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Neurotoxicity

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Description of key information

Acute exposures to high doses of 1,2,4-trimethylbenzene and other trimethylbenzene isomers indicate effects consistent with general CNS depression (reduced pain responses and locomotor co-ordination) in animals. Although there are a number of repeated dose inhalation studies in rats investigating neurotoxic effects, weaknesses in study design (i. e. only one sex evaluated, lack of dose response information, non-standard methods, lack of GLP) hinders any definitive conclusions on reliabity of the findings. No evidence of acute effects in humans were reported to at 120mg/3 in a volunteer study.  Overall there is no reliable evidence that 1,2,4 trimethylbenzene is neurotoxic.

Key value for chemical safety assessment

Additional information

Animal data

In a study to assess the potential for acute central nervous system effects, Korsak and Rydzynski (1996) evaluated the effects of acute exposure of 1,2,4-trimethylbenzene (>97% pure) in male Wistar rats. Rats were exposed to concentrations of 1227-9816 mg/m3 for 4 h. Acute central nervous system effects were assessed by measuring rotarod performance and pain sensitivity (the time until a paw-lick response when placed on a hot-plate) immediately following a 4 hour exposure. Acute exposures to all three TMB isomers caused concentration-dependent disturbance in rotarod performance of rats with an EC50 of 4920mg/m3 for 1,2,4-trimethylbenzene. Reduced pain response, as measured by increased paw-lick response latency, was also affected by in a concentration-dependent manner with an EC50 value of 5682 mg/m3. The data do not allow a NOAEC to be calculated.

Male Wistar rats exposed by inhalation to 5,000 mg/m3 1,2,4 -trimethylbenzene exhibited small but statistically significant effects on latency to response with a reduced frequency of short latencies and an increased frequency of long latencies to response (McKee et al., 2010). These effects were greater after one 8-hour exposure than after three consecutive daily 8-hour exposures, which correlated with the brain concentrations of 1,2,4 -trimethylbenzene also being higher after the first exposure than after the third exposure.

Several subchronic inhalation studies and one 12-month study have been conducted using trimethylbenzene isomers and C9 aromatic hydrocarbon solvents. At high exposure concentrations no significant clinical signs indicative of specific CNS activity have been reported. At lower concentrations, some possible neurological effects have been reported by Korsak and Rydzynski (1996), Gralewicz and Wiaderma (2001) and Gralewicz et al (1997). These studies used relatively low concentrations and examined animals using a variety of specific behavioural test methodology (e.g. rotarod performance, paw lick response to heat, radial maze performance, spontaneous activity, active and passive avoidance and spontaneous cortical spike wave discharges). However, weaknesses in study design (i. e. only one sex evaluated, lack of coherent dose response relationships, non-standard methods, lack of GLP) hinder any definitive conclusions on reliable NOAEC and LOAEC levels. In a subchronic inhalation study on high flash aromatic naphtha conducted according to EPA neurotoxicity screening battery guidelines no evidence of neurotoxicity was seen (Douglas et al, 1993). In particular a careful examination of the nervous system revealed no evidence of neuropathology.

Human data

In a well conducted study, Jarnberg et al (1996) assessed the toxicokinetics of inhaled trimethyl benzenes in man. Ten male volunteers were exposed to 120 mg/m3of 1,2,4-TMB for 2 hours in an exposure chamber at a constant work load of 50 W on an ergometer bicycle. Before, during and after exposure the subjects rated symptoms on a 100-mm visual analog scale graded from "no effect at all" to "almost unbearable" comprised central nervous system (CNS)-related symptoms: (i) headache; (ii) fatigue; (iii) nausea; (iv) dizziness and (v) intoxication. No central nervous system effects were reported, with 120 mg/m3 (the highest dose tested) being concluded to be a NOAEC for acute neurotoxic effects.

There is no clear evidence that 1,2,4 -trimethylbenzene has specific neurotoxic activity.

Justification for classification or non-classification

Data in animals and humans provide no definitive evidence of neurotoxicity and no specific labelling is required for this end-point.