Registration Dossier

Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study was conducted according to an appropriate OECD test guideline, with acceptable restrictions. The restrictions were limited observations regarding the FOB.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1986
Report Date:
1986

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
Deviations:
yes
Remarks:
limited observations regarding the FOB
GLP compliance:
yes (incl. certificate)
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: liquid
Details on test material:
- Name of test material (as cited in study report): Trimethylsilanol- Substance type: organosilane - Physical state: liquid- Analytical purity: Not clear from German report

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
castor oil
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
Four weeks
Frequency of treatment:
Daily
Doses / concentrations
Remarks:
Doses / Concentrations:0, 80, 250 and 750 mg/kg bw/dayBasis:actual ingested
No. of animals per sex per dose:
Five
Control animals:
yes, concurrent vehicle

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Apathy and short-lived staggering.
Mortality:
mortality observed, treatment-related
Description (incidence):
Apathy and short-lived staggering.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Body weight gain was reduced in males and females of the 750 mg/kg bw/day group by about 10 and 14%, respectively.
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Dose dependent increase in relative liver weights in females.
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Deposits of brown pigment in the bile ducts of 4/5 males at the highest dose level. Minimal bile duct proliferation in one animal at this dose level.
Histopathological findings: neoplastic:
not examined

Effect levels

Key result
Dose descriptor:
NOAEL
Effect level:
250 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
organ weights and organ / body weight ratios
histopathology: non-neoplastic

Target system / organ toxicity

Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
750 mg/kg bw/day (actual dose received)
System:
hepatobiliary
Organ:
bile duct
liver
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
not specified

Any other information on results incl. tables

Clinical signs: There were no deaths. Short lived staggering in highest dose male and female rats shortly after dosing. Apathy on the day of termination was also observed in this group. No effects on food and water consumption. Body weight gain was reduced in males and females of the 750 mg/kg bw/day group by about 10 and 14%, respectively. There were statistically significant differences in some haematology parameters in the 250 mg/kg bw/day dose group, but these were not considered toxicologically significant as there was no effect at the highest dose (no dose dependency) and individual values were all within the normal range. In males and females of the 750 mg/kg bw/day group alkaline phosphatase was significantly lower than the controls. Statistically significant reduction in glucose levels of males in the 80 and 750 mg/kg bw/day group, statistically significant reduction in urea and increased GOT in females of the 250 mg/kg bw/day group. These changes were not considered to be toxicologically significant as there was no dose-dependency and the values were all within the normal range of the historical controls. At 80 mg/kg bw/day there was a statistically significant decrease in male rat serum phosphate levels, which was not thought to be toxicologically significant as there were no changes at the two higher doses. Relative liver weights of female animals increased in a dose-dependent manner in the 250 and 750 mg/kg bw/day groups. There were statistically significant increases in adrenal weights in males of the 80 and 750 mg/kg bw/day groups, and kidney weights in females of the 80 mg/kg bw/day group. However, these effects were not considered to be toxicologically significant as there was no dose-dependency. Four of five male rats in the highest dose group had small deposits of brown pigment in the bile ducts. One of these animals also had minimal bile duct proliferation.

Applicant's summary and conclusion

Conclusions:
In an oral gavage study conducted to OECD test guideline 407, groups of Wistar rats (5/sex/dose) were given daily doses of either 0 (castor oil vehicle only), 80, 250 and 750 mg/kg bw/day for 28 days. Clinical observations, food and water intake, body weights, organ weights, clinical chemistry, haematology, and histopathology were all recorded. Toxicologically relevant adverse effects (reduced body weight gain, reduced alkaline phosphatase, reduced glucose (males), increased liver weights (females), and increased adrenal weights (males), and minor deposits in the bile ducts) were observed at the highest dose of 750 mg/kg bw/day. The NOAEL was 250 mg/kg bw/day, as effects observed at this or the lower dose of 80 mg/kg bw/day, were not dose-dependent and often values were within the normal range for historical controls.