Registration Dossier

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:
comparable to guideline study with acceptable restrictions

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1988
Report Date:
1988

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
data on animals age, in life data, acclimatization period or fasting not given, no data on test material or purity, no analytical verification of test material preparation, no comparision to historical data.
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
no further data provided
Specific details on test material used for the study:
- Name of test material (as cited in study report): XP 1452

Test animals

Species:
rabbit
Strain:
other: Grand Fauve de Bourgogne
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 2.06 to 2.70 kg
- Housing: individually
- Diet (e.g. ad libitum): diet contains 15% proteins, 1% calcium, 0.5% phosphorus and 10% ashes

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-24
- Humidity (%): 25-40

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: gum arabic
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: The suspension was prepared by mixing 4 g, 10 g, and 40 g of product, corresponding to groups 1, 2, and 3, in the gum solution at 5% made up to a litre for each mix.

Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
The female rabbits were mated with a male twice in 5 minutes. When the mating was observed, the female rabbits were considered to be gravid and were placed in the different groups at random. The mating day was taken as gestation day 0.
Duration of treatment / exposure:
from gestation day 6 through 18
Frequency of treatment:
daily
Duration of test:
fetuses were removed by Caesarean section on the 29th day
Doses / concentrations
Remarks:
Doses / Concentrations:
20, 50, 200 mg/kg bw /day
Basis:
actual ingested
No. of animals per sex per dose:
15
Control animals:
yes, concurrent vehicle

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: each day
- Cage side observations: behaviour and general state

BODY WEIGHT: Yes
- Time schedule for examinations: at intervalls of 3 to 4 days until the end of the test

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 29
- Organs examined: The abdominal cavity was opened up, the ovaries and the uterus were dissected, and the number of yellow bodies in each ovary was counted. The uterus was opened up and the number of live foetuses, together with any dead foetuses, the foetal reabsorptions and the distribution of the foetuses in the right and left cornua were noted. In the uterus, the number of glands in the endonecrium characterizing implantations was determined; these glands are found at the junction of the mesometrium and the uterine cornua. The live foetuses were observed in an incubator for 24 hours at 28°C. The number of live foetuses was counted after 24 hours.
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 resorptions: Yes
Fetal examinations:
The foetuses were dissected; the sex was determined by examining the gonads and the organs of the thorax and the abdomen; the foetuses were then examined for any possible malformation. The heads of the foetusea were fixed in a mixture of alcohol, acetic acid and formol. Sections were made by freezing in accordance with the Wilson (1964) method.

Statistics:
We determined the standard variation and the t-test; when the latter is above 5%, the results are non-significant when it is 5% or between 5% and 1%, the results are significant; when the results are 1% or below, they are very significant.
Historical control data:
not mentioned

Results and discussion

Results: maternal animals

Maternal developmental toxicity

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

Details on maternal toxic effects:
The behaviour of the animals in the test groups was not different from that of the animals in the control group. In group 3 (200 mg/kg), 3 rabbits miscarried on days 18, 20 and 23 p.c.. The behaviour of the other animals was normal and no different from those in the control group.
The increase in the weight of the animals in all the groups corresponded to that of the animals in the control group.
The animals in all the groups consumed more or less the same amount of food.
One animal died during first forced-feeding. No further animals died throughout the study.
One rabbit showed a recent gastric haemorrhage in the fundus.

Effect levels (maternal animals)

Dose descriptor:
NOEL
Effect level:
200 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity

Results (fetuses)

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

Details on embryotoxic / teratogenic effects:
In groups one (20 mg/kg) and two (100 mg/kg) no miscarriages were observed. In group 3 (200 mg/kg) 3 miscarriages were observed. There was no difference in premature or belated reabsorption between the treated animals and the reference animals.
The frequency of foetuses was the same among the reference animals and the animals in groups 1, 2 and 3; even in this last group the percentage of foetuses was no smaller.
Over 24 hours foetal mortality was not higher in any of the treated groups in relation to the control group.
In the first two groups the weight of the different foetuses was not lower than in the control group. In group 3, however, there was a slight reduction in the weight of the foetuses, but this was not significant.
No difference was found between the reference animals and the treated animals concerning dwarfism.
The distribution of sexes was similar to the control group.
In group 2 and 3 one rabbit showed a malformation. One foetus in group 2 showed aplasia of the head and in group 3 the foetus showed internal hydrocephalus.

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
200 mg/kg bw/day (actual dose received)
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:
The test substance has no effects on reproduction and is not teratogenic.