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Toxicological information

Neurotoxicity

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Description of key information

Oral Exposure
Thorpe E. (1981) - report number TLGR.80.067: Toxicology of 32899: The acute oral toxicity of 32899 to rats. It is concluded that a single dose of 2,700 mg/kg 32899 can produce degenerative changes in the sciatic/ posterior tibial nerve and trigeminal ganglia and that a single dose of 1,350 mg/kg can produce degenerative changes in the distal section of the nerve.
Dewar A.J. and Moffett B.J. (1980) - report number TLER.79.165: Preliminary studies on the neurotoxicity of 32899 to rats. It is concluded that 32899 is capable of producing a severe neuropathy in rats repeatedly dosed orally.
Dewar A.J (1979) - report number TLGR.80.037: The neurotoxicity of orally administered 32899 to rabbits - A preliminary study. It is concluded that 32899 is neurotoxic to rabbits and the neurotoxic effects have qualitative similarities to those previously observed in 32899 - dosed rats.
Dewar A.J (1981) - report number TLGR.80.130: The neurotoxicity of orally administered 32899 to rats. It is concluded that the repeated oral administration of 32899 to rats in doses of 22 mg/kg or above resulted in the development of peripheral neuropathy. Cumulative doses in excess of 1.8 g/kg could produce a very severe clinical neuropathy which was not readily reversible. The neuropathy produced by doses less than 1.8 g/kg, were minor and did not result in any signs of intoxication or functional deficit. No signs of neurotoxicity, functional deficit, reduced sciatic nerve MCV or biochemical and neuropathological evidence of peripheral nerve degeneration were found in the animals dosed with 0.5 mg/kg 32899 for six months.
Dermal exposure
Thorpe E. (1980) - report number TLGR.80.068: The neurotoxicity of dermally-administered 32899 to rats. It is concluded that 32899 is of negligible neurotoxicity when administered by the dermal route.

Key value for chemical safety assessment

Effect on neurotoxicity: via oral route

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
0.5 mg/kg bw/day
Study duration:
chronic
Species:
rat

Effect on neurotoxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
350 mg/kg bw/day
Species:
rabbit

Additional information

Oral Exposure

Acute

Thorpe E. (1981) - report number TLGR.80.067: Toxicology of 32899: The acute oral toxicity of 32899 to rats:

Electrophysiology Report.

Two males from the group dosed with 2,700 mg/kg had MCVs 15% and 11% lower than control. One male dosed with 432 mg/kg 32899 had an MCV 8% lower than control. The MCV of all other animals tested did not differ appreciably from control. Neurochemistry Report.

Substantial increases in both enzymes were found in all tissues analysed in the rats from the group dosed with 2,100mg/kg 32899. Small increases in both enzymes were detected in the distal section of the nerves from the rats in the group dosed with 1,350 mg/kg. These data suggest that a single dose of 2,700 mg/kg 32899 can produce degenerative changes in the sciatic/ posterior tibial nerve and trigeminal ganglia and that a single dose of 1,350 mg/kg can produce degenerative changes in the distal section of the nerve.

Repeat dose Dewar A.J. and Moffett B.J. (1980) - report number TLER.79.165: Preliminary studies on the neurotoxicity of 32899 to rats:

Mature Wistar rats were dosed orally with a 10% suspension of 32899 in 0.5% carboxymethylcellulose. Dosing took place either for five consectuive days or three times per week for up to one month. Individual doses ranged from 700 mg/kg (approximately one quarter of the reported acute oral LD50 value).

1. Acumulative dose of 32899 greater than 1/3 of the reported acute oral LD50 value, given to rats over a period of one month or less, can produce biochemical changes in the peripheral nervous system consistent with degeneration.

2. Clinical signs consistent with severe neuropathy (abnormal gait and hind limb paralysis) occurred following dosage of either a cumulative dose equivalent to the acute oral LD50 value over three weeks or a dose equivalent to 60% of LD50 over one week. Both males and females were affected.

3. The clinical signs of neuropathy were accompanied by a decrease of approximately 18% in the sciatic nerve MCV. There was no evidence that severeley affected animals recovered over a 6 month period. Some animals were still clinically affected 322 days after dosing when observations were terminated.

Dewar A.J (1979) - report number TLGR.80.037: The neurotoxicity of orally administered 32899 to rabbits - A preliminary study:

Rabbits were orally dosed with 700 mg/kg, 350 mg/kg, 175 mg/kg and 88 mg/kg three times per week for up to 8 weeks. The ß-glucuronidase and ß-galactosidase activities in the sciatic/posterior tibial nerves of the surviving rabbits were measured at 8 weeks to assess peripheral damage.

32899 administration produced clinical signs consistent with peripheral neuorpathy. The neuropathy once developed showed no signs of reversing over the 8 week observation perod and in most cases led to the death of the animal within one week of clinical signs developing.

Death and/or neuropathy resulted from 1 -2 doses of 700 mg/kg, 3 doses of 350 mg/kg and 4 -11 doses of 175 mg/kg. One rabbit developed a neuropathy after 6 doses of 88 mg/kg but the majority of rabbits could tolerate 24 doses of 88 mg/kg without developing overt signs of peripheral neuropathy. However, biochemical indications of sparse axonal damage were found in the surviving animals from the 88 mg/kg group.

Long-term repeat dose

Dewar A.J (1981) - report number TLGR.80.130: The neurotoxicity of orally administered 32899 to rats:

Groups of Wistar rats were orally dosed three times per week for up to six months with doses of 0.5, 22, 88 or 175 mg/kg 32899. During the experimental period neurotoxicity was assessed by regular clinical observations, functional testing and measurements of the sciatic nerve maximal motor conduction velocity (MCV). At the end of the experimental period degenerative changes in the nervous system were assessed either by biochemical methods (measurements of a-glucuronidase and a-galactosidase) or by neuropathological examination.

No signs of neurotoxicity, functional deficit, reduced sciatic nerve MCV or biochemical and neuropathological evidence of peripheral nerve degeneration were found in the animals dosed with 0.5 mg/kg 32899 for six months.

No clinical signs of neurotoxicity, functional deficit or reduction in the sciatic nerve MCV were found in the animals dosed with 22 mg/kg 32899 for six months. However small, but significant, biochemical changes consistent with degeneration were found in the sciatic and posterior tibial nerves and trigeminal ganglia and neuropathological examination revealed minor lesions in peripheral nerves of some males.

Most of the males dosed with 88 or 175 mg/kg 32899 developed clinical signs of neuropathy, a pronounced functional deficit and, in some cases, a reduced (by no more than 17%) sciatic nerve MCV. The time of onset of clinical signs varied considerably but no animal became severely affected before 6-7 weeks (minimum total dose required 1,848 mg/kg). Severely affected animals did not recover when dosing was stopped. They either died or survived with a gross disability. Biochemical changes consistent with degeneration were found in the sciatic and posterior tibial nerves and in the trigeminal ganglia. The intensity of these changes varied but was more severe in the clinicallyaffected animals. Neuropathological examination showed degeneration of Wallerian type in"the trigeminal and dorsal roots and in the sciatic and posterior tibial nerves. Apart from a minimal degree of chromatolysis the ganglion cells were unaffected and no spinal cord lesions were seen. A solitary degenerative lesion was seen in the trigeminal roots of one male control.

Females dosed with 88 or 175 mg/kg 32899 showed relatively few signs of intoxication and none developed a functional deficit, although there were a small number of mortalities. Two females had reduced sciatic nerve MCVs at the end of the experimental period. Significant biochemical changes consistent with degeneration were found in the sciatic and posterior tibial nerves and trigeminal ganglia and neuropathological examination revealed minor lesions in a small proportion of the animals. A solitary degenerating fibre was found in the sciatic nerve of one control female.

It is concluded that the repeated oral administration of 32899 to rats in doses of 22 mg/kg or above resulted in the development of peripheral neuropathy. Cumulative doses in excess of 1.8 g/kg could produce a very severe clinical neuropathy which was not readily reversible. The neuropathy produced by doses less than 1.8 g/k, were minor and did not result in any signs of intoxication or functional deficit.

Dermal Exposure

Thorpe E. (1980) - report number TLGR.80.068: The neurotoxicity of dermally-administered 32899 to rats:

Three groups of six male and six female rats were given twelve dermal doses of 175 mg/kg, 350 mg/kg and 700 mg/kg 32899 respectively over a period of four weeks. The top dose was equivalent to four times the neurotoxic oral dose. A fourth group received blank formulation. All rats were examined for evidence of neurotoxicity using the following techniques: clinical observation, functional testing (the narrowing bridge test), measurement of the sciatic nerve maximal motor conduction velocity, biochemical estimation of peripheral nerve damage by measurement of ß-glucuronidase and ß-galactosidase and neuropathological examination of the sciatic and posterior tibial nerves, dorsal root ganglia, spinal cord and cerebellum.

No evidence of neurotoxicity was found in the rats dosed with 12 x 175 mg/kg (2.1 g/kg) and 12 x 350 mg/kg (4.2 g/kg) 32899. The rats dosed with 12 x 700 mg/kg (8.4 g/kg) 32899 showed very small increases (no greater than 26%) in ß-glucuronidase and ß-galactosidase in th esciatic/posterior tibial nerve but no other evidence of neurotoxicity was seen.

It is concluded that 32899 is of negligible neurotoxicity when administered by the dermal route.

Justification for classification or non-classification

Based on the effects noted in all neurotoxicity studies, the test material is considered to be toxic for repeated oral administration. As such the substance is considered to be STOT-RE Cat 1 according to Regulation (EC) No 1273/2008.