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Neurotoxicity

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Description of key information

Not neurotoxic - Oral NOAEL = 967 mg/kg bw  rat (male), EPA OPP 82 -7, Classen 1999

Key value for chemical safety assessment

Effect on neurotoxicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
967 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
One oral subchronic study is available and two oral acute studies are available. All studies were conducted to GLP and in line with standardised guidelines. All studies were assigned a reliability score of 1 and hence the overall quality of the database is high.

Effect on neurotoxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Effect on neurotoxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Three studies are available to assess the neurotoxicity of the test material. All were conducted to GLP and in accordance with standardised guidelines and, as such, all were assigned a reliability score of 1.

In the first study, the acute oral neurotoxicity of the test material was determined in accordance with standardised guidelines OECD 424 and EPA OPPTS 870.6200. During the study 10 rats of each sex were dosed orally, by gavage, with a dose of 0 or 2000 mg/kg test material. Control animals received vehicle only. Mortality, clinical signs, bodyweight and food consumption were monitored throughout the study. A Functional Observational Battery and motor activity measurements were performed pretest, at the time of peak plasma concentrations (1 -2 hours post dose), and on test days 8 and 15. At necropsy, animals were sacrificed by in situ perfusion. The brain, spinal cord, peripheral nerves, muscle, and eyes were collected, prepared for histological evaluation and examined microscopically.

All animals survived to scheduled sacrifice. Food consumption and bodyweight development were not affected. At the end of the observational period one treated male had a slightly hunched posture and vocalised when held. During day 15 observations conducted as part of the Functional Observational Battery, hunched posture and tiptoe gait were observed in one treated female. Functional tests conducted were all unremarkable

At the time of peak plasma concentration, there was a statistically significant decrease in horizontal and vertical motor activity parameters as compared to controls in both sexes. At days 8 and 15 motor activity was comparable to that of controls.

Macroscopical and microscopical examination of the multiple areas of the central and peripheral nervous system, the eyes, optic nerves and skeletal muscle of the male and female, control and treated animals did not reveal any treatment-related neuropathic changes.

As changes in motor activity were transient and not accompanied by changes in sensorimotor functions or morphological changes in the nervous system, decreased motor activity was considered to be secondary to systemic toxicity or general malaise. Therefore, under the conditions of the study, the test material was considered to be devoid of any neurotoxicity when administered to rats at a single oral dose of 2000 mg/kg.

In the second study, the acute oral neurotoxicity of the test material was determined in accordance with standardised guidelines OECD 424 and EPA OPPTS 870.6200. During the study 10 rats of each sex were dosed orally, by gavage, with a dose of 0, 200, 600 or 2000 mg/kg test material. Control animals received vehicle only. Mortality, clinical signs, bodyweight and food consumption were monitored throughout the study. A Functional Observational Battery and motor activity measurements were performed pretest, at the time of peak plasma concentrations (1 -2 hours post dose), and on test days 8 and 15. At necropsy, animals were sacrificed by in situ perfusion. The brain, spinal cord, peripheral nerves, muscle, and eyes were collected, but not examined microscopically.

All animals survived to scheduled sacrifice. Food consumption and bodyweight development were not affected. Neither clinical signs nor changes in observations and functional tests conducted as part of the FOB were seen. At the time of peak plasma levels motor activity parameters of males were comparable to controls while females tended to be slightly less active. A slightly increased activity was seen in high dose males at test day 8 and/or 15.

Based on these results the test material was considered to be devoid of any neurotoxicity when administered to rats at a single oral dose of 2000 mg/kg. As motor activity was slightly reduced in top dose males at the time of peak plasma levels the no observed effect level was considered to be 600 mg/kg.

The key study investigated the subchronic oral neurotoxicity of the test material, in accordance with the standardised guideline EPA OPP 82 -7. During the study 10 rats of each sex were dosed orally, in the diet, at dose concentrations of 0, 2000, 8000 or 16000 ppm test material for a period of 90 days. Control animals received plain feed only. Mortality, clinical signs, bodyweight and food consumption were monitored throughout the study. A Functional Observational Battery and motor activity measurements were performed pretest and at test weeks 4, 8 and 13. At necropsy, animals were sacrificed by in situ perfusion. The brain, spinal cord, peripheral nerves, muscle, and eyes were collected, prepared for histological evaluation and examined microscopically.

There were no treatment-related deaths or clinical signs. Bodyweight development was moderately reduced in high dose males and slightly reduced in males dosed at 8000 ppm and in high dose females. In top dose males this was paralleled by reduced food consumption, while minimal effects on food intake were also seen in males dosed at 8000 ppm. In all treated animals a transient, dose-related reduction in food consumption was seen at week 1, most likely due to poor palatability of the diet admixture. Food consumption ratios reflected the changes in food intake and bodyweight.

There were neither treatment-related effects on observations and functional tests conducted as part of the functional observational battery nor on motor activity. Similarly, neuropathological examination of the peripheral and central nervous system, eyes and muscles did not reveal any effects that could be attributed to treatment.

Effects on bodyweight development and food consumption indicated systemic toxicity in males at doses of 8000 ppm and above and in females at 16000 ppm. Based on these effects 2000 ppm and 8000 ppm were considered to be the no observable effect levels in males and females, respectively. These doses correspond to daily intakes of 112 mg/kg bw in males and 553 mg/kg bw in females. In the absence of any functional or morphological changes induced in the nervous system at any of the dose levels tested, corresponding to a daily intake of up to 967 mg/kg bw in males and 1128 mg/kg bw in females, the test material was considered devoid of a neurotoxic potential when administered to rats.

 


Justification for selection of effect on neurotoxicity via oral route endpoint:
Key study investigates neurotoxicity of the test material following repeated dose exposure in the diet. Two supporting studies are available which investigate neurotoxicity of the test material following single oral administration (by gavage).

Justification for classification or non-classification

The available acute and subchronic data indicated that the test material is devoid of neurotoxic effects. The available data indicated that the central nervous system is not a specific target organ of the test material.

In accordance with the criteria for classification as defined in Annex I, Points 3.8 and 3.9 Regulation 1272/2008, the available data indicated that the central nervous system is not a target organ of the test material, and therefore does not require classification for specific organ toxicity for both repeat and single exposures based on the neurotoxicity of the test material.

In accordance with criteria for classification as defined by Directive 2001/59/EC, Annex VI, Points 3.2.1 and 3.2.8, the test material did not indicate a risk of irreversible serious effects or other neurological effects that would require classification.

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