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Toxicological information

Neurotoxicity

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Description of key information

In a guideline 90-day subchronic dietary study conducted in Wistar rats, effects occurred at the high dose of 750 ppm (equivalent to 49.7 mg/kg bw/day in males and 53.6 mg/kg bw/day in females), which consisted of changes in neurobehavioral parameters and associated brain histopathology. The NOAEL was the next lower dose of 150 ppm (equivalent to 9.8 mg/kg bw/day in males and 10.2 mg/kg bw/day in females).

Key value for chemical safety assessment

Effect on neurotoxicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
9.8 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Additional information

As part of the original dossier for MMTE two studies were included which utilized read-across from MMTC. These studies remain in the dossier to provide continuity to reviewers and an historical perspective of the changes which are being made to the dossier. New data on in vitro metabolism, cited in section 7.1.1 of this dossier, caused a change in the interpretation of the data cited. The new in vitro metabolism data support the conclusion that MMTE does not metabolise to MMTC under simulated mammalian gastric conditions [pH ~2 and 37 °C] as was formerly believed. It then follows that the toxicology of MMTE via the oral route in mammalian species cannot be accurately predicted based on studies conducted with MMTC via the oral route in mammalian species. The implications are clear: (a) dietary feeding and oral gavage studies conducted with MMTC cannot be read-across to MMTE, and (b) for studies conducted with MMTC, their relevance for hazard classification of MMTE must be reduced or eliminated. Therefore, the Klimisch score of the studies have been reduced to Klimisch 3 because the read-across strategy from this study to MMTE is no longer valid (though the study itself is still considered to be reliable).

In a guideline 90-day subchronic dietary study conducted in Wistar rats, effects occurred at the high dose of 750 ppm (equivalent to 49.7 mg/kg bw/day in males and 53.6 mg/kg bw/day in females), which consisted of changes in neurobehavioral parameters and associated brain histopathology, and changes in hematology, clinical chemistry, urinalysis, organ weights, and pathology of the thymus. The NOAEL was the next lower dose of 150 ppm (equivalent to 9.8 mg/kg bw/day in males and 10.2 mgkg bw/day in females).

In a Developmental Neurotoxicity study, the NOAEL of 94.3 mg/kg/day is based on treatment-related brain vacuolisation at all doses. No functional effects were seen.

There was no NOAEL in a behavioral screening study in drinking water.  Runway learning and swim escape effects were observed.

Justification for classification or non-classification