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Developmental toxicity / teratogenicity

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developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
The present range-finding study did no follow a guideline as the purpose was to assess the toxicity of the tested material in pregnant rabbit in view of a teratogenicity study. The test conduct however followed GLP. Thus the study was of scientifical acceptability.

Data source

Reference Type:
study report
Report Date:

Materials and methods

Test guideline
no guideline followed
Principles of method if other than guideline:
The present study was a range-finder which was conducted in order to obtain preliminary data to assess the toxicity of the tested material in pregnant rat in view of a teratogenicity study.
GLP compliance:
Limit test:

Test material

Details on test material:
- Name of test material (as cited in study report): Irgacare MP (C-P SampIe No.: 38328)
- Physical state: neat white powder
- Analytical purity: 99.8%
- Purity test date: no data provided
- Lot/batch No.: 19851206
- Stability under test conditions: assured for at least 4 weeks under the storage conditions given below (according to the sponsor)
- Storage condition of test material: at room temperature
- Remark: the test material was provided as suspensions in vehicle by the sponsor; the data referring to the test substance (e.g. purity) were provided by the sponsor in a sheet dated 24 May 1991 which was included as appendix to the study report.

Test animals

New Zealand White
Details on test animals and environmental conditions:
- Source: Hazleton Research Products, Inc., Denver, PA, USA
- Age at study initiation: approximatively 5 months old
- Weight range at study initiation: 3028 - 4190 g
- Fasting period before study: Feed was withheld on the day of arrival. On the first, second and third full days in-house, the animals received 25, 50 and 100 grams of Purina Certified Rabbit Chow No. 5325 (High-Fiber) feed, respectively.
- Housing: Individually, except during mating, in stainless steel, suspended cages with wire mesh floors, tops and fronts and sub-cage floor pans.
- Diet (e.g. ad libitum): approximately 150 g of the food were presented to each animal daily during the remainder of the acclimation period; once mated, animals were fed ad libitum.
- Water (e.g. ad libitum): tap water was offered ad libitum.
- Acclimation period: 40 days

- Temperature (°C): 15 - 24 °C
- Humidity (%): the scheduled humidity range was 40-60%; the measured range was 33 - 90%. In fact, the relative humidity in the animal quarters reached 90% on only one occasion. Exclusive of this interval, for the remainder of the study, relative humidity values generally ranged from 33-75%, with the exception of five recording intervals (6.3%) when the relative humidity ranged between 80-84%.
- Air changes (per hr): no data specified
- Photoperiod (hrs dark / hrs light): 12 hrs/ 12 hrs

Administration / exposure

Route of administration:
oral: gavage
other: 1% (w/w) carboxymethylcellulose in 20% aqueous glycerol
Analytical verification of doses or concentrations:
Details on mating procedure:
Natural mating was used. Each female selected for mating was placed together with two different males, with an interval of 1 to 2 hours between the first and the second mating. The day on which evidence of mating was observed with both males was defined as day 0 of gestation
Duration of treatment / exposure:
From day 6 to day 18 of gestation
Frequency of treatment:
Once daily
Duration of test:
30 days
Control animals:
yes, concurrent no treatment


Maternal examinations:
The animals were examined twice a day for clinical symptoms of toxicity, moribund state and mortality. In addition, each animal was subjected to a detailed physical examination on day 0, daily from day 6 to 19, on day 24 and at test ending, on day 30 of gestation.

The body weights were recorded on day 0, 6, 8, 10, 12, 14, 16, 19, 24, and 30 of gestation.

Food consumption was measured on day 1 and 3, daily from day 5 to 19, on day 24 and on day 29 of gestation.

All surviving females were sacrificed on day 30 of gestation by intravenous injection of sodium pentobarbital via the marginal ear vein. They were subjected to gross pathological examination. Animals that died or needed to be sacrificed in extremis during the experiment because of moribund state also were subjected to gross pathology.
The external surface, all orifices, the cranial cavity, the carcass, the external surface of the spinal cord and sectioned surfaces of the brain, the nasal cavity and paranasal sinuses, the thoracic, abdominal and pelvic cavities and their viscera, and the cervical tissues and organs were examined for all animals. Gross lesions were fixed in 10% neutral buffered formalin. The liver was weighed for all females sacrificed on day 30 of gestation; a liver to body weight ratio also was calculated using the corrected day 30 gestation weights.
Ovaries and uterine content:
The uteri of the sacrificed animals were removed, weighed intact and evaluated for the number of live, dead and resorbed foetuses and implantation sites. The ovaries were also dissected free and the number of corpora lutea recorded. When no uterine implants were grossly apparent, the uterus was stained with ammonium sulfide; when no foci were visualized post-staining, the female was considered not pregnant.
The uteri of females that died during the study were observed for the presence of implants. If the latter were found, the female was considered pregnant. If no uterine implants were seen, the uterus was stained with ammonium sulfide. If foci were present, the female was considered pregnant if foci were not present, the female was considered not pregnant.

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

Dose descriptor:
Effect level:
50 mg/kg bw/day
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Effect levels (fetuses)

Dose descriptor:
Effect level:
75 mg/kg bw/day
Basis for effect level:
other: teratogenicity

Fetal abnormalities

not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion