2-ethoxy-2-methylpropane

Neurotoxicity

Description of key information

The available 28 day inhalation study with rats indicates that ETBE caused transient signs of CNS depression at 4000 ppm (16720 mg/m3). The NOAEC for transient signs of CNS depression in this study was 2000 ppm (8400 mg/m3).

Additional information

A neurotoxicity study with rats and mice has been conducted as a part of the 90-day repeated dose inhalation toxicity study of CIIT (1996a) (highest tested concentration 5000 ppm (21000mg/m3)). There were no gross macroscopic changes in brain or nervous tissue. The FOB evaluation found no evidence of sensorimotor dysfunction, neuromuscular dysfunction, ataxia, piloerection, excessive vocalization, muscle tremors or spasms, clonic or tonic seizures, increased salivation, abnormal respiration or abnormal pupil reflex.

Decreased mean hindlimb grip strength and increase in mean hindlimb splay were observed in low exposure group males at first exposure, with a statistically significant increase in mean forelimb grip strength in high exposure males on day 10. A statistically significant decrease in mean forelimb grip strength was observed in low dose females following 65 exposures. The absence of any consistent dose-related trend suggests these observations are of doubtful toxicological significance. There was no treatment-related effect on overall motor activity during any observation period.

No gross, functional or microscopic abnormalities were observed in males and female rats exposed to 5000 ppm (21000 mg/m3) ETBE vapour for up to 13 weeks.

Regarding the available 28 days inhalation study with rats (IIT Research Institute, 1991), ETBE caused transient signs of CNS depression. Signs of general sedation and reduced motor activity were noted in rats exposed to 4000 ppm (16720mg/m3) ETBE vapour, with some animals exhibiting mild to moderate ataxia. Complete recovery from these signs (i.e., sedation and ataxia) of CNS depression was observed within 15 minutes following exposure termination. Body temperature was reduced after the fifth exposure in the 4000 ppm males and a significantly different trend in hindlimb splay was observed in both males and females of the 4000 ppm exposure group. Both of these alterations were most likely associated with the residual effect of the sedation observed during exposure since the FOB was performed approximately one hour following exposure termination.

No other indications of CNS depression or neurotoxicity were observed in any of the other FOB parameters. Another treatment-related clinical sign included salivation.

The NOAEC for transient signs of CNS depression in this study was 2000 ppm (8400 mg/m3).

Justification for classification or non-classification

The available 28 day inhalation study with rats indicates that ETBE caused transient signs of CNS depression at 4000 ppm (16720 mg/m3). Based on these effects, ETBE has to be labelled with R67 (Vapours may cause drowsiness and dizziness) in accordance with Directive 67/548/EEC.

According to the EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008, ETBE should be classified for Specific Target Organ toxicity – Single exposure, Cat. 3 (H336).