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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

Referenceopen allclose all

Reference Type:
review article or handbook
Title:
Unnamed
Year:
2011
Report date:
2011
Reference Type:
publication
Title:
Correlation between the molecular structure of N-alkylureas and N-alkylthioureas and their teratogenic properties
Author:
Teramoto S, Kaneda M, Aoyama H et al.
Year:
1981
Bibliographic source:
Teratology 23(3):335–342
Report date:
1981

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Urea (and 10 other urea compounds) were screened for developmental toxicity in pregnant Wistar rats and ICR mice. The animals received a single oral dose of urea at GD 12 (rats) or at GD 10 (mice). The progeny was examined at GD 20 rats or GD 18 (mice) respectively.
GLP compliance:
not specified

Test material

Constituent 1
Chemical structure
Reference substance name:
Urea
EC Number:
200-315-5
EC Name:
Urea
Cas Number:
57-13-6
Molecular formula:
CH4N2O
IUPAC Name:
urea
Test material form:
solid
Specific details on test material used for the study:
CAS number: 51-13-6
Purity: not stated

Test animals

Species:
rat
Strain:
Wistar
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: 15 weeks (rats) or 8 weeks (mice)

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on mating procedure:
no details specified in the assessment report
Duration of treatment / exposure:
single dose at GD 12 (rats) or GD 10 (mice)
Frequency of treatment:
one single treatment
Duration of test:
GD0 trough GD 20 (rats or GD 18 (mice)
Doses / concentrationsopen allclose all
Dose / conc.:
2 000 mg/kg bw (total dose)
Remarks:
single dose; rats
Dose / conc.:
2 000 mg/kg bw (total dose)
Remarks:
single dose, mice
No. of animals per sex per dose:
rats: 4 females
mice: 10 females
Control animals:
yes
yes, concurrent vehicle

Examinations

Maternal examinations:
Mortality
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes / No / No data
Examinations included:
- Number of implantations: Yes
- Number of fetal resorptions: Yes
- Number of malformnd fetuses: Yes

Other examinations:
- number of live and dead fetuses
- fetus weight
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: No data
- Skeletal examinations: No data
- Head examinations: No data

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
not specified
Mortality:
no mortality observed
Body weight and weight changes:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
no statistically significant difference between vehicle control and urea-treated rats regarding percent fetal resorptions (2.4 vs. 0%)
Total litter losses by resorption:
no effects observed
Early or late resorptions:
not specified
Dead fetuses:
no effects observed
Description (incidence and severity):
no statistically significant difference between vehicle control and urea-treated rats regarding number of live fetuses (13.3 ± 0.8 vs. 13.8 ± 2.2)
Changes in pregnancy duration:
not examined
Description (incidence and severity):
dams sacrificed before parturition
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not examined
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.DescriptionIncidenceAndSeverityEffectsOnPregnancyDuration): dams sacrificed before parturition
Changes in number of pregnant:
not examined
Description (incidence and severity):
only pregnant rats (or mice) were used

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
2 000 mg/kg bw (total dose)
Based on:
act. ingr.
Basis for effect level:
other: no maternal toxicity noted
Remarks on result:
other: one single dose was administered

Maternal abnormalities

Key result
Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
no statistically significant difference between fetuses from vehicle control and urea-treated rats: fetal body weight (3,671 ± 197 mg vs. 3,626 ± 104 mg)
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.DescriptionIncidenceAndSeverityFetalPupBodyWeightChanges): no statistically significant difference between fetuses from vehicle control and urea-treated rats regarding fetal body weight (3,671 ± 197 mg vs. 3,626 ± 104 mg)
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
no statistically significant difference between fetuses from vehicle control and urea-treated rats: number of live fetuses (13.3 ± 0.8 vs. 13.8 ± 2.2),
Changes in sex ratio:
not specified
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Description (incidence and severity):
no statistically significant difference between fetuses from vehicle control and urea-treated rats: percent fetuses malformed (0 vs. 1.8%)
Skeletal malformations:
not specified
Visceral malformations:
not specified

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
2 000 mg/kg bw (total dose)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: no adverse effects noted
Remarks on result:
other: one single dose administered

Fetal abnormalities

Key result
Abnormalities:
no effects observed

Overall developmental toxicity

Key result
Developmental effects observed:
no

Applicant's summary and conclusion

Conclusions:
No maternal effects noted in pregnant rats or mice receiving a single oral dose of 2000 mg/kf bw at GD 12 (rats) or GD 10 (mice)
Executive summary:

Teramoto et al. (1981) examined the developmental toxicity of urea compounds in pregnant Wistar rats (n=4) and pregnant ICR mice (n=10) that received a single oral dose of urea at 2000 mg/kg bw on gestational day 12 (rats) or GD 10 (mice). Rats were sacrificed on GD 20 (mice: GD 18). The number of implants and live and dead foetuses were counted. Living foetuses from each litter were divided into two groups after being weighed individually and examined for gross abnormalities. Foetuses from the right uterine horn were processed for skeletal examination and those from the left horn were processed for visceral examination. For statistical comparisons, the litter was considered the experimental unit.

No maternal toxicity was noted in rats or mice (data not shown). There were no statistical differences between the vehicle control and the urea-treated rats based on the mean ± SD for number of implants (13.7 + 1.0 vs.13.8 ± 2.2), number of live foetuses (13.3 ± 0.8 vs. 13.8 ± 2.2), percent foetal resorptions (2.4 vs. 0%), foetal body weight (3,671 ± 197 mg vs. 3,626 ± 104 mg), or percent foetuses malformed (0 vs. 1.8%). These endpoints also were unaffected in mice treated with urea (data not shown); (EPA, 2011).

 

Thus, no maternal or developmental toxicity was noted in pregnant rats or mice receiving a single oral dose of 2000 mg/kg bw. The study protocol does, however, not comply with current guidelines.