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EC number: 202-436-9
CAS number: 95-63-6
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.
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.
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.
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.
Data in animals and humans provide no
definitive evidence of neurotoxicity and no specific labelling is
required for this end-point.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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