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There is little, robust information available regarding the toxicokinetics of either ethyl phenols or xylenols. However, based on structural and toxicological similarities with cresols, it is expected that the absorption, distribution, metabolism and excretion of both xylenols and ethyl phenols are expected to share similarities with cresols. The toxicokinetic assessment on cresols is summarised from an authoritative review of extensive, relevant current published literature (ATSDR, 2008).

 

Introduction

Cresols can be absorbed following inhalation, oral and dermal exposure. Most of the evidence of absorption in humans is indirect, derived from cases of accidental dermal contact with these substances or accidental or intentional ingestion. Limited data from workers exposed to airborne cresols provide evidence of absorption by inhalation, although dermal absorption could have also occurred. Quantitative data are not available. Little is known about distribution of cresols in humans. In a fatal case of dermal intoxication, cresols were found in the brain and liver. Studies in animals dosed by oral gavage with a single dose of m- or p-cresol indicate that cresols can distribute rapidly into many organs and tissues. Cresols undergo oxidative metabolism in the liver and are rapidly eliminated, mostly in the urine as sulphate or glucornide conjugates. However, the relevance of available toxicokinetics information in animals to toxicokinetic of cresols in humans is unknown.

 

Absorption

The absorption of cresols following inhalation exposure in animals has not been quantified, but can be assumed to occur, since mortality and other effects have been reported in animals following exposure.

 

The rate and extent of absorption in humans following oral exposure to cresols have not been investigated. However, it can be assumed that cresols are absorbed orally

based on the many reports of adverse effects in subjects who ingested cresols accidentally or intentionally. In a study in rabbits administered all three cresols isomers by oral gavage under fasting conditions, from 65% to 85% of the administered dose was recovered in the urine within 24 hours, indicating that at least that amount had been absorbed. When p-cresol was administered 1-2 hours after the rabbits were fed, the rabbits exhibited less toxic effects than when given the compound under fasting conditions, indicating that the gastrointestinal contents retarded the absorption. After a single gavage dose of a cresol soap (p- and m-cresol) to rats, 50% of the administered dose disappeared within 8 hours. In blood, the unconjugated concentrations of p- and m-cresol decreased rapidly for 2 hours after peaking 30 minutes after dosing. No unconjugated cresols could be detected after 4 hours. The p-cresol glucuronide in blood was always higher than the p-cresol sulphate, where as the concentration of m-cresol sulphate was consistently higher than the m-cresol glucuronide. Based on the fact that the concentrations of the unconjugated cresols in liver and spleen were much higher than those in blood over a monitoring period of 8 hours, the author of the study suggested that cresols administered by oral gavage diffuse directly through the gastric and small intestine walls. 

 

The occurrence of coma, death and systemic effects in two humans dermally exposed to cresols indicates that these compounds can be absorbed through the skin. An in vitro study of the permeability of human skin to cresols found that these substances had permeability coefficients greater than that for phenol, which is known to readily absorb across the skin in humans. No studies were located regarding the rat and extent of absorption in animas following dermal exposure to cresols.

 

Distribution

No studies were located regarding the extent of distribution in humans or animals following inhalation exposure to cresols.

 

The distribution of m- and p-cresol has been studied in rats. Rats received a single gavage dose of a mixture of m- and p-cresol soap solution and conjugated and unconjugated cresols were determined in tissues at various times up to 8 hours after dosing. The concentrations of unconjugated m- and p-cresol in liver and spleen were always much higher than in blood and higher than the sulphate or glucuronide metabolites in those organs. The unconjugated concentration of both cresol in brain, lung and muscle were similar to those in blood. The concentration of glucuronidated cresols were always highest in the kidney followed by the liver. Comparison of the concentration of glucuronide and sulphate conjugates in tissues showed that the glucurnoide was always higher than the sulphate for both cresols, particularly in the liver and kidneys. In all tissues, m-cresol sulphate was always higher than p-cresol sulphate, suggesting a slightly different metabolic disposition for these two isomers.

 

Regarding dermal exposure, cresols were identified in the blood, liver and brain of a 1-year old baby who died 4 hours after 20 mL of a cresol derivative was spilled on his head. There are no studies located regarding the extent of distribution in animals following dermal exposure to cresols.

 

In rats administered a single intravenous dose of 3 mg/kg of p-cresol, the concentration of p-cresol in blood 5 minutes after dosing was 6.7 mg/L and decreased gradually to 0.6 mg/L near 240 minutes after dosing. The half-life of p-cresol in serum was 1.5 hours (twice as long as creatinine) and its total clearance was 23.2 mL/minute/kg (3 times that of creatinine). Also, the volume of distribution of p-cresol was 5 times that of creatinine; however, renal clearance of p-cresol (4.8 mL/minute/kg) was about half that of creatinine.

 

Metabolism

Only a few studies have investigated the metabolism of cresols in animals. Cresols in the urine are found primarily as sulphate and glucuronide conjugates. In the urine of rabbits, 60–72% of the orally administered dose was recovered as ether glucuronide, and 10–15% was recovered as ethereal sulphate. A similar result was obtained in an earlier study in rabbits in which 14.5–23.5% of the orally administered dose was found conjugated with sulphate in the urine (for simple phenols such as cresols, the proportions of the conjugates are known to vary with dose and to differ from one species to the next). Hydroxylation of a small percentage (3%) of the administered dose to 2,5-dihydroxytoluene (conjugated) occurred for both o- and m-cresol. No hydroxylation occurred for p-cresol, but p-hydroxybenzoic acid (both free and conjugated) was detected in the urine. Only 1–2% of the administered dose was found as unconjugated free cresol in the urine. A study in rats showed that m-cresol is preferentially metabolised to sulphate, and p-cresol to glucuronide.

 

Further studies have provided more detailed information on the metabolism of cresols. Using rat liver microsomes and precision-cut liver slices, p-cresol formed monoglutathione conjugates with a structure consistent with the formation of a quinone methide intermediate. The latter may be formed in two successive one electron oxidation steps by cytochrome P-450. Using human liver microsomes, activation of p-cresol by oxidation forms a reactive quinone methide which formed a conjugate, glutationyl-4-methyphenol. In addition, a new pathway was identified consisting of aromatic oxidation leading to the formation of 4-methyl-o-hydroquinone which is further oxidized to 4-methyl[1,2]benzoquinone. The latter formed three adducts with glutathione, but the predominant was found to be 3-(glutathione-S-yl)-5-methyl o-hydroquinone. It was also found that 4-hydroxybenzylalcohol, a major metabolite formed by oxidation of the methyl group in liver microsomes, was further converted to 4-hydroxybenzaldehyde. Experiments with recombinant P-450s demonstrated that the formation of the quinone methide intermediate was mediated by several P-450s including CYP2D6, 2C19, 1A2, 1A1, and 2E1. The ring oxidation pathway was found to be mediated primarily by the CYP2E1 and to a lesser extent by CYP1A1, 1A2, and 2D6. Formation of 4-hydroxybenzaldehyde was catalyzed by 1A2 and also 1A1 and 2D6. Human liver microsomes formed the same adducts as rat liver microsomes suggesting that the metabolism of p-cresol is similar in humans and rats.

 

Elimination and excretion

Studies of subjects occupationally exposed to cresols have demonstrated that cresols are eliminated in the urine. Workers employed in the distillation of the high temperature phenolic fraction of tar excreted p-and o-cresol in the urine at rates of 2.4 and 3.3 mg/hour, respectively. The highest concentrations in urine were found during the first 2 hours after the end of the work shift. A study of 76 men working at a coke plant where the geometric mean concentrations of o-, m-, and p-cresol in the breathing zone air were 0.09, 0.13, and 0.13 mg/m3, respectively, reported that the corresponding concentrations in hydrolyzed urine were 16.74, 16.74, and 0.53 mg/g creatinine.

 

Following oral exposure to cresols in rabbits, 65–84% of the dose was excreted in the urine within 24 hours, mostly as ethereal glucuronides and sulphates.

 

No studies were located regarding excretion in humans or animals following dermal exposure to cresols.

 

Intravenous injection of a single dose of p-cresol to rats resulted in approximately 23% of the injected dose being excreted in the urine as parent compound within 240 minutes, the duration of the experiment. The total clearance of p-cresol largely exceeded its renal clearance, which led to the suggestion that the presence of extra-renal elimination routes for p-cresol, namely, exsorption from the blood compartment into the gastrointestinal tract, biotransformation, or excretion via the bile. A subsequent study from the same group of investigators showed that in rats, 64% of an intravenous dose of p-cresol (9.6 mg/kg) was excreted as p-cresyl glucuronide. When the glucuronide and the unconjugated p-cresol were combined, approximately 85% of the injected dose was recovered in the urine.

 

References:

Agency for Toxic Substances and Disease Registry (ATSDR, September 2008). Toxicological profile for cresols. U.S.. Department of Health and Human Services. Public Health Service.http://www.atsdr.cdc.gov/toxprofiles/tp34.pdf