2,5-xylenol

Endpoint summary

Description of key information

There are no studies available in which the toxicokinetic behaviour of 2,5-Xylenol (CAS 95-87-4) was investigated. In accordance with Annex VIII, Column 1, 8.8.1, of Regulation (EC) 1907/2006 and with ‘Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance’ (ECHA, 2017), an assessment of the toxicokinetic behaviour of the substance 2,5-Xylenol was conducted to the extent that can be derived from the relevant available information. 2,5-Xylenol is expected to be absorbed via the oral, dermal and inhaltion route. Absorption factors of 100% are therefore 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

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

100

Absorption rate - inhalation (%):

100

Additional information

There are no studies available in which the toxicokinetic behaviour of 2,5-Xylenol (CAS 95-87-4) was investigated.

In accordance with Annex VIII, Column 1, 8.8.1, of Regulation (EC) 1907/2006 and with ‘Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance’ (ECHA, 2017), an assessment of the toxicokinetic behaviour of the substance 2,5-Xylenol was 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 the Chapter R.7c Guidance document (ECHA, 2017).

 

Physico-chemical properties

2,5-Xylenol is an organic, mono-constituent substance with a molecular weight of 122.16 g/mol. It is a white to yellowish solid at 20 °C with a phenolic odour. The melting point is at 74.85°C. The water solubility is 3.54 g/L (converted from the published value of 0.029 mol/L) at 25°C and pH 5.1. The log Pow was estimated to be 2.6 at 25°C (pH 3), and the vapour pressure was approximately 4.25 Pa at 25°C.

 

Absorption

Absorption is a function of the potential for a substance to diffuse across biological membranes. The most useful parameters providing information on this potential are the molecular weight, the octanol/water partition coefficient (log Pow) value and the water solubility. The log Pow value provides information on the relative solubility of the substance in water and lipids (ECHA, 2017).

 

Oral

In general, molecular weights below 500 and log Pow values between -1 and 4 are favourable for absorption via the gastrointestinal (GI) tract, provided that the substance is sufficiently water soluble (> 1 mg/L). Lipophilic compounds can be taken up by micellar solubilisation by bile salts, but this mechanism may be of particular importance for highly lipophilic compounds (log Pow > 4), in particular for those that are poorly soluble in water (≤ 1 mg/L) as these would otherwise be poorly absorbed. Solids must be dissolved before absorption; the degree depends on the water solubility (ECHA, 2017).

Due to the physico-chemical characteristics (log Pow of 2.6, water solubility of 3.53 g/L and a molecular weight of 122.16 g/mol)) of 2,5-Xylenol is expected to have a high absorption rate via the oral route. This assumption is confirmed by the results of two acute oral toxicity studies with 2,5-Xylenol (Maazik, 1968 and Lamson and Brown, 1934) in which signs of poisoning and mortality were observed in rats, showing also oral absorption of 2,5-Xylenol. For hazard and risk assessment purposes oral absorption of 2,5-Xylenol is therefore set to 100%.

Dermal

The dermal uptake of liquids and substances in solution is higher than that of dry particulates, since dry particulates need to dissolve into the surface moisture of the skin before uptake can begin. Molecular weights below 100 g/mol favour dermal uptake, while for those above 500 g/mol the molecule may be too large. Dermal uptake is anticipated to be low if the water solubility is < 1 mg/L; low to moderate if it is between 1 - 100 mg/L; and moderate to high if it is between 100 - 10000 mg/L. Log Pow values in the range of 1 to 4 (values between 2 and 3 are optimal) are favourable for dermal absorption, in particular if the water solubility is high. For substances with a log Pow above 4, the rate of penetration may be limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high. Log Pow values above 6 reduce the uptake into the stratum corneum and decrease the rate of transfer from the stratum corneum to the epidermis, thus limiting dermal absorption (ECHA, 2017).

If a substance shows skin irritating or corrosive properties, damage to the skin surface may enhance penetration. If the substance has been identified as a skin sensitizer then some uptake must have occurred although it may only have been a small fraction of the applied dose (ECHA, 2017).

2,5-Xylenol has a molecular weight of 122.16 g/mol, but is a solid with a low to moderate water solubility. The log Pow is 2.6 Pa, which means an optimal value with respect to dermal absorption. Due to the fact that 2,5-Xylenol is a solid with low to moderate water solubility, which needs to dissolve into surface moisture of the skin before uptake, the dermal absorption is considered to be possible but could be lower than the oral absorption. Based on a QSAR calculated dermal absorption a value of 60.38 µg/cm²/h (high) was predicted for 2,5-Xylenol (Dermwin calculation). In addition, the substance has corrosive properties and is classified for skin sensitisation. The classification for skin sensitisation is based on QSAR analysis. Thus, there is no proof for dermal absorption based on experimental skin sensitisation data, but based on all available data and also taken into account the harmonised classification for acute dermal toxicity (Acute Tox. 3, H311), a worst-case approach should be applied for risk assessment and the dermal absorption of 2,5-Xylenol should be regarded as 100%.

 

Inhalation

Substances that can be inhaled include gases, vapours, liquid aerosols (both liquid substances and solid substances in solution) and finely divided powders/dusts. To be readily soluble in blood, a gas or vapour must be soluble in water and increasing water solubility would increase the amount absorbed per breath. However, the gas or vapour must also be sufficiently lipophilic to cross the alveolar and capillary membranes. Therefore, a moderate log P value (between -1 and 4) would be favourable for absorption. Generally, liquids, solids in solution and water-soluble dusts would readily diffuse/dissolve into the mucus lining the respiratory tract. Lipophilic substances (log P > 0) would then have the potential to be absorbed directly across the respiratory tract epithelium (ECHA, 2017).

2,5-Xylenol is a solid with a low to moderate water solubility and a low vapour pressure of 4.25 Pa at 25°C). Thus, it is not expected that 2,5-Xylenol will reach the nasopharyncheal region or subsequently the tracheobronchial or pulmonary region. Therefore, under normal use and handling conditions, inhalation exposure and availability for respiratory absorption of the substance in the form of vapours, gases, or mists is considered to be limited. However, the substance may be available for inhalatory absorption after inhalation of aerosols, if the substance is sprayed (e.g. as a formulated product). In view of its moderate lipophilic character and water solubility, any 2,5-Xylenol reaching the tracheobronchial region may be taken up by passive diffusion. In humans, particles with aerodynamic diameters below 100μm have the potential to be inhaled. No data with respect to inhalation toxicity is available. Due to the limited information available and the available spraying applications a worst case approach is applied, and absorption via inhalation is assumed to be as high as via the oral route.

 

Distribution and accumulation

Distribution of a compound within the body depends on the physico-chemical properties of the substance, especially the molecular weight, the lipophilic character and the water solubility. In general, the smaller the molecule, the wider is the distribution. If the molecule is lipophilic, it is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration, particularly in fatty tissues (ECHA, 2017).

Due to the low molecular weight (122.16 g/mol) and its low to moderate water solubility (3.54 g/L at 25°C and pH 5.1) it is expected that 2,5-Xylenol is distributed through the body. Its moderate lipophilic character indicates that it is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration.

 

Metabolism

There is no data on the metabolism of 2,5- Xylenol available. As discussed before, as absorption of 2,5-Xylenol is expected, it is distributed within the body and reaches the liver, which is the organ with the greatest capacity for metabolism, and the kidney, where excretion processes, leading to excretion via the urine, take place. Due to the structure, it is likely that metabolic processes like Phase 1 metabolism including hydroxylation and / or oxidation take place leading to more water-soluble metabolites. In a second step Phase II metabolism (i.e. conjugation processes with sulphate or glucuronic acid) are likely to promote excretion.

 

Excretion

Water-soluble metabolites could be excreted via the bile and / or urine. Non-absorbed substance could directly be excreted via the faeces.

 

References

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