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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:
other: This study was selected as the key study because the information provided for the hazard endpoint is sufficient for the purpose of classification and labeling and/or risk assessment.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1978
Report Date:
1978

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
other: Food and Drug Administration (1966). Guidelines for Reproductive Studies for Safety Evaluations of Drugs for Human Use.
Deviations:
no
Remarks:
The study was conducted according to the guideline in effect at the time of study conduct.
Qualifier:
according to
Guideline:
other: Committee on Safety of Medicines. Guidelines on Reproduction Studies for the Guidance of Applicants for Product Licences and Clinical Trial Certificates, June 1974.
Deviations:
no
Remarks:
The study was conducted according to the guideline in effect at the time of study conduct.
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Purity: not reported

Test animals

Species:
rabbit
Strain:
other: Yellow-Silver
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: 3-4 months
- Weight at study initiation: 2.7-3.0 kg
- Housing: housed in individual stainless steel cages
- Diet (e.g. ad libitum): For all dose levels portions of 150 g food per day were given from 1st to 30th day of gestation.
- Water (e.g. ad libitum): ad libitum
- Acclimation period: acclimatized for a period of at least four weeks prior to the experiment

ENVIRONMENTAL CONDITIONS
- Temperature (°C): fully air-conditioned rooms at a temperature of 18 ± 1 ºC
- Humidity (%): 50-60 %
- Photoperiod (hrs dark / hrs light): 12 h/day lig

Administration / exposure

Route of administration:
oral: feed
Details on exposure:

DIET PREPARATION
- Mixing appropriate amounts with (Type of food): Sucrose baked into Nafag 814 food.


Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused: 10-15 healthy untreated Yellow Silver bucks of proven fertility were employed. Each doe was caged with a buck for one to three hours and copulation observed. Ideally following two copulations with the same male, the fertilized females were distributed to the experimental groups according to a table of random numbers.
Duration of treatment / exposure:
Gestation Days 7 to 19
Frequency of treatment:
Daily, females only
Duration of test:
Surviving does were sacrificed on the 30th day of gestation.
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 2 %, 5 %, 10 % and 20 %
Basis:
nominal in diet
No. of animals per sex per dose:
20 females
Control animals:
yes, plain diet

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 AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 30
- Organs examined: Mothers were examined for possible malformations and the number and uterine location of viable fetuses, dead fetuses, resorption sites and number of corpora lutea were recorded. Fetuses were examined for external malformations, sexed, weighed and their crownrump
length was measured.

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: No data
- Other: dead fetuses, viable fetuses
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: all per litter
- Head examinations: Yes: all per litter
Statistics:
Statistical analyses were performed using Student's "t" test for independent samples and the chi-square test (Fisher's exact probability test).

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
weight development during the treatment period was retarded at 20% (6770 mg/kg)

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
4 170 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
LOAEL
Effect level:
6 770 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
6 770 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity

Results (fetuses)

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

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
This study and the conclusions which are drawn from it fulfill the quality criteria (validity, reliability, repeatability).
There was no indication of any embryotoxic or teratogenic effect in the young; weight development during the treatment period was retarded in the does.
Executive summary:

The results of the experiment give no indications of any embryotoxic or teratogenic effect of the test substance in rabbits administered day 7 to 19 gestation as feed admix in concentrations of up to 20% in the diet. This corresponds to an average daily intake of 6770 mg/kg bodyweight, approximately, during the period of treatment. Weight development during the treatment period was retarded in the does at 6770 mg/kg.

The maternal NOAEL is 4170 mg/kg and the developmental NOAEL is 6770 mg/kg, the highest dose tested.