The Risk Assessment Information System

Toxicity Profiles

Formal 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.

EXECUTIVE SUMMARY
1. INTRODUCTION
2. METABOLISM AND DISPOSITION: 2.1 ABSORPTION 2.2 DISTRIBUTION 2.3 METABOLISM 2.4 EXCRETION
3. NONCARCINOGENIC HEALTH EFFECTS: 3.1 ORAL EXPOSURES 3.2 INHALATION EXPOSURES 3.3 OTHER ROUTES OF EXPOSURE 3.4 TARGET ORGANS/CRITICAL EFFECTS
4. CARCINOGENICITY: 4.1 ORAL EXPOSURES 4.2 INHALATION EXPOSURES 4.3 OTHER ROUTES OF EXPOSURE 4.4 EPA WEIGHT-OF-EVIDENCE 4.5 CARCINOGENICITY SLOPE FACTORS
5. REFERENCES

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.

EXECUTIVE SUMMARY

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).

1. INTRODUCTION

Toluene (C₆H₅CH₃; CAS No. 108-88-3), also known as methylbenzene and phenylmethane, is a colorless liquid with a sweet pungent odor (HSDB, 1992). It has a molecular weight of 92.15, a density of 0.8669 g/mL at 20C, and an octanol/water partition coefficient of 2.79 (Lide, 1991; Mabey et al., 1982). Toluene is isolated by distillation of reformed or pyrolized petroleum and coal tar; however, most of the toluene produced remains as a benzene-toluene-xylene (BTX) mixture for use in gasoline. The primary use of isolated toluene is in the production of benzene and for backblending into gasoline to increase octane ratings (EPA, 1990). Toluene is also used as raw material in the production of benzyl chloride, benzoic acid, phenol, cresols, vinyl toluene, TNT, and toluene diisocyanate (U.S. Air Force, 1989); as a solvent for paints and coatings; and in adhesives, inks, and pharmaceuticals (EPA, 1990).

Inhalation is the primary route of toluene exposure for the general population and for occupationally exposed individuals. Evaporation of gasoline and automobile exhaust is the largest source of toluene in the environment, and industries that use toluene as a solvent are the second largest source (EPA, 1984). Toluene is also a common indoor contaminant due to releases from common household products and from cigarette smoke (ATSDR, 1989). Nonatmospheric releases of toluene are relatively small (e.g., to water and soil) and are estimated to comprise less than 1% of total toluene releases (ATSDR, 1989). In the atmosphere, toluene is degraded by reaction with hydroxyl radicals, with a typical half-life of about 13 hours. It is highly volatile, and volatilization is likely to be the predominant removal process from soil and water. Toluene is also subject to microbial degradation. Because of volatilization and biodegradation, toluene levels in the environment are not expected to increase over time (EPA, 1990; ATSDR, 1989).

2. METABOLISM AND DISPOSITION

2.1. ABSORPTION

Toluene is readily absorbed from the respiratory and gastrointestinal tracts and, to a lesser extent, through the skin. Animal studies suggest that absorption from the gastrointestinal tract is complete. Absorption data for humans and animals indicate that pulmonary absorption is 85-90% during brief exposures but nearer to 50% during extended exposures (< 1 hour). In humans, toluene has been detected in the arterial blood within 10 seconds after initiation of inhalation exposures; exercise greatly increases the absorption of toluene (EPA, 1990). Cutaneous absorption is approximately 1% of that absorbed by the lungs when there is exposure to the vapor; however, dermal absorption of the liquid may be higher. Because toluene evaporates readily, it is unlikely that significant absorption will occur by this route.

2.2. DISTRIBUTION

Distribution of toluene following absorption occurs throughout the body, with accumulation in adipose tissue, other tissues with high fat content, and highly vascular tissues. High levels of toluene were found in the brain and liver of an individual who had died following an episode of glue sniffing (Paterson and Sarvesvaran, 1983). Autoradiography studies using mice indicate that immediately after inhalation exposure, a high level of radioactivity is present in the body fat, bone marrow, spinal nerves, spinal cord, and white matter of the brain. Radioactivity was also observed in the blood, kidney, and liver but at lower levels (Bergman, 1979). In one individual who died 30 minutes after ingestion of toluene, the liver had the highest concentration of toluene, followed by the pancreas, brain, heart, blood, body fat, and cerebrospinal fluid (Ameno et al., 1989). Since retention time of toluene is usually considered to be less than 24 hours, bioaccumulation of toluene is unlikely (EPA, 1990).

2.3. METABOLISM

The initial step in toluene metabolism is side-chain hydroxylation to benzyl alcohol by P-450 enzymes in the liver, followed by oxidation to benzaldehyde by alcohol dehydrogenase and subsequently to benzoic acid by aldehyde dehydrogenase. Benzoic acid is then conjugated with glycine to form hippuric acid, the major urinary metabolite. Benzoic acid can also react with glucuronic acid to form benzoyl glucuronide (ATSDR, 1989). Ring hydroxylation to o- and p-cresol is considered a minor metabolic pathway (EPA, 1990).

2.4. EXCRETION

Toluene excretion in humans and animals is dose-dependent and clearance from the body is rapid. Toluene is primarily excreted in the urine as the metabolite, hippuric acid, which accounts for 60-70% of absorbed toluene. Excretion of hippuric acid is usually complete within 24 hours after exposure. The glucuronide conjugate of benzoic acid excreted in the urine represents

10-20% of absorbed toluene. Elimination of unchanged toluene by the lungs and possibly by the skin may also account for 10-20% of the absorbed dose (EPA, 1990).

3. NONCARCINOGENIC HEALTH EFFECTS

3.1. ORAL EXPOSURES

3.1.1. Acute Toxicity

3.1.1.1. Human

Ingestion of approximately 60 mL toluene was fatal to a male mental patient, with death occurring within 30 minutes of ingestion (Ameno et al., 1989). Autopsy results showed constriction and necrosis of myocardial fibers, a markedly swollen liver, congestion and hemorrhage of the lungs, and acute tubular necrosis. Severe depression of CNS function was thought to be the probable cause of death.

3.1.1.2 Animal

The acute oral toxicity of toluene in rats appears to be age-dependent. For adult rats, the reported LD₅₀ values range from 5.5 to 7.3 g/kg. For younger adult, 14-day-old, or newborn rats, the LD₅₀ values are 5.3-5.9, 2.6, or <1 g/kg, respectively (EPA, 1990).

3.1.2 Subchronic Toxicity

3.1.2.1 Human

Information on the subchronic oral toxicity of toluene in humans was not available.

3.1.2.2 Animal

F344 and Sprague-Dawley rats administered daily doses of 620 mg/kg by gavage for 4 weeks developed hearing loss that was attributed to damage of the outer hair cells of the inner ear (Sullivan, 1986).

Depressed immune responses were reported in mice exposed to toluene in drinking water. Male mice administered doses of 105 mg/kg/day of toluene for 28 days had decreased thymus weights, mixed lymphocyte culture responses, and antibody plaque-forming cell responses (Hsieh et al., 1989). Mitogen-stimulated lymphocyte proliferation and interleukin-2 immunity were decreased at doses of 22 and 105 mg/kg/day. Other effects included increased levels of neurotransmitters in the brain at doses of 5, 22, or 105 mg/kg/day and increased liver weights at 105 mg/kg/day.

In an National Toxicology Program (NTP) study (1990), F344/N rats and B6C3F₁ mice of both sexes were administered toluene in corn oil by gavage at doses of 0, 312, 625, 1250, 2500, or 5000 mg/kg, 5 days/week for 13 weeks. All rats receiving 5000 mg/kg died within the first week, all mice receiving 5000 mg/kg died, and 40% of mice receiving 2500 mg/kg also died. Rats exposed to doses 2500 mg/kg of toluene exhibited prostration, hypoactivity, ataxia, piloerection, lacrimation, excess salivation, and body tremors. In male rats, absolute and relative liver and kidney weights were significantly (p < 0.05) increased at doses 625 mg/kg. In females, absolute and relative liver, kidney, and heart weights were all significantly increased at doses 1250 mg/kg (p < 0.01 for all comparisons except p < 0.05 for absolute kidney and heart weights at 1250 mg/kg). Histopathologic lesions were seen in the liver, kidneys, brain, and urinary bladder of rats. Hepatocellular hypertrophy occurred at 2500 mg/kg. Nephrosis was observed in rats that died, and damage to the tubular epithelium of the kidney occurred in terminally sacrificed rats. In the brain, mineralized foci and necrosis of neuronal cells were observed in male and female rats at 5000 mg/kg and males at 2500 mg/kg. Hemorrhage of the bladder (mucosa and muscularis) was seen in male and female rats at 5000 mg/kg and males at 2500 mg/kg. Signs of toxicity seen in mice receiving 2500 mg/kg included subconvulsive jerking, prostration, impaired grasping reflex, bradypnea, hypothermia, ataxia, and hypoactivity. By week 13, the mean body weight of males given 2500 mg/kg was significantly (p < 0.05) lower than that of controls. No adverse effects were reported in rats exposed to the lowest dose, 312 mg/kg/day, or in mice exposed to doses < 2500 mg/kg/day.

In an early subchronic gavage study, Wolf et al. (1956) observed no adverse effects in female Wistar rats treated with 0, 118, 354, or 590 mg/kg of toluene in olive oil, 5 days/week for 27-28 weeks (Wolf et al., 1956).

3.1.3 Chronic Toxicity

Information on the chronic oral toxicity of toluene in humans or animals was not available.

3.1.4 Developmental and Reproductive Toxicity

3.1.4.1 Human

Information on the developmental and reproductive toxicity of toluene in humans following oral exposure was not available.

3.1.4.2 Animal

Oral administration of a single dose of 2350 mg/kg/day of toluene on gestational days 7-14 had no effect on the number of viable litters of mice and single doses of 1800 or 2350 mg/kg/day did not cause developmental effects (Seidenberg et al., 1986; Smith, 1983).

Kostas and Hotchin (1981) exposed female NYLAR mice to 16, 80, or 400 ppm toluene in drinking water beginning at the mating period and continuing throughout gestation and lactation. Upon weaning, the offspring were exposed to the same drinking water solutions until the time of behavioral testing--45-55 days of age. Rotorod performance was affected in all toluene-exposed groups, but there was an inverse dose-relationship. Decreased open-field activity was seen at 400 ppm. Offspring mortality rate, development of eye or ear openings, and surface-righting response of offspring was not affected.

Nawrot and Staples (1979) administered 0.3, 0.5, or 1.0 mL/kg (260, 433, or 867 mg/kg) of toluene in cottonseed oil by gavage 3 times/day on days 6-15 of gestation or 1.0 mL/kg (867 mg/kg) on days 12-15 of gestation to pregnant CD-1 mice. Increased embryonic lethality was reported in all groups treated with toluene on days 6-15 of gestation. Fetal weight was reduced in the mid- and high-dosed groups, and the incidence of cleft palate was increased in high-dosed fetuses. Maternal toxicity (decreased weight gain) was the only effect noted in mice treated on days 12-15 of gestation.

3.1.5 Reference Dose

3.1.5.1 Subchronic

ORAL RfD: 2 mg/kg/day (U.S. EPA, 1993)

NOAEL: 223 mg/kg/day

LOAEL: 446 mg/kg/day

UNCERTAINTY FACTOR: 100

PRINCIPAL STUDY: NTP, 1990

COMMENTS: The same study, described in Subsect. 3.1.2.2, was used for the derivation of the subchronic and chronic RfD. The dose was adjusted for discontinuous exposure (5 days/week). An uncertainty factor of 100 was applied to account for interspecies extrapolation (10) and intraspecies variability (10).

3.1.5.2 Chronic

ORAL RfD: 0.2 mg/kg/day (U.S. EPA, 1992)

NOAEL: 223 mg/kg/day

LOAEL: 446 mg/kg/day

UNCERTAINTY FACTOR: 1000

CONFIDENCE:

Study: High

Data Base: Medium

RfD: Medium

VERIFICATION DATE: 6/20/90

PRINCIPAL STUDY: NTP, 1990

COMMENTS: The RfD is based on a gavage study with rats exposed to toluene for 13 weeks, with increased liver and kidney weights as critical effect. The dose was adjusted for discontinuous exposure (5 days/week). An uncertainty factor of 1000 was applied to account for interspecies extrapolation (10), intraspecies variability (10), and for the use of a subchronic study for chronic RfD derivation (10). Confidence in the data base and RfD is rated medium because the available oral studies are all subchronic and because of a lack of reproductive toxicity studies (EPA, 1992).

3.2. INHALATION EXPOSURES

3.2.1. Acute Toxicity

3.2.1.1. Human

Acute toxicity data of toluene in humans come from experimental exposures, case reports of intentional abuse (glue sniffing), and accidental occupational exposures. The major acute effects of toluene in humans are CNS dysfunction and neurological impairment. Studies reviewed by NTP (1990) showed that individuals developed fatigue, drowsiness, impaired cognitive function, incoordination, and irritation of the eyes and throat after a single exposure to toluene at concentrations ranging from 50 to 1500 ppm for 3-8 hours. These effects increased in severity with increases in concentration and progressed to nausea, staggering gait, confusion, extreme nervousness, muscular fatigue, and insomnia lasting for several days (NTP, 1990). Exposure to concentrations ranging from 10,000 to 30,000 ppm have resulted in narcosis and death (WHO, 1985).

In a controlled exposure study, Andersen et al. (1983) exposed human subjects to 0, 10, 40, or 100 ppm toluene for 6 hours on each of 4 consecutive days. Eye and nose irritation occurred at 100 ppm, without affecting nasal mucous flow or lung function. The subjects frequently reported headaches, dizziness, and a feeling of intoxication. These effects were not reported in the 10- or 40-ppm exposure groups. No effects were seen in performance tests.

3.2.1.2 Animal

LC₅₀ values for 6- to 7-hour exposures are 12,200 ppm for rats and 5300-7000 ppm for mice (EPA, 1990). Central nervous system effects are the primary toxic effects following acute inhalation exposure to toluene. The CNS response is biphasic, with an initial excitable phase followed by depression.

Rats exposed to 10,000 to 15,000 ppm toluene for 60 minutes exhibited an initial increase in locomotor activity; however, at continued exposure, locomotor activity decreased and eventually ceased (Hinman, 1987). Rats exposed to 125, 250, or 500 ppm toluene for 4 hours showed a decline in trained neuromuscular responses 20 hours after exposure (Kishi et al., 1988). Exposure of weanling or young rats to 7550 mg/m³ (2000 ppm), 8 hours/day for 3 days or to 5660 mg/m³ (1500 ppm) for 14 hours resulted in hearing loss (Pryor et al., 1984). Acute exposure of monkeys caused impaired cognitive and motor abilities when exposed to 1000 or 2000 ppm, concentrations that were below those causing overt clinical signs of neurotoxicity such as ataxia and tremors (Taylor and Evans, 1985).

3.2.2. Subchronic Toxicity

3.2.2.1 Human

Echeverria et al. (1989) exposed volunteers to 0, 74, or 151 ppm toluene for 7 hours over 3 days. This exposure sequence was repeated for a total of 42 exposures over a 3-month period. A battery of performance tests showed that visual perception was affected and manual dexterity differed from control values at both exposure levels. However, psychomotor test results were unaffected by toluene exposure. Subjective symptoms such as eye irritation, headache, and somnolence increased with exposure.

Individuals who had abused toluene for at least 1 year reported disturbed behavior; slow thought and speech; illusionary misinterpretations; tactile, auditory, and visual hallucinations; and delusional ideas (Evans and Raistrik, 1987).

3.2.2.2 Animal

Pryor et al. (1984) found irreversible high frequency hearing loss in rats exposed to toluene at concentrations of 1200 ppm, 12 hours/day for 5 weeks. Rats exposed at weaning age exhibited a more pronounced hearing loss than young adult rats.

Ungvary et al. (1980) exposed male and female CFY rats to 1000 mg/m³ (265 ppm) toluene 6 hours/day, 5 days/week for 6 months. No adverse effects were seen in males; however, females exhibited increased cytochrome P-450 levels, decreased body weights, and increased liver-to-body weight ratios. Exposure to 3500 mg/m³ (928 ppm) (males only), 8 hours/day, 5 days/week for 6 months produced effects similar to those elicited in females at the lower dose.

In an NTP (1990) study, F344/N rats and B6C3F₁ mice were exposed to 0, 100, 652, 1250, 2500, or 3000 ppm toluene 6.5 hours/day, 5 days/week for 15 weeks (rats) or 14 weeks (mice). All female rats survived exposure to 3000 ppm, but 8/10 male rats died within 2 weeks at this exposure level. Decreased body weights and increased relative liver, kidney, and heart weights were seen in rats exposed to the two higher concentrations compared with those of controls. All female mice and 5/10 male mice exposed to 3000 ppm and 7/10 female mice exposed to 2500 ppm died during the first 2 weeks. The body weights of all exposed groups were lower than those of controls. Relative liver weights were increased in mice exposed to 625 ppm. Increased relative lung weights were seen at 1250 ppm and increased relative kidney weights at 1250 ppm (females only). Centrilobular atrophy of the liver occurred in all male mice exposed to 2500 ppm and in 70% of male mice exposed to 3000 ppm.

No effects on the kidneys, lungs, spleen, or heart were observed in rats, guinea pigs, dogs, or monkeys continuously exposed to 107 ppm toluene for 90 days (Jenkins et al., 1970). In addition, no treatment-related effects were observed on the brain and spinal cord of dogs and monkeys, and no significant changes were observed in hematological parameters in any of the species tested.

3.2.3. Chronic Toxicity

3.2.3.1 Human

Occupational exposure studies that have investigated the potential neurotoxicity of toluene have not shown severe neurological effects. Rotogravure printers exposed to an estimated 117 ppm toluene for up to 22 years exhibited no clinically significant adverse effects on the nervous system (Juntunen et al., 1985). Occupational studies by Yin et al. (1987) and Lee et al. (1988) reported subjective symptoms such as headaches, sore throats, and dizziness following exposure to approximately 100 ppm toluene. Foo et al. (1990) conducted a cross-sectional study involving 30 female workers employed at an electronic assembly plant where toluene was emitted from glue. The toluene workers were employed for an average of 5.7 years and exposed to time-weighted-average (TWA) air concentrations of 88 ppm (332 mg/m³) toluene; a control group was exposed to 13 ppm (49 mg/m³) (TWA). A battery of eight neurobehavioral tests showed that the exposed group had a poorer performance in 6 of 8 tests administered when compared with the control group.

Cerebellar dysfunction, mental retardation, abnormal encephalograms, brain atrophy, and visual impairment were observed in long-term abusers of pure toluene (6-14 years) (NTP, 1990). Clinical studies of toluene sniffers suggest that ototoxicity as well as vestibular deficits may occur after prolonged inhalation exposure (Winneke, 1992).

Some studies have reported effects on the kidney and liver following inhalation exposure to toluene. Askergren (1984) reported increased protein excretion and increased excretion of erythrocytes and leukocytes/tubular epithelial cells in construction workers exposed to toluene. Renal tubular effects, indicated by metabolic acidosis (hypokalemia, hypophosphatemia, and hyperchloremia), have been associated with abusers of toluene-containing solvents (NTP, 1990). Krusell et al. (1985), however, indicated that there is no causal relationship between toluene exposure alone and renal injury. Hepatomegaly was observed in airplane painters exposed to 100-1150 ppm toluene in air for up to 5 years (Greenburg et al., 1942) and in 20-50% of workers exposed to toluene at 53-80 ppm for 2-14 years (Szilard et al., 1978).

Although early studies (before the mid-1950s) have associated chronic exposure to toluene with myelotoxic effects, most recent studies generally indicate that toluene does not cause toxic effects in blood and bone marrow. The previously observed hematologic effects are now attributed to concurrent exposure to benzene, a common contaminant of toluene at that time (NTP, 1990; ATSDR, 1989).

3.2.3.2 Animal

F344/N rats and B6C3F₁ mice were exposed by inhalation to 0, 600, or 1200 ppm toluene 6.5 hours/day, 5 days/week for 15 months or 2 years (NTP, 1990). Mean body weights and survival of rats and mice were generally similar to those seen in controls throughout the 2-year study. All rats exhibited nephropathy, with an increased severity in toluene-exposed animals. At 15 months, goblet cell hyperplasia and degeneration of olfactory and respiratory epithelium were increased in exposed rats. At 2 years, erosion of the olfactory epithelium and degeneration of respiratory epithelium were significantly (p < 0.05) increased in males and females at both doses. Mice exposed to 1200 ppm exhibited minimal hyperplasia of the bronchial epithelium. No other biologically important increases in non-neoplastic lesions were seen in exposed mice. The lesions observed in this study were considered mild and are not unusual with solvent exposures.

In an earlier 2-year inhalation bioassay, male and female F344 rats were exposed to 0, 30, 100, or 300 ppm toluene, 6 hours/day, 5 days/week (Gibson and Hardisty, 1983). Except for a dose-related decrease in hematocrit values in females exposed to 100 and 300 ppm and increased corpuscular hemoglobin concentrations in high-dosed females, all clinical chemistry, hematology, and urinalysis values were normal at the termination of the study. No other adverse effects were observed.

3.2.4 Developmental and Reproductive Toxicity

3.2.4.1 Human

Evidence for human developmental effects from case reports and occupational exposure studies is equivocal because these studies are confounded by exposure to multiple organic solvents during pregnancy. A retrospective study of 14 women exposed to mixed solvents, including toluene, suggested an increased risk of CNS abnormalities and defects of neural tube closure in children exposed in utero (Holmberg, 1979). In another study, microcephaly, CNS dysfunction, attentional deficits, minor craniofacial and limb abnormalities, developmental delay, and variable growth were observed in three children exposed in utero to toluene as a result of maternal solvent abuse (Hersh et al., 1985). A third study reported growth retardation and dysmorphism in five infants whose mothers were chronic paint sniffers (Goodwin, 1988).

3.2.4.2 Animal

Retarded bone ossification and growth inhibition were observed in fetuses of Charles River rats exposed to 400 ppm toluene, 6 hours/day on days 6-15 of gestation (Litton Bionetics, 1978), but no teratogenic effects were observed in the study. No compound-related effects on sperm or adverse effects on estrous cycle were seen in Fischer 344 rats or B6C3F₁ mice exposed to toluene at concentrations ranging from 100 to 3000 ppm, 6.5 hours/day, 5 days/week for 15 weeks (rats) or 14 weeks (mice) (NTP, 1990).

Pregnant CD-1 mice, exposed daily to 200 or 400 ppm toluene for 7 hours during gestational days 7-16, showed a significant increase in dilated renal pelves at 200 ppm but not at 400 ppm (Courtney et al., 1986). At 400 ppm, a significant shift in the fetal rib profile was observed. Both exposure concentrations caused maternal toxicity. Hudak and Ungvary (1978) observed decreased body weights but no malformations in fetuses of CFLP mice continuously exposed by inhalation to 133 ppm toluene on days 6-13 of gestation. Retarded skeletal development resulting in poorly ossified sternebrae, split vertebral centra, and shortened free ribs was reported in CFY rats continuously exposed to 230 or 399 ppm toluene on days 1-8 of development (Hudak and Ungvary, 1978). Fetuses of rats exposed to 399 ppm on days 9-14 of gestation exhibited extra ribs and fused sternebrae. No increases in visceral or external malformations were identified in mice or rats.

Deaths, but no teratogenic effects, were observed in fetuses of New Zealand rabbits continuously exposed to 266 ppm toluene on days 6-20 of gestation (Ungvary and Tatrai, 1985).

3.2.5 Reference Concentration

3.2.5.1 Subchronic

INHALATION RfC: 0.4 mg/m³ (U.S. EPA, 1993)

LOAEL: 332 mg/m³

UNCERTAINTY FACTOR: 300

PRINCIPAL STUDY: Foo et al., 1990

COMMENTS: The chronic inhalation RfC was adopted as the subchronic inhalation RfC. The study is described in Subsect. 3.2.3.1.

3.2.5.2 Chronic

INHALATION RfC: 0.4 mg/m³ (U.S. EPA, 1992)

LOAEL: 332 mg/m³

UNCERTAINTY FACTOR: 300

PRINCIPAL STUDY: Foo et al., 1990

CONFIDENCE:

Study: Medium

Data Base: Medium

RfC: Medium

COMMENTS: The chronic RfC was based on results of a battery of neurological tests in occupationally exposed females. Adverse neurological effects at atmospheric concentrations of 332 mg/m³ were considered the lowest-observed-adverse-effect level (LOAEL). An uncertainty factor (UF) of 300 was used to account for intraspecies variability (10), for the use of a LOAEL (10), and for data base deficiencies (3). The data base and RfC were given a medium rating because long-term data in humans are not available for neurotoxicity endpoints and the reproductive/developmental studies in animals were not comprehensive.

3.3. OTHER ROUTES OF EXPOSURE

3.3.1. Acute Toxicity

3.3.1.1. Human

Eye irritation has been reported in humans following exposure to toluene vapors (Andersen et al., 1983). The liquid splashed in the eyes has caused a transient disturbance of the eyes, with healing complete within 48 hours (Grant, 1986).

3.3.2.2 Animals

The LD₅₀ value reported for New Zealand rabbits following a single dermal application is 14.1 mL/kg (12.2 g/kg); for Wistar rats, the LD₅₀ following an intraperitoneal injection is 1.64 g/kg (EPA, 1990).

Undiluted toluene applied to intact and abraded skin of rabbits for 24 hours produced moderate skin irritation (Guillot et al., 1982). Direct application of toluene to the conjunctiva has resulted in slight to moderately severe irritation of rabbit eyes (ATSDR, 1989).

3.3.2 Subchronic Toxicity

3.3.2.1 Human

Prolonged or repeated skin contact may cause drying and dermatitis due to the degreasing action of toluene and its removal of protective skin oils (ATSDR, 1989; NIOSH, 1973).

3.3.2.1 Animal

Information on the subchronic toxicity of toluene by other routes of exposure in animals was not available.

3.3.3 Chronic Toxicity

Information on the chronic toxicity of toluene by other routes of exposure in humans or animals was not available.

3.3.4 Developmental and Reproductive Toxicity

Information on the developmental or reproductive toxicity of toluene by other routes of exposure in humans or animals was not available.

3.4. TARGET ORGANS/CRITICAL EFFECTS

3.4.1. Oral Exposures

3.4.1.1. Primary Target Organ(s)

1. Central nervous system: Subchronic exposure to toluene caused necrosis and mineralization of brain cells and hearing loss in rats and altered brain levels of neurotransmitters in mice. Pre- and post-natal exposure affected rotorod performance and open-field activity in mice.

2. Kidneys: Subchronic exposure to toluene produced nephrosis, damage to tubular epithelium, and increased kidney weights in rats.

3. Liver: Subchronic exposure to toluene produced increased liver weights in rats and mice and hepatocellular hypertrophy in rats.

4. Reproduction: Embryonic deaths, reduced fetal weights, and cleft palates were observed in mice exposed to toluene during gestation.

3.4.1.2 Other Target Organs

1. Immune system: Depressed immune responses were observed in rats following subchronic exposure to toluene.

2. Urinary bladder: Hemorrhage of the bladder mucosa and muscularis were observed in rats following subchronic exposure to toluene.

3.4.2 Inhalation Exposures

3.4.2.1 Primary Target Organs

1. Central nervous system: Chronic occupational exposure to toluene has resulted in headaches, dizziness, and impaired neurobehavioral performance. Brain dysfunction, abnormal encephalograms, brain atrophy, mental retardation, and visual and hearing impairment have been reported in long-term abusers of toluene. Subchronic exposure of rats produced a high frequency hearing loss.

2. Kidneys: Chronic exposure of workers to toluene has resulted in abnormalities of kidney function. Renal tubular effects have been associated with abuse of toluene-containing solvents. Chronic exposure to toluene has caused nephropathy in rats.

3. Liver: Hepatomegaly has been reported in workers chronically exposed to toluene. Increased liver weights were reported in rats following subchronic exposure to toluene.

4. Respiratory system: Sore throat was one of the symptoms reported in workers chronically exposed to toluene. Chronic exposure of rats has produced lesions in olfactory and respiratory epithelia.

3.4.2.2 Other Target Organs

Reproduction: Equivocal evidence shows that exposure to toluene in utero causes an increased risk of CNS abnormalities and developmental delay in humans. Exposure during gestation has resulted in delayed skeletal maturation in rats and mice.

3.4.3 Other Routes of Exposure

Skin: Repeated or prolonged contact may cause drying and dermatitis.

4. CARCINOGENICITY

4.1. ORAL EXPOSURES

4.1.1. Human

Information on the carcinogenicity of toluene in humans following oral exposure was not available.

4.1.2 Animal

In a 2-year gavage study, Maltoni et al. (1985) administered 500 mg/kg of toluene, 4 to 5 days/week to 40 male and 40 female Sprague-Dawley rats. At the end of the study, 8% of the treated males and 17.5% of the treated females developed hemolymphoreticular neoplasms compared with 7% of the treated males and 3% of the female controls, respectively.

4.2. INHALATION EXPOSURES

4.2.1. Human

Svensson et al. (1990) studied a cohort of 1020 rotogravure workers exposed to toluene and employed for a minimum of 3 months in eight plants from 1925 to 1985. The overall incidence of tumors during the time period 1958-1985 was not increased. Among specific tumors, only those of the respiratory tract were significantly increased (16 observed vs 9 expected). However, statistical significance was not attained when only workers with an exposure period of at least 5 years and a latency period of at least 10 years were considered. Results of a retrospective cohort mortality study of 1008 male oil refinery workers exposed to toluene and other chemicals indicated that worker mortality due to all causes of death and to cancer were lower than that for the general population (Wen et al., 1985).

4.2.2 Animal

Two long-term bioassays found no evidence of carcinogenicity in rats and mice following inhalation of toluene. Compared with controls, the incidence of treatment-related neoplastic lesions was not increased in male and female F344 rats exposed to 30, 100, or 300 ppm, 6 hours/day, 5 days/week for 24 months (Gibson and Hardisty, 1983). Similarly, there was no evidence of carcinogenic activity in male and female F344/N rats or male and female B6C3F₁ mice exposed to 600 or 1200 ppm toluene, 6.5 hours/day, 5 days/week for 24 months (NTP, 1990).

4.3. OTHER ROUTES OF EXPOSURE

4.3.1 Human

Information on the carcinogenicity of toluene in humans by other routes of exposure was not available.

4.3.2 Animal

Several studies examined the carcinogenicity of toluene following repeated dermal application in mice. Toluene applied to the shaved skin of male A/He, C3HeB, and SRW mice, three times weekly for life produced no carcinogenic response (Poel, 1963). No skin papillomas or carcinomas were observed in albino mice that received twice weekly dermal applications of toluene for 50 weeks (Coombs et al., 1973). One skin papilloma and one skin carcinoma was reported in a group of mice treated twice weekly for 72 weeks with 1 drop of a 0.2% solution of toluene (Lijinsky and Garcia, 1972). In initiation/promotion studies, toluene was reported to have little or no promoting activity after initiation with 7,12-dimethylbenz()anthracene (DMBA) (EPA, 1990). Toluene inhibited skin carcinogenesis in mice in the two-stage model using benzo[a]pyrene or DMBA as tumor initiators and phorbol-12-myristate-13-acetate as a tumor promoter (Weiss et al., 1986).

4.4. EPA WEIGHT-OF-EVIDENCE

Classification--Group D; not classifiable as to human carcinogenicity (EPA, 1992)

Basis: No human data and inadequate animal data. Toluene did not produce positive results in the majority of genotoxicity assays.

4.5. CARCINOGENICITY SLOPE FACTORS

No carcinogenicity slope factors were calculated.

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