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Description of key information

In a oral subacute repeated dose toxicity study a NOAEL of 100 mg/kg bw was determined for analogue substance 1 which is the analogue of the test article. 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
100 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
GLP-conform study according to OECD guideline. The study was performed with a test article analogue.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

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 analogue substance 1 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 bw/day). 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 bw/day) and one group 2 (20 mg/kg bw/day) 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 bw/day) 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 bw/day) by the end of the treatment-free 14-day recovery period. Therefore, the "no-adverse effect level" was set at 100 mg/kg bw/day, despite the finding of moderate hyaline degeneration in the kidneys of males of group 3 (100 mg/kg bw/day) at termination of treatment.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
one reliable study

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

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008

The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. As a result the substance is not considered to be classified for repeated dose toxicity under Regulation (EC) No 1272/2008,as amended for the sixth time in Directive EC 605/2014.