5,5-Dimethylimidazolidine-2,4-dione, reaction products with oxirane

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

5 February 2007 to 25 July 2007

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2007

Report date:

2007

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Deviations:

not specified

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

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

EC Number:

701-388-0

Cas Number:

26850-24-8

IUPAC Name:

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

Test material form:

other: pale yellow solid block

Details on test material:

- Name of test material (as cited in study report): Dantocol DHE
- Physical state: pale yellow solid block
- Lot/batch No.: M5469330
- Storage condition of test material: room temperature in the dark

Test animals

Species:

rat

Strain:

Sprague-Dawley

Remarks:

Crl:CD (SD) IGS BR

Sex:

male/female

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Twenty-eight consecutive days

Frequency of treatment:

Daily

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

15 mg/kg bw/day (nominal)

Doses / concentrations 2

Dose / conc.:

150 mg/kg bw/day (nominal)

Doses / concentrations 3

Dose / conc.:

1 000 mg/kg bw/day (nominal)

No. of animals per sex per dose:

Five/sex/dose

Control animals:

yes, concurrent vehicle

Positive control:

None.

Examinations

Observations and examinations performed and frequency:

Clinical signs, functional observations, bodyweight development (weekly monitoring) and food (weekly monitoring) and water consumption (daily monitoring) were monitored. Haematology and blood chemistry were evaluated for all animals at the end of the study.

Sacrifice and pathology:

All animals were subject to gross necropsy examination and histopathological evaluation of selected tissues.

Statistics:

The homogeneity of means was assessed using ANOVA or ANCOVA and Bartlett's test. The transformed data were analysed to find the lowest treatment level that showed a significant effect using the William's Test for parametric data or Shirley Test for non-parametric data. If no dose response was found, but the data showed non-homogeniety of means, the data were analysed by a stepwise Dunnett (parametric) or Steel (non-parametric) test to determine significant differences from the control group. Finally, if required, pair-wise tests were performed using the Student t-test (parametric) or the Mann-Whitney U test (non-parametric).

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food efficiency:

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

An increase in cholesterol and creatinine was detected for males treatred with 150 and 1000 mg/kg bw/day. No such effects were detected for females at any dose or for males at 15 mg/kg bw/day.

Urinalysis findings:

not examined

Behaviour (functional findings):

no effects observed

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

Slight increases in liver and kidney weights were detected at 1000 mg/kg bw/day in males. Heart weights were reduced in females receiving 1000 mg/kg bw/day.

Gross pathological findings:

no effects observed

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not specified

Effect levels

1

Key result

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Remarks on result:

not determinable due to adverse toxic effects at highest dose / concentration tested

2

Key result

Dose descriptor:

NOEL

Effect level:

150 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

organ weights and organ / body weight ratios

3

Key result

Dose descriptor:

NOEL

Effect level:

15 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

clinical biochemistry

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Oral administration of the substance to rats for 28 consecutive days at doses of 15, 150 or 1000 mg/kg bw/day resulted in minimal treatment-related changes at the top two doses. However, these changes were not considered to be adverse effects, therefore, the NOAEL was considered to be 1000 mg/kg bw/day.

A NOEL was identified in females as 150 mg/kg bw/day based on reduced heart weight. A NOEL of 15 mg/kg bw/day was identified in males based on an increase in cholesterol and creatinine.

Executive summary:

In a subacute toxicity study the substance was administered to male and female Sprague-Dawley rats (5/sex/dose in) by oral gavage at dose levels of 0, 15, 150 or 1000  mg/kg bw/day. Minimal effects were observed at the top two doses, however these effects are not considered to be adverse. The NOAEL is 1000 mg/kg bw/day.