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Neurotoxicity

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Description of key information

TS-ED 532 was found not to have effects on reproduction, pre natal development and post-natal development of the rat when administered to two successive generations. Assessment of pre-weaning offspring, adolescent and young adult animals in a programme of neurobehavioural tests, validated in advance using PTU, did not indicate any evidence of developmental neurotoxicity; neither did microscopic examination of the nervous system, including morphometric measurement on selected brain structures. The animals were exposed to 1500, 6000 or 25000 ppm TS-ED 532 in the feed. NOEL of TS-ED 532 for adult toxicity and reproduction over the two generations was 25000 ppm. Other than a decrease in spleen weights for female offspring, the NOEL of TS-ED 532 for offspring development was 25000 ppm and this dosage represents a clear NOAEL for offspring development. NOEL of TS-ED 532 for offspring survival and growth, and for developmental neurotoxicity was 25000 ppm. The mean achieved dosages at this exposure level were 1159 mg/kg bw/day (F0 male), 2197 mg/kg bw/day (F0 female), 1320 mg/kg bw/day (F1 male) and 2249 (F1 female). The lowest identified NOAEL at this exposure level was ≥ 1159 mg/kg bw/day (F0 male). 

Key value for chemical safety assessment

Effect on neurotoxicity: via oral route

Endpoint conclusion
Dose descriptor:
NOAEL
1 159 mg/kg bw/day

Additional information

The study performed represents a combination study design specifically taking into consideration the requirements of the OECD guideline 416 and 426. A combination study design was chosen based on the requirements of using the minimum number of test animals. The study was performed to investigate the effects of TS-ED 532 on reproduction, pre-natal development and post-natal development of the rat when administered to two successive generations. The study also investigated the potential of TS-ED 532 to cause developmental neurotoxicity in the offspring using a programme of neurobehavioural tests, validated in advance of the study using PTU. The animals were exposed to 1500, 6000 or 25000 ppm TS-ED 532 in the feed.

Assessment of F0-F1and F1-F2 pre-weaning offspring and F0-F1 post-weaning offspring in a programme of neurobehavioural tests did not give any indication that exposure to TS-ED 532 was associated with developmental neurotoxicity. For pre-weaning offspring,  no adverse effects of treatment were apparent on surface righting ability, air righting ability or motor activity. Post weaning adolescent animals did not show any adverse effects of treatment during assessments for motor activity, motor function or learning and memory and young adult animals did not show any adverse effects of treatment during assessments for motor activity, learning and memory or sensory function. Further, microscopic examination of the nervous system, including morphometric measurement on selected brain structures did not indicate any evidence of developmental neurotoxicity.

Overall, TS-ED 532 was found not to have effects on reproduction, pre-natal development and post-natal development of the rat when administered to two successive generations, including no endocrine disrupting effect using ano-genital distance and nipple count as effect parameters. Furthermore, TS-ED 532 was found not to induce any developmental neurotoxicity in the offspring. NOEL of TS-ED 532 for adult toxicity and reproduction over the two generations was 25000 ppm in the feed. Other than a decrease in spleen weights for female offspring, the NOEL of TS-ED 532 for offspring development was 25000 ppm and this dosage represents a clear NOAEL for offspring development. NOEL of TS-ED 532 for offspring survival and growth and, also, for developmental neurotoxicity was 25000 ppm. The mean achieved dosages at this exposure level were 1159 mg/kg bw/day (F0 male), 2197 mg/kg bw/day (F0 female), 1320 mg/kg bw/day (F1 male) and 2249 (F1 female). The lowest identified NOAEL at exposure level 25000 ppm was 1159 mg/kg bw/day (F0 male).

Justification for classification or non-classification

Based on these data, TS-ED 532 does not show any evidence of inducing any developmental neurotoxicity in the offspring when investigated over two successive generations using a high dosage level of 25000 ppm. The lowest identified NOAEL at this dose level was 1159 mg/kg bw/day (F0 male).

Based on these results, TS-ED 532 is not expected to have hazardous properties and is not classified according to GHS and DSD-DPD.