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Neurotoxicity

Description of key information

Toluene exposure can produce central nervous system pathology in animals after high oral doses. In an 8 -day inhalation study, rats exposed to high toluene levels (7000 ppm) showed significantly decreased hippocampal neurogenesis, which persisted until the 8th and final day of measurement (Yoon, 2015). However, abnormal neurological signs that were observed after toluene exposure disappeared within 24h.

Repeated dose inhalation studies (Slomianka 1990 and 1992; Huang 1992; Korbo 199; Ladefoged 1991; von Euler G 1993, 1994 and 2000) 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 region 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) hinders any definitive conclusions on reliable NOAEC and LOAEC levels.

Repeated inhalation studies discussed in section 7.5 suggested that toluene exposure can produce ototoxicity in the rat and high concentrations are associated with local toxicity (nasal erosion). In humans neuropsychological effects and disturbances of auditory function and colour vision have been reported, particularly when exposures are not well controlled and/or associated with noisy environments. The NOAEC for subchronic oral toxicity in rats is 625 mg/Kg/day based on neuropathology (Huff, 1990). The NOAEC for inhalation toxicity in the rat is 300 ppm (1131 mg/m3) based on effects on body weight, mortality and adverse local effects (nasal erosion) (Gibson and Hardisty, 1983). The NOAEC for neuropsychological effects, auditory dysfunction and disturbances of colour vision in humans is 26 ppm (98 mg/m3) (Seeber et al, 2004); Schaper et al, 2003, 2004).

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. Consequently human data will be used for DNEL determination.

SCOEL concluded there was a great deal of human data demonstrating no reliable evidence of neurological effects or mucosal irritation at or below 50 ppm (192 mg/m3), hence 50 ppm was an appropriate level for an 8 hr TWA.

Additional information

Ahmed et al. (2007) and Bale et al. (2007) found that exposure to toluene increased NMDA receptor subunit expression together with simultaneous induction of genes involved in regulation of the NMDA receptor in the adult female mouse hippocampus as well as suggested an interaction of toluene with the NMDA receptor. Additionally, Gotohda et al. (2007) found that sub-acute inhalation exposure to 1500 ppm toluene damages neurons in the spinal cord and decreases production of neurotrophic factors, while a study by Win-Shwe (2007) found that following a sub-acute exposure up to 9 ppm toluene vapour for 4 weeks resulted in recruitment of peripheral T cells in the hippocampus of wild type mice, which may be involved in the up-regulation of memory-related genes. Another study by Win-Shwe et al. (2007), O’Leary-Moore et al. (2007) and Liu et al. (2007) studies found that intraperitoneal injection as well as acute high levels of toluene vapour are associated with significant changes in glutamate and GABA as well as GABA-A receptor levels in the mouse and rat hippocampi.

In a sub-acute exposure study to high concentrations of toluene vapour (2000-8000 ppm), increases in spontaneous locomotor behaviour in rats in a manner that is dependent on postnatal age and sex of the animal were observed (Bowen, 2007). In addition, Armenta-Resendiz et al. (2019) found that toluene (2000 to 8000 ppm) produces anxiolytic-like effects and antinociception, impair memory, and diminish social interaction in male rats exposed. However, Beasley et al. (2010) found very limited evidence for persistent effects of repeated inhaled toluene exposure (up to 1000ppm for 13 weeks) on cognitive function in male and no support for changes in spontaneous motor activity, anxiety, or fear conditioning.

In humans neuropsychological effects have been reported, particularly when exposures are not well controlled. There was no evidence that long-term exposure to toluene at 26 ppm for 21 years had any effects on cognitive function (Seeber et al, 2004).

Justification for classification or non-classification

Distillates (Petroleum), steam-cracked, dimerised (C5-12, C10-rich) contains less than 10% toluene and does not require classification for this endpoint.