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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
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2001
Report Date:
2001

Materials and methods

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

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
Ro 1525 corresponds to Colipa A 155
SAT 000344
Batch-No. Ro-RN 6567
Description: grey powder
Descritpion: grey powder

Test animals

Species:
rat
Strain:
not specified

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: distilled water
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
Females were paired with male rats of the same strain obtained from the same supplier. Females were paired one to one in the horne cage ofthe male and left ovemight During the mating period, vaginal smears were obtained daily from all paired females. The day of mating, as judged by the
presence of vaginal plugs or sperm in the vaginal smear, was considered gestation Day 0 (or Day 0 post-coitum). Full mating records were main-
tained.
Duration of treatment / exposure:
from day 6 through day 15 of gestation
Frequency of treatment:
daily
Duration of test:
Gestation day 0-20
Doses / concentrations
Remarks:
Doses / Concentrations:
60, 80, 120 mg/kg/d
Basis:
actual ingested
No. of animals per sex per dose:
Each group contained 25 mated female rats.
Control animals:
yes

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
60 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity

Results (fetuses)

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

Effect levels (fetuses)

open allclose all
Dose descriptor:
NOAEL
Effect level:
120 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: fetotoxicity
Dose descriptor:
NOAEL
Effect level:
120 mg/kg bw/day
Based on:
test mat.
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:
Maternal toxicity was observed in high-dose animals receiving 120 mg/kg/day compared to controls. This toxicity was demonstrated by a statisti-
cally significant reduction in body weight, body weight gain, food intake and uterus and corrected body weights. Necropsy findings in dams and foe-
tuses did not show any abnormalities attributable to treatment. In particular, there was no evidence of any teratogenic effect of the test item.
Executive summary:

Study design

The effects ofRo 1525 on pregnancy and embryo-foetal development were assessed in the rat following daily administration during gestation. Ro 1525 was administered by oral gavage to groups of 25 female rats from Day 6 through Day 15 of gestation at dosages of 60, 80 and 120 mg/kg/day. Control animals received the vehicle alone (distilled water). The females were killed on gestation Day 20 and subjected to post-mortem examination. The numbers of corpora lutea, weight of intact gravid uterus, number and

distribution of live foetuses, number and distribution of intra-uterine deaths and individual foetal weight and sex were determined. All foetuses were examined externally. Approximately half of the foetuses in each litter were preserved in Bouin's solution for fixed-visceral examination. The remaining foetuses were eviscerated and the carcasses were fixed in 95% ethanol and stained for skeletal examination.

Fate of females

A total of four females proved not be pregnant at necropsy, one animal each in the control and in the high-dose group and two animals in the mid-dose group. In addition, in the high-dose group one animal showed total resorption at necropsy and four

animals died between gestation Day 9 and 14. The number of animals per group with live foetuses on gestation Day 20 was 19 to 25.

Clinical signs

Treatment-related clinical signs, such as, hunched posture, decreased activity and emaciation were observed in animals of the high-dose group.

Body weight, body weight gain

Statistically significant reductions in group mean body weight were noted starting from gestation Day 9 until termination in the mid and high-dose groups when compared to controls. A statistically significant reduction in group mean body weight gain was observed on gestation Day 9 in all treated groups and on gestation day 12 in the high-dose group when compared to controls. A slight recovery was observed after the treatment period.

Food consumption

Food consumption showed statistically significant reductions on gestation Day 9 and 12 in the high-dose group.

Uterus and corrected body weights

A trend towards a decrease in uterus weight and corrected body weight was observed in all treated groups when compared to controls. These changes were statistically significant in the high-dose group. Corrected body weight was also statistically significantly decreased in the mid-dose group.

Litter data

No treatment related changes were observed in litter parameters.

Sex ratios expressed as percentage of males were similar between groups.

Macroscopic observations of females

No macroscopic changes were observed m the treated females that could be considered treatment-related.

Externat examination of foetuses

There were a total of nine small foetuses, five in the low-dose group and four in the high-dose group.

Fixed visceral and skeletal examinations

Visceral and skeletal examinations did not show anY differences between the control and the treated groups.