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Repeated dose toxicity: oral

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repeated dose toxicity: oral
combined repeated dose and carcinogenicity
Type of information:
experimental study
Adequacy of study:
key study
1 (reliable without restriction)

Data source

Reference Type:
study report

Materials and methods

Test guideline
according to
other: US EPA 83-2
GLP compliance:

Test material

Details on test material:
- Analytical purity: 41.2%
- Lot/batch No.: 8508-P-166H

Test animals

Crj: CD(SD)
Details on test animals and environmental conditions:
- Source: Charles River UK Ltd
- Age at study initiation: 6 weeks
- Weight at study initiation: male 163-231g, female 128-172g

Administration / exposure

Route of administration:
oral: gavage
Duration of treatment / exposure:
104 weeks
Frequency of treatment:
Doses / concentrations
Doses / Concentrations:
0, 0.5, 1.5, and 5.0 mg/kg bw The 5.0-mg/Kg dose was reduced to 3.5 mg/Kg after 12 weeks

No. of animals per sex per dose:
Control animals:
yes, concurrent vehicle


Observations and examinations performed and frequency:
-Clinical signs: daily
-Mortality: twice daily
-Body weight: weekly for the first 16 weeks, then every 4 weeks
-Food consumption: weekly for the first 16 weeks, then every 4 weeks
-Ophthalmic examination: start of study and termination
Number of animals: 10 male and 10 female
Time points: weeks 27, 53, 78, and 104
Parameters: Haematocrit, haemoglobin concentration, erythrocyte count, total and differential leukocyte count, platelet count, prothrombin time, partial thromboplastin time, mean cell volume, reticulocyte count
-Clinical chemistry:
Number of animals: 10 male and 10 female
Time points: weeks 27, 53, 78, and 104
Parameters: sodium, potassium, calcium, inorganic phosphorus, glucose, total cholesterol, blood urea nitrogen, total bilirubin, creatinine, total protein, albumin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma glutamyl transpeptidase, triglycerides, creatinine phosphokinase.
number of animals: all animals
time points: 26, 52, 77, and 103
Parameters: appearance, volume, specific gravity, pH, protein, glucose, blood, specific gravity, ketones, bilirubin, deposits.
Sacrifice and pathology:
-Organ weights: liver, kidneys, adrenals, testes, ovaries, spleen, brain, heart, lungs, pituitary, and thyroids
-Gross and histopathology: The listed tissues in high dose group, controls, and all decedents. Also, the lungs, liver, kidneys, hind-limb skeletal muscle, skin (including panniculus muscle), spinal cord (including paravertebral muscle), eyes, and all gross lesions from animals of the low and intermediate dose groups. All tumours and masses suspected of being tumours from all animals.
Organs: Duodenum, harderian gland, jejunum, brain, spinal cord (three levels), pituitary, thyroid, parathyroid, thymus, oesophagus, salivary glands, stomach, small and large intestines, colon, ilium, liver, pancreas, rectum, kidneys, adrenals, spleen, heart, trachea, lungs, aorta, gonads, uterus, female mammary gland, prostate, seminal vesicles, epididymides, urinary bladder, lymph nodes (mesenteric, submandibular), sciatic nerve, skin, eyes, skeletal muscle, bone (sternum and femur), caecum.
Body weight, and organ weight data were analyzed by Bartlett’s test and if not significant by ANOVA. If there were significant differences, the data were log transformed and, if still significant, non-parametric methods were used (Wilcox rank sum test).
The statistical methodology used by Peto (1980) was applied to the survival and histopathological data. Refer to the report for a detailed summary

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
effects observed, treatment-related
Details on results:
-Clinical signs: Hind-limb muscle wastage in the high-dose males from week 95 and high-dose females from approximately week 89 to termination
-Mortality: No dose-related effects
-Body weight: A treatment -related reduction in body weight gain was seen in the high-dose females. Body weights were 8% lower than the controls at week 8. The high dose for males and females was reduced to 3.5 mg/Kg at week 12; however, the body weights remained 10-14% below controls for the remainder of the study. There was no strict dose response to weight gain. At termination, the overall weight gain for the high-dose females was 19% below the controls. Weight gain for the intermediate-dose females (1.5 mg/Kg) was within 2% of the controls, while weight gain for the low-dose females (0.5 mg/Kg) was 9% below the controls.
No effects on overall body weight gain were seen in the males at any dose, although body weights at the high dose were significantly (p < 0.05) below the controls at week 16.
-Haematology: Treatment-related changes were minor and confined to reductions in red cell mass in intermediate- and high-dose females during weeks 27 and 53. The changes comprised 5-7% reduction in RBC and haemoglobin concentration, which reach statistical significance (p < 0.05) at week 27, and 10% reduction in RBC alone at week 53 (p < 0.05 minimum). Additionally, at week 53, packed cell volume was reduced by 9% and was statistically different from controls (p < 0.001) in intermediate-dose females only
-Organ weights: Treatment-related changes were confined to the lungs and liver in the males. The relative weight of the lungs was increased (p < 0.05 minimum) at the intermediate and high doses, and the relative weight of the liver was increased (p < 0.05) at the high dose.
-Gross and histopathology: Macroscopic pathology showing a treatment relationship was confined to hind-limb muscle wasting in high-dose females and intermediate-dose and high-dose males, consistent with the in-life observations.
Histopathological changes related to treatment were observed mainly at the high dose in the skeletal muscle, sciatic nerve, and eyes of male and female rats, and in the spinal cord of the female rats. Degeneration of nerve fibers was observed in the spinal cord and sciatic nerve with associated neurogenic degeneration of skeletal muscle fibers. Similar degenerative changes were observed in muscle from other sites during the course of slide examination, i.e. paniculus and paravertabral muscles and those adjacent to the sternum and femur. In the eyes, there was an increased incidence of retinal atrophy in the high-dose males and females, with the females more affected

Effect levels

open allclose all
Dose descriptor:
Effect level:
1.5 mg/kg bw/day (nominal)
Basis for effect level:
other: based on minor effects on haematology (packed cell volume), relative weight of the lungs, and muscle and nerve fiber degeneration.
Dose descriptor:
Effect level:
0.5 mg/kg bw/day (nominal)
Basis for effect level:
other: no substance-related findings were observed

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

NOAEL=0.5 mg/kg
LOAEL=1.5 mg/kg
The information contained within this robust summary document comes from studies which are in the ownership of Arch Chemicals Inc. and which are protected in several regions globally. This information may not be used for any purpose other than in support of the Chemical safety Report submitted by Arch Chemicals Inc. under Regulation EC 1907/2006.