Registration Dossier

Diss Factsheets

Administrative data

Description of key information

28 day oral repeated dose toxicity: NOAEL = 100 mg/kg bw ; OECD 407 Guideline Study

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
100 mg/kg bw/day
Study duration:
subacute
Species:
rat

Additional information

In a subacute toxicity study according to OECD guideline 407 and following GLP principles, doses of 0, 20, 100 or 500 mg/kg body weight/day of test article were administered daily via gavage to rats of both sexes for 28 days (RCC, 1990). At the dose level of 500 mg/kg body weight/day an increase in organ weights (liver, kidney and adrenals) and slight changes in hematology (slight increase in the reticulocyte count and slight polychromatophilia for females) and clinical chemistry parameters (slightly increased urea, bilirubin, triglyceride, phospholipid and calcium concentrations, slightly decreased sodium concentrations) were seen. Absolute liver, kidney and adrenal weights and/or their ratios to body weight or brain weight were statistically significantly higher than the corresponding controls in both sexes of group 4 (500 mg/kg). Relative spleen weights were statistically significantly higher than controls in males of group 4. Except for the liver to body weight ratios of females of group 4, all of these findings had returned to normal in recovery individuals after an additional two weeks of abstinence from the test article. Many male and female rats of group 4 (500 mg/kg) and one group 2 (20 mg/kg) male animal were found to have discoloration of the gastro-intestinal tract, but there were no concomitant histological findings. The livers from Group 4, main test and recovery animals, showed a slight increase in periportal mononuclear cell infiltration. There was an increase in the number of animals showing moderate hyaline droplet degeneration in the male main test kidneys in groups 3 (100 mg/kg) and 4, which was not apparent in the recovery animals.

 

The liver was identified as a potential target organ because of the increases in liver weight, the severity of periportal mononuclear cell infiltration and in reticulocyte counts; the kidney because of the increases in kidney weight and in the number of males showing moderate hyaline droplet degeneration in the kidneys. The changes in the blood biochemistry parameters listed above were considered to be of metabolic nature possibly due to changes in the liver and kidneys. A further potential target organ may be the spleen, because of the increases in spleen weight in high dose males and the increases in reticulocytes in high dose females. Except for the histopathology findings in the liver and the liver to body weight ratio in females, the above findings had returned to normal in recovery individuals of group 4 (500 mg/kg) by the end of the treatment-free 14-day recovery period. Therefore, the "no-adverse effect level" was set at 100 mg/kg, despite the finding of moderate hyaline degeneration in the kidneys of males of group 3 (100 mg/kg) at termination of treatment.


Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: liver; urogenital: kidneys

Justification for classification or non-classification

A subacute 28 day oral toxicity study resulted in a NOAEL of 100 mg/kg bw/day and a LOAEL of 500 mg/kg bw/d.

Based on the nature of effects and the lowest effect level obtained in this OECD guideline study, no classification according to EU and GHS criteria is necessary.