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Diss Factsheets

Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1973
Report date:
1973

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
The study was conducted prior to implementation of OECD Test Guidelines. The study follows a protocol similar to OECD Test Guideline 414 with some deviations.
GLP compliance:
no
Remarks:
The study was conducted prior to GLP compliance
Limit test:
no

Test material

Constituent 1
Reference substance name:
Reference substance 001
Cas Number:
112926-00-8
Test material form:
other: Fine white powdered material

Test animals

Species:
hamster
Strain:
other: Virgin adult female golden hamsters
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: not specified
- Age at study initiation: not specified
- Weight at study initiation: not specified
- Fasting period before study: not specified
- Housing: individually housed in mesh bottom cages
- Diet (e.g. ad libitum): food was freely available, ad libitum
- Water (e.g. ad libitum): fresh tap water was freely available, ad libitum
- Acclimation period: not specified

ENVIRONMENTAL CONDITIONS
- Temperature (°C): temperature and humidity-controlled quarters
- Humidity (%): temperature and humidity-controlled quarters
- Air changes (per hr): not specified
- Photoperiod (hrs dark / hrs light): not specified

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
not specified
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: The test material was prepared and doses calculated according to Table 1.

VEHICLE
- Justification for use and choice of vehicle (if other than water): The controls were sham treated with the vehicle at a level equivalent to the group receiving the highest test dose.
- Concentration in vehicle: See Table 1
- Amount of vehicle (if gavage): See Table 1
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
The female animals were mated with mature adult males (1:1), and the appearance of motile sperm in the vaginal smear was considered day 0 of gestation.
Duration of treatment / exposure:
In the study pregnant female animals were given orally the test substance via intubation from gestation day 6 to 10.
Frequency of treatment:
daily
Duration of test:
10 days
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Remarks:
sham control
Dose / conc.:
250 mg/kg bw/day (actual dose received)
Remarks:
Aspirin - positive control
Dose / conc.:
16 mg/kg bw/day (actual dose received)
Remarks:
test item
Dose / conc.:
74.3 mg/kg bw/day (actual dose received)
Remarks:
test item
Dose / conc.:
345 mg/kg bw/day (actual dose received)
Remarks:
test item
Dose / conc.:
1 600 mg/kg bw/day (actual dose received)
Remarks:
test item
No. of animals per sex per dose:
Number of female animals per group before mating:
Sham control: 23 females
Positive control: 24 females
16 mg/kg bw/day test substance: 23 females
74.3 mg/kg bw/day test substance: 23 females
345 mg/kg bw/day test substance: 23 females
1600 mg/kg bw/day test substance: 24 females

Number of pregnant female animals per group on gestation day 0:
Sham control: 22 females
Positive control: 20 females
16 mg/kg bw/day test substance: 22 females
74.3 mg/kg bw/day test substance: 22 females
345 mg/kg bw/day test substance: 21 females
1600 mg/kg bw/day test substance: 21 females
Control animals:
yes

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: All animals were observed daily for appearance and behaviour.

DETAILED CLINICAL OBSERVATIONS: No data


BODY WEIGHT: Yes
- Time schedule for examinations: Body weights were recorded on days 0, 8, 10, and 14 of gestation.

FOOD CONSUMPTION: Yes
- Particular attention was given to food consumption and weight, in order to rule out any abnormalities which may have occurred as a result of anorexic effects in the pregnant female animal.

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 14
- Organs examined: genital tract

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: No data
- Number of implantations: Yes
- Number of resorptions: Yes
- The urogenital tract of each dam was examined in detail for anatomical normality
- Live and dead foetuses: Yes
Fetal examinations:
- External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: [one-third of the foetuses of each litter]
- Skeletal examinations: Yes: [two-thirds of the foetuses of each]
- Head examinations: Yes: No data

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined

Maternal developmental toxicity

Number of abortions:
effects observed, non-treatment-related
Description (incidence and severity):
Only one abortion occurred for one female at 74.3 mg/kg bw/day. No other effects were seen in any of the groups. This abortion was not considered to be test substance-related, but a biological variation.
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
There were no effects on the number of implantation sites in test substance-treated groups compared to the sham control animals.
Total litter losses by resorption:
effects observed, non-treatment-related
Description (incidence and severity):
Higher number of resorptions was seen in test item-treated groups 74.3 and 345 mg/kg bw/day than the control. There was no dose response relationship and this finding was not considered to be test item-related but a biological variation.
Early or late resorptions:
not examined
Dead fetuses:
effects observed, non-treatment-related
Description (incidence and severity):
There were 3 dead foetuses in 1600 mg/kg bw/day and 1 dead foetus in the sham and positive control groups. There was no dose response relationship and this effects was not considered to be test item-related but a biological variation.
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
No effects observed.
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
Only one abortion occurred for one female at 74.3 mg/kg bw/day. No other effects were seen in any of the groups. This abortion was not considered to be test substance-related, but a biological variation. There were no other changes in the number of pregnant animals in any of the test substance-treated groups throughout the study period.

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 600 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: No adverse effects observed.

Maternal abnormalities

Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
The average foetus weight was comparable among all groups.
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
The number of live foetuses was comparable among all groups.
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Description (incidence and severity):
The number of abnormalities seen did not differ from the number occurring spontaneously in the sham-treated controls.
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
The number of abnormalities seen in skeletal tissues of the test groups did not differ from the number occurring spontaneously in the sham-treated controls.
Visceral malformations:
no effects observed
Description (incidence and severity):
No soft tissue abnormalities were observed.

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 600 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects observed.

Fetal abnormalities

Abnormalities:
no effects observed

Overall developmental toxicity

Developmental effects observed:
no

Any other information on results incl. tables

See attachments for result tables.

Applicant's summary and conclusion

Conclusions:
The administration of up to 1600 mg/kg (body weight) of the test material to pregnant hamster for 5 consecutive days, during gestation days 6 to 10, had no clearly discernible effect on implantation or on maternal or foetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the sham-treated controls.