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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
04.12.1990 to 22.11.1993
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was conducted according to a test protocol that is comparable to the appropriate OECD test guideline, and in compliance with GLP.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1993
Report Date:
1993

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
Dosing during organogenesis only.
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Hazleton Dutchland Laboratories, Inc
- Age at study initiation: 5.5 months old
- Weight at study initiation: 3.0 to 4.0 kg
- Fasting period before study: No data, but probably not
- Housing: Individually in stainless steel, wire mesh cages
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: 16 days


ENVIRONMENTAL CONDITIONS
- Temperature (°F): 61-70 (16-21°C)
- Humidity (%): 40-60
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: 04.12.1990 To: 22.11.1993

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: The appropriate amount of A-187 was dissolved with Mazola corn oil. Solutions were mixed manually by repeated inversions and then transferred to a glass Erlenmeyer flask and mixed for at least 10 minutes. Dosing solutions were prepared based on the selected dose and administration of a constant dose volume of 2ml/kg/day. Target concentrations of solutions for the 50, 200 and 400 mg/kg/day dose levels were 25, 100 and 200 mg/ml, respectively. Dosing solutions were prepared three times during the study and were stored at room temperature. Dosing solutions were stirred using a magnetic stirrer for at least 10 minutes prior to each daily dosing period.

VEHICLE
-No details on vehicle.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Concentrations of the dosing solutions were verified prior to use in the study using gas chromatography. Homogeneity of A-187 in each solution was established. Homogeneity and stability of the dosing solutions were initiated prior to the onset of actual dosing.
Details on mating procedure:
- Impregnation procedure: No data. Report states that "females were mated to proven males from the BRRC breeding colony. Following successful copulation, the animals were returned to their respective cages"
- If cohoused:
- M/F ratio per cage: No data
- Length of cohabitation: No data
- Further matings after two unsuccessful attempts: No data
- Verification of same strain and source of both sexes: No data
- Proof of pregnancy: Date of copulation referred to as day 0 of pregnancy
Duration of treatment / exposure:
Test substance exposure occurred during the primary period of organogenesis, i.e., gestation days 6-18.
Frequency of treatment:
Once per day on gestation days 6-18
Duration of test:
25 days (animals sacrificed on gestational day 29)
Doses / concentrations
Remarks:
Doses / Concentrations:
50, 200 and 400 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
22 females
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Based on the results from three developmental toxicity range-finding studies of Union Carbide Organofunctional Silane A-187 in pregnant New Zealand white rabbits.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Observations for mortality and clinical condition were performed daily (twice daily during the dosing period).


DETAILED CLINICAL OBSERVATIONS: No data


BODY WEIGHT: Yes
- Time schedule for examinations: Maternal body weights were measured on gestational days 0, 6, 12, 15, 18 and 29.


FOOD CONSUMPTION: Yes, food consumption was measured daily throughout gestation (gd 0-29).
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes


WATER CONSUMPTION: No


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 29
- Organs examined: Uterus, ovaries (including corpora lutea), cervix, vagina and abdominal and thoracic cavities. Liver was weighed.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes, each uterus was externally examined for signs of haemorhage, removed from the peritoneal cavity, weighed and dissected longitudinally to expose the contents.
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: [half per litter]
- Skeletal examinations: Yes: [half per litter]
- Head examinations: Yes: [half per litter]
Statistics:
The unit of comparison was the pregnant female or the litter.  Data collected for nonpregnant females were not included in the statistical analyses.  Results of the quantitative continuous variables (e.g., maternal body weights, organ weights, etc.) were intercompared for the three exposed groups and the vehicle control group by use of Levene's test for equal variances (Levene, 1960), analysis of variance (ANOVA), and t-tests with Bonferroni probabilities for pairwise comparisons.  The t-tests were used when the F value from the ANOVA was significant.   When Levene's test indicated homogeneous variances and the ANOVA was significant, the pooled t-test was used.  When Levene's test indicated heterogeneous variances, all groups were compared by an ANOVA for unequal variances (Brown and Forsythe, 1974) followed, when necessary, by the separate variance t-test.  Nonparametric data obtained following laparohysterectomy were statistically treated using the Kruskal-Wallis test (Sokal and Rohlf, 1969) followed by the Mann-Whitney U test (Sokal and Rohlf, 1969) when appropriate.  Incidence data were compared using Fisher's Exact Test (Sokal and Rohlf, 1969).  For all statistical tests, the fiducial limit of 0.05 (two-tailed) was used as the criterion for significance.
Indices:
No data
Historical control data:
No data

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
One dam from the 400 mg/kg bw/day group was found dead on gestation day 29. This animal exhibited gasping, and laboured and audible breathing. No significant clinical signs were observed in any other treatment group. No statistically significant, treatment-related differences in body weight/body weight gain or food consumption were observed. There were no significant findings in the necropsy of the dam that died. There were no treatment-related findings from the necropsy of the surviving animals.

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
200 mg/kg bw/day
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
There were no effects of the treatment on the number of ovarian corpora lutea, on the number of total, viable or nonviable (early and late resorptions and dead fetuses) implantations per litter or on sex ratio (% males). Percent preimplantation and postimplantation losses were equivalent across groups. Fetal examination indicated no evidence of embryotoxicity or malformations in any of the treatment groups.  There were no effects on mean fetal body weight and no treatment-related differences in the incidences of external, visceral or skeletal variations.

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
>= 400 mg/kg bw/day
Basis for effect level:
other: teratogenicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
In a well conducted study (reliability score 1), conducted using a protocol similar to OECD 414 and GLP, the NOAEL for maternal toxicity and developmental toxicity were 200 and ≥400 mg/kg bw/day, respectively, in rabbits.
Executive summary:

In a well conducted study (reliability score 1), conducted using a protocol similar to OECD 414 and GLP, the NOAELs for maternal toxicity and developmental toxicity were 200 and ≥400 mg/kg bw/day, respectively, in rabbits.