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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
Study period:
1983-02-07, 1983-12-12
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1983
Report Date:
1983

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
treatment from day 6 to day 18 post coitum and caesarian section on day 29.
GLP compliance:
yes
Remarks:
Statement of compliance missing
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Substance type: organic
- Physical state: solid

Test animals

Species:
rabbit
Strain:
Chinchilla
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: IVANOVAS Kisslegg, Germany
- Age at study initiation: 4 - 5 months
- Weight at study initiation: 3.0 - 3.2 kg
- Fasting period before study: - Housing: singly in the cages of a Heinkel battery
- Diet: ad libitum, pelleted, certified standard diet (NAFAG No. 814)
- Water: ad libitum, tap water
- Acclimation period: 7 - 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 2
- Humidity (%): 55 ± 10
- Photoperiod (hrs dark / hrs light): 12 / 12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: PEG 400 / dist. water (1:1)
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
A mixture of one part of distilled water and one part of Polyethylene Glycol 400 was used as a vehicle. The suspension of the test material was freshly prepared daily by homogenization and stirring (magnetic stirrer), and administered at a rate of 4 mL/kg of body weight.

VEHICLE
- Justification for use and choice of vehicle (if other than water): test substance insoluble in water
- Concentration in vehicle: 200, 600, and 1200 mg/4 mL vehicle
- Amount of vehicle (if gavage): 4 mL/kg
Analytical verification of doses or concentrations:
no
Details on mating procedure:
- Impregnation procedure: cohoused- If cohoused:
- M/F ratio per cage: 1/1
- Length of cohabitation: 1 day
- Each doe was mated twice, the second time about one hour after the first time of the same day. This day was designated as day 0 of pregnancy.
Duration of treatment / exposure:
The test material was administered from day 6 until day 18 of pregnancy, inclusive.
Frequency of treatment:
daily
Duration of test:
29 days
No. of animals per sex per dose:
20
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: preliminary experiment carried out on 3 non-pregnant rabbits at the daily dose of 1200 mg/kg of body weight

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: yes
- Time schedule: daily
- Cage side observations: general bodily condition and symptoms

DETAILED CLINICAL OBSERVATIONS: no

BODY WEIGHT: yes
- Time schedule for examinations: daily

FOOD CONSUMPTION: Yes, on days 6, 11, 15, 19, 24, and 29 of pregnancy.

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 29
- Organs examined: the dams' organs, especially of the ovaries (corpora lutea counted) and uterus (mucosa and contents, including amniotic fluid and placentae as well as abortions ad resorption sites) the foetuses were removed and subjected to careful external inspection.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: YesExaminations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: abortions
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:
Whenever feasible, statistical evaluation of data was performed.
Historical control data:
Spontaneous data characteristic of the breed of rabbits used in the study refer to untreated controls ("historical" or cumulative control) observed over the period of 15 months (for reproduction data and skeletal maturation) and 75 months (for the spontaneous rate of anomalies and/or malformations)

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Description (incidence and severity):
No reactions to the treatment were recorded for the dams.
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, non-treatment-related
Description (incidence):
Some females of the dose groups died spontaneously while on test. Intubation error was the predominant cause of death; application was observed to become increasingly difficult during the treatment period. Date of death (day p.c. i.e. post coitum) and findings at autopsy are listed below:
200 mg/kg d:
Female No.423: day 14; Intubation error
Female No.428: day 15; Pneumonia, exudative pleurisy, adhesive pericarditis, purulent material in thoracic cavity
600 mg/kg d:
Female No.444: day 7; Intubation error
Female No.452: day 11; Intubation error
1200 mg/kg d:
Female No.468: day 16; Intubation error
Female No.472: day 15; Intubation error
Female No.477: day 14; Intubation error
Female No.478: day 8; Pneumonia, exudative pleurisy, adhesive pericarditis, subcutaneous abscess on left side of thoracic cage
Body weight and weight changes:
no effects observed
Description (incidence and severity):
In comparison with the vehicle control, body-weight gain was not altered in the dose-groups
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
food consumption was also comparable for all groups
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
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:
no effects observed
Other effects:
no effects observed
Description (incidence and severity):
Preliminary study
In a preliminary experiment 3 non-pregnant females were treated at a dose of 1200 mg/kg of body weight for 13 consecutive days. No reactions to the treatment were observed and no pathological changes were recorded at sacrifice two days after termination of treatment.

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
The mean numbers of corpora lutea and implantation sites as well as the ratio corpora lutea/implantation sites were comparable for all groups.
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Description (incidence and severity):
The rates of embryolethality and foetolethality (resorptions) were comparable for all groups
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
The overall pregnancy rates were 75.0 % in the vehicle control, 88.9 % in the low-dose, 94.4 % in the intermediate dose and 93.3% in the high-dose group. No significant intergroup differences were assumed.

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
1 200 mg/kg bw/day (actual dose received)
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
In comparison with the vehicle control, the average body weight of the live foetuses was not diminished at either dose. In the intermediate dose a slight but significant increase was noted (Student's t test, one-tailed, observed p < 0.01). In view of the data recorded for the historical control population, this finding, however, is not believed to be of a biological relevance.
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Description (incidence and severity):
The sex ratios (expressed as percent male foetuses) were not significantly altered in either group.
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
The skeletal assessment revealed instances of irregular sternebral ossification in the vehicle control as well as in the dose groups.
Concerning skeletal maturation of the foetuses, a slight but significant delay in ossification of in particular the 5th sternebra was recorded for the high-dose group in comparison with the vehicle control; with regard of the ranges recorded for the historical
control, no experimental significance is attached to this finding, the sternebral anomalies were considered to be of a spontaneous origin. Sternebral anomalies were recorded to occur at an incidence of 0.87% in tne historical control population.
Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
The gross and visceral examination of the live foetuses revealed anomalies and/or malformations in the intermediate and high-dose groups and in the vehicle control.
Omphalocele was recorded for one foetus each ot the intermediate dose group and the vehicle control, respectively. One instance of internal hydrocephaly was found in the intermediate dose group, excessive fluid in the abdominal and thoracic cavities was noted for one foetus of the vehicle control. Unilateral agenesis of kidney and unilateral agenesis of kidney and ureter occurred in one foetus each from one litter of the high-dose group. These malformations and/or anonalies were considered
to be of a spontaneous origin and not related to tne treatment, the incidence of agenesis ot kidney/ureter being 0.16% in the historical control population of the breed of rabbits used for the present study.

Effect levels (fetuses)

open allclose all
Dose descriptor:
NOAEL
Effect level:
1 200 mg/kg bw/day (actual dose received)
Basis for effect level:
other: embryotoxicity
Dose descriptor:
NOAEL
Effect level:
1 200 mg/kg bw/day (actual dose received)
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 article was devoid of embryotoxic activity and did not reveal teratogenic potency in the rabbit under the present experimental conditions.