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

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Reference

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)

Qualifier:

according to guideline

Guideline:

OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

other: CD

Sex:

male/female

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.

Remarks:

Doses / Concentrations:
2000ppm
Basis:
nominal in diet

Remarks:

Doses / Concentrations:
6000ppm
Basis:
nominal in diet

Remarks:

Doses / Concentrations:
20000ppm
Basis:
nominal in diet

No. of animals per sex per dose:

28

Control animals:

yes, plain diet

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

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: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

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.

Dose descriptor:

LOAEL

Effect level:

> 20 000 ppm

Based on:

test mat.

Sex:

male/female

Dose descriptor:

NOAEL

Effect level:

20 000 ppm

Based on:

test mat.

Sex:

male/female

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

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.

Dose descriptor:

LOAEL

Generation:

F1

Effect level:

20 000 ppm

Based on:

test mat.

Sex:

male/female

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

6 000 ppm

Based on:

test mat.

Sex:

male/female

Dose descriptor:

LOAEL

Generation:

F2

Effect level:

20 000 ppm

Based on:

test mat.

Sex:

male/female

Dose descriptor:

NOAEL

Generation:

F2

Effect level:

6 000 ppm

Based on:

test mat.

Sex:

male/female

Reproductive effects observed:

not specified

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.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 395 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Sufficient to meet data requirements. The study is Klimisch 1.

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Quality of whole database:

An inhalation toxicity study is scientifically unjustified and is not in the interests of animal welfare.

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Quality of whole database:

A dermal toxicity study is scientifically unjustified and is not in the interests of animal welfare.

Additional information

DMDMH readily undergoes hydrolysis to DMH and therefore chronic effects are most appropriately assessed by testing DMH rather than DMDMH. DMH was tested in a two generation reproductive toxicity study and did not demonstrate parental toxicity or adverse effects on reproductive performance or reproductive tissues at dietary concentrations as high as 20000ppm (equivalent to 1395 mg/kg in males and 1774 mg/kg in females).

Short description of key information:
DMDMH readily undergoes hydrolysis to DMH and therefore long-term data is provided for DMH. In a two generation study, DMH is not a reproductive toxin.

Justification for selection of Effect on fertility via oral route:
Only one study available

Effects on developmental toxicity

Description of key information

DMDMH readily undergoes hydrolysis to DMH and therefore long-term data is provided for DMH. DMH is not a developmental toxin.

Link to relevant study records

Reference

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)

Qualifier:

according to guideline

Guideline:

EPA OPP 83-3 (Prenatal Developmental Toxicity Study)

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

other: CD

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

Remarks:

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

Remarks:

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

Remarks:

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

No. of animals per sex per dose:

25 females/group

Control animals:

yes, concurrent vehicle

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

Details on maternal toxic effects:

Maternal toxic effects:no effects

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

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

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

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

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Abnormalities:

not specified

Developmental effects observed:

not specified

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.

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.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Sufficient to meet data requirements. The study is Klimisch 1.

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Quality of whole database:

An inhalation toxicity study is scientifically unjustified and is not in the interests of animal welfare.

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Quality of whole database:

A dermal toxicity study is scientifically unjustified and is not in the interests of animal welfare.

Additional information

DMDMH readily undergoes hydrolysis to DMH and therefore chronic effects are most appropriately assessed by testing DMH rather than DMDMH. DMH was tested in three developmental toxicity studies and did not demonstrate developmental toxicity. The structurally related substance EMH was also tested in three developmental toxicity studies and also did not demonstrate developmental toxicity.

Justification for selection of Effect on developmental toxicity: via oral route:
Six studies are available, three on the hydrolysis product DMH and three on the structurally related substance EMH. All are good quality, reliable, GLP, guideline studies which gave the same negative result. This study is the most recent study on the hydrolysis product DMH.

Justification for classification or non-classification

DMDMH readily undergoes hydrolysis to DMH which did not demonstrate adverse effects on reproductive performance, reproductive tissues or developmental toxicity. The structurally related substance EMH also did not demonstrate developmental toxicity. Therefore there is no justification for classification of DMDMH.