Toxicity Profiles

Formal Toxicity Summary for XYLENE

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

September 1994

Prepared by Carol S. Forsyth, Ph.D. and Rosmarie A. Faust, Ph.D., Chemical Hazard Evaluation Group, Biomedical and Environmental Information Analysis Section, Health Sciences Research Division, *, 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

Xylene (dimethylbenzene) is a colorless, flammable liquid that is used as a solvent in the printing, rubber, and leather industries and as a cleaner and paint thinner. It occurs naturally in petroleum and coal tar. Xylene is absorbed following oral, dermal, or inhalation exposure; can be stored in adipose tissue; and is eliminated in the urine after conjugation with glycine.

Human exposure to xylene by either oral or inhalation routes can cause death due to respiratory failure accompanied by pulmonary congestion (Sandmeyer, 1981). Nonlethal levels of xylene vapor may cause eye (Carpenter et al., 1975), nose, and throat (ATSDR, 1993) irritation, and contact with liquid may result in dermatitis (Sittig, 1985). Chronic occupational exposure to xylene has been associated with headaches, chest pain, electrocardiographic abnormalities, dyspnea, cyanosis of hands, fever, leukopenia, malaise, impaired lung function, and confusion (Hipolito, 1980).

Long-term gavage studies with mixed xylenes in laboratory animals resulted in decreased body weight gain in male rats given 500 mg/kg/day and hyperactivity in male and female mice given 1000 mg/kg/day (NTP, 1986). A chronic oral reference dose (RfD) of 2 mg/kg/day for mixed xylenes was calculated from a no-observed-adverse-effect level (NOAEL) of 250 mg/kg/day derived from a chronic gavage study with rats (EPA, 1994a). The critical effects were hyperactivity, decreased body weight, and increased mortality (males). An RfD of 2 mg/kg/day is also reported for the m- and o-xylene isomers (EPA, 1994b).

Inhalation of 3000 mg/m³ of the o-, p-, or m-xylene isomer by rats on gestation days 7-14 resulted in decreased fetal weights, skeletal anomalies, and altered fetal enzyme activities (Hood and Ottley, 1988). Rib anomalies and cleft palate occurred in mouse fetuses following maternal oral exposure of 2.06 g/kg/day of mixed xylenes on gestation days 6-15 (Marks et al., 1982). An inhalation reference concentration (RfC) is under review by EPA (1994a).

Oral (NTP, 1986) and topical (Berenblum, 1941; Pound, 1970) carcinogenic studies with xylene in laboratory animals gave negative results. EPA (1994a) has placed xylene in weight-of-evidence group D, not classifiable as to human carcinogenicity. No significant increase in tumor incidence was observed in rats or mice of both sexes following oral administration of technical grade xylene.

1. INTRODUCTION

Xylenes (dimethylbenzenes) are volatile solvents widely used in chemical synthesis, consumer products, and agricultural chemicals. The chemical has a molecular weight of 106.16, a boiling point of 137 C, a density of about 0.86, and is practically insoluble in water (Budavari et al., 1989). Xylenes occur naturally in petroleum and coal tar and are formed during forest fires; chemical industries produce xylenes from petroleum (ATSDR, 1993). They are also present as constituents in gasoline (Ransley, 1984). The commercial technical product "mixed xylenes" generally contains about 40% m-xylene and 20% each of oxylene, p-xylene, and ethylbenzene, as well as small quantities of toluene (Fishbein, 1985). In this summary, xylene or xylenes, refers to mixed xylenes unless the individual isomer is specified.

Because of its volatility, most of the xylene released to the environment will enter the atmosphere where it undergoes photodegradation (ATSDR, 1993). Xylenes have been measured in the air and drinking water of industrialized cities (ATSDR, 1993).

2. METABOLISM AND DISPOSITION

2.1 ABSORPTION

Xylene is readily absorbed after oral, dermal, or inhalation administration. After oral administration of 0.9-1.7 g/animal of each of the xylene isomers, rabbits absorbed >98% of p-xylene, 85% of m-xylene, and 66% of o-xylene, as indicated by metabolites recovered in the urine (Bray et al., 1949; 1950). Several studies with humans exposed by inhalation to xylene at concentrations of 100-1300 mg/m³ have shown that approximately 60% of the xylene present in inspired air is absorbed by the lungs, regardless of the isomer or mixture used (EPA, 1985). Dermal absorption is minor following exposure to xylene vapor, representing only 1-2% of that absorbed by the lungs. However, dermal absorption may be significant if liquid xylene contacts the skin (EPA, 1985). Dermal absorption as high as 9.6 mg/cm²/hour of xylene has been reported following application to the skin of the human forearm (Dutkiewicz and Tyras, 1968).

2.2 DISTRIBUTION

After absorption, xylene is rapidly distributed to the tissues and, because of its lipophilicity, xylene accumulates in adipose tissue. Approximately 90% of xylene distributed by the blood is bound to serum proteins (EPA, 1985). Whole-body autoradiography detected ¹⁴C - m-xylene in lungs, liver, kidney, brain, and adipose tissue of mice after a 10-minute inhalation exposure. Traces of xylene persisted in adipose tissue 4 hours after exposure (EPA, 1986). Rats exposed to 48 ppm ¹⁴C - p-xylene for up to 8 hours had the highest concentrations of radioactivity in kidney, subcutaneous fat, sciatic nerve, liver, blood, lungs, brain, muscle, and spleen. Levels of xylene in fat increased to 270 nmole/g after 8 hours (EPA, 1986). Biopsies from subcutaneous fat of human volunteers contained 6-8 µg/g xylene 22 hours after exposure to 100 or 200 ppm mixed xylene for 2 hours (Low et al., 1989). The body burden of xylene correlated with total body fat. After human ingestion of a lethal amount of xylene, levels of chemical in the blood, stomach, and intestine were 110 mg/L, 8800 mg/L, and 33,000 mg/L, respectively (ATSDR, 1993). The half-life for elimination of xylene from subcutaneous fat is estimated at 7 hours in the rat (Low et al., 1989) and greater than 40 hours in humans indicating accumulation may be possible (EPA, 1986).

2.3 METABOLISM

Xylene and its isomers are predominately metabolized by oxidation of the methyl group to methylbenzoic acids (toluic acids) which are further conjugated with glycine to form methylhippuric acids (toluric acids). Human volunteers were exposed to purified xylene isomers by inhalation at 870 or 1740 ppm for 8 hours. The major metabolites (85-95%) in urine over a 40-hour collection period were the methylhippuric acids of each isomer (EPA, 1986). Similar results were obtained after ingestion of o-xylene (EPA, 1986). Experimental animals vary slightly in the metabolism of xylenes. For example, the rat predominately excretes o-toluic acid conjugated with glucuronide instead of glycine (EPA, 1985). Reactive metabolites of p-xylene which inactivate pulmonary cytochrome P-450 have been isolated from rabbit lung (Low et al., 1989).

2.4 EXCRETION

In both humans and animals, xylene and its isomers are excreted by urinary elimination of 80-90% of the administered dose as the corresponding conjugated metabolites. Approximately 5% of the parent compound is released through pulmonary exhalation (EPA, 1986). Elimination of m-xylene in humans is triphasic following inhalation exposure of 100 ppm (Low et al., 1989). Based on the rate of elimination of mxylene in expired air, the half-life was 0.8 hours for the initial phase, 7.7 hours for the intermediate phase, and 17.7 hours for the slowest elimination phase. Overall, the elimination half-life of m-xylene from subcutaneous adipose tissue has been estimated to be 58 hours in man (Low et al., 1989).

3. NONCARCINOGENIC HEALTH EFFECTS

3.1 ORAL EXPOSURES

3.1.1 Acute Toxicity

3.1.1.1 Human

Ingestion of xylene (dose not given) has caused severe gastrointestinal distress in humans (Sandmeyer, 1981). Chemical pneumonitis, pulmonary edema, and hemorrhage may result if aspiration into the lungs occurs. Accidental ingestion of small quantities of a paint thinner containing 90% xylene has resulted in toxic hepatitis, which was reversible within 20 days (NIOSH, 1975).

Death in humans due to respiratory failure, accompanied by pulmonary congestion and edema observed at autopsy, has occurred after ingestion of a "large" quantity of xylene (ATSDR, 1993).

3.1.1.2 Animal

In general, xylene has a low acute oral toxicity. LD₅₀ values for rats range from 3.6 to 6.75 g/kg for the individual isomers and from 4.3 to 8.8 g/kg for mixed xylenes (EPA, 1985). Three of 5 male F344/N rats died after a single dose of 4000 mg/kg; this dose was not lethal to females, but a dose of 6000 mg/kg killed 5/5 females. Loss of coordination, prostration, loss of hind leg movement, and hunched posture were seen in males and females after doses of 4000 or 6000 mg/kg (NTP, 1986). Male and female F344/N rats receiving up to 1000 mg/kg/day of mixed xylenes for 14 days had only a slight decrease in body weight gain but no other compound-related effects (NTP, 1986). Mortality in B6C3F₁ mice receiving a single dose of 6000 mg/kg mixed xylenes was 3/5 in males and 4/5 in females. Doses of 4000 or 6000 mg/kg produced tremors, prostration, and labored breathing. Decreased body weight gain was seen only in male mice receiving 2000 mg/kg/day for 14 days (NTP, 1986).

Condie et al. (1988) administered the o-, m-, or p-xylene isomer to male and female Sprague-Dawley rats at doses of 250, 1000, or 2000 mg/kg/day for 10 days. The high dose of all three isomers caused increased liver weights in both sexes. This effect was also seen in both males and females at the middle dose of m-xylene, but the middle dose of o- and p-xylene caused increased liver weights in females only. Decreased spleen weights were seen in males at the high dose of m- and o-xylene, while a decrease in thymus weights occurred at the high dose of p-xylene in both sexes.

Alterations in the visual system were measured in male Long-Evans rats that received p-xylene at 125, 250, 500, 1000, or 2000 mg/kg. At the 250 mg/kg dose and higher, depression in amplitude of the flashevoked potential peak N3 was observed indicating altered processing of visual information (Dyer et al., 1988).

3.1.2 Subchronic Toxicity

3.1.2.1 Human

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

3.1.2.2 Animal

Male and female Sprague-Dawley rats were treated by gavage with 0, 100, 400, or 800 mg/kg/day of m- or p-xylene for 90 days (Hazleton Laboratories, 1986a, 1986b). The only effects resulting from exposure to p-xylene were a slight reduction in weight gain and excess salivation in high-dose males and females. The highest dose of m-xylene produced clinical signs of toxicity such as excess salivation, hyperactivity, convulsions, and epistaxis. Decreased body weight gains were noted for mid- and high-dose males and for high-dose females. Additional effects at the high dose were slight changes of heart, kidney, and brain weights in males, increased alanine aminotransferase (ALT) levels in males, and increased calcium and cholesterol levels in females.

In a 13-week gavage study with mixed xylenes, groups of male and female F344/N rats and B6C3F₁ mice received xylene in corn oil at daily doses up to 1000 mg/kg (rats) or 2000 mg/kg (mice) (NTP, 1986). No deaths or clinical signs of toxicity were recorded in rats. At 1000 mg/kg, male and female rats gained 15% and 8% less weight, respectively, than did controls. Two of 10 female mice died following administration of 2000 mg/kg. Within 5-10 minutes of dosing, male and female mice given 2000 mg/kg developed central nervous system (CNS) effects such as short and shallow breathing, unsteadiness, tremors, and paresis. At this dose, mean body weight gain was 7% less for males and 17% less for females as compared to controls (NTP, 1986).

Condie et al. (1988) exposed male and female Sprague-Dawley rats to mixed xylenes by gavage for 90 days at dose levels of 150, 750, or 1500 mg/kg/day. The most significant findings were enlarged livers and kidneys. Histopathologic evaluation of kidney tissue revealed minimal chronic kidney disease in females and mild hyaline droplet change in males. No treatment-related histologic changes of the liver were seen in either sex.

3.1.3 Chronic Toxicity

3.1.3.1 Human

Information on the chronic oral toxicity of xylene in humans was not available.

3.1.3.2 Animal

Groups of 50 F344/N rats of each sex were administered 0, 250, or 500 mg/kg mixed xylenes in corn oil by gavage, 5 days per week for 103 weeks (NTP, 1986). Groups of 50 B6C3F₁ mice of each sex were administered 0, 500, or 1000 mg/kg xylenes on the same schedule. Although there was a dose-related increased mortality in treated male rats (14/50, 25/50, and 30/50, respectively, for controls, low-dose, and high-dose males), many of the early deaths were attributed to gavage errors. Survival of dosed female rats and male and female mice was not significantly different from controls. Slightly decreased body weights (5%8% lower than controls) were seen in high-dose male rats after week 59; the body weights of low-dose male rats and those of all dosed female rats were comparable to those of controls. The only effect in mice was hyperactivity at the highest dose. There were no significant changes in non-neoplastic lesions in rats or mice of either sex that were considered to be treatment-related.

3.1.4 Developmental and Reproductive Toxicity

3.1.4.1 Human

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

3.1.4.2 Animal

No adverse histopathological changes were seen in the reproductive organs of rats or mice treated by gavage with mixed xylenes at doses of 1000 mg/kg/day and 2000 mg/kg/day, respectively, for 13 weeks or in rats given 500 mg/kg/day and mice given 1000 mg/kg/day for 103 weeks (NTP, 1986).

Marks et al. (1982) treated pregnant CD-1 mice on days 6-15 of gestation by gavage with mixed xylenes in cotton seed oil at total daily doses of 0.52, 1.03, 2.06, 2.58, 3.10, or 4.13 g/kg/day. (The authors incorrectly reported these doses as mg/kg/day.) The highest dose was lethal to 15 of 15 dams, while exposure to 3.10 g/kg/day caused decreased maternal weight gain and was lethal to 12 of 38 dams. Decreased fetal body weights were significantly lower from dams treated with doses of >= 2.06 g/kg/day. Increased resorptions occurred only at 3.10 g/kg/day. Malformations, cleft palate, and wavy ribs were significantly (p < 0.05) increased in litters from dams treated with >= 2.06 g/kg/day. Doses of 1.03 or 0.52 g/kg/day resulted in no apparent fetal or maternal toxicity.

Nawrot and Staples (1980) treated pregnant CD-1 mice three times daily by gavage with individual xylene isomers to total daily doses of 0.90, 2.25, or 3.00 g/kg on days 6-15 of gestation. (Again, it is believed that the authors incorrectly reported these doses as mg/kg/day.) Mice administered the high dose of m-xylene exhibited overt maternal toxicity and a significantly increased incidence of resorptions. These effects as well as an increased incidence of cleft palate were seen in offspring of mice given the mid and high doses of o- and p-xylene. A repetition of the experiment with m-xylene (2.25 and 3.0 g/kg/day) did not produce maternal toxicity but did produce a low but statistically significant increased incidence of cleft palate (4.4% vs. 0% in controls) in offspring of mice administered 3.0 g/kg/day.

As part of a developmental toxicity screen, ICR/SIM mice were administered m-xylene at 2000 mg/kg on gestation days 8-12 (Seidenberg and Becker, 1987). Maternal toxicity was observed, including 1 death, but none of the neonatal parameters evaluated were affected.

3.1.5 Reference Dose

3.1.5.1 Subchronic

Contact the Superfund Health Risk Technical Support Center, (513) 569-7300, concerning the subchronic oral RfD for mixed xylenes, m-xylene, o-xylene, and p-xylene.

3.1.5.2 Chronic

ORAL RfD: 2E+0 mg/kg/day (EPA, 1994a)
NOAEL: 250 mg/kg/day
FEL: 500 mg/kg/day
UNCERTAINTY FACTOR: 100
CONFIDENCE: Study: Medium Data Base: Medium RfD: Medium
VERIFICATION DATE: 3/19/87
PRINCIPAL STUDY: NTP, 1986
COMMENTS: The RfD is based on the results of a chronic gavage study in which rats were administered mixed xylenes by gavage. The critical effects were hyperactivity, decreased body weight, and increased mortality (males). The uncertainty factor of 100 reflects 10 for interspecies variability and 10 to protect sensitive individuals.

3.2 INHALATION EXPOSURES

3.2.1 Acute Toxicity

3.2.1.1 Human

Nose and throat irritation was reported following exposure to p-xylene at 100 ppm for 1-7.5 hours/day for 5 days (ATSDR, 1993). One worker died from breathing paint fumes inside a tank with an estimated xylene concentration of 10,000 ppm. Autopsy revealed lung congestion; focal intra-alveolar hemorrhage; acute pulmonary edema; and hepatic, anoxic, and neuronal damage. Two other workers in the tank were found unconscious after 18.5 hours but regained consciousness and fully recovered after a period of slight amnesia and impaired renal function (Sandmeyer, 1981).

3.2.1.2 Animal

Carpenter et al. (1975) reported a 4-hour inhalation LC₅₀ of 6700 ppm mixed xylenes for rats; necropsy of rats that died at higher doses revealed atelectasis, hemorrhage, and interlobular edema of the lung. Cats exposed to 6700 ppm died with CNS effects within 2 hours. In mice, 6-hour LC₅₀s for the m-, o-, and pxylene isomers are 5267 ppm, 4595 ppm, and 3907 ppm, respectively (ATSDR, 1993).

Molnàr et al. (1986) tested individual xylene isomers for their ability to induce changes in rat motor behavior. During 4-hour exposures at prenarcotic concentrations, p- and m-xylene caused a concentrationdependent increase in group motility (hyperactivity) within the exposure ranges of 400-1500 ppm and 130-1500 ppm, respectively. Higher concentrations produced narcosis. o-Xylene caused depression only over a range of 150-2180 ppm. Hyperactivity and impaired motor control were also observed in rats exposed to 1600 ppm p-xylene for 4 hours/day for 1 to 5 days (Bushnell, 1989).

Alterations in the visual system were measured in male Long-Evans rats that received p-xylene at 400 or 1600 ppm for 4 hours. At the highest concentration, depression in amplitude of the flash-evoked potential peak N3 was observed indicating altered processing of visual information (Dyer et al., 1988). Bushnell and Peele (1988) measured condition flavor aversion in male Long Evans rats exposed to p-xylene at 50, 100, 200, 400, 800, or 1600 ppm for 4 hours or to 400 ppm for 0.5, 1, 2, 4, or 8 hours. Reduction in consumption of saccharin-flavored water was dose- and time-dependent with maximum aversion at 800 and 1600 ppm; maximum aversion also occurred in 2 hours at 400 ppm exposure.

3.2.2 Subchronic Toxicity

3.2.2.1 Human

Information on the subchronic toxicity of xylene by inhalation exposure to humans was not available.

3.2.2.2 Animal

No adverse effects were observed in rats and beagle dogs exposed by inhalation to mixed xylenes at concentrations of 770, 2000, or 3500 mg/m³, 6 hours/day, 5 days/week for 13 weeks (Carpenter et al., 1975). However, mixed xylenes caused bone marrow hyperplasia and glomerulonephritis in rats and rabbits exposed to 3000 mg/m³, 8 hours/day, 6 days/week for 110-130 days (Fabre et al., 1960), and altered brain chemistry and decreased activity in rats exposed to 1300 mg/m³ xylenes, 6 hours/day, 5 days/week for =< 18 weeks (Savolainen et al., 1979). No changes in body weights, hematological parameters, or histopathologies were observed in rats, guinea pigs, monkeys, or dogs exposed to o-xylene at either 780 ppm, 8 hours/day, 5 days/week, for 6 weeks, or 78 ppm continuously for 90 days (Jenkins et al., 1970).

3.2.3 Chronic Toxicity

3.2.3.1 Human

Hipolito (1980) described symptoms in laboratory technicians exposed to xylenes over a period of 1.5 to 18 years. The symptoms included chronic headaches, chest pain, electrocardiographic abnormalities, dyspnea, cyanosis of hands, fever, leukopenia, malaise, impaired lung function, and confusion. Altered memory, mood, equilibrium, sleep patterns, and indigestion have been reported in histology technicians exposed to formaldehyde, xylene, and toluene (Kilburn et al., 1985). The EPA (1989) reviewed occupational studies of workers exposed to xylene and found associated renal, liver, ocular, neurophysiological, immunocompetency, and hematopoietic effects, but the data were confounded by multiple solvent exposures. One study failed to confirm functional damage to the nervous system from long-term exposure to industrial solvents, including xylene (Grasso et al., 1984). Xylenes failed to show any genotoxic effects on sister chromatid exchange in another occupational study (Pap and Varga, 1987).

3.2.3.2 Animal

Hepatic enzyme induction, accompanied by moderate proliferation of the smooth endoplasmic reticulum, occurred in CFY rats exposed to 1090 ppm xylenes (unspecified) 8 hours/day, 7 days/week, for 1 year (EPA, 1986). Rabbits exposed to either 46 ppm mixed xylenes, 2 hours/day, or to 12 ppm, 4 hours/day, for 10-12 month had altered hematological parameters, weakened adrenal cortex functions, disturbed intermediary metabolism, and decreased immunobiological activity (EPA, 1986).

3.2.4 Developmental and Reproductive Toxicity

3.2.4.1 Human

Information on the developmental and reproductive toxicity of xylene by inhalation exposure in humans was not available. Epidemiological studies have associated sacral agenesis and CNS defects including hydrocephaly, anencephaly, and meningomyelocele with infants whose mothers were exposed occupationally to organic solvents, including xylenes (Pradhan et al., 1988).

3.2.4.2 Animal

ICR mice were exposed to 500, 1000, 2000, or 4000 ppm xylene (isomer not specified) for 6 hours/day on gestation days 6-12 (Shigeta et al., 1983). On day 17, two-thirds of the mice in each group were sacrificed and fetuses weighed, examined for external malformations, and stained for skeletal examination; the remainder were allowed to deliver. Decreased fetal weights were observed from dams receiving 2000 and 4000 ppm, delayed development of body hair and teeth occurred in the highest dose group, and there was a dose-responsive delay in ossification of the sternebrae.

Continuous exposure of rats (strain not specified) to mixed xylenes at 1000 mg/m³ on gestation days 9-14 resulted in an increase in the incidence of fused sternebrae and extra ribs; no maternal toxicity was reported (Hood and Ottley, 1985). No effect on litter size or pup weight at birth was seen in Sprague-Dawley rats exposed to 3500 or 7000 mg/m³ p-xylene on gestation days 7-16 although maternal weight gain was less in the high dose group (Rosen et al., 1986).

Rats were exposed continuously to individual xylene isomers on gestation days 7-14 at concentrations of 150, 1500, or 3000 mg/m³ (Hood and Ottley, 1985). Exposure to o-xylene resulted in decreased maternal feed consumption and decreased fetal weights at the mid and high doses and reduced ossification and altered fetal enzymes at the high dose. The p- and m-isomers caused statistically significant decreased maternal feed consumption and body weight gain and decreased fetal weights, extra ribs, and altered fetal enzyme activities at the highest concentration. Post-implantation death occurred at the high concentration and reduced ossification at all concentrations of p-xylene. Decreased implantations occurred in the high dose m-xylene group.

In another experiment (Hood and Ottley, 1985), male and female rats were exposed to mixed xylenes at concentrations of 261, 1088, or 2175 mg/m³, 6 hours/day for 131 days prior to mating. Females were continued on exposure throughout gestation. One half of the dams in the low and high exposure groups were sacrificed for teratological examination of the fetuses and the remainder allowed to deliver. The only treatment related effect was decreased body weight in female fetuses and in female pups from dams in the high exposure group through day 49, which was the last day data were collected.

3.2.5 Reference Concentration

A risk assessment for xylene is under review by an EPA work group (EPA, 1994a).

3.3 OTHER ROUTES OF EXPOSURE

3.3.1 Acute Toxicity

3.3.1.1 Humans

Eye irritation was the only effect noted in humans exposed to vapors of mixed xylenes at a concentration of 460 ppm for 15 minutes (Carpenter et al., 1975). Hand immersion studies with m-xylene have shown transient irritation, redness, dryness, and scaling of the skin (ATSDR, 1993).

3.3.1.2 Animals

Rats were given 73 mg/kg of o-xylene by intraperitoneal injection on 3 consecutive days (Bowers et al., 1982). No gross or histopathological abnormalities were observed in hepatocytes, but extrahepatic lesions consisting of lipid droplets and inflammatory cells appeared at the injection site. No effects on renal function were observed in Sprague-Dawley rats given 0.75 g/kg m-xylene in 5 intraperitoneal injections per week for 2 weeks (Bernard et al., 1989).

3.3.2 Subchronic Toxicity

3.3.2.1 Human

Repeated dermal exposure to xylenes may cause drying and defatting of the skin leading to dermatitis (Sittig, 1985) while vapors may cause conjunctivitis of the eye (Sandmeyer, 1981).

3.4.2.2 Animal

Repeated dermal application of xylenes to rabbit skin produced moderate to marked irritation and moderate necrosis (Sandmeyer, 1981).

3.3.3 Chronic Toxicity

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

3.3.4 Developmental and Reproductive Toxicity

3.3.4.1 Human

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

3.3.4.2 Animal

Rats were exposed to xylene (mixture not specified) by dermal application of 100, 200, or 2000 mg/kg/day on gestation days 1-20 (Hood and Ottley, 1985). Decreased levels of cholinesterase and cytochrome oxidase activities and increased levels of maleate, isocitrate, and glucose-6-phosphate dehydrogenase activities were measured in fetal brains but no behavioral or functional tests were performed to assess the biological significance of these changes.

3.4 TARGET ORGANS/CRITICAL EFFECTS

3.4.1 Oral Exposures

3.4.1.1 Primary Target Organs

CNS: In a 13-week gavage study, CNS effects such as short and shallow breathing, unsteadiness, tremors, and paresis developed rapidly following administration of 2000 mg/kg/day of mixed xylenes to male and female mice.
Development: Decreased fetal body weight and skeletal malformations occurred when dams were given 2.06 ?/kg/day mixed xylenes on gestation days 6-15.

3.4.1.2 Other Target Organs

In some studies, enlargement of the liver and kidneys was observed after oral administration of mixed xylene.

3.4.2 Inhalation Exposures

3.4.2.1 Primary Target Organs

CNS: Occupational exposure to xylene vapor over a period of 1.5 to 18 years has been associated with headache, EKG abnormalities, altered memory, and confusion.
Developmental: Decreased fetal body weight and delays in development were observed in mice following maternal exposure to 2000 ppm xylene, 6 hours/day, on gestation days 6-12.

3.4.2.2 Other Target Organs

Lung congestion, difficulty in breathing, and altered hematological parameters have also been associated with inhalation of xylene. Nose and throat irritation have been reported following exposure to xylene vapor.

3.4.3 Other Routes of Exposure

3.4.3.1 Primary Target Organs

Skin: Contact with liquid xylene causes transient irritation, redness, dryness, and scaling of the skin.
Eyes: Xylene vapors are irritating to the eye.

3.4.3.2 Other Target Organs

Other target organs by other routes of exposure were not identified.

4. CARCINOGENICITY

4.1 ORAL EXPOSURES

4.1.1 Human

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

4.1.2 Animal

In a 2-year study conducted by NTP (1986), groups of 50 F344/N rats of each sex were administered 0, 250, or 500 mg/kg mixed xylenes in corn oil by gavage 5 days per week for 103 weeks. Groups of 50 B6C3F₁ mice of each sex were administered 0, 500, or 1000 mg/kg on the same schedule. An apparent doserelated increased mortality in male rats was attributed primarily to gavage errors. There were no significant changes of neoplastic lesions in rats or mice of either sex that were considered to be related to treatment with xylenes.

4.2 INHALATION EXPOSURES

4.2.1 Human

One occupational study suggested a possible relationship between coal-based xylene exposure and leukemia, but limitations in the data prevent definitive conclusions (Arp et al., 1983).

4.2.1 Animal

Information on the carcinogenicity of xylene in animals by inhalation exposures was not available.

4.3 OTHER ROUTES OF EXPOSURE

4.3.1 Human

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

4.3.2 Animal

Dermal application of undiluted xylene applied twice weekly produced tumors in 1/40 mice after 25 weeks (Berenblum, 1941). Negative results were reported in initiation-promotion experiments with xylene as the initiator and croton oil as the promoter (details not provided) (Pound, 1970).

4.4 EPA WEIGHT-OF-EVIDENCE

Classification D - Not classifiable as to human carcinogenicity (EPA, 1994a).
Basis - Orally administered technical xylene mixture did not result in a significantly increased tumor incidence in rats or mice of both sexes (EPA, 1994a).

4.5 CARCINOGENICITY SLOPE FACTORS

No carcinogenicity slope factors were calculated.

5. REFERENCES

Arp, E.W., Jr., P.H. Wolf, and H. Checkoway. 1983. Lymphocytic leukemia and exposures to benzene and other solvents in the rubber industry. J. Occup. Med. 25:598-602. (Cited in U.S. EPA, 1986)

ATSDR (Agency for Toxic Substances and Disease Registry). 1993. Toxicological Profile for Xylenes. Draft for Public Comment. Prepared by Clement International Corporation, under Contract No. 205-88-0608 for ATSDR, Public Health Service, U.S. Department of Health and Human Services.

Berenblum, I. 1941. The cocarcinogenic action of croton resin. Cancer Res. 1: 44-48. (Cited in U.S. EPA, 1994)

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