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EC number: 212-039-2 | CAS number: 753-73-1
The achieved concentrations in the present study were close to the nominal levels and were all in accordance with the criteria for content of the test substance (the acceptable maximum mean concentration).
The objective of this study was to examine the possible sub-chronic oral toxicity of the test substance MMTTC/DMTDC (30/70). The test substance was administered to main groups of 10 male and 10 female Wistar rats and satellite groups (for neuropathology) of 6 male and 6 female Wistar rats at constant concentrations of 0, 1, 6 or 15 ppm in the diet for 13 consecutive weeks or at a constant concentration of 200 ppm for approximately one month.
After about one month of treatment, neurotoxic effects of the test substance became evident at the highest dose-level. Three high-dose females died and a large number of high-dose animals of both sexes started to develop signs of neurotoxicity, including tremors and convulsions. On account hereof, all animals of the main and satellite high-dose groups were sacrificed after approximately one month of treatment. High-dose (200 ppm) males and females showed slight growth retardation, which was associated with decreased food intake during the first week and with slightly lower food conversion efficiency in weeks three and four. Body weight, food consumption or food conversion efficiency were not affected by the test substance at the lower dose levels. Neurobehavioural and motor activity testing showed clear treatment-related neurotoxic effects in animals of the 200 ppm group in week 4 of the study. In week 1 of the study these effects were not yet observed, which is in accordance with the onset of the neurological clinical signs in the 200 ppm group after about 4 weeks. No toxicologically relevant effects were observed in any of the other dose-groups, at any of the other time-points investigated. Ophthalmoscopy, haematology, clinical chemistry, urinalysis or absolute and relative organ weights did not reveal any treatment-related changes after dietary exposure to concentrations up to 15 ppm for 13 weeks. These parameters were not measured for animals of the 200 ppm group, because of the premature termination of this group. Microscopic examinations (general pathology) demonstrated clear treatment-related changes in the kidneys, thymus and brain of animals of the 200 ppm group. The effect on the thymus was not considered a direct toxic effect, but an effect caused by stress. The effects on the kidneys and brain were considered toxicologically relevant. None of the effects was present in the next lower dose-group treated with 15 ppm. Microscopic examinations (neuropathology) demonstrated treatment-related pathological changes in several parts of the brain (neuronal death) of animals of the 200 ppm group. No significant treatment-related changes were observed in the peripheral nervous system. The effects occurred in both sexes, but were most pronounced in female rats.
On the basis of the neurotoxic effects observed in the high-dose group the No-Observed-Adverse-Effect Level in the present study was placed at 15 ppm. This level was equivalent to 0.98 (males) and 1.02 (females) mg of MMTTC/DMTDC (30/70) per kg body weight per day.
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