[3-(2,3-epoxypropoxy)propyl]trimethoxysilane

Developmental toxicity / teratogenicity

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:

comparable to guideline study

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

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

yes

Remarks:

Dosing during organogenesis only.

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

[3-(2,3-epoxypropoxy)propyl]trimethoxysilane

EC Number:

219-784-2

EC Name:

[3-(2,3-epoxypropoxy)propyl]trimethoxysilane

Cas Number:

2530-83-8

Molecular formula:

C9H20O5Si

IUPAC Name:

trimethoxy[3-(oxiran-2-ylmethoxy)propyl]silane

Test animals

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system 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

Doses / concentrations 1

Dose / conc.:

50 mg/kg bw/day

Doses / concentrations 2

Dose / conc.:

200 mg/kg bw/day

Doses / concentrations 3

Dose / conc.:

400 mg/kg bw/day

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 (gestation days 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 haemorrhage, 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 non-pregnant 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

General toxicity (maternal animals)

Clinical signs:

effects observed, non-treatment-related

Description (incidence and severity):

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.

Dermal irritation (if dermal study):

not examined

Mortality:

mortality observed, treatment-related

Description (incidence):

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.

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

no effects observed

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

not examined

Ophthalmological findings:

not specified

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

no effects observed

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Other effects:

no effects observed

Maternal developmental toxicity

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)

1

Dose descriptor:

NOAEL

Remarks:

maternal toxicity

Effect level:

200 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

mortality

2

Dose descriptor:

NOAEL

Remarks:

maternal developmental toxicity

Effect level:

>= 400 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: no maternal developmental toxicity was observed.

Maternal abnormalities

Abnormalities:

no effects observed

Results (fetuses)

Fetal body weight changes:

no effects observed

Reduction in number of live offspring:

no effects observed

Changes in sex ratio:

no effects observed

Changes in litter size and weights:

no effects observed

Changes in postnatal survival:

no effects observed

External malformations:

no effects observed

Skeletal malformations:

no effects observed

Visceral malformations:

no effects observed

Other effects:

no effects observed

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 non-viable (early and late resorptions and dead fetuses) implantations per litter or on sex ratio (% males). Percent pre-implantation and post-implantation 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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: teratogenicity

Fetal abnormalities

Abnormalities:

no effects observed

Overall developmental toxicity

Developmental effects observed:

no

Any other information on results incl. tables

Please see attached tables in attachments.

Applicant's summary and conclusion

Conclusions:

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