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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:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data

Data source

Reference
Reference Type:
review article or handbook
Title:
Unnamed
Year:
2000

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
No guideline is specified in the report
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid

Test animals

Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: 18 - 26 weeks old
- Weight at study initiation: 3.31 - 5.04 kg

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
The volume of administration was fixed at 10 mL/kg bw.
Duration of treatment / exposure:
Day 6 - 19 of gestation
Frequency of treatment:
Daily
Duration of test:
Up to day 29 of gestation
Doses / concentrationsopen allclose all
Dose / conc.:
120 mg/kg bw/day
Dose / conc.:
600 mg/kg bw/day
Dose / conc.:
1 200 mg/kg bw/day
No. of animals per sex per dose:
15 pregnant females per group
Control animals:
yes, concurrent vehicle
Details on study design:
The selection of the doses were based on a preliminary teratology study in rabbits in which oral doses of 500, 1000 and 2000 mg/kg bw/day were used. Pregnant rabbits were treated from day 6 - 19 of gestation. Increased incidence of reduced or loose faeces were seen in mid and high dose treated rabbits. One high dose treated rabbit was found dead and the cause of death was most likely drug related. Additionally, one high dose treated female aborted during the study period. During the treatment period, body weights were decreased by 82% along with about 42% reduction in food consumptions in high dose treated females. No treatment related effects were seen at necropsy (day 29 of gestation). Based on these results the Sponsor selected 1200 mg/kg bw/day as the highest dose for the main study.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily

BODY WEIGHT: Yes
- Time schedule for examinations: Daily

FOOD CONSUMPTION: Yes
- Time schedule: Days 1-5, 6-12, 13-19, 20-23 and 24-28

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 29
- Organs examined:

OTHER: Histopathology was performed on all the rabbits that died during the study.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No data
- 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: No data
- Skeletal examinations: Yes: two-thirds of the foetuses
- Head examinations: No data
- Visceral examination: Yes: one-third of the foetuses

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Mortality:
mortality observed, treatment-related
Description (incidence):
One female from the low dose group was killed in extremis and the cause of death could not be established with certainty.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Body weight gains were decreased by 14% and 28% during the gestation period 0-20 at 600 and 1200 mg/kg bw/day, respectively when compared to the control values. However, during the post dosing period, the body weight gains were increased in animals treated with mid and high dose levels such that by termination day 29 their body weights were comparable to that of the controls.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Food intakes were also decreased by 11% during the dosing period at 1200 mg/kg bw/day dose levels.

Maternal developmental toxicity

Number of abortions:
effects observed, non-treatment-related
Description (incidence and severity):
Three females (1 from the control group, 1 from mid dose group and 1 from high dose group) aborted during the study period. These abortions were considered not to be treatment related.
Pre- and post-implantation loss:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in number of pregnant:
effects observed, treatment-related
Description (incidence and severity):
THe overall rate of pregnancies significantly decreased in mid and high dose treated rabbits (control = 100%, low dose = 100%, mid dose = 60% and high dose 67%).
Other effects:
no effects observed
Description (incidence and severity):
The number of corpora lutea showed no differences between the treated and control groups.

Effect levels (maternal animals)

Dose descriptor:
LOEL
Effect level:
600 mg/kg bw/day
Basis for effect level:
mortality
body weight and weight gain
food consumption and compound intake
changes in number of pregnant

Maternal abnormalities

Abnormalities:
effects observed, treatment-related
Localisation:
not specified

Results (fetuses)

Fetal body weight changes:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed

Effect levels (fetuses)

Remarks on result:
not determinable due to adverse toxic effects at highest dose / concentration tested

Fetal abnormalities

Abnormalities:
no effects observed

Overall developmental toxicity

Developmental effects observed:
no

Any other information on results incl. tables

Due to the apparent effect on the maintenance of pregnancy in females receiving 600 mg/kg bw/day and above, the sponsor repeared part of the experiment. In this repeat test three groups were included in which pregnant rabbits were given oral doses of 0 (vehicle), 300 and 600 mg/kg from day 6 to 19 of gestation. This experiment had a few problems, such as older rabbits were used and were not in an active growth phase (even control rabbits lost their weights during the gestation period). Hence, no conclusion could be made from this study.

Applicant's summary and conclusion

Conclusions:
Maternal toxicity was seen at 600 and 1200 mg/kg bw/day dose levels. Additionally, mid and high dose levels adversely affected the pregnancy rates (reason unknown). However, there was no evidence of a teratogenic potential.