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EC number: 284-895-5
CAS number: 84989-06-0
The fraction of tar acids, rich in 2,4- and 2,5-dimethylphenol, recovered by distillation of low-temperature coal tar crude tar acids.
acid, xylenol fraction is expected to be well absorbed via the oral,
dermal and inhalation route. Absorption factors of 100% are proposed for
all routes. The substance is anticipated to be widely distributed
through the body, metabolised and excreted mainly in the urine. No
bioaccumulation potential is expected.
There are no studies available in which the toxicokinetic behaviour of
tar acid, xylenol fraction (CAS 84989-06-0) has been investigated.
Therefore, in accordance with Annex VIII, Column 1, Section 8.8.1, of
Regulation (EC) No 1907/2006 and with Guidance on information
requirements and chemical safety assessment Chapter R.7c: Endpoint
specific guidance (ECHA, 2017), assessment of the toxicokinetic
behaviour of Tar acid, xylenol fraction is conducted to the extent that
can be derived from the relevant available information. This comprises a
qualitative assessment of the available substance-specific data on
physico-chemical and toxicological properties according to Guidance on
information requirements and chemical safety assessment Chapter R.7c:
Endpoint specific guidance (ECHA, 2017) and taking into account further
available information on surrogate substances and constituents,
Tar acid, xylenol fraction contains mainly xylenol isomers (>60%) with
2,4-xylenol and 2,5-xylenol as major components (>40%) and to a lesser
content cresol isomers (<25%).
The major physical-chemical parameters of the test substance and
its constituents are summarized in the following table:
Tar acid, xylenol fraction
133 @ 20°C
Liquid or solid
5.33 – 35.99 @ 25 °C
1.94 – 1.96
14.7 - 37 @ 25°C
MW = molecular weight
WS = water solubility
VP = vapour pressure
There is little, robust information available regarding the
toxicokinetics of Tar acid, xylenol fraction or xylenols. However, based
on structural similarities with cresols and as cresols are also a
constituent of tar acid, xylenol fraction, it is expected that the
absorption, distribution, metabolism and excretion of both tar acid,
xylenol fraction and xylenols are expected to share similarities with
cresols. The toxicokinetic assessment on cresols is therefore
additionally summarised from an authoritative review of extensive,
relevant published literature (ATSDR, 2008).
Mechanisms by which substances can be absorbed in the gastro-intestinal
(GI) tract include the passage of small water-soluble molecules
(molecular weight up to around 200) through aqueous pores or carriage of
such molecules across membranes with the bulk passage of water. As the
test substance and its constituents are soluble in water and have a
relatively low molecular weight, this passive diffusion will be the
predominant mechanism for absorption in the GI tract. In addition
moderate octanol/water partition coefficient (logPow) values (between -1
and 4) are favourable for absorption by passive diffusion, being
applicable for the test substance and it constituents. Following the
above it can be concluded that the test substance and its constituents
will result in a high systemic exposure after oral administration. For
hazard and risk assessment purposes oral absorption of the tar acid,
xylenol fraction is set to 100%. The results of the toxicity studies
with cresol isomers and xylenol isomers do not provide reasons to
deviate from this proposed oral absorption.
Tar acid, xylenol fraction can be solid and liquid around ambient
temperatures. Similarly this is also described for xylenol isomers and
cresol isomers. They all have low vapour pressure so it is not expected
that they will reach the nasopharyncheal region or subsequently the
tracheobranchial or pulmonary region. In addition, only particles with
aerodynamic diameters below 100 µm have the potential to be inhaled by
humans; as tar acid, xylenol fraction can change between liquid and
solid, particles below 100 µm are anticipated not to be present. In view
of its moderate lipophilic character and water solubility, any tar acid,
xylenol fraction reaching the tracheobranchial region may be taken up by
passive diffusion. For hazard and risk assessment purposes the
inhalation absorption of tar acid, xylenol fraction is set to 100%.
Tar acid, xylenol fraction and its constituents have relatively high
water solubility of at least 6000 mg/L up to 26000 mg/L. Its
octanol/water partition coefficient indicates a sufficiently lypophilic
character to penetrate the lipid rich stratum corneum. Thus, Tar acid,
xylenol fraction and its constituents are considered to partition
moderate to high from the stratum corneum into the epidermis. Its
chemical structures as well as its molecular masses do not indicate that
dermal uptake will be slowed. With a molecular mass below 500 and logPow
values in the range [1.94 – 2.35], the data meet the criteria for 100%
dermal absorption as given in the ECHA Endpoint Specific Guidance 7.c
for the implementation of REACH (R.7.12 “Guidance on Toxicokinetics”).
As tar acid, xylenol fratction is considered to be corrosive to the skin
as derived from its constituents; damage to the skin surface may enhance
penetration. The available results of the toxicity studies with cresol
isomers and xylenol isomers do not provide reasons to deviate from this
proposed dermal absorption of 100%.
For all routes absorption behaviour described above is supported by the
published information available for cresols (ATSDR, 2008):
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, 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 from the gastric contents in 15 minutes, and almost all
of the administered cresol disappeared within 8 hours. In blood, the
unconjugated concentrations of p- and m-cresol showed the highest peak
at 30 minutes after dosing and decreased rapidly afterwards. No
unconjugated cresols could be detected after 4 hours. The p-cresol
glucuronide in blood was always higher than the p-cresol sulphate,
whereas 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 rate and extent of absorption in
animals following dermal exposure to cresols.
Once absorbed the water soluble tar acid, xylenol fraction and its
constituents are expected to widely distribute through the body. Its
moderate lipophilic character indicates that they are likely to
distribute into cells and the intracellular concentration may be higher
than extracellular concentration. Wide distribution through the body is
confirmed from the histopathologic findings in the repeated dose studies.
The distribution assumption described above is supported by the
published information available for cresols (ATSDR, 2008):
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
cresols 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.. In
all tissues, m-cresol sulphate was always higher than p-cresol sulphate,
suggesting a slightly different metabolic disposition for these two
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.
Tar acid, xylenol fraction and its constituents are expected to undergo
Phase I reactions including aliphatic and aromatic hydroxylation and
further oxidation. Phase II reactions, including glucuronidation and
sulfation, will further increase water solubility.
In addition, the following information is available for cresols (ATSDR,
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.
Based on the high water solubility (6000 to 26000 mg/L) and the low
molecular weight, tar acid, xylenol fraction and its conjugation
products are expected to be mainly excreted in the urine.
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
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.
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.
ECHA (2017). Guidance on information requirements and chemical safety
assessment, Chapter R.7c: Endpoint specific guidance. Version 3.0.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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