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Neurotoxicity

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The neurotoxic potential of MBT was evaluated in an acute and subchronic neurotoxicity studies.

In the acute neurotoxicity study (CMA 1989) male and female Sprague-Dawley rats (12 per sex and dose) were dosed once by gavage with MBT at doses of 0, 500, 1250 or 2750 mg/kg bw/kg. The animals were observed for 14 days.

Motor activity testing and a functional observational battery were performed pre-study, at approximately 1, 6 and 24 hours post-dosing and on observation days 7 and 14. Motor activity testing was conducted pre-study and at approximately 12 hours following treatment during the dark phase of the light/dark cycle. Animals were subjected to a gross pathological examination at the completion of the study.

One high dose female rat died just prior to placement in the activity monitor (ca. 12 hours post-dosing). Prior to death, the animal was cold and showed signs of muzzle straining, salivation and decreased respiration. Males in the 2750 mg MBT/kg group and females in all MBT treated groups displayed an increase of muzzle staining during the first week, following treatment. This was an occasion accompanied by salivation. A significantly greater weight loss for males and a larger weight loss for females in the 2750 mg MBT/kg group compared to the control group occurred from day 0 (day of treatment) to day 1. The functional observational battery (FOB) revealed several transitory differences. These included an increased incidence of salivation at the 1 h assessment for males in the 2750 mg MBT/kg group and females in the 500, 1250 and 2750 mg MBT/kg groups, decreases in vocalization for males in the 1250 and 2750 mg/kg groups at 1 and 6 h observations, and an increased incidence of urinary staining for females in the 2750 mg/kg group at the 24 h assessment. Grip strength and hindlimb splay were unaffected by treatment with MBT. The motor activity test performed at ca. 12 h post-dosing showed significantly (P< 0.01) decreased activity levels for males in the 2750 mg/kg group and for females in the 1250 and 2750 mg MBT/kg groups. No pathological findings were seen at necropsy that could be related to treatment with MBT.

The authors suggested that the changes indicated did not give a clear indication of neurotoxicity. While the motor activity test did show decreased activity levels, for the most part, the differences found using the functional observational battery (FOB) were clinical observations typically associated with overt generalized toxicity. Assessments for CNS disorders (tremors, convulsions, bizarre behaviour), muscle tone and equilibrium (body and abdominal tones, grip strength, hindlimb splay, gait, air righting reflex), and sensory functions (olfactory response, visual placing, auricular startle, tail and toe pinch responses) gave negative findings. The pattern of effects seen was considered attributable to an acute non-specific toxicity without apparent neurotoxicity.

In a subchronic neurotoxicity study (CMA 1990) male and female Sprague-Dawley rats (12 per sex and dose) were feed with 0, 5000, 15000, 25000 ppm (ca. 0, 333, 1000, 1667 mg/kg bw/d) MBT in the diet for 13 weeks. A control group was handled in an identical manner, except that it was given untreated diet. The animals were examined using a functional observation battery (FOB) pre-study, at ca. 1, 6 and 24 hours post-feeding and on days 7, 14, 35, 64 and 91. Motor activity testing was conducted pre-test and on days 29, 63 and 90. Six animals per sex per group were perfused for neuropathology evaluations which were performed on the control and 25000 ppm MBT groups. The remaining 6 animals/sex in each group were subjected to a gross pathological examination.

There were no deaths or adverse clinical signs related to treatment with MBT. There was an initial significant weight loss in the15000 and 25000 ppm groups for both males and females. The body weights of the females in the 15000 ppm group and of males and females in the 25000 ppm group were significantly lower for most or all of the assessment occasions during the study. Initial reductions in food intake occurred for male and females in the 15000 and 25000 ppm groups. Subsequently, values for females were decreased during the second month of treatment and for males in the last week of the study. There were no effects upon behaviour in the qualitative or quantitative (grip strength and hind limb spray) functional observational battery assessment. The motor activity test revealed no treatment related affects. Neither gross nor neuropathological evaluations revealed any treatment related changes.

The authors concluded that treatment of male and female rats for 13 weeks with MBT by dietary incorporation, at levels of up to 25000 ppm resulted in significant effects upon body weight at the 25000 ppm level for males and at the 15000 ppm and 25000 ppm levels for females. Effects upon food intake were primarily transitory, occurring in the first week of the study except for females at the 25000 ppm level where the food intake was significantly decreased during the second week and in the second month of the study. The behavioural (functional observational battery and motor activity test) and neuropathological evaluations produced no evidence of neurotoxicity.

Justification for classification or non-classification

No classification is required according to the classification criteria 67/548/EWG and regulation no. 1272/2008 (GHS).