Registration Dossier

Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
Jun - Dec 2001
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2001
Report Date:
2002

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Version / remarks:
1998
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
other: HanBrl:WIST (SPF)
Sex:
male/female

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
90 days
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Dose / conc.:
50 ppm
Dose / conc.:
300 ppm
Dose / conc.:
2 000 ppm
Dose / conc.:
8 000 ppm
No. of animals per sex per dose:
10
Control animals:
yes, plain diet

Examinations

Observations and examinations performed and frequency:
- diet analyses and test item intake
- mortality
- functional observational battery
- motor activity
- ophthalmology
- in life observations
- body weight and body weight change
- food consumption
- food utilization efficiency
- water consumption
- hematology
- blood chemistry
- urine analysis
- organ weights
Sacrifice and pathology:
- macroscopic examination
- microscopic examination
Statistics:
Statistical analyses of in-life and organ weight data were carried out using the statistical routines contained in the NOVATOX System.
All statistical tests were two-sided: testing for an overall difference rather than a difference in only one direction.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, non-treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
effects observed, treatment-related
Water consumption and compound intake (if drinking water study):
effects observed, non-treatment-related
Ophthalmological findings:
effects observed, non-treatment-related
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
effects observed, non-treatment-related
Behaviour (functional findings):
effects observed, non-treatment-related
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, non-treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
300 ppm
Sex:
male/female
Basis for effect level:
body weight and weight gain
food consumption and compound intake
Dose descriptor:
NOAEL
Effect level:
17.8 mg/kg bw/day (nominal)
Sex:
male
Basis for effect level:
body weight and weight gain
food consumption and compound intake
Dose descriptor:
NOAEL
Effect level:
22.1 mg/kg bw/day (nominal)
Sex:
female
Basis for effect level:
body weight and weight gain
food consumption and compound intake

Applicant's summary and conclusion

Conclusions:
Oral administration of the test substance admixed to the diet for at least 90 days was tolerated in rats and most findings were restricted to the high dose group. At this dose level clinical signs were noted and ≥ 2000 ppm resulted in depression in body weight development and food consumption. Laboratory investigations and histopathological examinations point to the hematopoietic and lymphoreticular system, reproductive system, liver and pancreas as potential target organs. In addition, changes on laboratory parameters indicate disturbance in kidney function. However, some of these alterations may be related to nutritional deficiency. Based on food consumption and body weight, the No-Observable-Adverse-Effect Level (NOAEL) of 300 ppm was defined for both males and females, corresponding to a daily test item intake of 17.8 mg/kg bw/day for males and 22.1 mg/kg bw/day for females.