Thiophanate-methyl

Neurotoxicity

Description of key information

No test item related neurotoxicity was observed in a subchronic study according to OECD TG 424 in rats. A NOAEL of 149.6 mg/kg bw/day was derived.

Key value for chemical safety assessment

Effect on neurotoxicity: via oral route

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

149.6 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

OECD TG 424

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

Neurotoxicity-acute

In an acute neurotoxicity study according OECD TG 424, the substance was administered to male and female Sprague-Dawley (SD) rats (10 rats/sex/dose) by single-dose gavage in 0.5% aqueous methylcellulose. Doses in male and female rats were 0, 500, 1000 and 2000 mg/kg bw (main study) and at 0, 50, 125, 500 and 2000 mg/kg bw (extension study). In the main study, assessments included mortality, clinical signs, body weight, food consumption, functional observational battery (FOB) and motor activity evaluations, brain weight determination as well as macroscopical and neuropathological examinations. In the extension study, -in addition to mortality, clinical signs, body weight and food consumption, - home cage behaviour and landing foot splay (FOB components) in both sexes and motor activity were assessed prior to the administration and 2 hours after the administration of the test substance. No deaths occurred during either the extension study or the main study. Clinical signs included slight excess salivation, localized alopecia, scabs and/or ulcers on the skin, chromorhinorrhea, chromodacryorrhea, swelling of the prepuce, and sparse hair coat. Since the incidences were not dose-dependent and/or occurred in only one to three rats in one or more dose groups; all clinical signs were considered unrelated to the treatment with the test substance. Body weight and food consumption were unaffected at 50 and 125 mg/kg bw in the extension study. Transient reductions in body weight gain or body weight losses along with corresponding reductions in absolute and relative food consumption occurred initially (Days 1-3) in both sexes at 500 mg/kg bw, 1000mg/kg bw and 2000mg/kg bw in both the main and extension study.

In the main study, the FOB examinations conducted two hours after dosage, male and female rats at 500, 1000, and 2000 mg/kg bw had significantly reduced values for landing foot splay. The number of male rats that appeared to be sleeping when examined in the home cage were also significantly reduced and number showing other normal patterns (e.g. appeared awake and immobile or showed normal movement) were increased as compared to the control group. There were neither statistically significant nor exceptional differences among the groups in the measures of the FOB evaluated on the day prior to dosage and day 7 and 14 after dosage.

In the extension study, examinations conducted two hours after dosage, both male and female rats given test item at all doses had significantly reduced values for landing splay. The variations in normal home cage behaviour were not observed at 50, and 125 mg/kg bw and were not replicated at the 500 and 2000 mg/kg bw in the extension study. In the main study there were no statistically significant nor exceptional differences among the groups of male rats, in the motor activity test on the day prior to treatment at 7 and 14 days after administration (days 8 and 15). For female rats (500, 1000, and 2000 mg/kg bw) there were significantly reduced number of movements and time spent in the motor activity test two hours after dosage. The reduced activity was not observed seven days after dosage or 14 days post dosage.

In the extension study, there were no differences in the female rats at any dose 2 hours after dosage. In the main study, no gross lesions were observed at necropsy. Brain weights (absolute, relative) were comparable among the groups. No test substance related lesions were observed in the microscopic examination of neural and muscle tissues. The NOAEL for neurotoxicity was > 2000 mg/kg bw.

Neurotoxicity-subchronic

A study according OECD TG 424 was performed. Ten CD IGS rats/sex/dose group were treated via diet with the test substance at concentrations of 0, 100, 500, and 2500 ppm (males: 6.2, 30.2, and 149.6 mg/kg bw/day, females: 6.8, 34.9, and 166.3 mg/kg bw/day) for 13 weeks. Mortality, clinical observations, body weight, food consumption, and functional observational battery (FOB) and motor activity evaluations were recorded. Rats were sacrificed on day 91. A gross necropsy of the thoracic abdominal and pelvic viscera was performed. Liver, thyroid and individual kidney weights were recorded at necropsy, and brain weights were recorded following additional fixation of the tissue. For neurohistological examination, 5 rats/sex/dose group were selected and the tissues from control and high concentration group rats were evaluated. All rats survived to termination (13 weeks of exposure). Clinical signs included slight excess salivation, red perioral substance, chromorhinorrhea, chromodacryorrhea, misaligned and/or missing or broken incisors, and missing digit, and were considered unrelated to the test item because the incidences were low or, in the case of chromorhinorrhea, had an irregular frequency among individual rats. Body weights, body weight changes, and absolute and relative feed consumption values were significantly decreased at 2500 ppm in female rats (9.4-10.3%; days 71-85) for the entire exposure period, whereas these endpoints were unaffected in male rats. There were no test item-related adverse effects on FOB parameters and motor activity at any dietary concentration in either sex. There were no test item-related macroscopic findings at scheduled necropsy. Liver and thyroid weights were significantly increased in males (absolute, relative) and females (relative) at 2500 ppm. The brain weights of female rats at 2500 ppm (relative) were significantly increased. There were no microscopical lesions in the neural or muscle tissue of the examined control and 2500 ppm rats. The NOAEL for neurotoxicity was > 2500 ppm (males: 149.6 mg/kg bw/day, females: 166.3 mg/kg bw/day). The NOAEL for generalized systemic toxicity was 500 ppm (males: 30.3 mg/kg bw/day, females: 34.9 mg/kg bw/day) based on reduced body weight/body weight gain and food consumption and increased liver and thyroid weights noted at 2500 ppm.