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Toxicological information

Neurotoxicity

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Description of key information

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 reliable NOAEC and LOAEC levels. Neuropsychological effects in humans are reported to occur with high occupational exposure.  The LOAEC for psychological and cognitive effects in human above 59 ppm (222 mg/m3).  The availability of a great deal of human data indicated to SCOEL no reliable evidence of neurological effects at or below toluene concentrations of 50 ppm (192 mg/m3). It can be concluded that long-term occupational exposure of toluene at concentrations below the occupational exposure limit of 50 ppm (192 mg/m3) has no effect on psychological performance.

Key value for chemical safety assessment

Effect on neurotoxicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no study available

Effect on neurotoxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEC
222 mg/m³
Species:
other: human
Quality of whole database:
The available data provide information that is adequate for the purpose of hazard assessment

Effect on neurotoxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Non-human information

Repeated dose inhalation studies in rats have shown that toluene may cause a possibly transient reduction in the volume of hippocampal structures during postnatal development, neuron loss in the regio inferior of the hippocampus, reduction in the weight of the hippocampus, transient cognitive impairment in Morris maze, and changes in neurotransmitters and other neurochemical parameters. However, weaknesses in study design (i.e. only one sex evaluated, lack of dose response information, non-standard methods, lack of GLP) hinder any definitive conclusions on reliable NOAEC and LOAEC levels. More recent studies (Beasley et al., 2010) showed very limited evidence for persistent effects of repeated inhaled toluene exposure on cognitive function in rats. Consequently human data will be used for DNEL determination.

Human information

Acute exposures to toluene have been shown to produce neurological effects such as sleepiness, ataxia, confusion and neurobehavioural and neuropsychological effects. There are data from human toluene abusers that serious neurological effects such as tremor, ataxia, and memory impairment may occur with repeated extremely high level exposures. Several occupational exposure studies have also reported neurological effects as a consequence of occupational exposures although accurate data characterising exposures and hence allowing determination of NOAEC are generally lacking. The recent study by Seeber et al (2004) is considered to be the key study for risk characterisation. In that investigation, employees (total of 192) from 14 magazine rotary printing plants were classified into groups of "high" (printing area) vs "low" (end-processing) and "short" vs "long" exposure. Attention (symbol digit substitution, switching attention, simple reaction), memory (digit span forward and backwards, immediate and delayed reproduction of pictures), and psychomotor functions (steadiness, line tracing, aiming, tapping, peg board) were measured as dependent variables. There was no evidence that long-term exposure to toluene at 59 ppm for 21 years had any effects on cognitive function. Evidence for psychological performance effects due to long-term toluene exposure below 50 ppm could not be proved. A human NOAEC was not determined and the LOAEC was considered to be above 59 ppm (222 mg/m3).

SCOEL noted that toluene exposures in the range 90-150 ppm (345-575 mg/m3) for several hours lead to decrements in neurological test results although some of the findings were difficult to interpret due to uncertainties regarding the relationship between the effects monitored and contemporary / past levels of exposure. However the availability of a great deal of human data indicated no reliable evidence of neurological effects at or below toluene concentrations of 50 ppm (192 mg/m3).


Justification for selection of effect on neurotoxicity via inhalation route endpoint:
Studies on human toluene abusers have shown that serious neurological effects (tremor, ataxia, memory impairment) may occur following repeated extremely high level exposures, however no comparable deficits were present in workers exposed to average toluene levels of 59 ppm for an average of 21 years. A human NOAEC was not determined for this occupational population, however the long-term LOAEC was considered to be above 59 ppm (222 mg/m3)

Justification for classification or non-classification

After repeated dose exposure, toluene causes a number of adverse neurological effects including neuron loss in the central nervous system of animals and neuropsychological effects in humans. Consequently, toluene is classified as Category 2 (H373), according to GHS / CLP.