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Neurotoxicity

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Description of key information

Neurotoxicity:
- transient narcotic effects at high concentrations of the solvent are possible, no selective or cumulative neurotoxicity

Key value for chemical safety assessment

Effect on neurotoxicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
2 000 mg/kg bw/day
Species:
mouse
Quality of whole database:
Several reliable studies/publications are available for assessment and were used in a weight of evidence approach.

Effect on neurotoxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Species:
rat
Quality of whole database:
Several reliable studies/publications are available for assessment and were used in a weight of evidence approach.

Effect on neurotoxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Experimental data from studies conducted with pentan-1-ol and its structural analogue 3-methylbutan-1-ol were taken into consideration to assess the potential for neurotoxicity of pentan-1-ol.

The effect of pentan-1-ol on motor activity was investigated in a published study, where 20 – 25 male Swiss-Cox mice were orally administered doses of 500, 1000 and 2000 mg/kg bw in olive oil (Maickel & Nash Jr. 1985). Testing of motor performance was performed with a rotarod 10, 20, 40, 80 and 120 min after dosing, which was repeated on five different days. In addition, body temperature and levels of alcohol in blood were analyzed at the same time points. Examination of the data on body temperature showed that there was no consistent relationship between the time of maximal hypothermic effect and the time course of blood levels of the alcohol. In general, the maximum hypothermic response was observed at either 10 or 20 min after the administration of alcohol. Analysis of the data concerning rotarod performance indicated that no significant differences occurred for the different test days; consequently test days 1-5 were combined. A dose-related impairment of performance was observed for pentan-1-ol. This impairment was time-related and was positively correlated, in magnitude, with the levels of blood alcohol, i.e. the greater the blood level of alcohol, the greater was the degree of impairment of rotarod performance. The smallest dose was ineffective. All animals returned to normal activity by 120 min after the administration of alcohol.

Since the observed effects were reversible, the NOAEL can be set at the highest dose of 2000 mg/kg bw, under the conditions of this study.

 

In another publication, the effects of electrically evoked seizures were determined in male Wistar rats and female mice of the H strain after 4 h inhalation of pentan-1-ol vapours at 3 different concentrations (25 – 75% of the maximum effective dose) (Frantík et al. 1994). Most animals went through 3 - 4 exposures to each concentration, and the interval between exposures was at least 3 weeks. According to the authors the characteristics of generation, spreading, and maintenance of the seizure discharge were found to permit the detection and quantitative measuring of the acute solvent effects at very low concentrations. A short electrical impulse was applied through ear electrodes. The duration of tonic extension of hindlimbs in rats and the velocity of tonic extension in mice were the most sensitive and reproducible response measures.

The concentration that evoked a 30 % depression in the recorded activity in rats was determined to be 1600 ppm (= approx. 5.85 mg/L) after pentan-1-ol exposure. In the same study, the concentration that evoked a 30 % depression in the recorded activity in female H strain mice was 2600 ppm (= approx. 9.55 mg/L) after pentan-1-ol exposure (Frantík et al. 1994).

 

The loss of the righting reflex of Swiss Webster mice after a single intraperitoneal injection of pentan-1-ol in corn oil was investigated by Lyon et al. (1981). The concentration of 336.3 mg/kg bw was found to be the ED50 (effective dose that causes loss of righting reflex in 50 % of treated animals).

 

As further information a publication (Silver 1992) is available in which the potential of several volatile chemicals including pentan-1-ol to produce nasal irritation based on neural stimulation is described. The characteristics of responses of nasal trigeminal receptors to volatile chemicals were studied by recording electrophysiological responses from the rat ethmoid nerve. High concentrations of the stimulus elicited responses with an initial phasic component followed by a steady state tonic level. Low concentrations often produced a gradual increase in activity that last for the duration of the stimulus. The concentration (ppm) that first elicits a response larger than baseline is reported as the threshold. Responses at all concentrations rapidly returned to baseline levels after removal of the stimulus. A maximum response is the response to a saturated stimulus or the response at which the concentration-response curve began to plateau. This response is reported as a percentage of the response to the standard stimulus (approx. 550 ppm cyclohexanone). For pentan-1-ol, a discrimination dose of 59 ppm (0.22 mg/L air) was determined.The maximum response is 48 % compared to the response to cyclohexanone.

 

To summarize, the available study data do not give any indication on neurotoxicity. Although effect levels were determined regarding selected, but isolated behavioural parameters (Maickel & Nash Jr. 1985, Lyon et al. 1981, Frantík et al. 1994), these effects were not persistent and do not extend the knowledge about toxic effects obtained in acute and repeated dose toxicity studies.

 

In a combined repeated-dose / reproductive developmental toxicity study according to OECD TG 422 in rats treated orally with 3-methylbutan-1-ol at doses of 30, 100, and 300 mg/kg bw detailed clinical observations, manipulative tests and measurement of grip strength and motor activity were performed after an administration period of at least 39 days (see Chapter “Repeated Dose Toxicity”). Concerning the examined behavioural parameters no abnormalities in any animal in the main groups or in the recovery group were noted (Kuraray Co. Ltd. 2008).

  

Thus, based on the available data, pentan-1-ol was reported to cause transient effects indicative for CNS depression after acute and repeated test substance application which is a common effect of solvents at higher concentrations. These narcotic effects were not observed in an OECD TG 422 compliant study conducted with the structural analogue 3-methylbutan-1-ol. 

In summary, pentan-1-ol and its structural analogues do not exhibit selective or cumulative neurotoxicity in laboratory animals. Classification regarding neurotoxicity or CNS depression after inhalation exposure, STOT single exposure, Cat. 3 (for narcotic effects) according to 1272/2008/EC (CLP) criteria, is not considered necessary due to the minor degree and transient character of the observed effects.

 

 

 


Justification for selection of effect on neurotoxicity via oral route endpoint:
reliable publication describing an acute study

Justification for selection of effect on neurotoxicity via inhalation route endpoint:
reliable publication describing an acute study

Justification for classification or non-classification

The available data are considered reliable and suitable for classification purposes under Regulation (EC) No 1272/2008 (CLP).

As a result, the substance is not considered to be classified for neurotoxicity under Regulation (EC) No 1272/2008, as amended for the seventh time in Regulation No (EC) 1297/2014.