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Toxicological information

Neurotoxicity

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Description of key information

Acute and subchronic (90 day) neurotoxicity studies were performed to assess the neurotoxic potential of the test substance.

An acute neurotoxicity study at a limit dose (2000 mg/kg bw) did not reveal any signs of neurotoxicity.

There was no indication of clinical (general clinical observation, FOB and motor activity) or neurohistopathological neurotoxicity in a subchronic neurotoxicity study. Systemic signs of toxicity, namely body weight reduction in the 90-d study, were consistent with those seen in repeated dose studies with the test substance.

Key value for chemical safety assessment

Effect on neurotoxicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
238 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
GLP and guideline compliant

Effect on neurotoxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Effect on neurotoxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Key study: Neurotoxicity 90d oral 2015/1175552

The oral administration of the test substance at dose levels of 300, 1000 and 4000 ppm (20, 73 and 396 mg/kg bw (males) and 24, 92 and 438 mg/kg bw females respectively) to Wistar rats over a period of 3 months revealed neither adverse neurobehavioral effects nor test substance-related effects in the neurohistopathology investigation at any concentration. There was a significant reduction (-11.7%) in the final body weight of males at the highest dose tested (4000 ppm).

Under the conditions of this study the no observed effect level (NOEL) for neurotoxicity was 4000 ppm for male (238 mg/kg bw/d) and female animals (273 mg/kg bw/d).

The no observed effect level (NOEL) for general systemic toxicity was 4000 ppm for male (238 mg/kg bw/d) and female animals (273 mg/kg bw/d).

Supporting study: Neurotoxicity acute oral 2012/1219658

The test substance administered as a single oral gavage dose at 0, 200, 700 or 2000 mg/kg bw caused transient test substance-related adverse effects at 700 and 2000 mg/kg/bw. Test substance-related effects were observed on the day of test substance administration at dose levels of 700 and 2000 mg/kg bw, in a limited number of animals i.e. hypothermia and slight tremors in test group 3 (2000 mg/kg bw), unsteady gait and high-stepping gait in test groups 2 and 3 (700 and 2000 mg/kg bw), piloerection in test groups 2 and 3 (700 and 2000 mg/kg bw); and reduced motor activity in both sexes of test group 3 (2000 mg/kg bw) on study day 0. These findings were reversible and not observed on study days 7 and 14. All findings were assessed as being related to an impairment of the overall condition of the animals rather than being related to a neurotoxic mode of action.

Brain weight determination, necropsy and neuropathology examination by light microscopy did not reveal any neuropathological, treatment-related findings up to 2000 mg/kg bw. Therefore, the NOAEL for general effects was 200 mg/kg bw/d, the NOAEL for neurotoxicity was 2000 mg/kg bw/d.

Justification for classification or non-classification

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008.

No adverse neurobehavioral effects nor test substance-related effects in the neurohistopathology investigation at the highest concentration tested. As a result the substance is not considered to be classified for neurotoxicity under Regulation (EC) No 1272/2008, as amended for the eighth time in Regulation (EU) No 2016/918.