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Toxicological information

Developmental toxicity / teratogenicity

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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:
25.11.1991 to 18.12.1991
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
The study was conducted according to the appropriate OECD guideline and in compliance with GLP and is therefore considered to be reliability 1. Read-across of the study itself is considered to be reliability 2. Further information on read-across is given in the endpoint summary.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1991
Report Date:
1991

Materials and methods

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

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Type:
Constituent

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River UK Ltd, Manston, Kent.
- Age at study initiation: No data. Stated to be 44 to 70 days on arrival.
- Weight at study initiation: No data
- Fasting period before study: No
- Housing: Groups of five in polypropylene cages. During mating period the females were transferred to a similar type of cage with mature males.
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: 13 days

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

IN-LIFE DATES: From: 18.11.1991 To: 18.12.1991

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
arachis oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Prior to dose preparation the test substance was filtered to remove any sediment. It was then dissolved in dried arachis oil weekly by weighing individual quantities of the test substance into suitable containers and subsequently the vehicle was added to make the appropriate final volume. The test substance and vehicle were shaken until a homogenous mixture was observed. The control vehicle was prepared weekly.

VEHICLE
- Justification for use and choice of vehicle (if other than water): No justification given
- Concentration in vehicle: Various depending on dose level
- Purity: No data
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Prior to the start of the study a procedure was developed to prepare the test substance for dose administration. These preparations were analysed for achieved concentration, stability and homogeneity. During the dosing period dose preparations were analysed for achieved concentrations.
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:2
- Length of cohabitation: 9 days
- Further matings after two unsuccessful attempts: no
- Verification of same strain and source of both sexes: No data
- Proof of pregnancy: vaginal plug and sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
Mated female rats were dosed once daily from day six to 15 of gestation, inclusive.
Frequency of treatment:
Daily
Duration of test:
10 days
Doses / concentrations
Remarks:
Doses / Concentrations:
50, 250 and 1000 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
24
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Based on a dose range finding study

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: All females were checked twice daily for mortality/morbidity during the normal working week and once daily at weekends. All females were observed once daily for clinical signs of toxicity.

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: Females were weighed on days 0, 3, 6 to 15 inclusively, 18 and 20 of gestation.

FOOD CONSUMPTION: Yes
- Food consumption for each animal determined for discrete periods throughout the study on days 0-3, 3-6, 6-9, 9-12, 12-15, 15-18 and 18-20 of gestation.

WATER CONSUMPTION: No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: Each animal was examined externally and internally for macroscopic abnormalities. The uterus of any apparently non-pregnant female was dissected and examined for implantations. The ovaries and uteri of pregnant females were removed, examined and the following data recorded: i) Number of corpora lutea; ii) Number, position and type of intrauterine implantation. Implantation types were divided into: Live fetus, early death, late death or dead fetus.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: No
- Number of late resorptions: No
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:
Data processed to give litter mean values, group mean values and standard deviations. Body weight change and food consumption analysed by one way analysis of variance followed by pairwise analysis of group values by Student's 't' Test. Mean fetal weight, post-implantation loss and group mean incidence of specific fetal anomalies analysed by Kruskall-Wallis non-parametric analysis of variance followed by pairwise Mann-Whitney 'U' test.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
There were no mortalities or treatment-related clinical signs throughout the study. At 1000 mg/kg bw/day there was a slight but statistically significant (p<0.05) reduction in group mean bodyweight gain during days 6-9 of gestation. After this period the overall gain until termination was generally comparable to controls. At 1000 mg/kg bw/day there was a slight but statistically significant (p<0.01) reduction in the group mean food consumption over the days 6-9 of gestation. Food consumption over the rest of the gestation period remained slightly below the control value. At 50 mg/kg bw/day there was a statistically significant (p<0.05) decrease in food consumption compared to controls that was considered not to be toxicologically significant due to there being no effects in the mid dose group. There were no treatment-related macroscopic findings for adult females at necropsy.

At 1000 mg/kg bw/day there was a slight but statistically not significant increase in group mean post-implantation loss. This figure was increased as a result of an increase in early embryonic deaths particularly from the litter value from one dam. At 1000 mg/kg bw/day there was a slight, but not statistically significant decrease in group mean fetal weight. There were no such effects in the mid and low dose groups.

Effect levels (maternal animals)

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

Results (fetuses)

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

Details on embryotoxic / teratogenic effects:
Throughout all groups there were three fetuses with significant structural anomalies. At 1000 mg/kg bw/day one fetus had an interventricular septal defect, small left ventricle and atrium, stenosis of the mitral valve and right sided aorta, aortic arch and ductus arteriosus. At 50 mg/kg bw/day one fetus had an interventricular septal defect. At 0 mg/kg bw/day one fetus had an interventricular septal defect and stenosis of the preductal ascending aorta. These findings were considered incidental and not of toxicological significance. Skeletal development was comparable across the groups.

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
In an oral developmental toxicity study conducted to OECD 414 and to GLP (reliability score 1) there were no effects on rat fetal development and the NOAEL was therefore at least 1000 mg/kg bw/day (the highest dose tested) for the structural analogue substance triethoxy(isobutyl)silane.