Norflurane

Neurotoxicity

Description of key information

In two neurological studies on 1,1,1,2-tetrafluoroethane (HFC 134a) there were no significant effects on neurological endpoints. In an operant behaviour study there were no adverse effects on the neurobehavioural endpoints studied at concentrations upto 100000ppm.

Additional information

Alpk:ApfSD Wistar-derived rats (5/sex/group) were exposed to HFC-134a at target concentrations of 0, 150,000 or 200,000 ppm (0, 625,000, 834,000 mg/m3) for 1 to 2 hours. Further groups of 5 male or female rats were pre-treated with ethanol and were subsequently exposed to air or 150,000 ppm (1.0 g ethanol/kgbw) or 200,000 ppm (5.0 g ethanol/kgbw) HFC-34a for 1 to 2 hours. A neurological examination was conducted on each rat before treatment and a quantitative assessment of sensory perception (tail flick test) was performed on each animal approximately 1 hour after the initiation of exposure. No evidence of neurological dysfunction was observed in any of the treated groups, with or without pre-treatment with ethanol. Female rats exposed to 200,000 ppm HFC-134a showed a small but statistically significant increase in tail flick time. This effect was not seen in male rats exposed to HFC-134a, with or without ethanol pre-treatment, nor in pre-treated female rats. The study showed that there were no significant additive or synergistic effects between ethanol and HFC-134a on the neurological system in the rat (Pinto 1998).

In another study,

Male Wistar rats (10/group) were exposed to HFC-134a or dichlorodifluoromethane (CFC-12) while performing in either a rotarod/motorized running wheel apparatus to steadily increasing concentrations of HFC-134a or CFC-12 for up to 30 minutes, to a maximum concentration of 470,000 ppm (1,960,000 mg/m3), with or without replacement oxygen. The times to loss of equilibrium, loss of hind limb function, loss of forelimb function and loss of righting reflex were measured. In rats exposed to HFC-134a, loss of equilibrium occurred after about 200 seconds, at which time the test atmosphere concentration had reached approximately 200,000 ppm. Loss of righting reflex occurred after about 800 seconds at 380,000 ppm. The replacement of oxygen had marginal effects on the times to effect, although it appeared to protect against convulsions that were seen in some rats exposed to either HFC-134a or CFC 12 without oxygen replacement. In a separate experiment, rats showed a rapid (60s) recovery from these acute CNS effects and no evidence of long-term neurological deficits was seen 30 days following exposure (Ritchie et al, 2001).

In an operant behaviour study, male Wistar rats (4/group) were exposed (15 min/d) to HFC-134a or CFC-12 concentrations increasing from 40,000 to 140,000 ppm (167,000 - 584,000 mg/m3) for 20 successive days. Behaviour was assessed by the number of food rewards earned by the subject during exposure following a standard schedule of training, The number of food rewards earned by rats exposed to 140,000 ppm HFC-134a, but not 100,000 ppm (417,000 mg/m3) and below, was significantly reduced when compared to controls. For the neurobehavioral endpoints examined, HFC-134a was shown to induce deficits at somewhat lower concentrations when compared to CFC-12 exposure (Richie et al, 2001).

Justification for classification or non-classification

In two neurological studies on HFC 134a there were no significant effects on neurological endpoints. In an operant behaviour study there were no adverse effects on the neurobehavioural endpoints studied at concentrations upto 100000ppm. Therefore classification for neurological effects is not warranted according to EU Directive 67/548/EEC and EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.