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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1982

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Deviations:
yes
Remarks:
Urinalysis was not performed.
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
As described in guideline.

Administration / exposure

Route of administration:
oral: feed
Vehicle:
other: plain diet
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
90 days
Frequency of treatment:
Daily
Doses / concentrationsopen allclose all
Dose / conc.:
0 other: ppm nominal in diet
Dose / conc.:
300 other: ppm nominal in diet
Dose / conc.:
1 000 other: ppm nominal in diet
Dose / conc.:
3 000 other: ppm nominal in diet
Dose / conc.:
10 000 other: ppm nominal in diet
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Dose / conc.:
15 mg/kg bw/day (actual dose received)
Dose / conc.:
50 mg/kg bw/day (actual dose received)
Dose / conc.:
150 mg/kg bw/day (actual dose received)
Dose / conc.:
500 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
12
Control animals:
yes, concurrent vehicle
Details on study design:
As described in guideline.
Positive control:
Not required.

Examinations

Observations and examinations performed and frequency:
As described in guideline.
Sacrifice and pathology:
As described in guideline.

Results and discussion

Results of examinations

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):
effects observed, treatment-related
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Details on results:
BODY WEIGHT
Mean body weights of male rats fed 10,000 ppm and of females fed 10,000 and 3000 ppm test substance were significantly lower than control throughout the 13 week feeding study.

FOOD CONSUMPTION
Significantly reduced food intake and increased spillage of the 10,000 ppm diet were observed in both sexes; females fed 3000 ppm diet also had lower food intakes than control but the decrease was significant for only five of the 13 weeks.

HAEMATOLOGY
Haematological alterations observed in 3000 ppm males and in both sexes fed 10,000 ppm test substance were significant increases in total leukocytes and in absolute lymphocyte values. Females fed 10,000 ppm also showed significant depression in numbers of neutrophils (absolute and percent), mean cell volume and mean cell haemoglobin. Males in the upper two treatment groups showed shortened prothrombin times.

CLINICAL CHEMISTRY
Elevated clinical chemical values were, with the exception of plasma urea concentrations, confined to rats in the 10,000 ppm treatment group. Males in this group had significantly higher urea, calcium and potassium values, while females had significantly higher urea, chloride, calcium and cholesterol values. Urea concentrations of females in the 1000 and 3000 ppm groups were also higher than control.

ORGAN WEIGHTS
After correction for reduced terminal body weight, there were increases in mean liver weight in the 3000 and 10,000 ppm groups (both sexes) and in 1000 ppm females. Males fed 10,000 ppm test substance had significantly increased spleen weights and females in the 1000 ppm group had significantly heavier kidneys compared to controls.

Effect levels

Dose descriptor:
NOAEL
Remarks:
systemic
Effect level:
>= 500 mg/kg bw/day (nominal)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: see 'Remark'

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
No effects on the general health and behaviour of treated rats were evident. Significant treatment-related effects on body weight, food intake, organ weights, clinical chemistry and haematology were identified in one or both sexes at daily doses of 150 and 500 mg/kg bw/d.
Due to the fact that no compound-related gross or histopathological lesions were identified at any dose level, the changes reported are considered minor and not of toxicological significance. Hence, the NOAEL for systemic toxicity was set to greater than 500 mg/kg bw/d.