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Description of key information

Tar 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.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

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, respectively.

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:

 

MW [g/mol]

WS [mg/L]

Log Pow

VP [Pa]

Physical appearance

Tar acid, xylenol fraction

138

7670-11000

2.1-2.35

133 @ 20°C

Liquid or solid

Xylenol isomers

122

6000

around 2.3

5.33 – 35.99 @ 25 °C

Liquid or solid

Cresol isomers

108

21500-26000

1.94 – 1.96

14.7 - 37 @ 25°C

Liquid or solid

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).

Absorption:

Oral

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.

Inhalation

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%.

Dermal

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.

Distribution

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 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

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, 2008):

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.

Excretion

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.

In addition, the following information is available for cresols (ATSDR, 2008):

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.

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

ECHA (2017). Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance. Version 3.0.