Registration Dossier

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Clinical signs indicative of neurotoxicity were observed in male and/or female mice administered the test material by single oral gavage at doses of 250 mg/kg and above. These signs were evident beginning at 1 hr post-dosing and were no longer evident in surviving mice by day 2 post-dosing. These signs included: tremors, hyperactivity, straub tail, passiveness and ataxia. In addition to the neurotoxicity signs, scant feces was also noted on day 1. Surviving mice were normal by day 2.

 

Clinical signs indicative of neurotoxicity (tremors and salivation) were observed in male and/or female rats administered the test material by single inhalation exposure at airborne concentrations of 0.63 mg/l and above. These signs included tremors and salivation and disappeared rapidly upon cessation of exposure.

 

Clinical signs indicative of neurotoxicity (tremors and/or convulsions) were observed in male and/or female rats administered the test material by single dermal application at doses of 200 and 400 mg/kg. Surving animals recovered from these effects by day 1 following exposure.

 

Neurotoxic effects of the test material observed in single dose oral, dermal and inhalation exposure studies in mice and rats were further characterized in repeated-dose inhalation studies in rats. In this study, five groups of animals received nose-only inhalation exposures for six hours per day, 5 days per week, for four weeks. Exposure concentration levels were 0, 2, 19, 129, and 537 mg/m3.

 

Animals were examined for specific signs of neurotoxicity. Home cage observations were made noting animal posture, appearance and convulsions or unusual behavior. Each rat was removed from their cage and the ease of removal and reaction to handling noted. The animals were placed in an arena for one minute while gait, mobility and arousal levels were assessed. Descriptions of any convulsions, tremors, stereotypic or bizarre behaviors were noted. The responses to stimuli (pinch of tail, approach of a blunt object, touch on the rump, sudden loud sound) were evaluated. The ability of the animal to right itself was assessed and aerial righting reflexes were measured unless the procedure was deemed to be harmful to the animal. A pen flashlight was used to determine papillary response to light.

 

Transient signs of neurotoxicity consistent with those seen in the single exposure inhalation toxicity study in rats were seen at the 537 mg/m3 exposure level and included tremors and unsteady gait. However, as was seen in the acute study, removal of animals from exposure resulted in rapid recovery and disappearance of clinical signs. In-life neurologic evaluation of surviving animals at the end of the four week exposure period and specific histologic evaluations of the nervous system did not indicate any cumulative neurologic toxicity.

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