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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data

Data source

Referenceopen allclose all

Reference Type:
review article or handbook
Title:
Unnamed
Year:
2001
Reference Type:
study report
Title:
Unnamed
Year:
1994
Report Date:
1997

Materials and methods

Principles of method if other than guideline:
2-year chronic oral toxicity study in 200 rats.
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder

Test animals

Species:
rat
Strain:
other: Albino Sherman Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 100-150 g
- Housing: animals were housed together (no further information)
- Diet: animal colony diet supplemented twice weekly with fresh meat, ad libitum
- Water: ad libitum

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
DIET PREPARATION
The substance powder was mixed intimately with the diet in the desired concentrations.

Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
24 months
Frequency of treatment:
7 days/week
Doses / concentrations
Remarks:
Doses / Concentrations:
0.05, 0.2 and 1%
Basis:
other: nominal in the diet (Remark: the concentration of test material in the low dose group was increased to 2% after 6 months)
No. of animals per sex per dose:
25
Control animals:
yes, plain diet
Details on study design:
- Dose selection rationale: dosage levels, to be fed for two years, were premised on a maximum possible exposure in humans.

Examinations

Observations and examinations performed and frequency:
CLINICAL OBSERVATIONS: Yes (no further information)

BODY WEIGHT: Yes, at end of Week 1 and 2

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Day 30, Day 90, 6 months and 24 months
- Parameters: red and white blood cell count, haemoglobin content and differential count

OTHER
FERTILITY ASSESSMENT: Yes (no further information)
Sacrifice and pathology:
GROSS PATHOLOGY: Yes. Liver, spleen, heart, lungs, stomach, large intestine, small intestine, adrenal glands, gonads, pancreas and brain.
HISTOPATHOLOGY: Yes. Liver, spleen, heart, lungs, stomach, large intestine, small intestine, adrenal glands, gonads, pancreas and brain.
Rats were killed at 1, 3, 6 and 24 months for necropsy and tissues collected for microscopic examinations (no further information)

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
2% and 1 % in the diet: at 24 months minor hyperplasia of the stratified squamous epithelium with excess keratin formation of the cardiac mucosa of the stomach
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY: At 1, 3 and 6 months, no significant differences were observed in mortality.

BODY WEIGHT AND WEIGHT GAIN: At 1, 3 and 6 months, no significant differences were observed in body weight gain.

HAEMATOLOGY: At 1, 3 and 6 months, no significant differences were observed in haematology.

GROSS PATHOLOGY: At 24 months, the only consistent difference that could be attributed to the test article was minor hyperplasia of the stratified squamous epithelium with excess keratin formation of the cardiac mucosa of the stomach in rats receiving the highest exposure to the test article (group 1: 2% in the diet after 6 months, group 3: 1% in the diet).

OTHER FINDINGS: No significant differences were observed in fertility in the 2 year study.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
>= 2 other: % in the diet
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: overall effects
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: overall effects

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion