The Risk Assessment Information System

Toxicity Profiles

Formal Toxicity Summary for ETHYLBENZENE

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

Prepared by: Dennis M. Opresko, Ph.D., who is a member of the Chemical Hazard Evaluation Group in the Biomedical and Environmental Information Analysis Section, Health Sciences Research Division, Oak Ridge National Laboratory*.

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

Ethylbenzene is a colorless, flammable liquid with a pungent odor (Cavender 1994). The water solubility of ethylbenzene is 0.014 g/100 mL and its vapor pressure is 10 mm Hg at 25C (Budavari et al. 1989). Ethylbenzene is commonly used as a solvent, chemical intermediate in the manufacture of styrene and synthetic rubber and as an additive in some automotive and aviation fuels (Cavender 1994). Occupational exposure to ethylbenzene may occur during production and conversion to polystyrene and during production and use of mixed xylenes (Fishbein 1985). The general public can be exposed to ethylbenzene in ambient air as a result of releases from vehicle exhaust and cigarette smoke (Fishbein 1985).

Ethylbenzene can be absorbed through the lungs, digestive tract, and skin (Fishbein 1985). It also crosses the placenta (Cavender 1994). The liver is the major organ of ethylbenzene metabolism. In humans the major metabolites of ethylbenzene are mandelic acid (64 to 70%) and phenylglyoxylic acid (25%) (Bardodej and Bardodejova 1970, Fishbein 1985, Cavender 1994); however, these compounds are only minor metabolites in laboratory animals (EPA 1995). Excretion occurs primarily in the urine (NTP 1992, Climie et al. 1983).

Ingestion of sublethal amounts of ethylbenzene is likely to cause central nervous system (CNS) depression, oro-pharyngeal and gastric discomfort, and vomiting (HSDB 1995); however, specific experimental data are not available. Animal studies indicate that the primary target organs following chronic oral exposures are likely to be the liver and kidney. The oral RfD for chronic exposures is 0.1 mg/kg/day, based on increased weight and histopathological changes in the liver and kidneys of rats (EPA 1996).

Acute exposures to high atmospheric concentrations of ethylbenzene may cause eye and respiratory tract irritation and CNS effects (e.g., coordination disorders, dizziness, vertigo, narcosis, convulsions, pulmonary irritation, and conjunctivitis) (Ivanov 1962). Concentrations of 1000 ppm (434 mg/m3) can be highly irritating to the eyes of humans (Yant et al. 1930); the threshold for eye irritation has been reported to be 200 ppm (879 mg/m3) (Grabt 1986). No evidence is available to suggest that occupational exposures to ethylbenzene result in chronic toxic effects (Fishbein 1985); however, histopathological changes in the liver and kidney have been observed in experimental animals following prolonged inhalation exposures. Laboratory studies also indicate that exposure to ethylbenzene (4340 mg/m3) during gestation results in adverse developmental effects in rats (skeletal variants) and rabbits (reduced number of live offspring per litter). The no-observed-adverse-effect level (NOAEL) for developmental effects was reported to be 434 mg/m3. The inhalation RfC for chronic exposures is 1 mg/m3, based on developmental effects (EPA 1996).

No epidemiological information is available on the potential carcinogenicity of ethylbenzene in humans following oral or inhalation exposures. A statistically significant increase in total malignant tumors was observed in female rats dosed orally with ethylbenzene (Maltoni et al. 1985); however, because of study limitations, these results cannot be considered conclusive. Although ethylbenzene has been tested by NTP in a two-year rodent bioassay, the results of that study are not yet available (NTP 1995). Ethylbenzene is placed by EPA in Group D, not classifiable as to human carcinogenicity, based on a lack of data in humans and animals (EPA 1996).

1. INTRODUCTION

Ethylbenzene is commonly used as a solvent, chemical intermediate (especially in the manufacture of styrene and synthetic rubber), and as an additive in some automotive and aviation fuels (Cavender 1994). Ethylbenzene is a colorless, flammable liquid with a pungent odor (Cavender 1994). The water solubility of ethylbenzene is 0.014 g/100 mL and its vapor pressure is 10 mm Hg at 25C (Budavari et al. 1989). Exposure to ethylbenzene most likely occurs through inhalation of vapors and mists (NTP 1992). Occupational exposures may occur during production and conversion to polystyrene and during production and use of mixed xylenes (Fishbein 1985). The general public can be exposed to ethylbenzene in ambient air as a result of releases from vehicle exhaust and cigarette smoke (Fishbein 1985).

Ethylbenzene present in the atmosphere will photochemically degrade by reaction with hydroxyl radicals (half-life hours to 2 days) (Howard 1989). Releases into water will be reduced by volatilization (Henry's Law Constant 6.6 to 8.7 10-3 atm-m3/mol), photolysis, and biodegradation (ATSDR 1990). Representative half-lives in water are several days to 2 weeks. Based on its octanol-water partition coefficient (log Kow = 3.13), bioconcentration in fish (BCF 37.5) is not significant (ATSDR 1990). Ethylbenzene is only moderately adsorbed to soil and consequently, leaching into ground water may occur (ATSDR 1990). Degradation of ethylbenzene in soil or water is enhanced under aerobic conditions and limited under anaerobic conditions (ATSDR 1990).

2. METABOLISM AND DISPOSITION

2.1. ABSORPTION

Ethylbenzene is absorbed through the lungs, skin, and gastrointestinal tract (NTP 1992, Cavender 1994). It also crosses the placenta (Cavender 1994). In two inhalation studies conducted on humans, 49 to 64% of the inhaled dose was retained in the body (NTP 1992). Similarly, in a rat study, 44% of an inhaled dose (1000 mg/m3 for 6 hr) was retained (Chin et al. 1980). In humans, ethylbenzene is readily absorbed through the skin; the rate of absorption ranges from 22 to 33 mg/cm2/hr for hands immersed in pure solvent (Fishbein 1985). At a concentration of 112 to 156 mg/L, the rate of dermal absorption is 0.11 to 0.21 mg/cm2/hr (Dutkiewicz and Tyras 1968).

2.2. DISTRIBUTION

Forty-two hours following a 6-hr inhalation exposure of rats to radio-labeled ethylbenzene, radioactivity was distributed to the liver and adipose and gastrointestinal tissues (Chin et al. 1980). Following a single oral dose, distribution of radioactivity was primarily in the intestine, liver, and kidney (Climie et al. 1983). Ethylbenzene crosses the placenta and has been detected in cord blood samples (Cavender 1994).

2.3. METABOLISM

In humans, the major metabolites of ethylbenzene are mandelic acid (64 to 70%) and phenylglyoxylic acid (25%) (Bardodej and Bardodejova 1970, Fishbein 1985, Cavender 1994); however, these compounds are only minor metabolites in laboratory animals (EPA 1995). Metabolites reported in animals include: hippuric acid, glycine conjugates of benzoic acid, phenylacetic acid, mandelic acid, and glucuronide conjugates of methylphenylcarbinol and phenylethanol (Cavender 1994).

2.4. EXCRETION

In rats, ethylbenzene is excreted primarily in the urine (NTP 1992, Climie et al. 1983). In rats exposed to 1000 mg/m3 for 6 hr, approximately 83% of an absorbed dose was excreted in urine, 8% in expired gases, and 0.7% in feces (Chin et al. 1980). Following a single oral dose of 30 mg/kg to rats, 80% of the ethylbenzene was excreted in the urine in the first day (Climie et al. 1983).

3. NONCARCINOGENIC HEALTH EFFECTS

3.1. ORAL EXPOSURES

3.1.1. Acute Toxicity

3.1.1.1. Human

Information on the effects of ethylbenzene in humans following acute oral exposures was not found in the available literature.

3.1.1.2. Animal

Oral LD50 values range from 3.5 to 5.5 g/kg in rats (Cavender 1994). Ingestion of sublethal amounts is likely to cause CNS depression, oropharyngeal and gastric discomfort, and vomiting (HSDB 1995); however, specific experimental data are not available.

3.1.2. Subchronic Toxicity

3.1.2.1. Human

Information on the effects of ethylbenzene in humans following subchronic oral exposures was not found in the available literature.

3.1.2.2. Animal

Female rats (10 per dose group) receiving 408 or 680 mg/kg/day, 5 days per week for 6 months by oral intubation (in olive oil) exhibited slight, statistically significant increases in liver and kidney weights and cloudy swelling of the parenchymal cells of the liver and renal tubular epithelial cells (Wolf et al. 1956). No adverse effects were seen at dose levels of 13.6 and 136 mg/kg/day.

3.1.3. Chronic Toxicity

Information on the effects of ethylbenzene in humans or animals following chronic oral exposures was not found in the available literature.

3.1.4. Developmental and Reproductive Toxicity

3.1.4.1. Human

Information on the reproductive and/or developmental effects of ethylbenzene in humans following oral exposures was not found in the available literature.

3.1.4.2. Animal

Significant (p<0.05) decreases in luteinizing hormone and 17 -estradiol occurred in female CFY rats dosed orally with 500 or 1000 mg/kg ethylbenzene in the morning of estrus, two diestruses and pro-estrus (Ungvary 1986). Hormonal decreases were accompanied by uterine changes including increased stromal tissue with dense collagen bundles; cytolysis was observed in the ovary .

3.1.5. Reference Dose

3.1.5.1. Subchronic

ORAL RfD: 0.1 mg/kg/day (Superfund Technical Support Center)

UNCERTAINTY

FACTOR: 1000

MODIFYING

FACTOR: 1

NOAEL: 136 mg/kg/day (converted to 97.1 mg/kg/day)

COMMENT: This value is not on HEAST. Contact the Superfund Technical Support Center for additional information concerning the derivation of the subchronic RfD.

3.1.5.2. Chronic

ORAL RfD: 0.1 mg/kg/day (EPA, 1996)

UNCERTAINTY

FACTOR: 1000

MODIFYING

FACTOR: 1

LOAEL: 408 mg/kg/day (converted to 291 mg/kg/day)

NOAEL: 136 mg/kg/day (converted to 97.1 mg/kg/day)

CONFIDENCE:

Study: Low

Data Base: Low

RfD: Low

Confidence in the principal study is low because the study was performed using only female rats and was not of chronic duration. Confidence in the data base is low because no other oral toxicity studies were located (EPA 1995)

VERIFICATION DATE: 05/20/85

PRINCIPAL STUDY: Wolf et al. 1956

COMMENT: The LOAEL of 408 mg/kg/day was associated with increased weight and histopathological changes in the liver and kidney of female rats. The Uncertainty Factor of 1000 adjusts for uncertainties in interspecies and intraspecies variability and subchronic to chronic extrapolation.

3.2. INHALATION EXPOSURES

3.2.1. Acute Toxicity

Ethylbenzene is an irritant to the eyes, skin, and mucous membranes and, at high concentrations, it possesses narcotic properties (Fishbein, 1985). Symptomatology of acute exposures include coordination disorders, narcosis, convulsions, pulmonary irritation, and conjunctivitis (Ivanov 1962).

3.2.1.1. Human

Six volunteers exposed to 1000 ppm (434 mg/m3) reported severe eye irritation accompanied by profuse lacrimation (Yant et al. 1930). The irritation decreased within a few minutes. Extreme eye, nose, and throat irritation occurred within 6 min. following exposure to 2000 ppm (Yant et al. 1930). The effects gradually disappeared in one individual who was exposed for 5 min; however, this person developed vertigo. The threshold for eye irritation has been reported to be 200 ppm (879 mg/m3) (Gerarde 1963). No adverse effects were observed in two individuals exposed to 55.3 ppm (241 mg/m3) for 15 min. (Moscato et al. 1987), or in four individuals exposed to 85 ppm (370 mg/m3) for 8 hours (Bardodej and Bardodejova 1970).

3.2.1.2. Animal

The 4-hr LCLo in female rats is 4000 ppm (17,360 mg/m3) (Cavender 1994). Cragg et al. (1989) reported that male rats and mice died within 4 days when exposed to 2400 ppm (10,416 mg/m3) for 6 hr/day. At 1200 ppm (5208 mg/m3), 4 of 5 mice died, and the surviving animals showed respiratory distress, lacrimation, salvation, prostration, and anogenital staining. No adverse effects occurred in animals exposed to 400 ppm (1736 mg/m3), 6 hr/day for 4 days (Cragg et al. 1989). Guinea pigs exposed to 1000 ppm (4340 mg/m3) for up to 480 min. exhibited slight nasal irritation and lacrimation (Yant et al. 1930). Exposure to 2000 ppm (8680 mg/m3) resulted in moderate eye and nasal irritation in 1 min., apparent vertigo at the end of 390 min and static and motor ataxia after 480 min. A concentration of 5000 ppm (21,700 mg/m3) produced intense irritation to the conjunctiva and nasal mucous membranes, unsteadiness and staggering, apparent unconsciousness, intermittent tremors, twitching of the extremities, and a decrease in respiration after the animals became unconscious. The animals that died from the exposure exhibited intense cerebral congestion, congestion and edema of the lungs, and signs of passive congestion throughout the abdominal viscera (Yant et al., 1930). Narcotic effects were observed in rats exposed to ethylbenzene concentrations as low as 2180 ppm (9461 mg/m3) (Molnar et al. 1986).

The ethylbenzene vapor concentration causing a 50% decrease in respiration was reported to be 1432 ppm (6229 mg/m3) in male Swiss OF1 mice (De Ceaurriz et al. 1981) and 4060 ppm (17,661 mg/m3) in Swiss Webster mice (Nielsen and Alarie 1982).

Changes in brain dopamine have been reported in rats (Andersson et al. 1981) and rabbits (Mutti et al. 1988, Romanelli et al. 1986) exposed to ethylbenzene concentrations as low as 750 ppm (3255 mg/m3) for 3 to 7 days.

Exposure of rats and mice to 0, 99, 382, or 782 ppm ethylbenzene (0, 431, 1662, or 3402 mg/m3), 6 hr/day, 5 days/wk, for 4 weeks resulted in no changes in mortality patterns, clinical chemistries, and urinalyses, and no treatment-related gross or microscopic pathology (Cragg et al. 1989). However, sporadic lacrimation and salivation, as well as a significant increase in liver weight was seen in rats exposed to 382 and 782 ppm, and a small increase in leukocyte count was seen in rats exposed to 782 ppm. Significant increases in absolute and relative liver weights occurred in female mice exposed to 382 and 782 ppm; male mice exposed to 782 ppm had a significant increase in the ratio of liver-to-brain weight. Exposure of rabbits to 1610 ppm (7004 mg/m3), 6 hr/day, 5 days/week, for 20 days, resulted in a slight decrease in body weight gain which was not statistically significant (Cragg et al. 1989). Cragg et al. (1989) noted that the liver weight changes were indicative of induction of mixed function oxidase. The no-observed-adverse-effect level (NOAEL) for rats and mice was reported as 382 ppm and the NOAEL for rabbits 782 ppm.

3.2.2. Subchronic Toxicity

3.2.2.1. Human

Information on the effects of ethylbenzene in humans following subchronic inhalation exposures was not found in the available literature.

3.2.2.2. Animal

F344/N rats and B6C3F1 mice of each sex were exposed to ethylbenzene concentrations of 0, 100, 250, 500, 750, or 1000 ppm (0, 434, 1085, 3255, or 4340 mg/m3), 6 hr/day, 5 days/week for 13 weeks (NTP 1992). No animals died during the test period. Body weight gains were lower in rats in the high-dose group, but the differences were not statistically significant. Absolute and relative kidney, liver, and lung weights were elevated in rats; liver weight was elevated in mice. Chemically related histopathological changes were not observed in any tissues (including reproductive organs) in either rats or mice (NTP 1992).

Male Wistar rats exposed to an ethylbenzene concentration of 600 ppm (2604 mg/m3), 6 hr/day, 5 days/week for 16 weeks, exhibited reduced body weight gain but no other signs of overt toxicity (Elovaara et al. 1985). Elevated liver and kidney microsomal enzyme activities were indicative of mono-oxygenase stimulation typical of other aromatic monocyclic hydrocarbons (Elovaara et al. 1985).

Wistar rats exposed to 100 ppm ethylbenzene (434 mg/m3), 6 hr/day, 5 days/wk, for 12 weeks exhibited no clinical signs of toxicity and no statistically significant changes in body weight, hematology, urinalysis, organ weights, or histopathology (Clark 1983).

Rabbits exposed to 230 ppm ethylbenzene (997 mg/m3), 4 hr/day for 7 months exhibited changes in blood cholinesterase activity, decreased plasma albumen, increased plasma globulins, reticulocytosis, leukocytosis, cellular changes in the liver, dystrophic changes in the kidney, and muscle chronaxia (Ivanov 1964). No other information on this study was available.

3.2.3. Chronic Toxicity

3.2.3.1. Human

Little evidence is available to suggest that prolonged exposure to ethylbenzene, such as in an occupational exposure setting, results in chronic toxic effects (Fishbein 1985). From biomonitoring data obtained over a 20-year period, Bardodej and Cirek (1988) concluded that exposure to ethylbenzene caused no increase in the incidence of hematopoietic or hepatic disorders among 200 ethylbenzene production workers. Workplace exposure levels were reported to be no higher than the occupational exposure standard of 200 mg/m3 for an 8-hr time-weighted average.

Increases in the incidence of hepatitis have been observed among workers in polystyrene and synthetic rubber plants who were exposed to both styrene and ethylbenzene at concentrations of about 50 mg/m3; lower concentrations reportedly were associated with clinical chemistry changes indicative of liver dysfunction. Polystyrene workers may also suffer from asthenia, nasal mucosa changes, and disorders in ovulation and menstruation (Aldyreva 1983); however, there are no data to indicate whether ethylbenzene contributed significantly to these effects.

Angerer and Wulf (1985) reported significantly elevated lymphocytes and decreased erythrocytes and hemoglobin in workers involved in the spraying of varnishes containing alkyl-phenol and polyester resins dissolved in solvents consisting principally of xylene isomers and ethylbenzene. However, according to EPA (1995) these effects cannot be attributed to ethylbenzene, because numerous other organics (including xylene, methylchloroform, n-butanol, and toluene) were also detected in the workplace atmosphere.

3.2.3.2. Animal

Slight increases in liver and kidney weights, without histopathological changes, occurred in rats exposed to 400 and 600 ppm ethylbenzene (1740 and 2610 mg/m3), 7-8 hr/day, 5 days/week for up to 214 days (NOAEL = 200 ppm), and in guinea pigs and rhesus monkeys exposed to 600 ppm (Wolf et al. 1956). Changes in liver and kidney weight were accompanied by histopathological changes in kidney and liver of female and male rats exposed to 1250 ppm (5438 mg/m3) and in male rats exposed to 2200 ppm (9570 mg/m3). The concentration of 600 ppm reportedly caused slight degeneration of the germinal epithelium in the testes of rabbits and monkeys, but these changes were not seen in rabbits exposed to 1250 ppm (600 ppm was the highest test concentration for monkeys).

Faustov and Kramsakov (1968) reported decreased antibody titers in rabbits chronically exposed to 1500 mg ethylbenzene/m3. No other information is available.

3.2.4. Developmental and Reproductive Toxicity

Evidence for teratogenicity and reproductive toxicity of ethylbenzene in humans and laboratory animals is inconclusive; however, there is some evidence for adverse developmental effects in the offspring of rats and rabbits exposed to ethylbenzene during gestation.

3.2.4.1. Human

Disorders in ovulation and menstruation have been reported for female workers in the polystyrene industry (Aldyreva 1983); however, because the workers may have been exposed to multiple chemicals, it cannot be determined to what extent ethylbenzene contributed to the reported effects.

3.2.4.2. Animal

An increased incidence of extra ribs (p<0.05) was observed in the offspring of female Wistar rats exposed to 100 ppm (435 mg/m3) or 1000 ppm (4350 mg/m3) ethylbenzene, 7 hr/day, 5 days/week, on gestation days 1 to 19 (Hardin et al. 1981, Andrew et al. 1981). The biological significance of extra ribs is not clear and is considered a skeletal variant that may predict the potential for teratogenesis at higher exposure levels (Kimmel and Wilson 1973). Pre-mating exposure to 100 or 1000 ppm for 3 weeks resulted in a significant decrease (p<0.05) in the number of sperm positive female rats that were subsequently found to be pregnant (77% vs. 89% in the controls). Maternal toxicity, as evidenced by increased liver, kidney and spleen weights, was seen in rats exposed to 1000 ppm. In rabbits, a significantly (p<0.05) reduced number of live kits per litter was observed following exposure to 100 or 1000 ppm, 6 to 7 hr/day on gestation days 1 to 24; however, the number of implantations per litter and the number of dead and resorbed per litter did not differ from controls (Hardin et al. 1981).

Retarded skeletal development, increased incidence of extra ribs, depressed fetal weight gain, and abnormal tail development were observed in the offspring of rats exposed to 2400 mg/m3 but not to 600 or 1200 mg/m3 ethylbenzene for 24 hr/day on gestation days 7 to 15 (Tatrai et al. 1982).

Resorption and retarded skeletal development occurred in fetuses of rats exposed 24 hr/day for 9 days during gestation to 138 to 552 ppm ethylbenzene (600 to 2400 mg/m3) (Ungvary and Tatrai 1985). Maternal toxicity was reported to be dose-related. An increase in extra ribs and anomalies of the uropoietic system were observed in fetuses of rats exposed to 552 ppm. No adverse developmental effects were seen in the fetuses of rats exposed 6 hr/day for 9 days to 138 ppm (Ungvary and Tatrai 1985). Uropoietic abnormalities were observed in the fetuses of mice exposed during gestation to 115 ppm ethylbenzene (500 mg/m3), but similar effects were not observed in fetuses of rabbits exposed to 115 ppm (Ungvary and Tatrai 1985). In the latter case, however, female fetuses exhibited reduced body weights.

3.2.5. Reference Concentration

3.2.5.1. Subchronic

COMMENT: The chronic RfC for ethylbenzene on IRIS is to be adopted for the subchronic RfC (EPA 1995)

3.2.5.2 Chronic

RfC: 1 mg/m3 (EPA 1996)

UNCERTAINTY FACTOR: 300

MODIFYING FACTOR: 1

LOAEL: 4340 mg/m3; rats and rabbits

NOAEL: 434 mg/m3; rats and rabbits

CONFIDENCE:

Study: Low

Data Base: Low

RfD Low

VERIFICATION DATE: 12/20/90

PRINCIPAL STUDY: Andrew et al. 1981, Hardin et al. 1981

COMMENT: The LOAEL of 4340 mg/m3 was associated with developmental effects in rats (skeletal variants) and rabbits (reduced number of live kits per litter). The Uncertainty Factor of 300 reflects a factor of 10 to protect sensitive individuals, 3 to adjust for interspecies conversion, and 10 to adjust for the absence of multigenerational reproductive and chronic studies (EPA 1996).

For developmental effects, the experimental animal concentration is not adjusted. Furthermore, the equivalent human NOAEL was calculated for a gas:extrarespiratory effect, assuming periodicity was attained. Since b:a lambda values are unknown for the experimental animals species (a) and humans (h), a default value of 1.0 was used for this ratio; therefore, the NOAEL(HEC) is 434 mg/m3 (EPA 1996).

3.3. OTHER ROUTES OF EXPOSURE

3.3.1. Acute Toxicity

3.3.1.1. Human

Erythema and inflammation may result from contact of the skin with liquid ethylbenzene (HSDB 1995); however, the chemical does not appear to be a sensitizing agent (Fishbein 1985). No sensitization reactions occurred in 25 volunteers exposed to 10% ethylbenzene in petrolatum in a maximization test (Kligman and Epstein 1975).

3.3.1.2. Animal

Dermal LD50 values range from 15.5 to 17.8 g/kg (Cavender 1994). Undiluted ethylbenzene caused erythema, edema, and superficial necrosis when applied repeatedly (10 to 20 times) to the skin of rabbits (Wolf et al. 1956). A single application to the eyes of rabbits resulted in slight irritation but no corneal injury (Wolf et al. 1956). Rats injected subcutaneously with 1 mL/kg/day for 2 weeks developed leukocytosis but not leukopenia (HSDB 1995). Total femoral marrow nucleated cell count was not affected by the exposure to ethylbenzene.

3.3.2. Subchronic Toxicity

Information on the effects of ethylbenzene in humans or animals following subchronic, non-oral or non-inhalation exposures was not found in the available literature.

3.3.3. Chronic Toxicity

Information on the effects of ethylbenzene in humans or animals following chronic, non-oral or non-inhalation exposures was not found in the available literature.

3.3.4. Developmental and Reproductive Toxicity

Information on the developmental and reproductive toxicity of ethylbenzene in humans or animals following non-oral or non-inhalation exposures was not found in the available literature.

3.4. TARGET ORGANS/CRITICAL EFFECTS

3.4.1. Oral Exposures

3.4.1.1. Primary Target Organ(s)

Animal studies suggest that the primary target organs following chronic oral exposures are likely to be the liver and kidney.

3.4.1.2. Other Target Organ(s)

Acute exposures may cause CNS depression.

3.4.2. Inhalation Exposures

3.4.2.1. Primary Target Organ(s)

Animal studies indicate that exposure to ethylbenzene during gestation may result in adverse developmental effects (skeletal variants and reduced number of live offspring per litter).

Histopathological changes in the liver and kidney have been observed in experimental animals following prolonged inhalation exposures.

3.4.2.2. Other Target Organ(s)

Acute exposures to high concentrations are likely to cause irritation of the respiratory tract, and CNS effects such as dizziness and vertigo (ATSDR 1990).

4. CARCINOGENICITY

4.1. ORAL EXPOSURES

4.1.1. Human

Information was not found in the available literature on the potential carcinogenicity of ethylbenzene in humans following oral exposures.

4.1.2. Animal

A statistically significant increase in total malignant tumors was observed in female rats dosed with 500 mg ethylbenzene/kg/day, by gavage, for 104 weeks (Maltoni et al. 1985). However, in this study only one dose was used and survival data and tumor type were not reported; therefore, the results cannot be considered conclusive.

4.2. INHALATION EXPOSURES

4.2.1. Human

Information was not found in the available literature on the potential carcinogenicity of ethylbenzene in humans following inhalation exposures. Bardodej and Cirek (1988) reported that over a 10-year period, no cases of malignancies were observed in 200 ethylbenzene production workers.

4.2.2. Animal

Ethylbenzene has been tested in a two-year rodent bioassay for carcinogenicity; however, the results of that study are not currently available (NTP 1995).

4.3. OTHER ROUTES OF EXPOSURE

Information on the potential mutagenicity and genotoxicity of ethylbenzene has been summarized by EPA (1986), ATSDR (1990) and NTP (1992). Ethylbenzene did not induce mutations in the Salmonella typhimurium, Saccharomyces cerevisiae, or Escherichia coli; did not induce chromosomal aberrations or sister chromatid exchanges (SCE) in Chinese hamster ovary cells in vitro; did not produce a clastogenic response in rat liver cell cultures; and was negative in micronuclei assays using peripheral blood of mice (NTP 1992). A weakly positive response was reported for SCE induction in cultured human lymphocytes with S9 (Norppa and Vainio 1983). An increase was observed in trifluorothymidine-resistant colonies of L5178Y/TK mouse lymphoma cells exposed to ethylbenzene without S9 activation (McGregor et al. 1988). Exposure of Drosophila melanogaster to ethylbenzene did not result in an increased incidence of recessive lethal mutations.

4.4. EPA WEIGHT-OF-EVIDENCE

Classification: D, not classifiable as to human carcinogenicity (EPA 1996).

Basis: Lack of data concerning carcinogenicity in humans or animals.

4.5. CARCINOGENICITY SLOPE FACTORS

Slope factors have not been calculated for ethylbenzene (EPA 1996).

5. REFERENCES

Aldyreva, M. V. 1983. Styrene and Ethylbenzene. Encyclopedia of Occupational Health and Safety, vol. 2. pages 2113-2115. International Labour Organization, Geneva, Switzerland.

Andersson, K., K. Fuxe, O. G. Nilsen, et al. 1981. Production of discrete changes in dopamine and noradrenaline levels and turnover in various parts of the rat brain following exposure to xylene, ortho-, meta-, and para-xylene, and ethylbenzene. Toxicol. Appl. Pharmacol. 60:535-548. (Cited in ATSDR 1990)

Andrew, F. D., R. L. Buschbom, W. C. Cannon, et al. 1981. Teratologic Assessment of Ethylbenzene and 2-Ethoxyethanol. Battelle Pacific Northwest Laboratories, Richland, WA, Final Report to the National Institute for Occupational Safety and Health, contract No. 210-79-0037). (Cited in Hardin et al. 1981, EPA, 1995)

Angerer, J., and H. Wulf. 1985. Occupational chronic exposure to organic solvents. XI. Alkylbenzene exposure of varnish workers: Effects on hematopoietic system. Int. Arch. Occup. Environ. Health. 56:(4):307-321. (Cited in EPA 1995)

ATSDR (Agency for Toxic Substances and Disease Registry). 1990. Toxicological Profile for Ethylbenzene. TP-90-15. U.S. Public Health Service, Agency for Toxic Substances and Disease Registry, Atlanta, GA, 129 pp.

Bardodej, Z., and A. Cirek. 1988. Long-term study on workers occupationally exposed to ethylbenzene. J. Hyg. Epidemiol. Microbiol. Immunol. 32:1-5.

Bardodej, Z., and E. Bardodejova. 1970. Biotransformation of ethylbenzene, styrene, and alpha-methylstyrene in man. Am. Indust. Hyg. Assoc. J. 31:206-209.

Budavari, S., M. J. O'Neil, A. Smith, and P. E. Heckelman, Eds. 1989. The Merck Index. 11th ed. Merck and Co., Rahway, New Jersey.

Cavender, F. 1994. Ethylbenzene. In: Patty's Industrial Hygiene and Toxicology, 4th rev. ed., vol. II, part B, G. D. Clayton and F. E. Clayton, Eds. Wiley Interscience, New York. pp. 1342-1346.

Chin, B. H., J. A. McKelvey, T. R. Tyler, et al. 1980. Absorption, distribution, and excretion of ethylbenzene, ethylcyclohexane, and methylethylbenzene isomers in rats. Bull. Environ. Contam. Toxicol. 24:477-483.

Clark, D. G. 1983. Ethylbenzene hydroperoxide (EBHP) and ethylbenzene (EB): 12 week inhalation study in rats. Shell Oil Company research report. EPA OTS Public Files, Document No. 86870001629, Fiche No. 0516206(2). (Cited in EPA 1995)

Climie, I. J. G., D. H. Hutson, and G. Stoydin. 1983. The metabolism of ethylbenzene hydroperoxide in the rat. Xenobiotica 13:611-618.

Cragg, S. T., E. A. Clarke, I. W. Daly, et al. 1989. Subchronic inhalation toxicity of ethylbenzene in mice, rats, and rabbits. Fund. Appl. Toxicol. 13:399-408.

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