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Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
From 25 Nov 1991 to 13 Dec 1991
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was conducted in accordance with an appropriate OECD test guideline and in compliance with GLP, using a closely related substance.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1992
Report date:
1992

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Reference substance name:
17980-47-1
EC Number:
605-871-6
Cas Number:
17980-47-1
IUPAC Name:
17980-47-1
Constituent 2
Reference substance name:
Triethoxyisobutylsilane
EC Number:
402-810-3
EC Name:
Triethoxyisobutylsilane
IUPAC Name:
Triethoxyisobutylsilane

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Ltd, Manston Kent, UK
- Age at study initiation: 44-70 days
- Weight at study initiation: post coitum (day 0): approx 244-247 g
- Housing: after mating, 1/polypropylene cage with autoclaved sawdust bedding
- Diet: standard diet ad libitum
- Water: drinking water ad libitum
- Acclimation period: at least 13 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25
- Humidity (%): 40-75
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12 h/12 h

IN-LIFE DATES: From: 1991-11-18 To: 1991-12-18

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
arachis oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Test substance was dissolved in dried arachis oil by shaking to achieve a homogenous mixture. Control vehicle was prepared weekly.

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
GC
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:2
- Length of cohabitation: 9 days
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
gestation days 6-15
Frequency of treatment:
daily
Duration of test:
Mating to sacrifice on GD20
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 50, 250, 1000 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
24 pregnant females
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: range finding study
- Rationale for animal assignment: random with adjustment for body weight

Examinations

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

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once or twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: days 0, 3, 6-16 inclusive, 18 and 20

FOOD CONSUMPTION: Yes
- Food consumption for each animal determined : Yes

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: uterine contents
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes / No / No data
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes / No / No data

Also - position and type of implantations
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes (incl. eyes and ossification)
Statistics:
Body weight and food consumption: one way analysis of variance followed by pair wise analysis of group values by students t test.
Mean foetal weight, post-implantation loss and group mean incidence of specific foetal anomalies: Kruskall-Wallis non-parametric analysis of variance followed by pair wise Mann-Whitney U test.
Indices:
Values given as percentages (e.g. preimplantation and postimplantation loss)
Historical control data:
None given.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
1000 mg/kg bw/day: slight reduction in body weight gain on day 9 (significant p<0.05); weights remained below controls for the rest of the study but the difference was not statistically significant.
1000 mg/kg bw/day: reduction in food intake on days 6-9 (significant p<0.01); intake remained below controls but the difference was not statistically significant.
50 mg/kg bw/day: significant (p<0.05) reduction in food consumption; considered of no toxicological significance as this effect was not seen at 250 mg/kg bw/day.
Slight maternal toxicity at the top-dose.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
LOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Dose descriptor:
NOAEL
Effect level:
250 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
1000 mg/kg bw/day:slight increase in post implantation loss (not statistically significant: 8.4% compared to 2-4.5% in other treated groups and the control group). Corresponding reduction in preimplantation loss.
1000 mg/kg bw/day: slight reduction in mean foetal weight (not statistically significant: 3.86 g compared to 3.94-3.98 in every other treated and untreated group). Three foetuses were described as small (compared to controls); one in each of the other treated groups was similarly described.
No clear evidence of treatment-related foetal abnormalities

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
A well reported prenatal developmental toxicity study conducted according to the current guideline (OECD 414) and GLP found that gavage administration of 1000 mg/kg bw/day to rats on gestation days 6-15 caused slight maternal toxicity but gave no evidence developmental effects. No maternal toxicity was seen at the lower dose of 250 mg/kg bw/day. The observed reduction in food consumption can be explained by reduced acceptance of food, and the subsequent reduction in body weight was reversible. The applicant therefore considers that these are not true adverse effects and NOAEL for maternal toxicity was greater than or equal to 1000 mg/kg/day.