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Diss Factsheets

Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: No guideline followed. The study performed with relatively small numbers of animals and a single dose
Justification for type of information:
Data in reference was deemed to sufficiently applicable to potassium carbamoylcarbamate.
Cross-reference
Reason / purpose for cross-reference:
read-across source
Reference
Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: The study is printed in German and only a study summary was reviewed. The study only investigated effects of in utero exposure on the kidneys and; therefore, is not comparable to current prenatal developmenetal toxicity study guidelines.
Justification for type of information:
Data of reference deemed sufficiently applicable to potassium carbamoylcarbamate.
Reason / purpose for cross-reference:
read-across source
Qualifier:
no guideline followed
Principles of method if other than guideline:
The test group was dosed, by gavage, with urea for 14 days starting 6 days after the last estrus. The dams were allowed to give birth naturally. The total number of fetuses as well as the fresh and dry weight of the fetal kidneys were compared between the test and vehicle control groups.
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
other: albino Wistar
Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
The test group was dosed, by gavage, with urea for 14 days starting 6 days after the last estrus.
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
No data
Duration of treatment / exposure:
14 days
Frequency of treatment:
Administered in two doses totaling ca. 50 g/kg bw/day
Remarks:

Doses / Concentrations:

Basis:
nominal in water
50 g/kg bw/day
No. of animals per sex per dose:
6
Control animals:
yes, concurrent vehicle
Details on study design:
Within 48 hours of birth, pups were sacrificed by decapitation and kidneys removed and weighed; the right kidney was then dried at 105 ºC and weighed.
Maternal examinations:
No data
Ovaries and uterine content:
No data
Fetal examinations:
No data
Details on maternal toxic effects:
Maternal toxic effects:no data

Details on maternal toxic effects:
No maternal toxicity was reported
Dose descriptor:
other: Not provided
Effect level:
50 other: -
Basis for effect level:
other: Not provided
Remarks on result:
other: No maternal toxicity was reported
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No evidence of teratogenicity was seen in this study.
Dose descriptor:
NOEL
Effect level:
ca. 50 other: g/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: teratogenicity
Abnormalities:
not specified
Developmental effects observed:
not specified
Conclusions:
A toxicity study was conducted to investigate the effects of urea, added to the dams' diet, on fetal kigney weights. Based on the study, no maternal toxicity was reported and there were no statistical differences in the fresh or dry weight of the kidneys from the test group compared to the vehicle controls.

Data source

Reference
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, and Shirasu Y
Year:
1981
Bibliographic source:
Teratology 23(3): 335–42

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Dams were dosed via oral gavage to pregnant rats on day 12 of pregnancy and sacrificed on day 20 of pregnancy.
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
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:
not specified
Details on test material:
Urea from Wako Pure Chemical Industries, Ltd

Test animals

Species:
rat
Strain:
Wistar
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: purchased from CLEA, Japan
- Age at study initiation: (P) 15 wks
- Diet: laboratory chow (Oriental Yeast MF), ad libitum
- Water: tap water ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 ±1
- Humidity (%): 55 ± 5

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
Aqueous solutions of the compounds (10 mL/kg) were prepared and orally administered to dams.
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
Females were paired overnight with a male. The following morning they were examined for the presence of vaginal plug and were designated as being in day 0 of pregnancy when the plug was observed.
Duration of treatment / exposure:
Dams were dosed at day 12 of pregnancy
Frequency of treatment:
Single dosing
Duration of test:
Dosed on day 12 of pregnancy, and sacrificed at day 20 of pregnancy
Doses / concentrations
Remarks:

Doses / Concentrations:
Basis:
nominal conc.
2000 mg/kg
No. of animals per sex per dose:
4
Control animals:
yes, concurrent vehicle

Examinations

Fetal examinations:
- External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: [ half per litter]
- Skeletal examinations: Yes: [ half per litter]
- Head examinations: No data

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
Mortality was not observed.

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
2 000 mg/kg bw (total dose)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No significant changes were observed in number of implants, number of live fetuses, % of fetal resorptions, fetal weight or % fetal malformation.

Effect levels (fetuses)

Dose descriptor:
other: Not provided
Effect level:
50 other: -
Basis for effect level:
other: Not provided
Remarks on result:
other: Embryotoxic / teratogenic effects:no effects Details on embryotoxic / teratogenic effects: No significant changes were observed in number of of implants, number of live fetuses, % of fetal resorptions, fetal weight or % fetal malformation.

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Based on the study, no adverse developmental/teratogenicity effects were observed due to a single, high-dose urea treatment.