1,3-bis(hydroxymethyl)-5,5-dimethylimidazolidine-2,4-dione

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1992

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:

5,5-dimethylhydantoin

EC Number:

201-051-3

EC Name:

5,5-dimethylhydantoin

Cas Number:

77-71-4

Molecular formula:

C5H8N2O2

IUPAC Name:

5,5-dimethylimidazolidine-2,4-dione

Details on test material:

The test material is the hydrolysis degradation product of DMDMH which was considered relevant for long term testing

Test animals

Species:

rat

Strain:

other: CD

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Duration of treatment / exposure:

Day 6-15 post mating

Frequency of treatment:

Once daily

Duration of test:

To gestation day 21

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
100 mg/kg
Basis:
actual ingested

Doses / concentrations 2

Remarks:

Doses / Concentrations:
300 mg/kg
Basis:
actual ingested

Doses / concentrations 3

Remarks:

Doses / Concentrations:
1000 mg/kg
Basis:
actual ingested

No. of animals per sex per dose:

25 females/group

Control animals:

yes, concurrent vehicle

Examinations

Maternal examinations:

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily (twice daily during dosing)

BODY WEIGHT: Yes
- Time schedule for examinations: gd 0, 6, 9, 12, 15, 18 and 21

FOOD CONSUMPTION: Yes
- Time schedule for examinations: measured at 3 day intervals throughout the study (gd 0-21)

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes

Fetal examinations:

- General examinations: Yes, litter Size, no. of dead foetuses, foetal weight, sex ratio, early and late resorptions
- Soft tissue examinations: Yes, approximately one-half of the live foetuses
- Skeletal examinations: Yes, pproximately one-half of the live foetuses

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:no effects

Effect levels (maternal animals)

1

Dose descriptor:

LOAEL

Effect level:

> 1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

2

Dose descriptor:

NOAEL

Effect level:

>= 1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

3

Dose descriptor:

LOAEL

Effect level:

> 1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

4

Dose descriptor:

NOAEL

Effect level:

>= 1 000 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

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

Maternal Examinations: No females died, aborted, delivered early or were removed from the study prior t sacrifice. All females that bore litters had one or more viable fetuses. No treatment-related clinical signs were observed during or subsequent to treatment at any dose level. There were no dose related changes in maternal body weights or body weight changes throughout gestation. Statistically significant reductions in average weight gain for days 9-12 at 1000mg/kg/day were not considered to be related to treatment but rather were considered to reflect stabilization of body weight in the 1000mg/kg/day group which exhibited a slightly higher weight gain for days 6-9. There were no differences in body weight gain at 1000mg/kg/day fro the entire treatment period. There were no treatment-related effects on food consumption during or subsequent to dosing. There were no treatment related findings observed at necropsy. There were no effects on terminal body weight, gravid uterine weight, corrected body weight, corrected weight change, or relative and absolute liver weights.

Fetal Examinations: No treatment-related effects on fetal body weights for male and female were observed in any group. There were no differences in individual external, visceral or skeletal malformations by category, or in total malformations among groups. There were no treatment-related increases in the incidences of individual fetal external, visceral or skeletal variations by category, or of total variations among groups. Statistically significant decreases in 1 external variation, excessive bleeding at the umbilicus, and 1 skeletal variation, majority of proximal phalanges unossified at 1000mg/kg/day were not considered to be treatment related or biologically significant due to the lack of a dose-related trend.

Applicant's summary and conclusion

Conclusions:

NO(A)EL maternal toxic effects >=1000 mg/kg/day
NO(A)EL embryotoxic / teratogenic effects >=1000mg/kg/day

Executive summary:

DMH is not a developmental toxin.