Registration Dossier

Administrative data

Description of key information

WoE QSAR predictions VEGA/CAESAR, result: 2,5-xylenol is predicted to be a skin sensitiser

WoE QSAR prediction QSAR Toolbox v4.1, result: 2,5-xylenol is predicted to be sensitising

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin sensitisation: in vivo (LLNA)
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
Study period:
January 2018
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification
Justification for type of information:
please refer to 'Attached justification'
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 429 (Skin Sensitisation: Local Lymph Node Assay)
Guideline:
other: ECHA Guidanc R.6
Principles of method if other than guideline:
- Software tool(s) used including version: Vega v1.1.4
- Model(s) used: Skin sensitization model CAESAR v2.1.6
- Model description: see field 'Attached justification'
- Justification of QSAR prediction: see field 'Attached justification'
Key result
Remarks on result:
positive indication of skin sensitisation based on QSAR/QSPR prediction

Prediction is Sensitizer. The result appears reliable due to calculated index values:

The predicted compound is into the Applicability Domain of the model (AD index = 0.931). Strongly similar compounds with known experimental value in the training set have been found (Similarity index = 0.867). Accuracy of prediction for similar molecules found in the training set is good (Accuracy index = 1). Similar molecules found in the training set have experimental values that agree with the predicted value (Concordance index = 1). Descriptors for this compound have values inside the descriptor range of the compounds of the training set (Descriptors range check = True). All atom centered fragment of the compound have been found in the compounds of the training set (ACF index = 1).

The prediction relies on 6 similar compounds (each with concordant experimental and predicted values) in the test and training data sets of the model: Creosol (CAS No 93-51 -6), anethole (CAS No 104-46-1), 1-naphthole (CAS No 90-15-3), 1-methoxy-4 -(2-propenyl)benzene (CAS No 140 -67-0), hydratropic acid (93-53-8), and benzaldehyde (CAS No 100 -52 -7).

Conclusions:
2,5-Xylenol is predicted by the CAESAR QSAR model for skin sensitization (v.2.1.6) to be a skin sensitiser. The result is considered to be reliable.
Executive summary:

2,5-Xylenol is predicted by the CAESAR QSAR model for skin sensitisation (v.2.1.6) to be a skin sensitiser. The model is implemented inside the VEGA platform and provides a qualitative prediction of skin sensitisation in the mouse Local Lymph Node Assay (LLNA).

The prediction relies on 6 similar compounds (each with concordant experimental and predicted values) in the test and training data sets: Creosol (CAS No 93-51 -6), anethole (CAS No 104-46-1), 1-naphthole (CAS No 90-15-3), 1-methoxy-4 -(2-propenyl)benzene (CAS No 140 -67-0), hydratropic acid (93-53-8), and benzaldehyde (CAS No 100 -52 -7).

The result appears reliable due to calculated index values: The predicted compound is into the Applicability Domain of the model (AD index = 0.931). Strongly similar compounds with known experimental value in the training set have been found (Similarity index = 0.867). Accuracy of prediction for similar molecules found in the training set is good (Accuracy index = 1). Similar molecules found in the training set have experimental values that agree with the predicted value (Concordance index = 1). Descriptors for this compound have values inside the descriptor range of the compounds of the training set (Descriptors range check = True). All atom centered fragment of the compound have been found in the compounds of the training set (ACF index = 1).

Endpoint:
skin sensitisation, other
Remarks:
QSAR
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
Study period:
2018-01-29
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Justification for type of information:
please refer to 'Attached justification'
Guideline:
other: ECHA Guidance R.6
Principles of method if other than guideline:
- Software tool(s) used including version: OECD QSAR Toolbox v4.1
- Model(s) used: Read-across (skin sensitisation)
- Model description: see field 'Attached justification'
- Justification of QSAR prediction: see field 'Attached justification'
Key result
Remarks on result:
positive indication of skin sensitisation based on QSAR/QSPR prediction
Remarks:
OECD QSAR Toolbox v4.1

The substance is predicted to be sensitising by the OECD QSAR Toolbox v4.1. This prediction lies within the applicability domain of the model.

Conclusions:
2,5-xylenol is predicted to be sensitising. This prediction lies within the applicability domain of the model.
Executive summary:

Skin sensitisation of 2,5-xylenol was predited with the using the OECD QSAR Toolbox v4.1 (read-across approach), the substance is predicted to be sensitising. This prediction is based on data from LLNAs of three analogue substances: 2,3,6 -trimethylphenol (CAS 2416 -94 -6), 4 -tert-amylphenol (CAS 80 -46 -6) and Resorcin (CAS 108 -46 -3), which are concordantly positive. It lies within the applicability domain of the model.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (sensitising)
Additional information:

Skin sensitisation

As 2,5-xylenol is classified as Skin Corr. 1B testing for the assessment of the skin sensitisation potential may be omitted. Available in vivo data on the isomer analogues 2,6-xylenol and 2,4-xylenol show conflicting results, cf. REACH registration dossier of these compounds. Therefore, this information does not clearly suggest 2,5-xylenol to be a skin sensitiser.

A modified Landsteiner technique (Landsteiner, K., and Jacob, J., Exptl. Med. 61, 643, 1935; Draize, J.H., Woodard, G., and Calvery, H.O., J. Pharmacol. Exptl. Therap. 82, 337, 1944) was used to evaluate the possibility of skin sensitisation from 2,6-xylenol (study dating from 1962, Klimisch score 2). A positive control substance (1-chloro-2,4-dinitrobenzene) was included in this study. There were 6 guinea pigs in the positive control group and 9 guinea pigs in the test group. The test substance did not produce sensitisation effects in this study. A known sensitiser, 1-chloro-2,4-dinitrobenzene evoked apparent sensitisation in 4 of the 6 exposed guinea pigs.

In contrast, 2,4-xylenol was found to be a skin sensitiser in a guinea pig maximization test conducted according to OECD Guideline 406 (study dating from 1998, Klimisch score 1). Guinea pigs (20/sex) received intradermal injections of 0.5% 2,4-xylenol (administered in Lutrol E 400 DAB and Freund’s Complete Adjuvant / 0.9% NaCl (1:1)). The treatment regime involved induction of sensitisation by intradermal injection on day 1, induction of sensitisation by topical administration on day 8 (25% 2,4-xylenol in Lutrol E 400 DAB), challenge by topical administration on day 21 (5% 2,4-xylenol in Lutrol E 400 DAB), followed by a rechallenge on day 28 (5% 2,4-xylenol in Lutrol E 400 DAB).

Following intradermal induction, 0.5% 2,4-xylenol caused swelling and moderate erythema. Percutaneous induction with 25% 2,4-xylenol in Lutrol E 400 DAB after one week resulted in swelling and necrotic changes. Following challenge, 11/20 test animals test animals showed a positive allergic reaction. Following rechallenge, 8/20 test animals showed a positive allergic reaction. The 5% 2,4-xylenol applied to control animals was tolerated, and no skin reactions were observed in the control groups.

2,5-Xylenol is predicted by the CAESAR QSAR model for skin sensitisation (v.2.1.6) to be a skin sensitiser. The model is implemented inside the VEGA platform and provides a qualitative prediction of skin sensitisation in the mouse Local Lymph Node Assay (LLNA). The prediction relies on 6 similar compounds (each with concordant experimental and predicted values) in the test and training data sets: Creosol (CAS No 93-51 -6), anethole (CAS No 104-46-1), 1-naphthole (CAS No 90-15-3), 1-methoxy-4 -(2-propenyl)benzene (CAS No 140 -67-0), hydratropic acid (93-53-8), and benzaldehyde (CAS No 100 -52 -7). It lies within the applicability domain of this model.

The result obtained by the VEGA/CAESAR QSAR model appears reliable due to calculated index values: The predicted compound is into the Applicability Domain of the model (AD index = 0.931). Strongly similar compounds with known experimental value in the training set have been found (Similarity index = 0.867). Accuracy of prediction for similar molecules found in the training set is good (Accuracy index = 1). Similar molecules found in the training set have experimental values that agree with the predicted value (Concordance index = 1). Descriptors for this compound have values inside the descriptor range of the compounds of the training set (Descriptors range check = True). All atom centered fragment of the compound have been found in the compounds of the training set (ACF index = 1).

Also using the OECD QSAR Toolbox (read-across approach), the substance is predicted to be sensitising. This prediction is based on data from LLNAs of three analogue substances: 2,3,6 -trimethylphenol (CAS 2416 -94 -6), 4 -tert-amylphenol (CAS 80 -46 -6) and Resorcin (CAS 108 -46 -3). It lies within the applicability domain of the model.

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

As 2,5-xylenol is classified as Skin Corr. 1B testing for the assessment of the skin sensitisation potential may be omitted. Available in vivo data on the isomer analogues 2,6-xylenol and 2,4-xylenol show conflicting results. Reliable predictions by the CAESAR QSAR model (v. 2.1.6), which is implemented in the VEGA platform, as well as the OECD QSAR Toolbox (v.4.1) showed a positive result. On the basis of the prediction, the substance is classified as skin sensitiser (Category 1, H317) according to Regulation (EC) No 1272/2008 (CLP Regulation).


Route: .live1