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EC number: 215-089-3
CAS number: 1300-71-6
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).
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 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.
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
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.
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
were located regarding the extent of distribution in humans or animals
following inhalation exposure to cresols.
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
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.
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.
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.
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.
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.
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.
were located regarding excretion in humans or animals following dermal
exposure to cresols.
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.
Toxic Substances and Disease Registry (ATSDR, September 2008).
Toxicological profile for cresols. U.S.. Department of Health and Human
Services. Public Health
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