Generally in animals, the metabolism of xylenes is similar to that of humans but there are some qualitative differences. The major difference is in the metabolism of methylbenzoic acid ... . Metabolism of xylenes may be influenced by prior exposure. Rats pretreated with m-xylene showed an approximately 10% increase in the percentages of methylhippuric acid and thio ethers in urine. Gastric intubation of rats with 1.1-1.4 mL/kg of m-xylene for 3 consecutive days was found to induce CYP2B and CYP2E1 in liver microsomes. In the Wistar rat, 4 days of inhalation of xylene at 4 g/cu m, 20 hours/day, induced CYP2B1 but reduced CYP2E1.
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.
The ortho, meta, and para isomers, in decreasing order, are demethylated to phenol. In the rabbits exposed to 1 mg/L, 4 hr/day for 32 days, m-xylene produced 57.3 to 63.9 mg of m-methylhippuric acid. The metabolite was completely cleared 24 hr following exposure.
Meta & para isomers are ... Extensively oxidized to toluic acids (about 90% of the dose), & these are conjugated mostly with glycine. Hydroxylation to corresponding xylenols also occurs to small extent.
IDENTIFICATION AND USE: 3-Xylene (m-xylene) is a clear colorless liquid. It is used as a solvent; intermediate for dyes and organic synthesis, especially isophthallic acid; in insecticides; in aviation fuel. m-Xylene is also used in the manufacturing of polyester and alkyl resins. HUMAN EXPOSURE AND TOXICITY: The effects of exposure to m-xylene on the central nervous system were investigated in humans. Male volunteers were exposed to m-xylene vapor, at stable concentration of 8.2 umol/L or fluctuating concentration with peaks (16.4 umol/L) for 4 hr a day. Body balance of subjects was clearly impaired in the anteroposterior direction, especially when subjects closed their eyes during the peaks at rest. Body balance improved when subjects exercised, even in the presence of the high m-xylene concn in the blood. Complex motor reactions were impaired after the peaks combined with exercise. In other experiment volunteers exposed to m-xylene were subjected to tests of numerical ability, reaction time, short-term memory and critical flicker fusion. There was evidence of reduction in the performance on 3 of the 4 tests in the second set of experiments. Slight, but statistically significant, increases in the average rating for subjective symptoms of neurological effects were observed following exposure to 50 ppm m-xylene vapor compared to controls. After 60 and 118 minutes of exposure, severity ratings for feelings of intoxication were elevated in men and women, and ratings for headache were elevated in men. The ratings for dizziness were increased in exposed men after 118 minutes of exposure. For biomonitoring purposes the m-and p-xylene isomers usually are measured together and reported as m/p-xylene. ANIMAL STUDIES: Exposure of rats to 2000 ppm of m-xylene for 3 days increased hepatic cytochrome P450 concentration and reduced nicotinamide adenine dinucleotide cytochrome c reductase activity. Adverse respiratory effects noted in rats, mice, and guinea pigs following acute and intermediate inhalation exposure to m-xylene are similar to those observed in humans. They include decreased respiration, labored breathing, irritation of the respiratory tract, pulmonary edema, pulmonary hemorrhage, and pulmonary inflammation. In a study of levels of noradrenaline and dopamine in various parts of the forebrain and hypothalamus, rats (six males/group) were exposed to 0 or 2000 ppm m-xylene, 6 hr/day for 3 days. The animals were killed within 18 hr after the last exposure. A significant increase in catecholamine levels and turnover was observed in various parts of the hypothalamus of exposed animals. There was no effect on dopamine levels. Histological damage to the outer hair cells of the organ of Corti provided evidence of ototoxicity in rats exposed by oral gavage to p-xylene, but not m- or o-xylene, at a dose of 900 mg/kg/day, 5 days/week for 2 weeks. No effect on absolute or relative heart weights was observed in male rats intermittently exposed to m-xylene at concentrations as high as 100 ppm for 13 weeks. Exposure of rats to 1 mg/L of m-xylene, 4 hr/day for 6 months caused inhibition of the phagocytic activity of leukocytes. Mice were exposed to m-xylene at 150, 1500, or 3000 mg/cu m, 24 hr/day from days 7-14 of gestation. Toxic effects were decreased weight of fetuses, decreased activity of succinic dehydrogenase, alkaline and acid phosphatase, and glucose 6-phosphatase. Also m-xylene changed characteristic features of functional maturity of the nephron, retardation of fetus was dose related. At highest dose level it increased preimplantation fetal losses, increased incidence of extra ribs and interfered with process of implantation. 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. Each xylene isomer was administered to male rats intraperitoneally in 2 similar doses, 24 hours apart over a range of concentrations from 0, 0.12-0.75 mL/kg (105-650 mg/kg) and evaluated femoral bone marrow 30 hours after the first injection. No increase in micronucleated polychromatic erythrocytes was observed for any xylene isomer. In an Ames assay, m-xylene did not revert Salmonella typhimurium strains TA1535, TA1537, TA1538, TA98, & TA100, either with or without metabolic activation. ECOTOXICITY STUDIES: The xylene isomers have a similar degree of toxicity as mixed xylenes to estuarine/marine invertebrates. For m-xylene and p-xylene, the respective 48-hour LC50 values are 19.3 and 24.5 mg/L in brine shrimp, suggesting that the m-xylene and p-xylene isomers are slightly toxic to estuarine/marine invertebrates on an acute basis.
m-Xylene is a cholinesterase or acetylcholinesterase (AChE) inhibitor. A cholinesterase inhibitor (or 'anticholinesterase') suppresses the action of acetylcholinesterase. Because of its essential function, chemicals that interfere with the action of acetylcholinesterase are potent neurotoxins, causing excessive salivation and eye-watering in low doses, followed by muscle spasms and ultimately death. Nerve gases and many substances used in insecticides have been shown to act by binding a serine in the active site of acetylcholine esterase, inhibiting the enzyme completely. Acetylcholine esterase breaks down the neurotransmitter acetylcholine, which is released at nerve and muscle junctions, in order to allow the muscle or organ to relax. The result of acetylcholine esterase inhibition is that acetylcholine builds up and continues to act so that any nerve impulses are continually transmitted and muscle contractions do not stop. Among the most common acetylcholinesterase inhibitors are phosphorus-based compounds, which are designed to bind to the active site of the enzyme. The structural requirements are a phosphorus atom bearing two lipophilic groups, a leaving group (such as a halide or thiocyanate), and a terminal oxygen.
Evaluation: There is inadequate evidence in humans for the carcinogenicity of xylenes. There is inadequate evidence in experimental animals for the carcinogenicity of xylenes. Overall classification: Xylenes are not classifiable as to their carcinogenicity to humans (Group 3)./Xylenes, o,m,p isomers/
CLASSIFICATION: D; not classifiable as to human carcinogenicity. BASIS FOR CLASSIFICATION: Orally administered technical xylene mixtures did not result in significant increases in incidences in tumor responses in rats or mice of both sexes. HUMAN CARCINOGENICITY DATA: None. ANIMAL CARCINOGENICITY DATA: Inadequate. /based on former classification system/
Under the Draft Revised Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1999), data are inadequate for an assessment of the carcinogenic potential of xylenes. Adequate human data on the carcinogenicity of xylenes are not available, and the available animal data are inconclusive as to the ability of xylenes to cause a carcinogenic response. Evaluations of the genotoxic effects of xylenes have consistently given negative results. /Xylenes/
Xylenes are rapidly absorbed by the respiratory tract with uptake increased by physical exercise. Absorption is also positively correlated with the amount of body fat. Liquid m-xylene is well absorbed through the skin, but dermal absorption of m-xylene vapor (up to 600 ppm) does not appear to be appreciably absorbed. Xylenes are highly soluble in blood and fat, and are distributed widely in the body. Xylenes undergo extensive metabolism and are primarily excreted as metabolites in the urine with small amounts released unchanged in expired air. About 90% of the absorbed dose is excreted in the urine as methylhippuric acid, the glycine conjugate of methylbenzoic acid, following inhalation or dermal (liquid) exposure.
Whole body exposure of mice to 14C-m-xylene vapor for 10 minutes showed that absorption was mainly via respiration. ... Almost complete absorption of 1.8 g m-xylene ...was observed in orally dosed rodents. Absorption after oral administration was rapid and peak levels of m-xylene were seen 20 minutes after a dose of 0.27 mg/kg. After oral administration, absorption rate was faster in females.
Dermal absorption has been studied by in vivo exposure of rat skin to liquid or vapor. Permeability constants were determined and were higher than those for humans. In excised rat skin preparations, duration of exposure correlated with level of skin penetration; rate was 0.967 nmole/sq cm/min. Skin:air partition coefficient for m-xylene was 50.4+/-1.7 and this correlated with the permeability constant.
In rats and mice, m- and p-xylene are distributed primarily to lipid-rich tissues, such as fat, blood, and brain and also in organs highly perfused with blood such as kidney and liver. Small amounts of p-xylene and o-xylene cross the placenta and distribute to amnionic fluid and fetal tissue. Oral administration of m-xylene to rats led to distribution of 14C-m-xylene in adipose tissue, approximately 0.3% of dose in female and 0.1% in males.
