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Toxicological information

Neurotoxicity

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Administrative data

Description of key information

7.9.1 Neurotoxicity: 
KS - Acute. Sheets, 1996. KL.1, NOAEL 10 mg/kg; 
KS - 90d rat. Sheets & Cain, 1999. KL.1, NOAEL M: 66.5 mg/kg/day; F: 7.8 mg/kg/day; 
KS - Dev rat. Sheets, 2001. KL.1, NOAEL Maternal 7.8 mg/kg/day; Offspring 39.3 mg/kg/day; 
SS - Mod. Irwin rat. Hense, 1996. KL.1, NOAEL 1 mg/kg; 
SS - Mod. Irwin rat (NOAEL). Hense, 1996. KL.1, NOAEL 5 mg/kg;  
SS - Open field test rat (NOAEL). Hense, 1996. KL.1, NOAEL 1 mg/kg; 
SS - Balance rod test mouse. Hense, 1996. KL.1, NOAEL 20 mg/kg

Key value for chemical safety assessment

Effect on neurotoxicity: via oral route

Endpoint conclusion
Dose descriptor:
NOAEL
10 mg/kg bw/day

Additional information

The acute neurotoxicity study in rats (Sheets, 1996) showed several signs of neurotoxicity, including ptosis, decreased approach response and red nasal staining. Of the acute safety pharmacology studies conducted in rats (Hense, 1996) and mice (Hense, 1996) signs of neurotoxicity were also evident in both species. These included ptosis, sedation, decreased response to nociceptive stimuli and decreased motor co-ordination. In the developmental study (Sheets & Cain, 1999) the most sensitive toxicological parameter was body weight reductions in both dams and offspring. Even in the presence of maternal toxicity no neurotoxic effects were observed in the offspring. As with the developmental study, no neurotoxic effects were observed in the sub-chronic study (Sheets, 2001), with the NOAEL in excess of 66.5 mg/kg/day for males (no toxic effects observed up to the highest dose tested) and limited to 7.8 mg/kg/day for females due to decreases in body weight and food consumption.

 

Table 7.9.1 Summary of neurotoxic and acute safety pharmacology data

Study

Effect

NOAEL

LOAEL

NEUROTOXICITY DATA

Acute rat (gavage)

Male / female neurotoxicity

10 mg/kg (due to ptosis, decreased approach & red nasal staining)

20 mg/kg

Sub-chronic (90 day) rat (dietary)

Male toxicity

(no evidence of neurotoxicity)

>66.5 mg/kg/day (highest dose tested)

-

Female toxicity

(no evidence of neurotoxicity)

7.8 mg/kg/day (due to decreases in body weight and food consumption). No evidence of neurotoxicity

38.2 mg/kg/day

Developmental rat (dietary)

Maternal toxicity

(no evidence of neurotoxicity)

7.8 mg/kg/day (due to reductions in body weight)

39.3 mg/kg/day

Offspring toxicity

(no evidence of neurotoxicity)

39.3 mg/kg/day (reductions in body weight)

90.8 mg/kg/day

ACUTE SAFETY PHARMACOLOGY DATA

Modified Irwin test, rat (gavage)

Male CNS effects

1 mg/kg (transient, dose-dependent effects on the CNS)

20 mg/kg

Modified Irwin test, rat (gavage)

Male CNS effects

5 mg/kg (transient, dose-dependent effects on the CNS)

10 mg/kg

Open field test, rat (gavage) (assessment of cataleptic potential)

Male CNS effects

(no cataleptic potential)

1 mg/kg (transient dose-dependent effects on CNS)

20 mg/kg

Balance rod test, mouse (gavage)

Male CNS effects

20 mg/kg (minimal CNS impairment)

100 mg/kg

Justification for classification or non-classification

Neurotoxic effects were seen in the acute neurotoxicity study in rats.