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Neurotoxicity

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Description of key information

LOAEL oral = 25 mg/kg bw/d based on decreased in motor and sensory conduction velocities and amplitude of the sensory action potentials. (kr.3)
NOAEC inhalation > 300 ppm, the highest tested dose (kr. 4)

Key value for chemical safety assessment

Effect on neurotoxicity: via oral route

Endpoint conclusion
Dose descriptor:
LOAEL
25 mg/kg bw/day

Additional information

INHALATION EXPOSURE 

In a subacute inhalation neurotoxicity study with reliability 2 (Malley, 1994), CRL:CD®BR Rats (15/sex/group) were exposed nose-only to cis-2-pentenenitrile vapor for 6 hours/day over approximately a 4-week period (total of 20 exposures) at concentrations of 0, 3, 30, 100 and 300 ppm. There were no compound-related changes in FOB or MA parameters at any exposure concentration in either males or females. There were no compound-related gross or microscopic morphological changes in nervous tissue at any exposure concentration in either males or females. Under the test condition of this study, no neurotoxicity was observed in rats after cis-2 -pentenenitrile inhalation. Therefore, the NOAEC for neurotoxicity (inhalation exposure) is considered to be greater than 300 ppm in both males and females.

ORAL EXPOSURE

Several studies discussed the neurotoxicity potential of cis-2 -pentenenitrile by oral route both following acute and repeated exposure, thus a weight of evidence was used to evaluate this potential.

Acute exposure

In an acute neurotoxicity study (Tanii et al.,1991), 2 -pentenenitrile was administered orally to male Wistar rats, at dose levels of 112, 123, 136 and 150 mg/kg bw, dissolved in olive oil. Their behavioral abnormalities were observed over a period of 40 days. The rats given 2 -PN began to exhibit behavioral abnormalities from day 1 to 3 after treatment. These abnormalities, except for head-twitching which latest until the end of the examination period, disappeared in a few days. Increased locomotor activity was also observed at about 4 days after treatment. Increases in the levels of 5 -HT and 5 -HIAA and in the ratio of 5 -HIAA/5 -HT in various parts of the brain were seen at one day after treatment with 2-PN, but not at 6, 15 and 30 days. The content of 5 -HT was increased in all brain areas studied. Over the 30 day period, no difference was detected in the level of dopamine abd its metabolites between the treated and control groups. The present study demonstrates that 2 -pentenenitrile induced behavioral abnormalities in rats.

Moreover, in the key study (Rondot, 1981) of the acute oral toxicity endpoint, clinical signs observed included increased spontaneous activity, with a lack of coordination in the movements at all the doses tested (200 to 400 mg/kg bw). In the high-dose group, these symptoms persist up to the end of the reversibility period (45 days).

 

Repeated exposure

In a subchronic neurotoxicity study (Gagnaire and Merignac, 1999), cis-2-pentenenitrile (> 95 % pure) was administered to male Sprague-Dawley rats (12/groups) at doses of 0, 25, 50 or 100 mg/kg bw/d for 12 weeks followed by 8 weeks recovery period. Motor and sensory conduction velocities and amplitudes of the sensory and motor action potentials of the tail nerve were studied. The rats in the high and medium dose group presented deafness, restlessness, opacity of cornea, and lack of response to falling. These symptoms persisted until the end of the recovery period, except for the opaque cornea which again returned to being limpid between the 4th and the 8th weeks of the recovery period. Moreover, all rats exhibited both time- and concentration-dependent decreases in motor and sensory conduction velocities and amplitudes of the sensory action potentials. Nerve conduction velocities were partially reversible after 8 weeks of recovery.

Brainstem auditory and visual evoked-potentials were studied in male Sprague-Dawley rats during the same subchronic oral treatment (Gagnaire et al., 2001). Oral administration produced deafness and absence of reaction when the animals were subject to droptest. Rats in the high dosage group exhibited a complete disappearance of the five waves of the auditory evoked-potentials. Those changes were not reversible at the 8th week of the recovery period. A dose-dependent effect on inner and outer hair cells was observed in the organ of Corti. The basal part of the cochleae was the most affected. Rats also showed a corneal opacity as well as a decrease in the amplitude and lenghtening of the peak latenties of the visal evoked-potentials. These latter changes were reversible by the end of the 8th week of the recovery period and appeared to be related to the opacity of the cornea.

The decreases in motor and sensory conduction velocities and amplitude of the sensory action potentials reflect changes in the magnitude of the neural population responsive to stimulation (see EPA/630/R-95/001F). Therefore these decreases may be indicative of a neurotoxic effect. Based on the overall data, the LOAEL for neurotoxicity (oral exposure) is considered to be 25 mg/kg bw/d as a worst case.

Justification for classification or non-classification

A self-classification is proposed for the neurotoxicity of cis-2 -pentenenitrile:

- Cause damage to organs (nervous system) through prolonged or repeated exposure (oral route of exposure) (STOT RE Cat. 1 H372) according to the CLP Regulation (1272/2008)

- Danger of serious damage to health by prolonged exposure (Xn;R48/22) according to the Directive 67/548/EC.