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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
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:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
Deviations:
not specified
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
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 / concentrationsopen allclose all
Dose / conc.:
15 mg/kg bw/day (nominal)
Dose / conc.:
150 mg/kg bw/day (nominal)
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

open allclose all
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
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
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.