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Diss Factsheets

Administrative data

Description of key information

A combined 28-day oral repeated dose study and reproductive/development study in rats was available. The dose levels for this study were based on a 14-day range-finding study.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
10 mg/kg bw/day
Study duration:

Additional information

Oral administration of NTAN to Sprague-Dawley rats at doses of 1, 10 and 45 mg/kg/day resulted in overt signs of parental toxicity at the 45 mg/kg/day dose including death, clinical signs of toxicity (including convulsions, labored breathing, etc.), decreased food consumption, body weight, body weight gain, and motor activity changes. It was noted that the clinical signs of toxicity occurred in females only (6/15) and the change in motor activity was only exhibited in males. It is difficult to discern whether the clinical signs of toxicity and change in motor activity are indicative of a neurotoxic effect as they occurred at a dose level which produced overt systemic toxicity (death). Interpretation of these types of indicators “as neurotoxic effects is dependent on the dose at which such changes occur and the possibility that damage to other organ systems may contribute to or cause such changes indirectly”.

Treatment-related gross necropsy findings were low/singular in incidence, limited to the 45 mg/kg group and consisted of red fluid/blood in the cranial cavity/cranium (observed in four animals that died spontaneously during the study), pigmentation of the brain, thymus and liver, urinary bladder dilatation and an enlarged thymus. No treatment-related histopathological changes were observed in the tissues examined from rats in the 45 mg/kg group; all findings were considered spontaneous or incidental changes commonly observed in rats of this age and strain. Based on the results of this study, the no-observed-adverse-effect level (NOAEL) for systemic toxicity of NTAN was 10 mg/kg/day. the NOAEL in the 14 -day range-finding study was 25 mg/kg bw/day.

Justification for classification or non-classification

Based on the severe toxicity observed at 45 mg/kg bw (death and severe clinical signs of toxicity), NTAN should be classified with R48/22 and STOT repeated exposure Cat. 2.