Registration Dossier

Diss Factsheets

Toxicological information

Endpoint summary

Currently viewing:

Administrative data

Description of key information

Toluene exposure can produce central nervous system pathology in animals after high oral doses. Repeated inhalation 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.  The NOAEC for inhalation toxicity in the rat is 300 ppm (1131mg/m3) based on effects on body weightand mortality, with a LOAEC for local effects (nasal errosion) of 2261 mg/m3.  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.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
625 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
The available data provide information that is adequate for the purpose of hazard assessment

Repeated dose toxicity: inhalation - systemic effects

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

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEC
2 261 mg/m³
Study duration:
chronic
Species:
rat
Quality of whole database:
The available data provide information that is adequate for the purpose of hazard assessment

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

The toxicity of toluene following repeated exposures was reviewed and reported in the EU RAR (2003). No additional relevant animal data have been found in the updated literature review.

Non-human information

Oral

Two key studies were identified, one in rats and one in mice (Huff, 1990). In both studies groups of 10 animals/sex received 0, 312, 625, 1250, 2500, or 5000 mg toluene/kg in corn oil by gavage for 13 weeks. Deaths were seen before termination of the study as follows: all rats and mice in the 5000 mg/kg groups within the first week; 8 male and 1 female rat, 4 male and 4 female mice at 2500 mg/kg; 1 female mouse at 1250 mg/kg. The final mean body weight of male rats and mice that received 2500 mg/kg was lower than that of vehicle controls. Clinical signs in both species included prostration, hypoactivity, ataxia, piloerection, lachrymation, and excessive salivation in the 5000 and 2500 mg/kg groups. There were no treatment related effects in the haematological and serum chemical analyses or urinalyses in either species.

In rats at 1250 and 2500 mg/kg there were differences in the weight of a number of organs and neuropathological changes in the brain, consisting of neuronal cell necrosis in the dentate gyrus and Ammons horn of the hippocampus. In addition to the hippocampal lesions, necrosis and/or mineralisation were present in the granular layer of the cerebellar cortex. Haemorrhage was present in the mucosa, sub-mucosa, or muscularis of the urinary bladder of males and females. At 625 mg/kg increases in absolute and relative liver and kidney weight, unaccompanied by histopathological findings, were interpreted as toxicologically non-significant effects. A dose of 312 mg/kg/kg did not cause any effects.

In mice, increases in absolute and/or relative liver weights in males at 1250 or 2500 mg/kg and in females at all doses were not accompanied by histopathological effect and, therefore, considered to be of no toxicological significance. Relative brain and testis weight, and absolute kidney weight was increased in male mice at 5000 mg/kg. Myocardial degeneration was found in 3 male and 2 female mice from this group.

The NOAEL for repeat dose oral toxicity is considered to be 625 mg/kg in rats and mice.

Dermal

No data have been identified.

Inhalation

Toluene toxicity via inhalation has been investigated in sub-chronic and chronic toxicity studies the rat and mouse. The key studies are considered to be the 15 week and chronic studies in rats (Gibson and Hardisty, 1983; Huff, 1990).

In a 15 week study in rats, rats were exposed via inhalation to 0, 100, 625, 1250, 2500, or 3000 ppm toluene 6.5 hours/day for 5 days/week (Huff, 1990). Eight male rats of the 3000 ppm group died during week 2. Treatment-related effects at 3000, 2500 and 1250 ppm included lower body weights, adverse clinical signs and differences in absolute or relative organ weights (particularly liver and kidney). Plasma cholinesterase activity decreased as exposure concentration increased, and the leukocyte count was decreased for female rats at 1250 ppm or higher. 625 ppm toluene was the NOAEC on the basis of a lower leukocyte count in females and increased relative liver and kidney weights at 1250 ppm and above.

In the chronic toxicity study using 600 or 1200 ppm toluene body weight was slightly lower than control at 1200 ppm during the second year of the study. No effects of toluene exposure were found on absolute and relative weight of kidney, liver or brain. The severity of nephropathy was slightly increased in exposed female rats. Results of haematological analyses did not indicate any substance-related effects. In the nasal cavity, mild to moderate degeneration of the olfactory and respiratory epithelium was more obvious in toluene-exposed rats and goblet cell hyperplasia somewhat increased. No other treatment-related lesions were observed. 600 ppm (2261 mg/m3) was the LOAEC for local toxicity and the NOAEC for systemic toxicity.

Supporting sub-chronic and chronic toxicity inhalation toxicity studies were conducted in B6C3F1 mice (Huff, 1990). Concentrations ≥ 625 ppm, 6h/day, 5 days per week for 15 weeks caused mortality but no other evidence of significant target organ toxicity.

The overall NOAEC for local effects and chronic toxicity can be derived from the chronic toxicity study of Gibson and Hardisty (1983). Fischer-344 rats were exposed to 0, 30, 100 or 300 ppm 6 h/day, 5 days/week for 6, 12, 18 or 24 months. There were no toxicologically significant effects on bodyweight, clinical signs, ophthalmoscopy, haematology, blood and urine clinical chemistry, organ weights or gross and microscopic pathology. The NOAEC for chronic systemic and local toxicity from this study was 300 ppm (1131 mg/m3) for an exposure duration of 18 months.

Special studies addressing neurotoxicity and ototoxicity (see CSR section 5.10) demonstrate that toluene is ototoxic in the rat and can produce neurochemical and pathological changes. However, the data are insufficient to determine NOAEC values. Therefore, the NOAEC of 300 ppm (1131 mg/m3) based on the study of Gibson and Hardisty (1983) will be taken forward to the risk characterisation.

Human information

Human data addressing a number of adverse effects associated with exposure to toluene are reviewed under the relevant section of the dossier (section 5.10). After repeated dose exposure via inhalation in humans toluene causes a number of adverse effects including neuropsychological effects, auditory dysfunction and disturbances of colour vision. Key data published since the EU RAR (2003) addressing these effects are those of Seeber et al (2004) and Schaper et al (2003, 2004). 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). There was no evidence of ototoxicity resulting from occupational exposure to toluene below 50 ppm (mean exposure 26 ppm / 98 mg/m3) in a longitudinal study over 5 years (Schaper et al, 2003). Similarly no effect of human occupational exposures to toluene on colour vision were found in a follow up study over 4 years with three repeated examinations (Schaper et al, 2004). These studies demonstrate that 26 ppm (98 mg/m3) is a NOAEC for human adverse effects.

When reviewing the effects of repeated human exposure to toluene vapour, SCOEL (2001) noted that concentrations 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. High concentrations of toluene vapour were also associated with symptoms of eye and upper respiratory tract irritation in human volunteers exposed to 75-100 ppm (286 – 383 mg/m3) for 4.5 – 6.5 hr, with the lower end of this range a threshold for mucous membrane irritation. Based on a great deal of human data indicating no reliable evidence of neurological effects or irritation at or below toluene concentrations of 50 ppm (192 mg/m3), SCOEL concluded that 50 ppm (8 hour TWA) was an appropriate level for an IOELV.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Two key sub-chronic oral studies were identified, one in rats and one in mice. The NOAEL (625 mg/kg) is based on neuropathological changes recorded in rats

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
Key studies are available that report the sub-chronic and chronic inhalation toxicity of toluene in rats (chronic NOAEC = 1131 mg/m3, based on neuropathy). Other animal studies demonstrate that toluene is ototoxic in the rat and can produce neurochemical and pathological changes. Human data (reported under Epidemiological studies) demonstrate no evidence that long-term exposure to toluene (98 mg/m3 for 21 years) adversely effects human neurological or cognitive function.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
Mild to moderate degeneration of the olfactory and respiratory epithelium was more obvious in toluene-exposed rats, and goblet cell hyperplasia somewhat increased, in rats exposed chronically to 2261 mg/m3 toluene vapour.

Repeated dose toxicity: via oral route - systemic effects (target organ) neurologic: other

Repeated dose toxicity: inhalation - systemic effects (target organ) neurologic: behaviour

Justification for classification or non-classification

After repeated dose exposure, toluene causes a number of adverse effects including impairment of auditory function and morphological evidence of cell loss in the rat cochlea, neuron loss in the central nervous system of animals and in humans neuropsychological effects, auditory dysfunction and effects on colour vision have been reported. Consequently, toluene is classified as Category 2 (H373), according to GHS / CLP.