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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:
1986-08-14 to 1986-10-31
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1987
Report date:
1987

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
EPA OPP 83-3 (Prenatal Developmental Toxicity Study)
Version / remarks:
1982
GLP compliance:
yes (incl. QA statement)
Limit test:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
1-(3,5-dichloro-2,4-difluorophenyl)-3-(2,6-difluorobenzoyl)urea
EC Number:
617-441-5
Cas Number:
83121-18-0
Molecular formula:
C14 H6 Cl2 F4 N2 O2
IUPAC Name:
1-(3,5-dichloro-2,4-difluorophenyl)-3-(2,6-difluorobenzoyl)urea
Test material form:
solid: crystalline

Test animals

Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: commercial rabbit breeding organisation (H. Fortkamp, 4540 Lengerich, Germany).
- Age at study initiation: 14 to 17 weeks
- Weight at study initiation: range of 3.0 to 3.7 kg
- Fasting period before study: no
- Housing: housed individually in metal cages with perforated bottoms
- Diet: ad libitum, pelleted form (Rabbit Diet, DEUKA Deutsche Kraftfutterwerke GmbH, Germany)
- Water: ad libitum
- Acclimation period: at least one week prior to start of mating

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 25
- Humidity (%): 40 - 70
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The test article was prepared as a suspension in the vehicle at least once weekly. During dosing, the suspensions were kept homogeneous with a magnetic stirrer. The formulations were stored in a refrigerator at approximately 4 to 8 °C.

VEHICLE
- Justification for use and choice of vehicle (if other than water): Test item can be suspended in CMC.
- Concentration in vehicle: 100 mg/L
- Amount of vehicle: 10 mL/kg
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The analysis of three samples of a 100 g/L suspension of test item in CMC show that the suspension was homogeneous and accurately prepared. The test article is stable in the suspension for at least three days at room temperature.
Details on mating procedure:
- Impregnation procedure: natural mating
- Does that successfully completed coitus received an intravenous injection of 50 I.U. of a luteinizing hormone to ensure ovulation.

The day of mating was designated as day 0 of gestation.
Duration of treatment / exposure:
from day 6 to 18 post-coitum
Frequency of treatment:
daily
Duration of test:
13 days
Doses / concentrations
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
22 (treatment group), 16 (ctr group)
Control animals:
yes, concurrent vehicle

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: All female rabbits were examined at Ieast twice daily for signs of ill-health, toxicity, and behavioural change. All changes were recorded. Daily mortality checks were also performed.

DETAILED CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes
- Time schedule for examinations: The body weight of each inseminated female rabbit was recorded on days 0, 6 to 18, 24, and 28 post-coitum and evaluated for days 0, 6, 12, 18, 24, and 28 post-coitum.

FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
- The food consumption was determined weekly.

WATER CONSUMPTION AND COMPOUND INTAKE: No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on day 28 post coitum
- Organs examined: ovaries, uteri

Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Blood sampling:
not performed
Fetal examinations:
- External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: [all per litter]
- Skeletal examinations: Yes: [all per litter]
- Head examinations: Yes: [half per litter]
- Anogenital distance of all live rodent pups: No
Statistics:
For body weight, body weight gain, food consumption, Iitter weight, and fetal weights (overall, males, females), the student's t-test was performed. Number of corpora lutea, number of implantations, number of fetuses, post-implantation loss, pre-impIantation loss, and proportion of male fetuses (sex ratio) were statistically analyzed using the Mann-Whitney U-test.
Indices:
see table 1
Historical control data:
yes

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
No treatment-related clinical signs were observed in the treated animals
Mortality:
mortality observed, non-treatment-related
Description (incidence):
One control animal died on day 16-post coitum. Necropsy showed pulmonary findings. One animal in the treated group aborted on day 18-post coitum and was sacrified. Autopsy revealed pulmonary findings. Another animal in this group aborted on day 26-post coitum and was sacrificed. The occurrence of those 2 abortions was not considered to be treatment related.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Group mean body weight gain of the treated animals was comparable with the control group.
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
effects observed, non-treatment-related
Description (incidence and severity):
Reduced water consumption was occasionally observed in control and compound treated animals. This finding was considered to be not treatment-reIated.
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Endocrine 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:
effects observed, treatment-related
Description (incidence and severity):
At necropsy on day 28 p.c., occasional minor findings (mainly grossly granulated cut surface of the liver) were detected at higher incidence in the dose group than in the control group. The finding might be treatment-reIated. No further changes were observed at necropsy. One female in the treatment group showed 100 % intra-uterine death at necropsy. It was not possible to determine whether or not this effect was resulting from an effect of the treatment.
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):
One animal in group 2 (1000 mg/kg bw/day) aborted on day 18 p.c. and was killed. Autopsy revealed pulmonary findings. One further female in group 2 (1000 mg/kg bw/day) aborted on day 26 p.c. and was killed.
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
There was no effect of treatment on implantations.
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
The mean number of total intra-uterine death was lower in group 2 (1000 mg/kg bw/day) than in the control group.
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Description (incidence and severity):
The mean number of fetuses per dam was higher in the treated group than in the control group.
Changes in pregnancy duration:
not examined
Changes in number of pregnant:
not examined

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Remarks:
maternal
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: highest dose tested

Maternal abnormalities

Key result
Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
The mean fetal weight in the treated group was comparable with the control group.
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
The mean number of foetuses per doe was higher in group 2 (1000 mg/kg) than
in the control group.
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
not examined
Anogenital distance of all rodent fetuses:
not examined
Changes in postnatal survival:
not examined
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
In one fetus of the treated group, an aplasia of the tail was noted.
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Two control fetus showed fused ribs.
Two fetuses of the treated group showed skeletal malformations as fused or fissured ribs.
Due to the nature and incidence of these effects, their occurrence was considered to be incidental.
The incidence of skeletal variations in the treated animals was comparable with the controls.
Visceral malformations:
no effects observed

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Remarks:
developmental
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: highest dose tested

Fetal abnormalities

Key result
Abnormalities:
effects observed, non-treatment-related

Overall developmental toxicity

Key result
Developmental effects observed:
no

Applicant's summary and conclusion