Methylurea

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

other information

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

other: non-guideline study with significant methodological deficiencies (single application, small number or animals per dose group, only one dose tested (= MTD))

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Correlation Between the Molecular Structure of N-Alkylureas and N-Alkylthioureas and Their Teratogenic Properties

Author:

Teramoto, S

Year:

1981

Bibliographic source:

Teratology 23 :335-342

Reference 2

Reference Type:

publication

Title:

Teratogenicity of ureas in rats and mice.

Author:

Kaneda M

Year:

1980

Bibliographic source:

Teratology 22 (1): 18A; abstract

Materials and methods

Principles of method if other than guideline:

Eleven urea compounds were administered individually as a single maximum tolerated oral dose to pregnant rats either on day 12 or 14 of gestation and to pregnant mice on day 10 of gestation. Teratogenicity in rats and mice was investigated.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Methylurea

EC Number:

209-935-0

EC Name:

Methylurea

Cas Number:

598-50-5

Molecular formula:

C2H6N2O

IUPAC Name:

methylurea

Details on test material:

- Name of test material (as cited in study report): methylurea
- no further data

Test animals

Species:

rat

Strain:

Wistar

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: CLEA, Japan
- Age at study initiation: 15 weeks
- Weight at study initiation: No data
- Fasting period before study: No data
- Housing: No data
- Diet (e.g. ad libitum): aboratory chow (Oriental Yeast MF), ad libitum
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: No data


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 ± 1 °C
- Humidity (%): 55 ± 5 %
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): No data

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
Aqueous solutions were prepared and given orally to female rats by intubation.

VEHICLE
- Amount of vehicle (if gavage): 10 ml/kg

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: No data
- Length of cohabitation: overnight
- Proof of pregnancy: vaginal plug referred to as day 0 of pregnancy

Duration of treatment / exposure:

day 12 of gestation

Frequency of treatment:

single application

Duration of test:

cesarean section at day 20 of pregnancy

Doses / concentrations

Remarks:

Doses / Concentrations:
2000 mg/kg bw
Basis:

No. of animals per sex per dose:

6 females

Control animals:

yes, concurrent vehicle

other: urea as negative control... (see attached file)

Details on study design:

- Dose selection rationale:
A maximum-tolerated dose was first determined by treating nonpregnant female rats with a single oral dose of the compound in dosages of 1000 and 2000 mg/kg. The animals were examined for deaths or toxic signs such as depression, diarrhea, etc ., for one week. When neither death nor any sign of toxicity was observed for a dose, that dose was selected as the maximum-tolerated dose that could be used.

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: No data

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 20
- Organs examined: No data

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: No data
- Number of implantations: Yes
- Number of resorptions: Yes

Other examinations:
- live and dead fetuses

Fetal examinations:

• Living fetuses from each litter were divided into two groups after they were weighed individually and examined for gross abnormalities.
• One group which was derived from the right uterine horn was processed for skeletal examinations according to the differential staining method of Inouye
• The other group of fetuses was fixed in Bouin's fluid and examined for visceral anomalies by the razor-blade sectioning method (Barrow and Taylor, 1969).

- External examinations: Yes, all per litter
- Soft tissue examinations: Yes, half per litter
- Skeletal examinations: Yes, half per litter
- Head examinations: No data

Statistics:

Student's t test was used for analysing differences in numbers of implants and live fetuses and fetal body weights between treated and control groups.
Differences in resorption and malformation incidences, assessed on the basis of number of affected fetuses, were analyzed by the Chisquare test .

Indices:

No indices were calculated.

Historical control data:

No data

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:no data

Details on maternal toxic effects:
No obvious signs of toxicity and no mortality in rats at dosages up to 2000 mg/kg body weight were observed.

Effect levels (maternal animals)

Dose descriptor:

NOAEL

Effect level:

>= 2 000 mg/kg bw/day (actual dose received)

Basis for effect level:

other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
1-methylurea had no observable effect on fetal development in rats. Fetal survival and weight of the group treated with this compound were comparable to those of the control group.

- Mean No. of implants (± SD): 1-Methylurea: 13.8 ± 1.0; Control: 13.7 ± 1.0; Urea: 13.8 ± 2.2
- Mean No. of live fetuses (± SD): 1-Methylurea: 13.2 ± 0.8; Control: 13.3 ± 0.8; Urea: 13.8 ± 2.2
- % Fetal resorptions: 1-Methylurea: 4.8; Control: 2.4; Urea: 0.0
- Mean fetal weight (mg ± SD): 1-Methylurea: 3697 ± 253; Control: 3671 ± 197; Urea: 3626 ± 104
- % Fetuses malformed: 1-Methylurea: 0.0; Control: 0.0; Urea: 1.8

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified