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

Toxicity to reproduction

Administrative data

Endpoint:

two-generation reproductive toxicity

Remarks:

based on test type (migrated information)

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:

1994

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 416 (Two-Generation Reproduction 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

Sex:

male/female

Administration / exposure

Route of administration:

oral: feed

Vehicle:

other: diet

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

Continuously for 2 generations

Frequency of treatment:

Continuously in diet

Details on study schedule:

P and F1 generation were exposed to the diet for a 10 week pre-breed period, a 21 day mating period and through gestation, parturition and lactation. F2 generation were exposed through lactation and until one week after weaning.

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
2000ppm
Basis:
nominal in diet

Doses / concentrations 2

Remarks:

Doses / Concentrations:
6000ppm
Basis:
nominal in diet

Doses / concentrations 3

Remarks:

Doses / Concentrations:
20000ppm
Basis:
nominal in diet

No. of animals per sex per dose:

28

Control animals:

yes, plain diet

Examinations

Parental animals: Observations and examinations:

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Twice daily for mortality and moribund status and once daily for any clinical signs of toxicity. Detailed clinical examinations were conducted weekly.

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Time schedule for examinations: Weekly

WATER CONSUMPTION: Yes
- Time schedule for examinations: Weekly

Oestrous cyclicity (parental animals):

Not evaluated

Sperm parameters (parental animals):

Not evaluated

Litter observations:

PARAMETERS EXAMINED
The following parameters were examined in offspring:
number and sex of pups, weight gain, physical abnormalities

Postmortem examinations (parental animals):

ORGAN WEIGHTS
- not evaluated

HISTOPATHOLOGY
Control and high dose groups:
Vagina, uterus, ovaries, testis, epididymis, seminal vesicle, prostate, Other tissues with gross lesions
For low and intermediate dose groups:
Testes and epididymides from males which did not sire litters and any tissues which exhibited gross lesions.

Postmortem examinations (offspring):

ORGAN WEIGHTS
- not evaluated

HISTOPATHOLOGY
F1, Control and high dose groups:
Vagina, uterus, ovaries, testis, epididymis, seminal vesicle, prostate, Other tissues with gross lesions
For low and intermediate dose groups:
Testes and epididymides from males which did not sire litters and any tissues which exhibited gross lesions.

F1 not selected for mating, F2
Vagina, uterus, ovaries, testis, epididymis, seminal vesicle, prostate, Other tissues with gross lesions

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

no effects observed

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Organ weight findings including organ / body weight ratios:

not examined

Histopathological findings: non-neoplastic:

no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Details on results (P0)

Parent males: In the 20000 ppm treatment group consistently increased food consumption values and increases in body weight were noted throughout the treatment period.
Parent females: Maternal food consumption was consistently increased in the 20000 ppm treatment group during gestation.

Effect levels (P0)

1

Dose descriptor:

LOAEL

Effect level:

> 20 000 ppm

Based on:

test mat.

Sex:

male/female

2

Dose descriptor:

NOAEL

Effect level:

20 000 ppm

Based on:

test mat.

Sex:

male/female

Results: F1 generation

General toxicity (F1)

Clinical signs:

no effects observed

Body weight and weight changes:

effects observed, treatment-related

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

no effects observed

Histopathological findings:

no effects observed

Details on results (F1)

F1 males: Reduced body weights in the 20000ppm treatment group in the last two weeks of lactation and one week after weaning (postnatal day 28). Weight gains substantially reduced from postnatal days 7 to 14 and slightly reduced from postnatal days 14 to 28.

F1 females: Reduced body weights in the 20000ppm treatment group in the last two weeks of lactation and one week after weaning (postnatal day 28) Weight gains substantially reduced from postnatal days 7 to 14 and slightly reduced from postnatal days 14 to 28

F2 males: Reduced body weights in the 20000ppm treatment group for days 14-28 but not sufficient to reach statistical significance.

F2 females: Reduced body weights in the 20000ppm treatment group for lactation days 14, 21 and one week after weaning.

Effect levels (F1)

1

Dose descriptor:

LOAEL

Generation:

F1

Effect level:

20 000 ppm

Based on:

test mat.

Sex:

male/female

2

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

6 000 ppm

Based on:

test mat.

Sex:

male/female

Results: F2 generation

Effect levels (F2)

1

Dose descriptor:

LOAEL

Generation:

F2

Effect level:

20 000 ppm

Based on:

test mat.

Sex:

male/female

2

Dose descriptor:

NOAEL

Generation:

F2

Effect level:

6 000 ppm

Based on:

test mat.

Sex:

male/female

Overall reproductive toxicity

Reproductive effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

The NO(A)ELs are as follows:
Parent males = 20000 ppm (~1395 mg/kg bw/d)
Parent females = 20000 ppm (~1774 mg/kg bw/d)
F1 males = 6000 ppm (~379 mg/kg bw/d)
F1 females = 6000 ppm (~475 mg/kg bw/d)
F2 males = 6000ppm
F2 females = 6000ppm

Executive summary:

DMH is not a reproductive toxin in this study but there may be an effect on lactation.