Toluene

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

other: Composite record

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Non guideline, non-GLP studies contributing to a weight of evidence.

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Toluene levels in blood and brain of rats after respiratory exposure

Author:

Benignus VA, Muller KE, Barton CN and Bittikofer JA

Year:

1981

Bibliographic source:

Toxicology and Applied Toxicology, 61, 326-334.

Reference 2

Reference Type:

publication

Title:

Differences following skin or inhalation exposure in the absorption and excretion kinetics of trichloroethylene and toluene

Author:

Sato A, Nakajima T

Year:

1978

Bibliographic source:

Br. J. Ind. Med. 35, 43-49.

Reference 3

Reference Type:

publication

Title:

Exposure of animals and man to toluene.

Author:

Carlsson A, Lindqvist T

Year:

1977

Bibliographic source:

Scand. J. Work. Environ. Health 3, 135- 143.

Reference 4

Reference Type:

publication

Title:

Percutaneous absorption of organic solvents. III. On the penetration rates of hydrophobic solvents through the excised rat skin.

Author:

Tsuruta H

Year:

1982

Bibliographic source:

Ind. Health 20, 335-345

Reference 5

Reference Type:

publication

Title:

Toluene risk assessment report

Author:

EU RAR

Year:

2003

Bibliographic source:

European Union Risk Assessment Report, Volume 30

Reference 6

Reference Type:

publication

Title:

Toluene toxicological profile

Author:

ASTDR

Year:

2000

Bibliographic source:

US Dept Health and Human Services

Materials and methods

Objective of study:

toxicokinetics

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

The data for toxicokinetics, metabolism and distribution of toluene conform with the requirements of Annex VIIA of Directive 67/548/EEC

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Toluene

EC Number:

203-625-9

EC Name:

Toluene

Cas Number:

108-88-3

Molecular formula:

C7H8

IUPAC Name:

toluene

Radiolabelling:

no

Test animals

Species:

rat

Strain:

other: various

Administration / exposure

Route of administration:

other: Oral, dermal and inhalation

Vehicle:

unchanged (no vehicle)

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

Oral ~100%; Inhalation ~50% (dependent upon pulmonary ventilation); Dermal (in vitro rat skin, liquid toluene) 8.5 nmol/cm2min (0.78µg/cm2min)

Main ADME results 2

Type:

distribution

Results:

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.

Main ADME results 3

Type:

metabolism

Results:

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

Main ADME results 4

Type:

excretion

Results:

About 20% of the absorbed toluene is eliminated via the lungs in expired air. The remainder is rapidly metabolised in the liver and excreted as conjugated metabolites in the urine (mainly as hippuric acid).

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Toluene is almost completely absorbed following oral exposure although uptake is more rapid following inhalation. The major uptake of toluene vapour is through the respiratory system and the amount absorbed (approximately 50%) depends on pulmonary ventilation. Liquid toluene can be absorbed through the skin to a limited degree. Skin penetration was investigated in isolated rat skin. At steady state, a penetration rate of 8.5 nmol/cm2min (0.78µg/cm2min) was determined (Tsuruta, 1982). Dermal uptake from toluene vapours is not likely to be an important route of exposure. 

Details on distribution in tissues:

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.

Any other information on results incl. tables

The major uptake of toluene vapour is through the respiratory system. In rats during a 3h exposure to 575 ppm (2,167 mg/m3) blood and brain toluene levels reached estimated asymptotic levels in 53 and 58 minutes, respectively (Benignus et al, 1981). Liquid toluene can be absorbed through the skin. Skin penetration was investigated in isolated rat skin. At steady state, a penetration of 8.5 nmol/cm²min (0.78µg/cm²min) was determined (Tsuruta, 1982). In conclusion, dermal uptake after skin exposure to liquid toluene occurs to a limited degree. Dermal exposure to toluene vapours is not likely to be an important route.

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.

Applicant's summary and conclusion

Conclusions:

Toluene is absorbed rapidly from the lung (approximately 50% absorbed), but uptake from skin exposure is limited. Toluene is readily metabolised, mainly to benzoic acid. A proportion of around 20% of absorbed toluene is eliminated in expired air and the remaining 80% is metabolised and excreted in the urine.

Executive summary:

Toluene is absorbed rapidly via inhalation and the amount absorbed (approximately 50%) depends on pulmonary ventilation. The capability of liquid toluene to penetrate the skin was investigated in isolated rat skin. At steady state, a penetration of 8.5 nmol/cm²min (0.78µg/cm²min) was determined indicating that dermal uptake occurs to a very limited degree. Dermal exposure to toluene vapours is not likely to be an important route. 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. 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. There are no indications of particular species differences in the toxicokinetics, metabolism or distribution of toluene.