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Neurotoxicity

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Description of key information

WoE study: Delayed Neurotoxicity of Organophosphorus Substances Following Acute Exposure; Limit test (similar to OECD 418): NOAEL (neurotoxicity, based on neurobehaviour): ≤ 120000 mg/kg bw (total dose) (≤ 20000 mg/kg bw/day): no neurotoxic potential.

Key value for chemical safety assessment

Effect on neurotoxicity: via oral route

Endpoint conclusion
Dose descriptor:
NOAEL
20 000 mg/kg bw/day

Additional information

Two neurotoxicity studies were available which were used in a Weight of Evidence approach. In the first study, which was performed according to an equivalent of OECD418, acute delayed neurotoxicity was studied by administration of 2EHDPP via gavage to each test animal (10 mature chickens) at a rate of 10000 mg/kg bw. Dosing was carried out twice daily for 3 consecutive days. The procedure was repeated following a 21-day observation period. The total dosage of 2EHDPP administered to each chicken was 120000 mg/kg. Ten positive control birds received a single oral dose of 0.5 g/kg tri-ortho cresyl phosphate (TOCP). Test and control-birds appeared normal throughout the 42-day test period. No signs of neurotoxicity (extreme weakness of legs and wings) were noted. Gross pathological examination of all animals revealed no abnormal tissue-alterations. Histopathologic examination of sections of brain, spinal cord and sciatic nerve revealed no lesions related to treatment with 2EHDPP. Based on these results, it is therefore concluded that 2EHDPP did not induce the neuropathologic alterations characteristic of delayed neurotoxicity in the hen. A NOAEL of 20000 mg/kg bw/day was established. In the second study, not conducted according to a guideline, delayed neurotoxicity was determined by clinical observation of dosed hens for behavioural signs characteristic of neurotoxin action. Ten hens were dosed by gastric intubation with 20000 mg/kg (5000 mg/kg per day for 4 consecutive days) of 2EHDPP. The hens were observed for 21 days post dose. A second dose was given (20000 mg/kg (5000 mg/kg per day for 4 consecutive days) of 2EHDPP and hens observed an additional 21 days. Hens were rated for clinical symptoms of neurotoxicity at least once daily at least 5 times a week for the duration of the test. Body weights were recorded at the start of the test, after 22 days, and at termination of the test. For the biochemical assay, hens were dosed with 25000 mg/kg (5000 mg/kg per day for 5 consecutive days) of 2EHDPP. The hens were observed for 21 days post dose. A second dose was given (20000 mg/kg (5000 mg/kg per day for 4 consecutive days) of 2EHDPP. Hens were sacrificed 24 hours after dosing, brains removed and assayed for neurotoxic esterase enzyme activity. Inhibition of approx. 90% of the neurotoxic esterase enzyme activity was used as a guideline when the biochemical method was employed to supplement clinical results. No clinical neurotoxic response was detected during the first and second test period. No mortality occurred. Results from the biochemical method support the clinical findings. However, moderate inhibition of the neurotoxic esterase was detected at the high dose level of 45000 mg/kg (60 - 82%). Based on these results, it is concluded that the test compound did not induce the neuropathologic alterations characteristic of delayed neurotoxicity in the hen. A NOAEL of 5000 mg/kg bw/day was established.

Justification for classification or non-classification

Based on the available data, there is no evidence that 2EHDPP causes neurotoxic effects. Therefore, based on the EU criteria outlined in 67/548/EEC and 1272/2008/EC, 2EHDPP does not have to be classified with regard to neurotoxicity.