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Category name:
Xylenol Isomere

Justifications and discussions

Category definition:
Xylenole, Isomers
Category order description:
Category approach – Scenario 4 of RAAF
Category rationale:
REPORTING FORMAT FOR THE CATEGORY APPROACH

1. CATEGORY HYPOTHESIS
[Describe why the category can be formed (e.g. common functional group(s), common precursor(s)/breakdown product(s), common mechanism(s) of action, trends in properties and/or activities)]

The chemical category with source compounds and the target chemical comprises six distinct structural, position isomers of xylenol as mono constituent substances, which are monocyclic aromatic hydrocarbons with one hydroxyl substituent and two aliphatic substituents (methyl group). Synonyms of the aromatic compounds are dimethyl phenol, or methyl cresol. The isomers only differ in the relative position of two methyl and one hydroxyl group which are substituted onto a benzene ring. In addition, a mixture of isomers as multi constituent substance xylenol (CAS No 1300-71-6, EC No 215-089-3) is included in the chemical category.
The read-across hypothesis, which is proposed for toxicological endpoints, follows Scenario 4 of the RAAF document (ECHA, 2017) presuming that different compounds, i.e. xylenol isomers, show qualitatively similar biological effects. In this case, quantitative variations in the biological effects observed among members of the chemical category can occur and may potentially be associated with differing steric hindrance of the reactive phenolic hydroxyl group, dependent on the relative position of the methyl groups on the benzene ring. The quantitative variation in biological effects of members of the chemical category is generally not considered to form a regular pattern which for example is observed within a category of chemicals with acyl substitutes of variable, increasing chain length. Therefore, the prediction can be based on a worst-case approach for specific endpoints, notably the skin sensitization endpoint. This means that that the source chemical for the specific endpoint is the xylenol isomer with the maximum strength of toxicity effects observed.
For further details, please refer to the attached document “Read-across justification for 2,5-xylenol (CAS No 95-87-4) from structurally similar position isomers”.


2. CATEGORY JUSTIFICATION
[Summarise here based on available experimental data how these results verify that the category is robust]

As structural isomers, the members of the category share the same molecular weight. Physico-chemical properties of the isomers are quite similar, due to the structural similarities. Of particular relevance are values for partition coefficient and water solubility which determine the toxicokinetic behaviour. The values for partition coefficient vary between 2.34 and 2.61. Water solubility values at 25°C are reported to range from 3.18 to 7.87 g/L. The vapor pressure of the xylenol isomers is low, with values between 2.2 and 60 Pa.
Like the physicochemical properties, similar biological responses derive from the structural similarities of the isomers. There are examples from groups of structurally related isomers (methyl phenols, cresols) which have been investigated in the U.S. National Toxicological Program, that target organs for toxicity and toxic effect dose levels were relatively consistent across the isomers. For most of the relevant toxicological endpoints as acute oral toxicity, skin and eye irritation/corrosion effects and genetic toxicity in the bacterial reverse mutation assay, this is also the case for xylenols. For 4 different xylenol isomers including 2,5-xylenol, oral LD50 values in albino rabbits between 296 ± 36 mg/ kg bw and 727 ± 70 mg/kg bw were determined (Kalina, 1967). Skin sensitization versus the absence of sensitizing effects, observed during exposure of Guinea pigs to 2,4-xylenol and 2,6-xylenol, respectively, represent a variation in properties within the chemical category of xylenol isomers. Therefore, a worstcase approach is chosen for the skin sensitization endpoint.
For further details, please refer to the attached document “Read-across justification for 2,5-xylenol (CAS No 95-87-4) from structurally similar position isomers”.


3. APPLICABILITY DOMAIN OF THE CATEGORY
[Describe the set of inclusion and/or exclusion rules that identify the ranges of values within which reliable estimations can be made for category members]

Predictions are made between members of the chemical category. The preferred source chemical for the specific endpoint is the xylenol isomer or mixture of isomers with the maximum strength of toxicity effects observed.