Toluene

Endpoint summary

Description of key information

Toluene is absorbed rapidly via inhalation (approximately 50% uptake). Dermal absorption of liquid toluene, as predicted using a two stage model (permeation of the stratum corneum followed by transfer from the stratum corneum to the epidermis) is characterised by a maximum flux of 0.0000581 mg/cm2/min giving a dermal absorption value of approximately 3.6% of the applied dose. Oral uptake is estimated to be complete (100% of the dose). Once absorbed, toluene is distributed systemically with the amount present in body tissues reflecting the tissue/blood partition coefficient, the duration and level of exposure, and the rate of elimination. Around 80% of an absorbed dose of toluene is metabolised in the liver by the P450 system, mainly via benzyl alcohol and benzaldehyde to benzoic acid. Benzoic acid is conjugated with glycine and excreted in the urine as hippuric acid. Elimination of unchanged toluene is rapid, with around 20% of an absorbed dose eliminated via expired air. Within a few hours after termination of exposure, blood and alveolar air contain very little toluene, with most toluene eliminated from fat after 12 hours.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

3.6

Absorption rate - inhalation (%):

50

Additional information

LOA is currently reviewing the human and animal data supporting Human Health for Toluene. It is expected to be completed by Q4 2020.

Absorption

The major uptake of toluene vapour is through the respiratory system. Toluene is absorbed rapidly via inhalation and the amount absorbed (approximately 50%) depends on pulmonary ventilation. Studies in humans (e.g. Carlsson and Lindqvist, 1977) have shown that at rest a three-hour exposure to toluene vapour will result in an uptake amounting to approximately 50% of the inhaled toluene. Data from experimental exposure of volunteers show that physical work results in increased toluene uptake (Carlsson, 1982). Using a 50 W workload, exposure to 300 mg/m³(80 ppm) toluene for 2 hours toluene uptake was 2.4 times higher than the uptake at rest. In rats during a 3 hour exposure to 575 ppm (2167 mg/m³) blood and brain toluene levels reached estimated asymptotic levels in 53 and 58 minutes, respectively (Benignus et al, 1981).

Toluene is almost completely absorbed from the gastrointestinal tract.

Distribution

Toluene is distributed to various tissues, the amount depending on the tissue/blood partition coefficient, the duration and level of exposure, and the rate of elimination. 

Metabolism

Biotransformation of toluene occurs mainly by oxidation. The endoplasmic reticulum of liver parenchymal cells is the principal site of oxidation which involves the P450 system. Analysis of blood and urine samples from workers and volunteers exposed to toluene via inhalation in concentrations ranging from 100 to 600 ppm (377-2,261 mg/m³) indicate that of the biotransformed toluene, ~ 99% is oxidised via benzyl alcohol and benzaldehyde to benzoic acid. The remaining 1% is oxidised in the aromatic ring, forming ortho-, meta- and para-cresol (Woiwode and Drysch, 1981).

Elimination

In the rat, elimination of toluene is rapid with most toluene eliminated from fat after 12 hours. Within a few hours after termination of exposure the blood and alveolar air contains very little toluene. A proportion (around 20%) of the absorbed toluene is eliminated in the expired air. The remaining 80% of the absorbed toluene is metabolised in the liver by the P450 system, mainly via benzyl alcohol and benzaldehyde to benzoic acid. Benzoic acid is conjugated with glycine and excreted in the urine as hippuric acid.

Dermal absorption

The capability of liquid toluene to penetrate the skin was investigated in isolated rat skin (Tsurutu, 1982). At steady state, a penetration of 8.5 nmol/cm²min (0.78 µg/cm²min) was determined indicating that dermal uptake occurs to a very limited degree. In five volunteers exposed to toluene by immersing a hand up to the wrist in liquid toluene for 30 minutes, maximum concentrations of toluene in blood (0.17 mg/L) were found 30 minutes after start of the exposure. The maximum blood toluene concentration was maintained for 10-15 minutes after exposure had ended and was a quarter of that achieved in a 2 hour inhalation exposure to 100 ppm (377 mg/m³) toluene vapour (Sato and Nakajima, 1978). These results demonstrate that liquid toluene can be absorbed through the skin.

Dermal absorption of liquid toluene was predicted using a model which considers absorption as a two stage process, permeation of the stratum corneum followed by transfer from the stratum corneum to the epidermis (ten Berge, 2009). The QSAR for each process was derived by fitting each model equation to experimentally derived values using an iterative non-linear least squares approach. Dermal flux and percent absorption were predicted using physicochemical values (see section 4) determined at approximately 25°C. The model predicted a maximum flux of 0.0000581 mg/cm²/min giving a dermal absorption value of approximately 3.6% of the amount applied as liquid toluene.

Dermal absorption from toluene vapours is not likely to be an important route of exposure.