Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: Qualitative judgement on the toxicokinetic behaviour based on physico-chemical characteristics
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The reliability of this qualitative judgement is limited as it is predominantly based on available phys/chem data. No experimental data on toxicokinetics are available.

Data source

Materials and methods

Objective of study:
toxicokinetics
Principles of method if other than guideline:
This qualitative judgement on the toxicokinetic behaviour based on physico-chemical characteristics follows the recommendations of ECHA (ECHA Endpoint specific guidance, Chapter R.7c; section R.7.12.2.1).
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
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 2,6-xylenol is soluble in water (6 g/L) and has a relatively low molecular weight (122), this passive diffusion will be the predominant mechanism for absorption in the GI tract. Although ionized substances do not readily diffuse across biological membranes, the pKa of 2,6-xylenol (10.6) indicates that the hydroxyl group will not significantly be dissociated in the biologically relevant pH range (up to pH 8). In addition moderate octanol/water partition coefficient (logPow) values (between -1 and 4) are favourable for absorption by passive diffusion, being applicable for 2,6-xylenol (logPow = 2.3). Following the above it can be concluded that 2,6-xylenol will show a high systemic exposure after oral administration.
For risk assessment purposes oral absorption of 2,6-xylenol is set at 100%. The results of the toxicity studies do not provide reasons to deviate from this proposed oral absorption factor.

Due to the low vapour pressure (20 Pa) and relatively high boiling point (202°C) it is not expected that 2,6-xylenol will reach the nasopharyncheal region or subsequently the tracheobranchial or pulmonary region. In addition, only particles with aerodynamic diameters below 100µm have the potential to be inhaled by humans; as 2,6-xylenol is described a s a molten mass, particles below 100µm are anticipated not to be present.
In view of its moderate lipophilic character (logPow = 2.3) and water solubility (6 g/L), any 2,6-xylenol reaching the tracheobranchial region may be taken up by passive diffusion. For risk assessment purposes the inhalation absorption of 2,6-xylenol is set at 100%.

2,6-Xylenol is a solid substance and hence will have to dissolve into the surface moisture of the skin before uptake can begin. Although 2,6-xylenol has a relatively high water solubility (6 g/L) its octanol/water partition coefficient (log Po/w = 2.3) indicates a sufficiently lypophilic character to penetrate the lipid rich stratum corneum. 2,6-Xylenol is sufficiently soluble in water to partition from the stratum corneum into the epidermis. Its chemical structure as well as its molecular mass do not indicate that dermal uptake will be slowed. With a molecular mass below 500 and logPow in the range [-1, 4], 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 2,6-xylenol is corrosive to the skin, damage to the skin surface may enhance penetration. The further results of the toxicity studies do not provide reasons to deviate from this proposed dermal absorption factor of 100%.
Details on distribution in tissues:
Once absorbed the water soluble 2,6-xylenol is expected to widely distribute through the body. Its moderate lipophilic character indicates that 2,6-xylenol is 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. Once exposure stops, the concentration within the body will decline at a rate determined by the half-life of the substance.
Details on excretion:
2,6-Xylenol is expected to undergo Phase I reactions including aliphatic and aromatic hydroxylation and further oxidation. Phase II reactions, including glucuronidation and sulfonation, will further increase water solubility. The mutagenic response in the presence of metabolic activation, compared to the negative response without metabolic activation in the in-vitro Chromosome aberration study indicates metabolism of 2,6-xylenol. Finally, based on the high water solubility and the low molecular weight, 2,6-xylenol and its conjugation products are expected to be mainly excreted in the urine.

Applicant's summary and conclusion

Conclusions:
A qualitative judgement on the toxicokinetic behaviour was performed based on physico-chemical characteristics. 2,6-Xylenol is expected to be well absorbed via the oral, dermal and inhaltion route. Absorption factors of 100% are proposed. The substance is anticipated to be widely distributed through the body, metabolised and excreted mainly in the urine.