4-fluoroaniline

Neurotoxicity

Description of key information

The clinical signs and the neurohistopathological changes indicate neurotoxicity of the test item.

Key value for chemical safety assessment

Effect on neurotoxicity: via oral route

Link to relevant study records

Reference

Endpoint:

neurotoxicity: acute oral

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Peer reviewed literature. Neither guideline nor GLP compliant study only basic information is available.

Principles of method if other than guideline:

Well reported study with basic information

GLP compliance:

not specified

Limit test:

yes

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS

- Age at study initiation: 4 weeks old
- Housing: Polycarbonate cages (three rats per cage)
- Diet: MF, Oriental Yeast Co., Ltd, Tokyo, Japan ad libitum
- Water: Sterilized water ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24 °C
- Humidity (%): 40-70%
- Photoperiod: 12-h light/dark cycle.

Route of administration:

oral: gavage

Analytical verification of doses or concentrations:

not specified

Frequency of treatment:

Once

Remarks:

Doses / Concentrations:
600 mg/kg bw
Basis:
nominal conc.

No. of animals per sex per dose:

9 (males)

Control animals:

yes, concurrent vehicle

Observations and clinical examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: 30 min and 5 h after dosing and once a day thereafter for the following 15 days

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: all rats 2 days before dosing and on day 9, and on all the surviving rats on day 15

BODY WEIGHT: Yes
- Time schedule for examinations: Before dosing and on days 2, 4, 8, 15 and 16

Sacrifice and (histo)pathology:

- Time point of sacrifice: On day 10 and the other rats were killed on day 16
- Number of animals sacrificed: Three rats from each experimental group
- Procedures for perfusion: Phosphate buffer solution
- Tissues evaluated: Forebrain, including cerebral cortex, basal ganglia and corpus callosum; midbrain, including hippocampus, thalamus and hypothalamus; mesencephalon, including substantia nigria, colliculi, tectum and tegmentum; hindbrain, including cerebellum, pons and medulla oblongata; spinal cords, including cervical, thoracic and lumbar levels; trigeminal nerves with gasserian ganglia; and sciatic nerves.

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Neuropathological findings:

effects observed, treatment-related

Details on results:

CLINICAL SIGNS AND MORTALITY
Cyanosis between days 1 and 4

NEUROBEHAVIOUR
Reduced response to extensor thrust of the hindlimb was found on days 9 and 15. Gait abnormalities, including ataxia or hindlimb paralysis
A significant decrease in grip strength of the hindlimbs was found in the on day 9 compared with the corresponding control group.
Abnormal landing, such as on the animal’s side in the aerial righting reflex, was found on day 9.

NEUROPATHOLOGY
Neuronal cells were not damaged in any rats of the treated groups. No histopathological abnormalities in the nervous tissues were found in any rats in the control group.

Histopathological findings:
- A spongy change in the white matter of the spinal cords was found
- The lesions arose symmetrically and they were prominent in the lateral and ventral funiculi of the white matter. The lesions in the thoracic level were most prominent throughout the spinal cord. A spongy change in the tegmentum of the mesencephalon or the spinocellebelar tracts of the pons and medulla oblongata, and nerve fibre degeneration in the spinal nerves, trigeminal nerves, or sciatic nerves were also found.

Conclusion:
Previous study demonstrated that a bolus dose of aniline to rats induces neurotoxicity characterized by hindlimb paralysis on clinical observation and spongy change in the white matter of the spinal cord on histopathological examination. The results of the present study indicate that 4-halogenated anilines also cause neurotoxicity in rats.
The clinical signs (including hindlimb paralysis) and the neurohistopathological changes (including the spongy change in the white matter of the spinal cord) were of the same character as those induced by aniline intoxication.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Quality of whole database:

Peer reviewed literature. Neither guideline nor GLP compliant study only basic information is available.

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

Supporting study

In the published report at Okazaki et al. (2003) the potential for neurotoxicity after a single oral dose of four halogenated aniline derivatives was given to rats was investigated at or near the lethal dosage level of 600 mg/kg bw.

Hindlimb paralysis was found in the test item group on clinical observation, with the maximum incidence of 100% in the test item group.

Detailed clinical observations with functional tests identified the following effects: reduced response of hindlimb extensor thrust, gait abnormality in the open field and decreased grip strength in the foreor hindlimbs, abnormal landing in the aerial righting reflex. Spongy change in the white matter of the spinal cord and brainstem and nerve fibre degeneration in the peripheral nerves were found in all haloaniline-treated groups.

This study demonstrates that a bolus dose of 4-haloanilines to rats induces neurotoxicity similar in character to that evoked by the parent aniline.

Justification for selection of effect on neurotoxicity via oral route endpoint:
Peer reviewed literature. Neither guideline nor GLP compliant study only basic information is available.

Justification for classification or non-classification

Dangerous Substance Directive (67/548/EEC)
The available study is considered reliable and suitable for classification purposes under Directive 67/548/EEC. As a result the substance is considered not to be classified for neurotoxicity under Directive 67/548/EEC, as amended for the 31st time in Directive 2009/2/EG.

 

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008
The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. As a result the substance is considered not to be classified for neurotoxicity under Regulation (EC) No 1272/2008, as amended for the sixth time in Regulation (EC) No 605/2014.