEIGHT: Yes
Time schedule for examinations: Body weights were recorded weekly during pretreatment and treatment, and before necropsy.

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes (see table 1)
- Time schedule for collection of blood: after week 4
- Anaesthetic used for blood collection: Yes, light ether anaesthesia
- Animals fasted: Yes, for 18 hours
- How many animals: all the animals
- Parameters checked in table [No.?] were examined.

CLINICAL CHEMISTRY: Yes (see table 1)
- Time schedule for collection of blood: after week 4
- Animals fasted: Yes, for 18 days
- How many animals: all the animals
- Parameters checked in table [No.?] were examined.

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: week 4
- Dose groups that were examined: all the animals
- Battery of functions tested: grip strength and motor activity

FOOD CONSUMPTION:
- Time schedule for examinations: once daily during the pretreatment, then weekly for the rest of the study period.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes (see table 2)
HISTOPATHOLOGY: Yes (see table 2)

Statistics:

- Dunnett-test: comparison of treated groups with the control group
- Steel-test: applied instead of Dunnett-test when data could not be assumed to follow a normal distribution
- Fisher's exact-test: applied to macroscopic findings

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):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

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: all animals survived until scheduled death.

BODY WEIGHT AND WEIGHT GAIN: No changes in expected body weight gain were observed.

HAEMATOLOGY: No test article-related differences were noted. A few incidences of statistical significance noted were not dose-related and therefore were considered to be incidental.

CLINICAL CHEMISTRY: No test article-related differences were noted. A few incidences of statistical significance noted were not dose-related or restricted to only one sex and therefore were considered to be incidental.

NEUROBEHAVIOUR: No qualitative or quantitative differences were noted in any of the test animals when compared to the control group. The hindlimb grip strength of males and females, and the forelimb grip strength of females treated with 1000 mg/kg bw/day was significantly increased when compared with the control animals. This slight increase was not considered to be an adverse effect. Locomotor activity of females treated with 50 and 200 mg/kg bw/day were significantly more active when compared to the control group. These findings were considered to be incidental as no such observations were noted for females treated with 1000 mg/kg bw/day.

ORGAN WEIGHTS: No test article-related differences were noted. The mean relative and absolute thymus weights were reduced in males treated with 50 mg/kg bw/day. No such changes were noted in the animals treated with 200 and 1000 mg/kg bw/day.

GROSS PATHOLOGY: No treatment-related macroscopic changes were observed in any of the animals. The macroscopical findings were within the range of spontaneous alterations that can appear in rats at this age and strain. The abnormalities included: dilated renal pelvises, discoloured foci in various organs, dilated uterine horns with filled with fluid and size reduction of testes, epididymides and adrenal glands.

HISTOPATHOLOGY: NON-NEOPLASTIC: A number of microscopical findings were noted. The type, incidence and severity of these findings were not considered treatment-related.

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 treatment-related abnormalities were observed in any of the test animals.

Target system / organ toxicity

Critical effects observed:

no

Applicant's summary and conclusion

Conclusions:

In the 28-day oral study in rats the reported NOAEL value for dimethylbis(octadecyloxy)silane was ≥1000 mg/kg bw/day.