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

Carcinogenicity

Description of key information

DMDMH readily undergoes hydrolysis to DMH and therefore long-term data is provided for DMH. DMH did not demonstrate a carcinogenic response in either the rat or the mouse.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: oral

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 83-5 (Combined Chronic Toxicity / Carcinogenicity)

GLP compliance:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Route of administration:

oral: feed

Vehicle:

other: diet

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

104 weeks

Frequency of treatment:

7 days per week

Remarks:

Doses / Concentrations:
100 mg/kg/day
Basis:
nominal in diet

Remarks:

Doses / Concentrations:
300 mg/kg/day
Basis:
nominal in diet

Remarks:

Doses / Concentrations:
1000 mg/kg/day
Basis:
nominal in diet

No. of animals per sex per dose:

60/ sex/dose level

Control animals:

yes, plain diet

Observations and examinations performed and frequency:

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Overt clinical signs were checked twice daily, detailed clinical observations were performed once each week. Mortality twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly for the first 14 weeks of the study and every other week thereafter

FOOD CONSUMPTION: Yes
- Time schedule for examinations: Weekly for the first 14 weeks of the study and every other week thereafter

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Prior to first exposure and following study period of 104 weeks.

HAEMATOLOGY: Yes
- Time schedule for collection of blood: At 6, 12, 18, and 24 months
- How many animals: Performed on 15/sex/group
- Parameters: Haematocrit, haemoglobin concentration, erythrocyte count, total and differential leukocyte count, platelet count, reticulocyte count, MCV, MCH, MCHC.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At 6, 12, 18, and 24 months
- How many animals: Performed on 15/sex/group
- Parameters: sodium, potassium, chloride, calcium, phosphorous,, glucose (fasting), total cholesterol, urea nitrogen, total bilirubin, direct bilirubin, indirect bilirubin, creatinine, total protein, albumin, globulin, A/G ratio, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma glutamyl transpeptidase, creatine kinase

URINALYSIS: Yes
- Time schedule for collection of urine: At 6, 12, 18, and 24 months
- How many animals: Performed on 15/sex/group
- Parameters: colour and appearance, volume, specific gravity, pH, protein, glucose, ketones, bilirubin, blood, urobilinogen, microscopic elements

Sacrifice and pathology:

ORGAN WEIGHTS: Yes, performed for liver, kidneys, adrenals, testes, ovaries, spleen, brain, heart

GROSS AND HISTOPATHOLOGY:

Yes, performed on high dose group and control group
organs: brain, spinal cord, pituitary, thyroid, parathyroid, thymus, oesophagus, salivary glands, stomach, small and large intestines, liver, pancreas, kidneys, adrenals, spleen, heart, trachea, lungs, aorta, uterus, vagina, mammary gland, prostate, testes, epididymis, seminal vesicles, urinary bladder, lymph nodes, sciatic nerve, sternum, femur, skin, skeletal muscle (thigh), eyes.

Performed on low and intermediate dose groups:
kidneys, pituitary gland and all gross lesions and mammary glands of female rats.

Statistics:

Levene’s test for equality of variances, analysis of variance (ANOVA) and t tests (when F value from ANOVA was significant).
Non-parametric data were evaluated using Kruskal-Wallis test followed by the Mann-Whitney U test when appropriate.
Two untreated controls were included in the study in order to collect data that would provide information regarding the range of normal or control values for the parameters evaluated in the study. These data were used as an aid in the identification of false positive statistical citations as well as confirmation of true treatment-related effects. Based on the independent manner in which the animals were handled and the data collected, it was not considered appropriate to combine the data from the two control groups for the purposes of comparing the combined control data to those from the treated groups.

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

no effects observed

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

The incidences of mammary gland tumors (adenomas, fibroadenomas and carcinomas) was slightly increased in the high dose group of female rats although these were not statistically significant therefore the slight increase was attributed to random biologic variation.

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Remarks on result:

other: Effect type: toxicity (migrated information)

The dosages obtained in terms of test substance consumed for the 100, 300, and 1000mg/kg/day groups ranged from 88.9 to 112.2, 265.3 to 342.5, and 896.9 to 1132.4mg/kg/day for the males and 90.9 to 117.6, 269.0 to 347.7, and 908.8 to 1147.9mg/kg/day for the females respectively.

Conclusions:

DMH did not demonstrate a carcinogenic response in this study

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

Exceeds data requirements. The study is Klimisch 1.

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Quality of whole database:

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

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Quality of whole database:

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

Justification for classification or non-classification

DMDMH readily undergoes hydrolysis to DMH which did not demonstrate a carcinogenic response. Therefore DMDMH is not classified.

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 two carcinogenicity studies (rat and mouse) and did not demonstrate a carcinogenic response in either study.

Justification for selection of carcinogenicity via oral route endpoint:
Two studies available on DMDMH. Both are good quality, reliable, GLP, guideline studies which gave the same negative result. There is a larger toxicology database available in the rat.