Toxicity Profiles
Toxicity Summary for TOLUENE
NOTE:
Although the toxicity values presented in these toxicity profiles
were correct at the time they were produced, these values are subject to change.
Users should always refer to the
Toxicity Value Database
for the current toxicity values.
JANUARY 1994
Prepared by: Rosmarie A. Faust, Ph.D., Chemical Hazard Evaluation Group, Biomedical and
Environmental Information Analysis Section, Health Sciences Research Division, Oak Ridge
National Laboratory*, Oak Ridge, Tennessee.
Prepared for: Oak Ridge Reservation Environmental Restoration Program.
*Managed by Martin Marietta Energy Systems, Inc., for the U.S. Department of Energy under
Contract No. DE-AC05-84OR21400.
Toluene is a colorless liquid widely used as raw material in the production of organic
compounds and as a solvent (EPA, 1990). It is readily absorbed from the gastrointestinal and
respiratory tracts and, to a lesser degree, through the skin. Toluene is distributed throughout the
body, with accumulation in tissues with high lipid content. It is metabolized in the liver, primarily
to hippuric acid and benzoyl glucuronide, compounds that are rapidly excreted in the urine (EPA,
1990; ATSDR, 1989).
In humans and animals, the primary effect associated with inhalation exposure to toluene is
central nervous system (CNS) depression. Short-term exposure of humans to 100-1500 ppm has
elicited CNS effects such as fatigue, confusion, incoordination, and impairments in reaction time,
perception, and motor control and function (NTP, 1990). Exposure to concentrations ranging from
10,000-30,000 ppm has resulted in narcosis and deaths (WHO, 1985). Prolonged abuse of toluene
or solvent mixtures containing toluene has led to permanent CNS effects. Exposure to high
concentrations of toluene (1500 ppm) has produced hearing loss in rats (Pryor et al., 1984).
Hepatomegaly and impaired liver and kidney function have been reported in some humans
chronically exposed to toluene (Askergren, 1984; Szilard et al., 1978; Greenburg et al., 1942).
Toluene vapors may cause eye irritation (Andersen et al., 1983), and prolonged or repeated dermal
contact may produce drying of skin and dermatitis (ATSDR, 1989; NIOSH, 1973).
In experimental animals, subchronic inhalation exposure to 2500 ppm toluene resulted in
increased liver and kidney weights (rats and mice), increased heart weights (rats), increased lung
weights, and centrilobular hypertrophy of the liver (mice) (NTP, 1990). Chronic inhalation
exposure to 600 or 1200 ppm for 2 years produced degeneration of olfactory and respiratory
epithelia of rats and minimal hyperplasia of bronchial epithelia in mice (NTP, 1990).
Subchronic oral administration of toluene at doses ranging from 312 to 5000 mg/kg/day produced
clinical signs of neurotoxicity at 2500 mg/kg in rats and mice. Other effects observed at higher
doses in rats included increased relative liver, kidney, and heart weights (females only) and
necrosis of the brain and hemorrhage of the urinary bladder (NTP, 1990).
Equivocal evidence shows that exposure to toluene in utero causes an increased risk of CNS
abnormalities and developmental delay in humans (Goodwin, 1988; Hersh et al., 1985; Holmberg,
1979). Animal studies, in which toluene was administered by inhalation, showed that exposure
results in fetotoxicity and delayed skeletal development but does not cause internal or external
malformations in rats (Courtney et al., 1986; Litton Bionetics, 1978). An oral study noted an
increased incidence of embryonic deaths, cleft palate, and maternal toxicity in mice administered
1 mL/kg toluene during gestation (Nawrot and Staples, 1979).
An oral reference dose (RfD) of 2 mg/kg/day for subchronic exposure (EPA, 1993) and
0.2 mg/kg/day for chronic exposure (EPA, 1992) to toluene was calculated based on a no-observed-adverse-effect level (NOAEL) of 223 mg/kg/day and a lowest-observed-adverse-effect
level (LOAEL) of 446 mg/kg/day from a 13-week subchronic gavage study in rats (NTP, 1990).
Increased liver and kidney weights in males were identified as the critical effects. A subchronic
(EPA, 1993) and chronic inhalation reference concentration (RfC) of 0.4 mg/m3 (EPA, 1992) was
calculated based on results of a battery of neurological tests with occupationally exposed female
subjects (Foo et al., 1990).
An increased incidence of hemolymphoreticular neoplasms was reported in rats exposed to 500
mg/kg of toluene by gavage for 2 years (Maltoni et al., 1985); however, results from two long-term inhalation studies (NTP, 1990; Gibson and Hardisty, 1983) indicate that toluene is not
carcinogenic at concentrations up to 1200 ppm. Based on U.S. Environmental Protection Agency
(EPA) guidelines, toluene was assigned to weight-of-evidence group D, not classifiable as to
human carcinogenicity (EPA, 1992).
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