National Toxicology Program

Selected toxicity information from HSDB, one of the National Library of Medicine's databases. ¹

Names (NTP)

• Xylenes (mixed)
• DIMETHYLBENZENE (9CI)

Human Toxicity Excerpts

• Xylene is a central nervous system depressant that produces lightheadedness, nausea, headache, and ataxia at low doses and confusion, respiratory depression, and coma at high doses. Above 200 ppm, xylene causes conjunctivitis, nasal irritation, and sore throats; it is a potent respiratory irritant at high concentrations. ... Xylene produces a defating dermatitis with prolonged cutaneous exposure. [Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988., p. 962]**PEER REVIEWED**
  
• Transient mildly elevated hepatic aminotransferase levels and reversible renal failure were reported in an estimated 10,000 ppm xylene exposure occurring during the painting of a poorly ventilated ship compartment. Two men were comatose and one was dead on arrival after this prolonged exposure over 18 hours. The survivors developed no long-term sequelae. The contributions of hypoxia and a toluene solvent could not be quantitated. [Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988., p. 962]**PEER REVIEWED**
  
• In workers exposed to organic solvents (acetone, benzene, toluene, ethyl acetate, butyl acetate, xylene, gasoline, and turpentine) the incidence of chronic bronchitis was higher, and the volume of expiratory air was lower than in normal control subjects. In smokers the incidence was higher than nonsmokers of /exposed and nonexposed/ groups. Smoking increases risk of chronic bronchitis in ... subjects /exposed to organic solvents/. [Sykut E; Przegl Lek 38 (4): 399-402 (1981)]**PEER REVIEWED**
  
• Dermal application of xylene caused a 20-40% decr in electrical impedance of human skin. [Kiss G; Munkavedelem 27 (1-3): 25-6 (1981)]**PEER REVIEWED**
  
• CNS DEFECTS WERE MORE COMMON IN CHILDREN OF MOTHERS EXPOSED TO ORG SOLVENTS & DUSTS DURING PREGNANCY. HYDRANENCEPHALY OCCURRED IN CHILDREN WHOSE MOTHERS HAD BEEN EXPOSED TO THE SOLVENTS TOLUENE, XYLENE, & WHITE SPIRIT DURING MANUFACTURE OF RUBBER PRODUCTS. [HOLMBERG PC, NURMINEN M; AM J OF INDUST MED 1: 167 (1980)]**PEER REVIEWED**
  
• Women are liable to suffer from menstrual disorders (menorrhagia, metrorrhagia). It has been reported that female workers exposed to ... xylene in concn which periodically exceeded the exposure limits were also affected by pathological pregnancy conditions (toxicosis, danger of miscarriage, hemorrhage during child birth) and infertility. [International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I&II. Geneva, Switzerland: International Labour Office, 1983., p. 2335]**PEER REVIEWED**
  
• Mixed xylenes ... at exposures of one to four times TLV (threshold limit value) /SRP: 400 ppm/ levels were used. Subjective reports of irritation, as well as polygraph records of eyeblink and respiration rate were recorded during 30 min exposures. Psychomotor tests were administered before, during, and after exposure. Both a higher incidence of eye irritation and rate of eyeblink were reported by exposed subjects compared to controls, but the effects were mild. There were no significant differences in respiration rates or in tests of psychomotor function. [Hastings GP et al; Adv Mod Environ Tox 6: 255-70 (1984)]**PEER REVIEWED**
  
• USING A STANDARDIZED INTERVIEW SCHEDULE, OCCUPATIONAL EXPOSURE TO ORG SOLVENTS WAS INVESTIGATED IN 61 MALE PATIENTS WITH DIAGNOSIS OF NON-HODGKIN'S LYMPHOMA. RESULTS INDICATE A RELATION BETWEEN EXPOSURE TO ORG SOLVENTS & SUPRADIAPHRAGMATIC PRESENTATION OF NON-HODGKIN'S LYMPHOMA. ELEVEN REPORTED EXPOSURE TO XYLENE. HOWEVER, IN MOST CASES EXPOSURE TO MORE THAN ONE SOLVENT WAS REPORTED. [OLSSON H, BRANDT L; ACTA MED SCAND 210: 415 (1981)]**PEER REVIEWED**
  
• For the period 1961-80, 118 cases of industrial gassings caused by the solvents methlyene chloride, xylene, toluene and styrene were reported to Her Majesty's Factory Inspectorate. The data were collated and analyzed according to the predetermined criteria of age, sex, mode and circumstances of use, clinical effect and outcome. The study shows the /SRP: CNS depressant/ effect of these solvents and underlines the dangers of their use in confined spaces. Symptoms were most commonly attributable to the nervous and respiratory system. [Bakinson MA, Jones RD; Br J Ind Med 42 (3): 184-90 (1985)]**PEER REVIEWED**
  
• Disturbances of memory, mood, equilibrium and sleep that occurred simultaneously with headache and indigestion, were experienced more frequently among women working in histology who had daily exposure to formaldehyde, xylene and toluene than in unexposed female clerical workers in the same hospitals. Neurobehavioral symptoms were accompanied by irritation of the eyes, upper air ways and trachea. Formaldehyde exposure correlated better with neurobehavioral symptoms and with respiratory and mucous membrane symptoms than did exposure to xylene/toluene or to other agents. [Kilburn KH et al; Arch Environ Health 40 (4): 229-33 (1985)]**PEER REVIEWED**
  
• ... Inhalation of xylenes at concn of 435-1300 mg/cu m for 15 min to 6 hr/day for 4 days results in CNS disturbances including changes in numerative ability, reaction time, short-term memory and electroencephalograph. [USEPA; Advisory Opinion for Xylenes (Dimethyl benzenes) (Draft) p.6 (1981)]**PEER REVIEWED**
  
• An adverse health effect disturbance to equilibrium has been observed in humans. ... This effect has been correlated with blood concn ... of 30 umol/l (equivalent to 318 ug/100 ml) ... . [USEPA; Advisory Opinion for Xylenes (Dimethyl benzenes) (Draft) p.6 (1981)]**PEER REVIEWED**
  
• Mixtures of organic solvents, which include xylenes, have been implicated as the cause of lens change in car painters. ... [National Research Council. Drinking Water and Health. Volume 3. Washington, DC: National Academy Press, 1980., p. 179]**PEER REVIEWED**
  
• Among nine pregnancies producing offspring with caudal regression syndrome five mothers had exposure to fat solvents. These included ... xylene. [Shepard, T.H. Catalog of Teratogenic Agents. 5th ed. Baltimore, MD: The Johns Hopkins University Press, 1986., p. 612]**PEER REVIEWED**
  
• The concentration of xylene present in the blood, its serum or plasma, that has been reported to cause death, or is so far above reported therapeutic or toxic concentrations that one can judge that it might cause death in humans is 3-40 ug/ml. [Winek, C.L. Drug and Chemical Blood-Level Data 1985. Pittsburgh, PA: Allied Fischer Scientific, 1985., p. ]**PEER REVIEWED**
  
• The correlation between xylene exposure and urinary excretion of methyl hippuric acid (MHA) was studied in 40 workers (35 men, 5 women) employed in the paint industry. Subjects were exposed primarily to xylene although exposure to 11 other solvents was possible. Personal sampling showed 8-hr TWA's for xylene ranged from 0-865 mg/cu m with a median exposure of 69 mg/cu m. Urine was collected over one 24-hr period for each worker. Personal air samples were collected for each worker over the course of a complete workday. MHA excretion was linearly correlated to the 8-hr TWA for xylene exposure after adjustment for body weight. The total amount of MHA excreted in the urine over 24 hr showed virtually the same correlation to xylene exposure (r = 0.84) as the MHA excretion during the latter part of the workshift (r = 0.81, sampling time 4-5 hr) among 37 workers exposed to 8-hr TWA xylene concentrations of 0-200 mg/cu m. [Lundberg I, Sollenbert J; Scand J Work Environ Health 12:149-53 (1986)]**PEER REVIEWED**
  
• Vapor irritates eyes and mucous membranes and may cause dizziness, headache, nausea, and mental confusion. Liquid irritates eyes and mucous membranes. Swallowing or absorption through skin would cause poisoning. Prolonged exposure to skin contact may result in dermatitis. [Armour, M.A. Hazardous Laboratory Chemicals Disposal Guide. Boca Raton, FL: CRC Press Inc., 1991., p. 461]**PEER REVIEWED**
  
• Serum concentrations of liver enzymes were determined for Swedish paint industry workers exposed to a mixture of organic solvents including xylene. Mean xylene exposure for 44 individuals was 82 mg/cu m (19 ppm) with a range of 1 to 6070 mg/cu m; five workers were exposed to a mean concentration of 865 mg/cu m (199 ppm). Serum alanine aminotransferase, aspartate aminotransferase, ornithine carbamoyltransferase, and gamma-glutamyltransferase activities were not elevated by these exposures. ... Occupational experience reveals complaints of dermatitis, eczema, and irritation of the eyes and respiratory tract but rarely serious illness. It is likely that untoward effects on the hematopoietic system reported in the past as being caused by xylene resulted from benzene contamination of commercial xylene. [Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 2. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991., p. 644]**PEER REVIEWED**
  
• Six volunteers were able to detect the odor of mixed xylenes at a concentration of 60 mg/cu m; four could detect 6 mg/cu m, but none could detect 0.6 mg/cu m. The odor threshold was calculated as 4.5 mg/cu m or about 1 ppm for a 10-sec exposure. In a 15-min exposure period, the only common sign of discomfort at 2000 mg/cu m (460 ppm) was eye irritation in four of six subjects. Some transitory olfactory fatigue occurred, with recovery in 10 min. [Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 2. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991., p. 644]**PEER REVIEWED**
  
• Exposure of volunteers to technical xylene by inhalation caused irritation of the airways; very high accidental exposure caused pneumonitis. Ingestion of xylene caused irritation of the gastrointestinal tract. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V47 142 (1989)]**PEER REVIEWED**
  
• Repeated, prolonged exposure to fumes may produce conjunctivitis of the eye and dryness of the nose, throat, and skin. Direct liquid contact may result in flaky or moderate dermatitis. Inhalation of vapors may cause CNS excitation then depression, characterized by paresthesia, tremors, apprehension, impaired memory, weakness, nervous irritation, vertigo, headache, anorexia, nausea, and flatulence, and may lead to anemia and mucosal hemorrhage. Clinically, no bone marrow aplasia, but hyperplasia, moderate liver enlargement, necrosis, and nephrosis may occur. [Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982., p. 3295]**PEER REVIEWED**
  
• During an informal study in 1973 it was noted that approx 1/3 of patients with congenital heart disease lived in a small area in the Tucson Valley. In 1981 groundwater for nearly identical area was found to be contaminated with trichloroethylene and to a lesser extent with dichloroethylene and chromium. Contamination probably began during the 1950s. Affected wells were closed after discovery of contamination. This sequence of events allowed investigation of the prevalence of congenital heart disease in children whose parents were exposed to the contaminated water area as compared with children whose parents were never exposed to the contaminated water area. The contaminated water area contained 8.8% of the Tucson Valley population and 4.5% of the labor force. Using their case registry, the authors interviewed parents of 707 children with congenital heart disease who, between 1969 and 1987, 1) conceived their child in the Tucson Valley, and 2) spent the month before the first trimester and the first trimester of the case pregnancy in the Tucson Valley. Two random dialing surveys showed that only 10.5% of the Tucson Valley population had ever had work or residence contact, or both, with the contaminated water area, whereas 35% of parents of children with congenital heart disease had had such contact (p < 0.005). The prevalence of congenital cardiac disease (excluding syndromes, children with atrial tachycardia or premature infants with patent ductus arteriosus) in the Tucson Valley was 0.7% of live births and with syndromes was calculated to be 0.82%. The odds ratio for congenital heart disease for children of parents with contaminated water area times that for those without contact (p < 0.005) and decr to near unity for new arrivals in the contaminated water area after well closure. The proportion of infants with congenital heart disease as compared with the number of live births was significantly higher for resident mothers in the contaminated water area than for mothers with no exposure. No other environmental agent could be identified that was localized to the contaminated water area, but one could have been missed. The data show a significant assoc but not a cause and effect relation between parental exposure to the contaminated water area and an incr proportion of congenital heart disease among live births as compared with the proportion of congenital heart disease among live births for parents without contaminated water area contact. [Goldberg SJ et al; J Am Coll Cardiol 16 (1): 155-64 (1990)]**PEER REVIEWED**
  
• The quantitative relationship between exposure to xylene vapor and urinary excretion in methylhippuric acid isomers were studied in the second half of a working wk. The participants in the study were 121 male workers engaged in dip-coating of metal parts who were predominantly exposed to three xylene isomers. The intensity of exposure measured by diffusive sampling during an 8-hr shift was such that the geometric mean vapor concn was 3.8 ppm for xylenes (0.8 ppm for o-xylene, 2.1 ppm for m-xylene, and 0.9 ppm for p-xylene), 0.8 ppm for toluene, and 0.9 ppm for ethylbenzene. Urine samples were collected at the end of the shift and analyzed for metabolites by HPLC. The statistical analysis showed that there is a linear relationship between the intensity of exposure to xylenes and the concn of methylhippuric acid in urine, that the regression line passes very close to the origin, and that the increment in observed (i.e., noncorrected) methylhippuric acid concn as a function of incr xylene concn was 17.8 mg/ppm. Further exam on the basis on individual xylene isomers showed that the slopes of the regression lines for o- and m-isomers were similar (i.e., 17.1 and 16.6 mg/L/ppm, respectively), whereas that for p-xylene was larger (21.3 mg/L/ppm). [Kawai T et al; Int Arch Occup Environ Health 63 (1): 69-76 (1991)]**PEER REVIEWED**
  

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Non-Human Toxicity Excerpts

• INVESTIGATORS: ... FOUND NO ADVERSE EFFECTS ON THE HEMATOPOIETIC SYSTEM /OF THE GUINEA PIG/ AFTER SC ADMIN AT 300 MG/KG/DAY FOR 6 WK OR 700 MG/KG/DAY FOR 9 WK. OTHER REPORTS OF MYELOTOXICITY OF XYLENE ARE PROBABLY RELATED TO BENZENE CONTAMINATION. [National Research Council. Drinking Water & Health Volume 1. Washington, DC: National Academy Press, 1977., p. 788]**PEER REVIEWED**
  
• ... RABBITS EXPOSED TO BENZENE-FREE XYLENE (AT 5 MG/L, OR 1,150 PPM) FOR 40-55 DAYS HAD DECREASED RED & WHITE CELL COUNTS. [National Research Council. Drinking Water & Health Volume 1. Washington, DC: National Academy Press, 1977., p. 789]**PEER REVIEWED**
  
• RATS WERE EXPOSED TO XYLENE VAPORS COMPOSED OF THE 3 XYLENE ISOMERS, ETHYLBENZENE, TOLUENE, AROMATICS & NONAROMATICS. LC50 FOR RATS WAS 29 MG/L/4 HR (6700 PPM). CATS SUCCUMBED WITHIN 2 HR AT 41 MG/L (9500 PPM) WITH SIGNS OF CNS DAMAGE. NO DIFFERENCES FROM CONTROL ANIMALS WERE OBSERVED IN BEAGLE DOGS & RATS THAT INHALED 3.5, 2.0 OR 0.77 MG/L CONCN FOR 6 HR/DAY, 5 DAYS/WK FOR 13 WK. [CARPENTER CP ET AL; TOXICOL APPL PHARMACOL 33 (3): 543-58 (1975)]**PEER REVIEWED**
  
• The embryotoxic effects of xylene were studied by exposing rats to 1000 mg/cu m of air during days 9 through 14 /of pregnancy/ ... found no teratogenic results although minor skeletal anomalies occurred. [Shepard, T.H. Catalog of Teratogenic Agents. 5th ed. Baltimore, MD: The Johns Hopkins University Press, 1986., p. 612]**PEER REVIEWED**
  
• Data obtained from rodents indicates that maternal exposure to mixed xylenes or individual xylene isomers can have adverse effects on the conceptus. Fetotoxic effects were reported following maternal inhalation exposure to mixed xylenes; altered enzyme activities were also found in rat pups. Dermal application resulted in apparent changes in fetal enzyme activities, while oral treatment was followed by prenatal mortality, growth inhibition, and malformations, primarily cleft palate. Maternal inhalation of individual isomers was associated with all the above mentioned effects, with the exception of cleft palate. The o- and p- isomers appeared more hazardous to the offspring than did the m-isomer. Malformations (ie cleft palate) associated with mixed or individual isomers were primarily reported at maternally toxic doses. Thus, a clear case for a selective teratogenic effect due to the exposure to xylene has yet to be presented. [Hood RD, Ottley MS; Drug Chem Toxicol 8 (4): 281-97 (1985)]**PEER REVIEWED**
  
• EFFECTS OF COAL TAR-ASSOCIATED CHEMICALS WERE TESTED BY SINGLE TOPICAL APPLICATION (1 MG/10 G BODY WT) TO NEONATAL RATS. THE INDUCIBILITY OF XYLENE ON SKIN ARYL HYDROCARBON HYDROXYLASE (AHH) WAS 8% & ON LIVER ARYL HYDROCARBON HYDROXYLASE 10%. [MUKHTAR H ET AL; TOXICOL APPL PHARMACOL 64: 541-9 (1982)]**PEER REVIEWED**
  
• Male rats exposed to different concentrations of xylene for three days /exhibited/ small but statistically significant increase in cytochrome p450 content. Reduced nicotinamide adenine dinucleotide cytochrome c reductase activity and O-deethylation of 7-ethoxyresorufin in liver microsomes were detected already at an exposure level of 75 ppm. Morphological studies of livers from rats exposed to relatively high concentrations showed marked proliferation of smooth endoplasmic reticulum with little changes of the rough endoplasmic reticulum. No pathological alterations were observed. Castration of male rats influenced the response of xylene exposure only to a minor extent. Hypophysectomy alone was shown to cause significant increases in cytochrome p450 and cytochrome b5 content and epoxide hydrolase activity. Induction of cytochrome p450 dependent enzymatic activities after exposure to xylenes was reduced but qualitatively similar to that obtained with normal male rats whereas the induction of epoxide hydrolase activity was prevented. ... [Toftgard R et al; Toxicol 27 (2): 119-37 (1983)]**PEER REVIEWED**
  
• XYLENE WAS ADMIN ORALLY TO FEMALE WISTAR CFT STRAIN RATS. XYLENE DID NOT PROVE LETHAL UP TO THE DOSAGE OF 6 ML/KG. HOWEVER, THE MINIMUM LETHAL DOSE WAS 7 ML/KG. SYMPTOMS MANIFESTED AT FATAL DOSES WERE DULLNESS, STUPOR, ANESTHESIA, CNS DEPRESSION, & COMA. MORTALITY WAS DOSE-DEPENDENT. [MURALIDHARA, KRISHNAKUMARI MK; IND J EXPER BIOL 18: 1148 (1980)]**PEER REVIEWED**
  
• Xylene, a widely used industrial solvent, is a mixture of ortho-, meta-, and para- isomers. In this study, ... the effects of each isomer, as well as a commercial-grade mixture of xylenes, on two behavioral measures /were examined/: 1) Operant performance of 15 mice trained to lever-press under a DRL (differential reinforcement of low rates) 10 sec schedule, and 2) motor performance of mice on an inverted screen test. The 15 min operant sessions immediately followed 30 min exposures to solvent vapors (500 to 7000 ppm), or air, in static inhalation chambers. Ortho-, meta-, para-, and mixed xylenes produced similar biphasic effects on response rates, and concentration dependent decreases in reinforcement rates. [Moser VC et al; Toxicol Appl Pharmacol 80 (2): 293-8 (1985)]**PEER REVIEWED**
  
• SUBACUTE EXPOSURE OF MALE RATS TO 2000 PPM OF XYLENE, ORTHO-XYLENE, META-XYLENE, PARA-XYLENE, & ETHYLBENZENE PRODUCED DISCRETE INCREASES OF DOPAMINE & NORADRENALINE LEVELS & TURNOVER IN VARIOUS PARTS OF HYPOTHALAMUS. XYLENE ITSELF PRODUCED WIDESPREAD INCR OF DOPAMINE TURNOVER WITHIN NEOSTRIATUM & SUBCORTICAL LIMBIC FOREBRAIN. [ANDERSSON K ET AL; TOXICOL APPL PHARMACOL 60: 535-48 (1981)]**PEER REVIEWED**
  
• EXPOSURE 6 HR/DAY FOR 3 DAYS TO 2000 PPM INCREASED HEPATIC CYTOCHROME P450 CONCENTRATIONS & NADPH CYTOCHROME C REDUCTASE ACTIVITY IN RATS. IN KIDNEY MICROSOMES AN INCR CONCN OF CYTOCHROME P450 WAS OBTAINED. IN LUNG MICROSOMES XYLENE CAUSED A DECR IN CYTOCHROME P450 CONTENT. [TOFTGARD R, NILSEN OG; TOXICOL 23: 197-212 (1982)]**PEER REVIEWED**
  
• MALLARD EGGS WERE TREATED BY IMMERSION IN XYLENE (1% & 10%) FOR 30 SECONDS AT ROOM TEMP. XYLENE HAD NO SIGNIFICANT EFFECTS AT CONCENTRATIONS OF 10% ON EMBRYONIC WT & LENGTH WHEN COMPARED TO CONTROLS. [HOFFMAN DJ, EASTIN WC; TOXICOL LETT 6: 35-40 (1981)]**PEER REVIEWED**
  
• HAMSTERS RECEIVED XYLENE TOPICALLY FOR 2 HR BETWEEN DAYS 7 & 11 & WERE KILLED AT DAY 15 OF GESTATION. FETAL SIZE & WEIGHT DECREASED & THE INCIDENCE OF PRENATAL DEATHS INCREASED. FETAL HEMORRHAGE & GASTROSCHISIS WERE ALSO NOTED. NO MALFORMATIONS WERE FOUND IN CONTROLS. [OVERMAN DO; TERATOLOGY 23: 56A (1981)]**PEER REVIEWED**
  
• PREGNANT OUTBRED ALBINO MICE RECEIVED BY GAVAGE, 3 TIMES/DAY IN COTTONSEED OIL, A XYLENE MIXT ON DAYS 6-15 OF GESTATION. THE MICE WHERE KILLED ON DAY 18. AT 3.6 ML/KG/DAY, XYLENE KILLED 12 OF 38 DAMS & CAUSED A SIGNIFICANTLY SMALLER AVG WT GAIN DURING PREGNANCY THAN DID THE COTTONSEED OIL. FETUSES FROM DAMS TREATED @ 2.4 ML/KG/DAY HAD AVG FETAL WT SIGNIFICANTLY LOWER THAN THAT OF CONTROL FETUSES. AT 2.4, 3.0, & 3.6 ML/KG/DAY XYLENE PRODUCED A SIGNIFICANTLY GREATER AVG % OF MALFORMED FETUSES THAN DID THE CONTROL. CLEFT PALATE WAS THE MAJOR MALFORMATION AT ALL 3 DOSES. WHEN BILATERAL WAVY RIBS WERE COUNTED AS A MALFORMATION, THE AVG % OF MALFORMED FETUSES INCR FROM 7.8 TO 10.5 @ 3.0 ML/KG/DAY & FROM 9.1 TO 13.4 @ 3.6 ML/KG/DAY. THUS, XYLENE (MIXED ISOMERS) IS TERATOGENIC TO MICE @ 2.4 & 3.0 ML/KG/DAY. [MARKS TA ET AL; J TOXICOL ENVIRON HEALTH 9 (1): 97-105 (1982)]**PEER REVIEWED**
  
• By exposing cats for several hours to concentrations of xylene vapor which were just sublethal /the laboratory/ succeeded in producing vacuoles in the corneal epithelium which appeared to be analogous to those occurring in vacuolar keratopathy occurring in workmen from exposure to solvent vapors. [Shepard, T.H. Catalog of Teratogenic Agents. 5th ed. Baltimore, MD: The Johns Hopkins University Press, 1986., p. 612]**PEER REVIEWED**
  
• Rats /exposed to/ xylene at 230, 1900, or 3360 mg/cu m for 24 hr/day from day 7-14 of pregnancy showed no maternal toxicity. However, bone formation was retarded in the fetuses at all 3 concn, and the number of nephrons with enzyme activity and the activity ... of succinic dehydrogenase, alkyl phosphatase, acid phosphatase, and glucose 6-phosphatase were decreased in fetuses at the highest concn. ... The incidence of extra ribs in fetuses increased, however, none of the concn were teratogenic. The incidence of postimplantation fetal loss increased. [Balogh T et al; Egeszsegtudomany 26 (1): 42-8 (1982)]**PEER REVIEWED**
  
• In rats, exposure to xylene (50 or 500 mg/cu m) resulted in embryotoxic and teratogenic effects. The brain, liver, lung, and heart were affected. The number of postimplantation losses increased by 9.7 and 168% in the 50 and 500 mg/cu m xylene group, respectively. The incidence of fetal skeletal abnormalities was increased by 62 and 177%, respectively. [Mirkova E et al; J Hyg Epidemiol Microbiol Immunol 27 (3): 337-43 (1983)]**PEER REVIEWED**
  
• Rats were exposed to ... xylene at 200-800 ppm for 30 days. After exposure, changes in the dopamine, norepinephrine, serotonin, acetylcholine (ACH), CAMP, CGMP, GCBA, Gln, Asp, Tau, Gly, and Ala content of different areas of the brain were investigated. Acetylcholine in the striatum and the whole brain was reduced dose dependently by ... xylene. ... Xylene caused different changes in monoamine content ... but the changes were not dose dependent. ... Glutamine content was increased by ... xylene at 800 ppm. [Honma T et al; Ind Health 21 (3): 143-52 (1983)]**PEER REVIEWED**
  
• In rats exposed to /xylene/ by inhalation for 2 wk (5 days/wk, 6 hr/day) ... kidney 7-ethoxycoumarin O-deethylase activity was increased >200% ... /and/ liver UDP-glucuronosyltransferase activity was increased ... approx 100%. ... [Heinonen T et al; Extrahepatic Drug Metag Chem Carcinog Proc Int Meet 29-31 (1983)]**PEER REVIEWED**
  
• ... Xylene reduced the number and weight of /Agaricus bisporus/ sporophores. [Flegg PB; Sci Hortic 21 (4): 301-10 (1983)]**PEER REVIEWED**
  
• Kucera reports studies in chick embryos exposed for 60 to 240 minutes to a xylene atmosphere at developmental periods up to the 10 somite stage. A high malformation rate was found and nearly one-half of the defects were rumplesness, a defect resembling caudal regression syndrome. [Shepard, T.H. Catalog of Teratogenic Agents. 5th ed. Baltimore, MD: The Johns Hopkins University Press, 1986., p. 1548]**PEER REVIEWED**
  
• Exposure of male rats to /250-2000 ppm/ of xylene for 3 days induced, in a dose related way, the in vitro liver microsomal metabolism of antipyrine. The degree of induction was significant at an exposure level of 250 ppm and maximal (2.5-fold incr) at 2000 ppm. This incr was of the same magnitude as after phenobarbital treatment. Female rats had lower basal antipyrine metabolism than males but exhibited a greater relative incr in antipyrine metabolism following xylene exposure. ... Exposure to lower xylene levels did not produce significant alterations in antipyrine elimination half-life. ... [Toftgaard R; Toxicol 28 (1-2): 117-31 (1983)]**PEER REVIEWED**
  
• Quail eggs were treated directly by spraying the shell with 2 or 0.05% aq suspensions of ... xylene, or indirectly by repeated ingestion by the parental quail of contaminated feed. /Xylene/ significantly acted upon the quail biotic potentials by reducing the hatching rate and the embryonic viability and increasing the fecundation rate and the weight of eggs, chickens, and adults. /Xylene/ reversed the sex ratio, so that the male birds had an advantage in number and acted more specifically on the embryonic genital development. [David D; Arch Anat Microsc Morphol Exp 71 (3): 159-74 (1982)]**PEER REVIEWED**
  
• ... Xylene at 2 mmol/kg decreased the metabolism of (14)C labeled benzene (2 mmol/kg) to phenol and other metabolites in rats. The metabolism of (14)C toluene was not inhibited by ... xylene. ... [Gut I; Prac Lek 33 (6-7): 202-8 (1981)]**PEER REVIEWED**
  
• Groups of Sprague Dawley rats were exposed, by inhalation, to ... xylene (600 ppm, 2625 mg/cu m) ... for 4 wk. Increased liver weights and liver to body wt ratios were observed. ... An increase in in vitro formation of certain metabolites of all substrates was found in rats exposed to xylene. ... Xylene was a 'phenobarbital-like' inducer of rat liver microsomal cytochrome p450. [Toftgard R et al; Scand J Work Environ Health 7 (1): 31-7 (1981)]**PEER REVIEWED**
  
• In single administration studies, groups of five F344/N rats and B6C3F1 mice of each sex received 500, 1,000, 2,000, 4,000, or 6,000 mg/kg /gavage in corn oil/. Administration of xylenes caused deaths at 6,000 mg/kg in rats and mice of each sex and at 4,000 mg/kg in male rats. Clinical signs observed /from 24 hr to 2 wk/ of dosing at 4,000 mg/kg included prostration, muscular incoordination, and loss of limb movement. Tremors, prone position, and slowed breathing were recorded for mice on day 3, but all mice appeared normal by the end of the 2 wk observation period. [NTP; Toxicology and Carcinogenesis Studies of Xylenes (Mixed) p.3 Report No TR 327 (1986) NIH Pub No 87-2583]**PEER REVIEWED**
  
• In 14 day studies, groups of five /rats/ ... of each sex ... were administered 0, 125, 250, 500, 1,000, or 2,000 mg/kg and mice received 0, 250, 500, 1,000, 2,000, or 4,000 mg/kg. Chemical related mortality occurred only at 2,000 mg/kg in rats and 4,000 mg/kg in mice. Rats and mice exhibited shallow breathing and prostration within 48 hr following dosing at 2,000 mg/kg. These signs persisted until day 12 for rats, but no clinical signs were noted during the second wk for mice. [NTP; Toxicology and Carcinogenesis Studies of Xylenes (Mixed) p.3 Report No TR 327 (1986) NIH Pub No 87-2583]**PEER REVIEWED**
  
• In 13 wk studies, groups of 10 rats of each sex received 0, 62.5, 125, 250, 500, or 1,000 mg/kg, and groups of 10 mice of each sex received 0, 125, 250, 500, 1,000, or 2,000 mg/kg. No deaths or clinical signs of toxicity were recorded in rats. However, high dose male rats gained 15% less and females gained 8% less weight than did the vehicle controls. Two female mice died at the 2,000 mg/kg level. Lethargy, short and shallow breathing, unsteadiness, tremors, and paresis were observed for both sexes in the 2,000 mg/kg group within 5-10 min after dosing and lasted for 15-60 min. [NTP; Toxicology and Carcinogenesis Studies of Xylenes (Mixed) p.3 Report No TR 327 (1986) NIH Pub No 87-2583]**PEER REVIEWED**
  
• ... It is of importance to note that coal-based solvents (eg, xylene) have been suggested to be possible potent lymphocytic leukemogens, such as benzene, in a limited study of the relationship between lymphocytic leukemia and exposures to benzene and other solvents in the rubber industry. Available animal data on the carcinogenicity of xylene(s) are inadequate to permit an evaluation. In limited studies thus far, the individual isomers were not found genotoxic when tested in a number of short-term tests. [Fishbein L; Sci Total Environ; 43 (1-2): 165-83 (1985)]**PEER REVIEWED**
  
• Two laboratories tested multiple forms of xylene for their developmental toxicity hazard potential (A/D ratio) by means of the hydra assay. The three isomers, as well as a solution of mixed xylenes, all interfered with development (D) at or near to concn that also were toxic to adult (A) hydra. The development/adult ratios ranged from 1 to 2 in hydra as they had in conventional tests made in pregnant laboratory animals. Each testing laboratory concluded that xylenes were not primary development hazards but coeffective agents capable of disrupting development only at or near to concn also toxic to adults. In each instance every xylene tested interfered with the same stage or developmental sequence and in a concn related manner. The hydra assay may be useful for establishing priorities to test agents in a more elaborate system, but substances less soluble than xylene may exceed the test's applicability. [Johnson EM et al; Toxicol Appl Pharmacol 82 (2): 323-8 (1986)]**PEER REVIEWED**
  
• ... Pregnant CFY rats /were exposed/ by continuous inhalation to 1,000 mg/cu m (230 ppm) of a xylene mixture (10% o-, 50% m-, 20% p-xylene, and 20% ethylbenzene) on gestational days 9 through 14. At this concn, the xylene mixture produced skeletal effects including an increased incidence of supernumerary ribs (9/143 alizarin-stained fetuses in the dosed group compared to 2/143 in the control group). ... Two cases of agnathia (absence of mandible) /were reported/ in 286 pups. [Hudak A, Ungvary G; Toxicol 11: 55-63 (1978)]**PEER REVIEWED**
  
• RATS PRETREATED WITH XYLENE OR PHENOBARBITAL & THEN EXPOSED TO N-HEXANE, SHOWED A MARKEDLY INCR PEAK SERUM CONCN OF THE NEUROTOXIC METABOLITE 2,5-HEXANEDIONE. [TOFTGAARD R ET AL; MOL PHARMACOL 23 (1): 265-71 (1983)]**PEER REVIEWED**
  
• Admin of xylenes to rats caused decr in liver glutathione (GSH) concn, reduction in glutathione concn was most pronounced after treatment with o-xylene isomer (4.0 mmol/kg). [Van Doorn R et al; Arch Toxicol 43 (4): 293-304 (1980)]**PEER REVIEWED**
  
• Hepatocytes isolated from male Sprague-Dawley rats (200-275 g) were exposed to halogenated and non-halogenated hydrocarbons. Leakage of cellular enzymes and inhibition of respiration were monitored as indicators of toxicity. Cell suspensions contained 2-3X10+6 cells/ml and were viable for 6 hr as indicated by a < 10% increment in the fractional release of aspartate aminotransferase activity. The hydrocarbons were added to the cell suspension as 20% solutions in ethanol. The addition of 20 mM dimethylbenzene (DMB) caused a rapid release, which peaked within 60 min, into the medium. Approximately 22% (n= 4) of the total aspartate aminotransferase was found in the medium and the release was concentration dependent. Cellular oxygen consumption was reduced when DNB was present, and the reduction was dose dependent. The relationship of the effects of cellular respiration to alteration in mitochondrial function was studied using dinitrophenol (DNP) and succinate, an NADH-independent mitochondrial substrate. DNP-induced oxygen stimulation was abolished by 10 mM DMB. Succinate-stimulated respiration was unaffected by 2.5 mM DMB, but DPN-stimulated respiration was significantly reduced. Mitochondrial function returned to normal within 1 hr. /Dimethylbenzene/ [Berger ML, Sozeri T; Toxicology 45 (3): 319-30 (1987)]**PEER REVIEWED**
  
• In some rats exposed to 3000 mg/cu m mixed xylenes for 8 hours per day on six days per week for 110-130 days, exposure resulted in paralysis of the hind legs, weight loss, a slight decrease in leukocytes, increases in blood urea, urinary blood and albumin, and hyperplasia of the bone marrow. Slight congestion of kidney, liver, heart, adrenal, lung and spleen were observed. Cellular desquamation of glomeruli and necrosis of the convoluted tubules were also reported. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V47 138 (1989)]**PEER REVIEWED**
  
• Ten to 20 applications of undiluted mixed xylenes on the ears or shaved abdomen of rabbits for two or four weeks resulted in moderate to marked erythema and oedema, with superficial necrosis at both sites. After introduction of two drops of mixed xylenes into the rabbit eye, slight conjunctival irritation and transient corneal injury were observed. Application of undiluted xylene to the eye caused corneal lesions in cats. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V47 137 (1989)]**PEER REVIEWED**
  
• ... Two drops of mixed xylenes instilled into rabbit eyes induced slight conjunctival irritation with very slight, transient corneal injury. [American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991., p. 1732]**PEER REVIEWED**
  
• Nine rats inhaled 690 ppm of mixed xylenes, 8 hours/day, 6 days/week for 110 to 130 days, while six rabbits inhaled 1200 ppm 8 hours/day, 6 days/week for 40 to 50 days. In some animals, exposure resulted in paralysis of hind legs; weight loss; a slight decrease in leukocytes; increases in blood urea, urinary blood, and albumin; and hyperplasia of the bone marrow. Slight congestion of the kidney, liver, heart, adrenal, lung, and spleen was observed. [American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991., p. 1733]**PEER REVIEWED**
  
• Fertility and pregnancy indices were no different among male and female rats inhaling 60, 250, or 500 ppm xylene, 6 hours/day for 131 premating days, during 20 mating days, and throughout gestation and lactation as compared with the concurrent control animals. [American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991., p. 1734]**PEER REVIEWED**
  
• Rats exposed to 300 ppm, 6 hours/day, 5 days/week for 18 weeks showed increased hepatic monooxygenation. /From table/ [American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991., p. 1733]**PEER REVIEWED**
  
• The effects of acute xylene exposure on the enkephalinergic neuromodulatory system were studied in rats. Male Sprague-Dawley rats were injected ip with 0 or 1.6 mL/kg xylene daily for 3 consecutive days. Three hr after the last dose, they were killed and the brains were removed. The brains were dissected into the parietal cortex. caudate putamen, medial preoptic areas of the hypothalamus, globus pallidus, olfactory tubercle, and central amygdaloid nuclei (CA). The various brain parts were analyzed for changes in their met-enkephalin content by an immunostaining technique. Xylene decr the extent of immunostaining for met-enkephalin in the globus pallidus, olfactory tubercle, and the CA. The decr in the globus pallidus and CA were statistically significant. The decr in the olfactory tubercle was not significant. Immunostaining for met-enkephalin in the other brain regions was not affected by xylene. The authors conclude that xylene decr the met-enkephalin content of specific brain regions. The regional specificity of these decr suggests that enkephalins are involved in xylene neurotoxicity. [de Gandarias JM et al; Ind Health 33 (1): 1-6 (1995)]**PEER REVIEWED**
  
• ... Mixed xylenes (60% m-, 14% p-, 9% o-xylene, and 17% ethylbenzene) in corn oil were administered by gavage to mice and rats 5 days/week for 103 weeks. Mice received daily doses of 500 or 1000 mg/kg; rats received 250 or 500 mg/kg. No gross or histopathological lesions were related to these treatments; tumor incidence was similar for treated and control groups of either species. There was no evidence for carcinogenicity. When tested for mutagenicity, o-, m-, and p-xylene were negative by assay in the Ames system using Salmonella typhimurium strains TA1535, TA1537, TA1538, TA98, and TA100 with or without metabolic activation by S9 fraction derived from livers of rats either untreated or induced with Aroclor 1254. Xylene did not change the number of sister chromatid exchanges or the number of chromosomal aberrations in human lymphocytes in vitro. /Xylenes/ [Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 2. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991., p. 644]**PEER REVIEWED**
  
• Teratogenicity has been evaluated for a xylene mixture (9.1% o, 60.2% m, 13.6% p, and 17.0% ethylbenzene) in pregnant albino CD-I mice given the mixture at dosages of 2.4, 3.0, and 3.6 ml/kg/day by gavage on days 6-15 of gestation. At these near-lethal doses, xylene produced a significant increase in malformations, with cleft palate being the major malformation observed. Exposure of CFY rats to 1000 mg/cu m (230 ppm) xylene for 24 hr/day from day 9 to 14 of gestation was not teratogenic, although there was an increase in skeletal anomalies consisting of extra ribs and fused sternebrae. [Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 2. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991., p. 644]**PEER REVIEWED**
  
• Rats exposed 6 hr/day for 3 days to 2000 ppm of a xylene mixture of the o, m, and p isomers showed an increase in hepatic cytochrome p450 and NADPH-cytochrome c reductase. The p isomer was less potent in inducing this effect that the other isomers or the mixture. Microsomes from lung and kidney also showed increases in cytochrome p450 for the xylene mixture and isomers except the p isomer failed to induce cytochrome p450 in microsomes from kidney. [Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 2. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991., p. 644]**PEER REVIEWED**
  
• ... Under the conditions of these 2 yr gavage studies, there was no evidence of carcinogenicity of xylenes (mixed) for male or female F344/N rats given 250 or 500 mg/kg or for male or female B6C3F1 mice given 500 or 1,000 mg/kg. [Toxicology & Carcinogenesis Studies of Xylenes in F344/N Rats and B6C3F1 Mice (gavage Studies). Technical Report Series No. 327 (1986) NTIS Publication No. PB87-189684/AS U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709]**QC REVIEWED**
  

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Human Toxicity Values

• LDLo Human oral 50 mg/kg [USEPA; Advisory Opinion for Xylenes (Dimethyl benzenes) (Draft) p.3 (1981)]**PEER REVIEWED**
  

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Non-Human Toxicity Values

• LD50 Rat oral 4.3 g/kg [Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 2. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991., p. 643]**PEER REVIEWED**
  
• LD50 Rat oral 10 mL/kg /Xylene/ [Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 2. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991., p. 643]**PEER REVIEWED**
  
• LD50 Mouse oral 1590 mg/kg /Xylene/ [Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 2. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991., p. 643]**PEER REVIEWED**
  
• LC50 Rat inhalation 6,350 ppm/4 hr [Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982., p. 3292]**PEER REVIEWED**
  
• LCLo Rat inhalation 8,000 ppm/4 hr [BDM Corp; The AAR Haz Mater Database (1981) as cited in Environment Canada; Tech Info for Problem Spills: Xylene (Draft) p.80 (Dec 1981)]**PEER REVIEWED**
  
• LC50 Rat inhalation 6,350 ppm/4 hr [Clayton GD, Clayton FE; Patty's Ind Hyg and Toxicol 2A, 2B : (1981) as cited in Environment Canada; Tech Info for Problem Spills: Xylene (Draft) p.80 (Dec 1981)]**PEER REVIEWED**
  
• LC50 Mouse inhalation 3,907 ppm/6 hr [US National Research Council; The Alkyl Benzenes (1981) as cited in Environment Canada; Tech Info for Problem Spills: Xylene (Draft) p.81 (Dec 1981)]**PEER REVIEWED**
  
• LD50 Rat oral 4.3 g/kg and 10 ml/kg /Xylene/ [Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 2. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991., p. 643]**PEER REVIEWED**
  
• LD50 Mouse oral 1590 mg/kg /Xylene/ [Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 2. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991., p. 643]**PEER REVIEWED**
  
• LC50 Rat oral 29,000 mg/cu m (6670 ppm) /Xylene/ [Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 2. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991., p. 644]**PEER REVIEWED**
  
• LD50 Rat oral range from 3523 mg/kg to 8600 mg/kg. /Mixed Xylenes/ [American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991., p. 1732]**PEER REVIEWED**
  
• LD50 Mouse (B6C3F1) oral 5251 mg/kg (female) and 5627 mg/kg (male). /Mixed Xylenes/ [American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991., p. 1732]**PEER REVIEWED**
  
• LD50 Rabbit dermal > 5 ml/kg (43 g/kg). /Mixed Xylenes/ [American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991., p. 1732]**PEER REVIEWED**
  

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Absorption, Distribution and Excretion

• For exposure to xylene at concn averaging 100 ppm, the mean methyl hippuric acid concn should average 1.5 to 2 g/g creatinine (range 1.0-3.0) in a sample collected during the second part of the exposure period. Almost total urinary excretion of xylene occurs by 24 hours. The rapid xylene clearance from blood (plasma half-life of 4 hours) prevents adequate biological monitoring of serum samples. ... [Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988., p. 963]**PEER REVIEWED**
  
• XYLENES HAVE BEEN REPORTED TO CROSS THE HUMAN PLACENTA. [National Research Council. Drinking Water and Health. Volume 3. Washington, DC: National Academy Press, 1980., p. 180]**PEER REVIEWED**
  
• XYLENE, WHEN INGESTED, IS READILY ABSORBED BY THE HUMAN SYSTEM, AS HAS BEEN SHOWN IN ACCIDENTAL INGESTIONS. ABSORPTION THROUGH INTACT & BROKEN SKIN OCCURS READILY. ... XYLENE IS ABSORBED MAINLY THROUGH MUCOUS MEMBRANES & PULMONARY SYSTEM. ... ABSORBED XYLENE IS TRANSLOCATED THROUGH THE VASCULAR SYSTEM. ... [Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982., p. 3296]**PEER REVIEWED**
  
• The uptake of solvent by man during whole body exposure to toluene and xylene occurs almost exclusively through the lung; dermal uptake represents about 1% of the total uptake. [Wallen M et al; Brit J Indust Med 42: 111-6 (1985)]**PEER REVIEWED**
  
• Male rats were injected ip with benzene, toluene, or a mixt or xylene isomers at 20 mmol hydrocarbon/kg daily for 3 days. The effects of administration of these hydrocarbons upon their own in vitro metabolism, as well as upon cytochrome p450, NADPH-cytochrome c reductase, aminopyrine N-demethylase, aniline hydroxylase, glutathione, glutathione S-transferase, and UDP-glucuronyltransferase in liver were studied. [Pathiratne A et al; Toxicol Appl Pharmacol 82 (2): 272-80 (1986)]**PEER REVIEWED**
  
• The correlation between xylene exposure and urinary excretion of methyl hippuric acid (MHA) was studied in 40 workers (35 men, 5 women) employed in the paint industry. Subjects were exposed primarily to xylene although exposure to 11 other solvents was possible. Personal sampling showed 8 hr time weighted average for xylene ranged from 0-865 mg/cu m with a median exposure of 69 mg/cu m. Urine was collected over one 24 hr period for each worker. Personal air samples were collected for each worker over the course of a complete workday. Methyl hippuric acid excretion was linearly correlated to the 8 hr time weighted average for xylene exposure after adjustment for body weight. The total amount of methyl hippuric acid excreted in the urine over 24 hr showed virtually the same correlation to xylene exposure (r= 0.84) as the methyl hippuric acid excretion during the latter part of the workshift (r= 0.81, sampling time 4-5 hr) among 37 workers exposed to 8 hr time weighted average xylene concentrations of 0-200 mg/cu m. [Lundberg I, Sollenbert J; Scand J Work Environ Health 12: 149-53 (1986)]**PEER REVIEWED**
  
• Humans exposed to 46 or 92 ppm of o-, m-, p-xylene or a mixture (1:1:1) of the three for 8 hr absorbed approx 64% of the inhaled xylene. No difference in the absorption rate was reported due to level of exposure, length of exposure, or the type and/or mixture of the xylene isomers. The absorption of xylene appeared to vary among individuals due to differences in ventilation rate. ... Individuals with an incr ventilation rate retained less xylene. [NCI; Monograph on Human Exposure to Chemicals in the Workplace: Xylene p.4-2 (July/1985)]**PEER REVIEWED**
  
• Male Wister rats exposed to xylene in air (80% m-xylene, 12% p-xylene) for 6 hr/day, 5 days/week for 2 weeks accumulated 64.8 mg/xylene/g of perirenal fat after five exposures and 127.0 mg/xylene/g of perirenal fat after 10 exposures to xylene. [NCI; Monograph on Human Exposure to Chemicals in the Workplace: Xylene p.4-4 (July/1985)]**PEER REVIEWED**
  
• Groups of five male Wister rats were exposed to 300 ppm of technical grade xylene (85% m-xylene, 15% other isomers) for 6 hr/day, 5 days a week for 5, 9, 14, or 18 weeks. Analysis of the perirenal fat by gas chromatography indicated that 67.6, 57.4, 40.7, and 36.6 mg/g of tissue was present after 5, 9, 14, or 18 weeks of exposure, respectively. The gradual decr in the xylene content of perirenal fat as the length of exposure was incr may have been the result of an incr metabolic rate. [NCI; Monograph on Human Exposure to Chemicals in the Workplace: Xylene p.4-4 (July/1985)]**PEER REVIEWED**
  
• Groups of six male human volunteers were exposed to 200 or 100 ppm of a xylene mixture (49.4% ethylbenzene) for 30 min through a breathing valve. The first group, while being exposed to 200 ppm of the xylene mixture, exercised on a bicycle ergometer for 90 min. The second group, exposed to 100 ppm, ... incr their level of exercise at 30 min intervals. At rest and during light work, pulmonary uptake ... was about 63% during the 2 hr exposure period. At a more strenuous work level, pulmonary uptake ... was only 51% after a correction had been applied for the incr breathing vol that occurs during heavy exercise. [NCI; Monograph on Human Exposure to Chemicals in the Workplace: Xylene p.4-1 (July/1985)]**PEER REVIEWED**
  
• 15 human male volunteers exposed for 70 min periods to 100 and 300 ppm at rest and 300 ppm while exercising absorbed a mean of 180, 541, or 1210 mg of xylene, respectively. The xylene absorption rate for both exposure levels was 43% while resting and 64% while exercising, assuming inhalation volumes of 20 cu m/24 hr at rest and 10 cu m/8 hr at work. [NCI; Monograph on Human Exposure to Chemicals in the Workplace: Xylene p.4-2 (July/1985)]**PEER REVIEWED**
  
• Xylene possesses marked solubility in adipose tissue (distribution coefficient fat/blood approximately 100). ... [Riihimaki V et al; Arch Toxicol 49: 253-63 (1982)]**PEER REVIEWED**
  
• Xylene vapor is absorbed rapidly from the lungs, and xylene liquid and vapor are absorbed slowly through the skin. Of the xylene absorbed, about 95% is metabolized in the liver to methylhippuric acid and 70 to 80% of metabolites are excreted in the urine within 24 hr. However, the many variables which affect the absorption, metabolism and clearance of xylene incl exercise, alcohol intake, cigarette smoking, co-exposure to other solvents, gender, and GI, hepatic and renal pathology. [Langman JM; Pathol 26 (3): 301-309 (1994)]**PEER REVIEWED**
  
• FOLLOWING EXPOSURE OF RABBITS TO ATMOSPHERE OF ABOUT 3,000 MG/CU M FOR 8 HR/DAY, 6 DAYS/WK, FOR 130 DAYS, XYLENE WAS FOUND AT SLIGHTLY HIGHER AVG CONCENTRATIONS IN THE ADRENAL (148 PPM), BONE MARROW (130 PPM), SPLEEN (115 PPM), & BRAIN (100 PPM) THAN IN BLOOD (91 PPM) OR IN OTHER ORGANS. /XYLENES/ [Hayes, Wayland J., Jr. Pesticides Studied in Man. Baltimore/London: Williams and Wilkins, 1982., p. 123]**PEER REVIEWED**
  
• IN HUMANS ... EXPOSED TO APPROX 0.2-0.4 MG/L XYLENE ISOMERS (O-, M-, P-XYLENE) OR 1:1:1 MIXT FOR UP TO 8 HR ... PULMONARY RETENTION WAS 64%, WHICH WAS ... INDEPENDENT OF DOSAGE OR DURATION OF EXPOSURE. AFTER EXPOSURE, ONLY 5% OF RETAINED XYLENES WERE ELIM IN EXPIRED AIR. MORE THAN 95% ... EXCRETED BY HUMANS INTO URINE IN FORM OF METHYLHIPPURIC ACIDS. ... SMALL PORTION ... EXCRETED INTO URINE AS CORRESPONDING XYLENOLS. [National Research Council. Drinking Water and Health. Volume 3. Washington, DC: National Academy Press, 1980., p. 179]**PEER REVIEWED**
  

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Metabolism/Metabolites

• IN HUMANS ... EXPOSED TO APPROX 0.2-0.4 MG/L XYLENE ISOMERS (O-, M-, P-XYLENE) OR 1:1:1 MIXT FOR UP TO 8 HR ... MORE THAN 95% ... EXCRETED BY HUMANS INTO URINE IN FORM OF METHYLHIPPURIC ACIDS. ... SMALL PORTION ... EXCRETED INTO URINE AS CORRESPONDING XYLENOLS. [National Research Council. Drinking Water and Health. Volume 3. Washington, DC: National Academy Press, 1980., p. 179]**PEER REVIEWED**
  
• Quantitative determination of urinary metabolites in humans exposed to xylene using colorimetric determination is widely used. The metabolites of ... xylene are measured as ... methyl hippuric acid (MHA), paper chromatography and thin layer chromatography are necessary as pretreatments of samples. The addition of pyridine, p-dimethylaminobenzaldehyde (DAB) and acetic anhydride to glycine conjugates gives the most stable color development. Excellect analytical sensitivity and specificity with gas chromatographic methods requires pretreatment with diazomethane for methylesterification of methyl hippuric acid. [Ogata M; Acta Med Okayama 35 (6): 385-94 (1981)]**PEER REVIEWED**
  
• ... Xylene is metabolized to a toxic aldehyde, methylbenzaldehyde ... . [Riihimaki V et al; Scand J Work Environ Health 8: 77-9 (1982)]**PEER REVIEWED**
  
• The principal difference between human and animal xylene metabolism is the production of p-methylbenzaldehyde catalyzed by rabbit and rodent lung and liver alcohol dehydrogenase. Glucuronidation apparently occurs after saturation of normal glycine metabolic pathways that predominate in humans as evidenced by the methylhippuric acids in urine. Methylbenzyl alcohol and dimethylpheonl have not been reported in human studies. [American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991., p. 1735]**PEER REVIEWED**
  
• Generally, the xylenes are metabolized to the corresponding o-, m-, or p-toluic acids, and excreted in urine free or conjugated with glycine as methylhippuric acid. [Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982., p. 3296]**PEER REVIEWED**
  

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TSCA Test Submissions

• Acute oral toxicity was evaluated in groups of 7 Sprague-Dawley male albino rats administered single doses of undiluted xylenes by oral gavage at levels of 0.85, 2.55, 4.25, 5.95, 7.65, and 8.65 g/kg of body weight. Mortality was observed in 3 animals in the 4.25 g/kg dose group, 5 in the 5.95 g/kg dose group, and in all animals in the two highest dose groups. The LD50 value was calculated to be 4.5 g/kg (3.3 - 6.2 g/kg confidence limits) by the Litchfield and Wilcoxon method. Clinical observations included shallow, rapid respiration and bloody discharge around the nose in the 4.25 and 5.95 g/kg dose group and marked depression to coma, shallow respiration, lacrimation, and bloody crusts around the eyes and nose in the 7.65 and 8.50 g/kg dose group. Gross necropsy revealed congested to hemorrhagic lungs, pale, mottled livers and kidneys, and excessive hyperhemia to a grey-green discoloration of the walls of the stomach and upper intestinal tract in decedents; survivors appeared normal.[Hazleton Nuclear Science Corporation; Acute Oral LD50 - Rats. (1962), EPA Document No. 878220853, Fiche No. OTS0215109]**UNREVIEWED**
  
• Xylene (CAS No. 1330-20-7) was tested for dermal irritation. The test substance was applied at 0.5 ml to intact and abraded skin of three groups of 6 rabbits (sex not reported). The first group had the sites occluded for 4 hours, the second for 24 hours, and the third were unoccluded. Well-defined to moderate erythema and edema were noted in the unoccluded and the 4-hour occluded groups. Well-defined to moderate erythema and well-defined to severe edema were observed in the 24-hour occluded group. The primary irritation scores were 4.2, 5.2, and 4.8 for 4-hour occluded, 24-hour occluded and non-occluded groups, respectively.[STANDARD OIL CO; The Eye and Skin Irritation Potential of Xylene; 02/09/77; Document No. 878220855; Fiche No. OTS0215109]**UNREVIEWED**
  
• Xylene (CAS No. 1330-20-7) was tested for eye irritation. The test substance was applied at 0.1 ml to the conjunctival sac of one eye of each of 6 rabbits (sex not reported) Mild iritis was observed in most eyes at 1 hour; slight corneal opacity was observed in 2 eyes at 24 hours, and 1 eye at 48 hours. Moderate conjunctival irritation was present in most eyes at 1 and 24 hours, but was slight at 48 and 72 hours. All eyes were normal by 7 days.[STANDARD OIL CO; The Eye and Skin Irritation Potential of Xylene; 02/09/77; Document No. 878220855; Fiche No. OTS0215109]**UNREVIEWED**
  
• Xylene (CAS# 1330-207) was evaluated for developmental effects in mice administered the test substance by gavage at dose levels of 0, 0.6, 1.2, 2.4, 3.0, 3.6 or 4.2 mL/kg/day. There were 15/15 mortalities at 4.2 mL/kg/day and 12/38 at 3.6 mL/kg/day. Maternal body weight gain was reduced in survivors at 3.6 mL/kg/day (p<0.05). The average maternal liver weight was increased at 2.4 and 3.0 mL/kg/day and the average fetal weight was reduced at 2.4 and 3.0 mL/kg/day (p<0.05). The average percent of malformed fetuses was increased at 2.4, 3.0, and 3.6 mL/kg/day (p<0.01). Cleft palate was observed in the 1.2, 2.4, 3.0, and 3.6 mL/kg/day groups.[Research Triangle Inst.; Initial Submission: Teratogenicity Study with Xylene in Mice with Cover Letter Dated 072292, (1979), EPA Doc. No. 88-920005518, Fiche No. OTS0544772]**UNREVIEWED**
  
• Mixed xylenes (CAS# 1320-20-7) were evaluated for developmental effects in groups of male and female Charles River rats administered the test substance for 6 hours/day by inhalation at concentrations of 0 (group I), 60 (group II), 250 (group III), 500 ppm (groups IV, V, and VI). Group I consisted of 30 untreated males and 30 untreated females, groups II and III consisted of 10 treated males and 10 treated females in each, group IV contained 20 treated males and 40 treated females, group V contained 10 treated males and 20 untreated females, and group VI contained 10 untreated males and 20 treated females. Treated animals were exposed for 131 days pre-mating and 20-day mating period. Females continued to be exposed during days 1-20 of gestation and on days 5-20 of lactation. Twenty group I (control) and 12 group IV females were sacrificed on day 21 of gestation in order to evaluate mating performance and pregnancy data. Group III and group VI showed mating indices which were significantly lower than controls. High dose females (groups IV and VI) showed an increased mean number of resorption sites. Mean fetal weight was lower in the high dose group than in the control group (this difference was only significant for female fetuses).[Bio/dynamics Inc.; Initial Submission: Parental and Fetal Reproduction Inhalation Toxicity Study in Rats with Mixed Xylenes (Volume I of II) (Final Report) with Cover Letter Dated 012092, (1983), EPA Doc. No. 88-920000699, Fiche No. OTS0533862]**UNREVIEWED**
  
• Mixed xylenes (CAS# 1320-20-7) were evaluated for developmental effects in groups of male and female Charles River rats administered the test substance for 6 hours/day by inhalation at concentrations of 0 (group I), 60 (group II), 250 (group III), 500 ppm (groups IV, V, and VI). Group I consisted of 30 untreated males and 30 untreated females, groups II and III consisted of 10 treated males and 10 treated females in each, group IV contained 20 treated males and 40 treated females, group V contained 10 treated males and 20 untreated females, and group VI contained 10 untreated males and 20 treated females. Treated animals were exposed for 131 days pre-mating and 20-day mating period. Females continued to be exposed during days 1-20 of gestation and on days 5-20 of lactation. Twenty group I (control) and 12 group IV females were sacrificed on day 21 of gestation in order to evaluate mating performance and pregnancy data. Group III and group VI showed mating indices which were significantly lower than controls. High dose females (groups IV and VI) showed an increased mean number of resorption sites. Mean fetal weight was lower in the high dose group than in the control group (this difference was only significant for female fetuses).[Bio/dynamics Inc.; Initial Submission: Parental and Fetal Reproduction Inhalation Toxicity Study in Rats with Mixed Xylenes (Volume I of II) (Final Report) with Cover Letter Dated 012092, (1983), EPA Doc. No. 88-920000699, Fiche No. OTS0533862]**UNREVIEWED**
  
• Xylene (CAS# 1330-20-7) was evaluated for acute dermal toxicity. The test substance was applied undiluted to the skin of New Zealand albino rabbits for 24-hours. Dosages and mortality data are as follows: 2000 (0/1 M); 3160 (0/1 F); 5010 (1/1 M in 2-days); 7940 mg/kg body weight (1/1 F in 2-days). Clinical signs included weight loss, increasing weakness, collapse, and death. Necropsy findings included hemorrhagic areas of the lungs, liver, and kidney discoloration, enlarged gall bladder, and gastrointestinal inflammation. The LD50 was determined to be greater than 3160 mg/kg b.w.[MONSANTO CO; Initial Submission: Toxicity Studies with Ortho Xylene in Rats and Rabbits with Cover Letter Dated 08/17/92; 09/11/78; EPA Doc. No. 88-920007141; Fiche No. OTS0545480]**UNREVIEWED**
  

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Footnotes

¹ Source: the National Library of Medicine's Hazardous Substance Database, 10/28/2007.