1-[1,3-bis(hydroxymethyl)-2,5-dioxoimidazolidin-4-yl]-1,3-bis(hydroxymethyl)urea

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Well reported study performed under GLP and using a standard test method.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1991

Report date:

1991

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

EPA OPP 83-3 (Prenatal Developmental Toxicity Study)

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

1-[1,3-bis(hydroxymethyl)-2,5-dioxoimidazolidin-4-yl]-1,3-bis(hydroxymethyl)urea

EC Number:

278-928-2

EC Name:

1-[1,3-bis(hydroxymethyl)-2,5-dioxoimidazolidin-4-yl]-1,3-bis(hydroxymethyl)urea

Cas Number:

78491-02-8

Molecular formula:

C8H14N4O7

IUPAC Name:

1-[1,3-bis(hydroxymethyl)-2,5-dioxoimidazolidin-4-yl]-1,3-bis(hydroxymethyl)urea

Test material form:

solid: particulate/powder

Remarks:

migrated information: powder

Test animals

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

238-308g at study start. Individually caged in room designed to maintain 22+/-3C and 30-70% humidity, with a 12h light/dark cycle.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Remarks:

deionised

Details on exposure:

Oral dosing with dose volume 10 ml/kg.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Colourimetric analysis (samples heated with reagent under acidic conditions, absorption measured at 520 nm). Measured concentrations of samples of formulated doses (1/per test dosage) confirmed to be within 10% of nominal values, and test substance absence in vehicle controls confirmed.

Details on mating procedure:

Females mated 1F:1M or 2F:1M until vaginal plug or sperm was seen (Day 0).

Duration of treatment / exposure:

10 days (gestation days 6-15).

Frequency of treatment:

Daily

Duration of test:

Treated females terminated on Day 20.

Doses / concentrations

Remarks:

Doses / Concentrations:
125, 250, 500 mg/kg
Basis:
analytical conc.
administered dose

No. of animals per sex per dose:

27 females treated.

Control animals:

yes, concurrent vehicle

Examinations

Maternal examinations:

Observed at least daily; bodyweights and food consumption measured during test period. Bodyweights and uterine weights recorded at necropsy.

Ovaries and uterine content:

Corpora lutea, early/late resorptions, viable/non-viable foetuses counted and recorded.

Fetal examinations:

Sexed, weighed, examined externally. Approximately half of each litter stained for skeletal abnormalities, remainder prepared and examined for soft tissue abnormalities.

Statistics:

Analysis of variance and non-parametric tests were applied to compare control and test group data.

Indices:

Maternal bodyweights and food consumption.
Dams with resorptions only, dams with viable foetuses.
Viable foetuses/dam
Total implants/dam
Total implant losses/dam
Pre-implantation loss (corpora lutea - implants/corpora lutea), % by dam
Post-implantation loss (implants - viable foetuses/implants), % by dam.

Foetal sex distribution
Foetuses with soft tissue malformations
Foetuses with skeletal malformations
Foetuses with soft tissue and/or skeletal malformations.

Litters with with soft tissue malformations
Litters with skeletal malformations
Litters with soft tissue and/or skeletal malformations.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:no effects. Remark: post-dose salivation (seen at 250 mg/kg/day and in all but one animal at 500 mg/kg/day) was the only significant clinical sign

Details on maternal toxic effects:
There were no treatment-related effects on bodyweights and food consumption; no dams aborted or showed late delivery. Deaths of 1 low-dose and 2 high-dose test dams during the dosing period were attributed to maldosing.

Effect levels (maternal animals)

1

Dose descriptor:

NOAEL

Effect level:

500 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

2

Dose descriptor:

NOAEL

Effect level:

500 mg/kg bw/day (actual dose received)

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 treatment-related effects on any reproductive indices (for embryo/foetal toxicity).

Malformations:
- no soft tissue malformations were seen
- two cases of skeletal malformation were seen (1 foetus with a short tail in the 250 mg/kg/day group, 1 case of fused ribs in the 500 mg/kg/day group) but these were deemed spontaneous and not treatement-related.

The types and incidences of observed skeletal variations (mainly of the sternebrae, ribs, skull and vertebrae) did not differ significantly between controls and test groups.

Effect levels (fetuses)

Dose descriptor:

NOAEL

Effect level:

500 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: teratogenicity

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

Females pregnant at termination were 25 (controls) and 26, 27, 23 in low-, mid- and high-dose test groups respectively: all had viable foetuses at termination.

Group mean data.

Embryo/foetal index	Vehicle controls	Test substance 125 mg/kg/day	Test substance 250 mg/kg/day	Test substance 500 mg/kg/day
Viable foetuses/dam	14.2 +/- 2.28	14.9 +/- 2.04	14.1 +/- 3.41	14.7 +/- 1.89
% Post-implantation loss	9.4	7.4	8.1	6.8
% Pre-implantation loss	9.4	10.0	10.2	8.1
Foetal sex distribution: % male	52.8	50.4	49.6	49.0
Foetal bodyweight	3.8 +/- 0.36	3.7 +/- 0.35	3.7 +/- 0.51	3.7 +/- 0.56

Applicant's summary and conclusion

Conclusions:

In this study repeated oral application of the test substance to pregnant rats at dosages up to 500 mg/kg/day produced no significant maternal toxicity and no evidence of teratogenicity or embryo/foetal toxicity.