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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

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Diss Factsheets

Administrative data

Description of key information

WoE (OECD QSAR Toolbox 4.5 Automated Workflow for Defined Approaches for Skin Sensitisation; KeratinoSens™, OECD 442D): skin sensitiser

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin sensitisation, other
Remarks:
Automated workflow prediction for skin sensitization
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
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:
1. SOFTWARE
OECD QSAR Toolbox v4.5.

2. MODEL (incl. version number)
EC3 from LLNA or Skin sensitization from GPMT assays for defined approaches (SS AW for DASS).

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
See “Test material information”.

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
See attached information on the model provided by the developer. Further information on the OECD criteria as outlined by the applicant is provided below under "Any other information of materials and methods incl. tables".

5. APPLICABILITY DOMAIN
See attached information and information as provided in "Any other information on results incl. tables".

6. ADEQUACY OF THE RESULT
See assessment of adequacy as outlined in the "Overall remarks, attachments" section.
Qualifier:
according to guideline
Guideline:
other: Protocol for OECD QSAR Toolbox predictions for DASS AW (Defined Approaches for Skin Sensitisation Automated Workflow)
Version / remarks:
14 June 2021
Principles of method if other than guideline:
- Software tool(s) used including version: OECD QSAR Toolbox 4.5 .
- Model(s) used: EC3 from LLNA or Skin sensitization from GPMT assays for defined approaches (SS AW for DASS).
Full reference and details can be found in:
Yordanova, D. et al (2019). Automated and standardized workflows in the OECD QSAR Toolbox. Computational Toxicology, 10, 89-104.
- Model description: see field 'Justification for non-standard information', 'Attached justification' and 'any other information on Material and methods'.
- Justification of QSAR prediction: see field 'Justification for type of information', 'Attached justification' and/or 'overall remarks'.
GLP compliance:
no
Parameter:
other: QSAR
Remarks on result:
positive indication of skin sensitisation
Outcome of the prediction model:
other: Skin sensitisation potential predicted

The automated workflow for EC3 from LLNA or Skin sensitization from GPMT assays for defined approaches (SS AW for DASS) predicts the molecule as POSITIVE (i.e. skin sensitizer), based on read-across from 3 sources. For detailed information on the results, please refer to the prediction report and the data matrix provided as attached information.

Interpretation of results:
other: The result is positive for skin sensitization, based on read-across prediction (OECD QSAR Toolbox 4.5, DASS AW). The result may be used together with other in chemico/in vitro information in a weight-of-evidence approach.
Conclusions:
The skin sensitization potential is predicted as positive using OECD QSAR Toolbox 4.5 (DASS AW), based on read-across of 3 sources, of which 2 have positive experimental data. The target molecule falls within the applicability domain. The result may be used together with other in chemico/in vitro information in a weight-of-evidence approach.
Endpoint:
skin sensitisation, other
Remarks:
Automated workflow prediction for skin sensitization
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
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:
1. SOFTWARE
OECD QSAR Toolbox v4.5.

2. MODEL (incl. version number)
EC3 from LLNA or Skin sensitization from GPMT assays for defined approaches (SS AW for DASS).

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
See “Test material information”.

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
See attached information on the model provided by the developer. Further information on the OECD criteria as outlined by the applicant is provided below under "Any other information of materials and methods incl. tables".

5. APPLICABILITY DOMAIN
See attached information and information as provided in "Any other information on results incl. tables".

6. ADEQUACY OF THE RESULT
See assessment of adequacy as outlined in the "Overall remarks, attachments" section.
Qualifier:
according to guideline
Guideline:
other: Protocol for OECD QSAR Toolbox predictions for DASS AW (Defined Approaches for Skin Sensitisation Automated Workflow)
Version / remarks:
14 June 2021
Principles of method if other than guideline:
- Software tool(s) used including version: OECD QSAR Toolbox 4.5 .
- Model(s) used: EC3 from LLNA or Skin sensitization from GPMT assays for defined approaches (SS AW for DASS).
Full reference and details can be found in:
Yordanova, D. et al (2019). Automated and standardized workflows in the OECD QSAR Toolbox. Computational Toxicology, 10, 89-104.
- Model description: see field 'Justification for non-standard information', 'Attached justification' and 'any other information on Material and methods'.
- Justification of QSAR prediction: see field 'Justification for type of information', 'Attached justification' and/or 'overall remarks'.
GLP compliance:
no
Parameter:
other: QSAR
Remarks on result:
no indication of skin sensitisation
Outcome of the prediction model:
other: no skin sensitisation potential predicted

The automated workflow for EC3 from LLNA or Skin sensitization from GPMT assays for defined approaches (SS AW for DASS) predicts the molecule as NEGATIVE (i.e. not skin sensitizer), based on read-across from 5 sources. For detailed information on the results, please refer to the prediction report and the data matrix provided as attached information.

Interpretation of results:
other: The result is negative for skin sensitization, based on read-across prediction (OECD QSAR Toolbox 4.5, DASS AW). The result may be used together with other in chemico/in vitro information in a weight-of-evidence approach.
Conclusions:
The skin sensitization potential is predicted as negative using OECD QSAR Toolbox 4.5 (DASS AW), based on read-across of 5 sources with negative experimental data. The target molecule falls within the applicability domain. The result may be used together with other in chemico/in vitro information in a weight-of-evidence approach.
Endpoint:
skin sensitisation, other
Remarks:
Automated workflow prediction for skin sensitization
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
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:
1. SOFTWARE
OECD QSAR Toolbox v4.5.

2. MODEL (incl. version number)
EC3 from LLNA or Skin sensitization from GPMT assays for defined approaches (SS AW for DASS).

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
See “Test material information”.

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
See attached information on the model provided by the developer. Further information on the OECD criteria as outlined by the applicant is provided below under "Any other information of materials and methods incl. tables".

5. APPLICABILITY DOMAIN
See attached information and information as provided in "Any other information on results incl. tables".

6. ADEQUACY OF THE RESULT
See assessment of adequacy as outlined in the "Overall remarks, attachments" section.
Qualifier:
according to guideline
Guideline:
other: Protocol for OECD QSAR Toolbox predictions for DASS AW (Defined Approaches for Skin Sensitisation Automated Workflow)
Version / remarks:
14 June 2021
Principles of method if other than guideline:
- Software tool(s) used including version: OECD QSAR Toolbox 4.5 .
- Model(s) used: EC3 from LLNA or Skin sensitization from GPMT assays for defined approaches (SS AW for DASS).
Full reference and details can be found in:
Yordanova, D. et al (2019). Automated and standardized workflows in the OECD QSAR Toolbox. Computational Toxicology, 10, 89-104.
- Model description: see field 'Justification for non-standard information', 'Attached justification' and 'any other information on Material and methods'.
- Justification of QSAR prediction: see field 'Justification for type of information', 'Attached justification' and/or 'overall remarks'.
GLP compliance:
no
Parameter:
other: QSAR
Remarks on result:
no indication of skin sensitisation
Outcome of the prediction model:
other: no skin sensitisation potential predicted

The automated workflow for EC3 from LLNA or Skin sensitization from GPMT assays for defined approaches (SS AW for DASS) predicts the molecule as NEGATIVE (i.e. not skin sensitizer), based on read-across from 5 sources. For detailed information on the results, please refer to the prediction report and the data matrix provided as attached information.

Interpretation of results:
other: The result is negative for skin sensitization, based on read-across prediction (OECD QSAR Toolbox 4.5, DASS AW). The result may be used together with other in chemico/in vitro information in a weight-of-evidence approach.
Conclusions:
The skin sensitization potential is predicted as negative using OECD QSAR Toolbox 4.5 (DASS AW), based on read-across of 5 sources with negative experimental data. The target molecule falls within the applicability domain. The result may be used together with other in chemico/in vitro information in a weight-of-evidence approach.
Endpoint:
skin sensitisation, other
Remarks:
Automated workflow prediction for skin sensitization
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
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:
1. SOFTWARE
OECD QSAR Toolbox v4.5.

2. MODEL (incl. version number)
EC3 from LLNA or Skin sensitization from GPMT assays for defined approaches (SS AW for DASS).

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
See “Test material information”.

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
See attached information on the model provided by the developer. Further information on the OECD criteria as outlined by the applicant is provided below under "Any other information of materials and methods incl. tables".

5. APPLICABILITY DOMAIN
See attached information and information as provided in "Any other information on results incl. tables".

6. ADEQUACY OF THE RESULT
See assessment of adequacy as outlined in the "Overall remarks, attachments" section.
Qualifier:
according to guideline
Guideline:
other: Protocol for OECD QSAR Toolbox predictions for DASS AW (Defined Approaches for Skin Sensitisation Automated Workflow)
Version / remarks:
14 June 2021
Principles of method if other than guideline:
- Software tool(s) used including version: OECD QSAR Toolbox 4.5 .
- Model(s) used: EC3 from LLNA or Skin sensitization from GPMT assays for defined approaches (SS AW for DASS).
Full reference and details can be found in:
Yordanova, D. et al (2019). Automated and standardized workflows in the OECD QSAR Toolbox. Computational Toxicology, 10, 89-104.
- Model description: see field 'Justification for non-standard information', 'Attached justification' and 'any other information on Material and methods'.
- Justification of QSAR prediction: see field 'Justification for type of information', 'Attached justification' and/or 'overall remarks'.
GLP compliance:
no
Parameter:
other: QSAR
Remarks on result:
no indication of skin sensitisation
Outcome of the prediction model:
other: no skin sensitisation potential predicted

The automated workflow for EC3 from LLNA or Skin sensitization from GPMT assays for defined approaches (SS AW for DASS) predicts the molecule as NEGATIVE (i.e. not skin sensitizer), based on the Skin Sensitization for DASS profiler. For detailed information on the results, please refer to the prediction report provided as attached information.

Interpretation of results:
other: The result is negative for skin sensitization, based on profiling prediction (OECD QSAR Toolbox 4.5, DASS AW). The result may be used together with other in chemico/in vitro information in a weight-of-evidence approach.
Conclusions:
The skin sensitization potential is predicted as negative using OECD QSAR Toolbox 4.5 (DASS AW), based on the Skin Sensitization for DASS profiler, which has not found any alert for skin sensitization potential in the target molecule nor in the generated metabolites. The target molecule falls within the applicability domain. The result may be used together with other in chemico/in vitro information in a weight-of-evidence approach.
Endpoint:
skin sensitisation, other
Remarks:
Automated workflow prediction for skin sensitization
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
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:
1. SOFTWARE
OECD QSAR Toolbox v4.5.

2. MODEL (incl. version number)
EC3 from LLNA or Skin sensitization from GPMT assays for defined approaches (SS AW for DASS).

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
See “Test material information”.

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
See attached information on the model provided by the developer. Further information on the OECD criteria as outlined by the applicant is provided below under "Any other information of materials and methods incl. tables".

5. APPLICABILITY DOMAIN
See attached information and information as provided in "Any other information on results incl. tables".

6. ADEQUACY OF THE RESULT
See assessment of adequacy as outlined in the "Overall remarks, attachments" section.
Qualifier:
according to guideline
Guideline:
other: Protocol for OECD QSAR Toolbox predictions for DASS AW (Defined Approaches for Skin Sensitisation Automated Workflow)
Version / remarks:
14 June 2021
Principles of method if other than guideline:
- Software tool(s) used including version: OECD QSAR Toolbox 4.5 .
- Model(s) used: EC3 from LLNA or Skin sensitization from GPMT assays for defined approaches (SS AW for DASS).
Full reference and details can be found in:
Yordanova, D. et al (2019). Automated and standardized workflows in the OECD QSAR Toolbox. Computational Toxicology, 10, 89-104.
- Model description: see field 'Justification for non-standard information', 'Attached justification' and 'any other information on Material and methods'.
- Justification of QSAR prediction: see field 'Justification for type of information', 'Attached justification' and/or 'overall remarks'.
GLP compliance:
no
Parameter:
other: QSAR
Remarks on result:
no indication of skin sensitisation
Outcome of the prediction model:
other: no skin sensitisation potential predicted

The automated workflow for EC3 from LLNA or Skin sensitization from GPMT assays for defined approaches (SS AW for DASS) predicts the molecule as NEGATIVE (i.e. not skin sensitizer), based on read-across from 5 sources. For detailed information on the results, please refer to the prediction report and the data matrix provided as attached information.

Interpretation of results:
other: The result is negative for skin sensitization, based on read-across prediction (OECD QSAR Toolbox 4.5, DASS AW). The result may be used together with other in chemico/in vitro information in a weight-of-evidence approach.
Conclusions:
The skin sensitization potential is predicted as negative using OECD QSAR Toolbox 4.5 (DASS AW), based on read-across of 5 sources with negative experimental data. The target molecule falls within the applicability domain. The result may be used together with other in chemico/in vitro information in a weight-of-evidence approach.
Endpoint:
skin sensitisation, other
Remarks:
Automated workflow prediction for skin sensitization
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
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:
1. SOFTWARE
OECD QSAR Toolbox v4.5.

2. MODEL (incl. version number)
EC3 from LLNA or Skin sensitization from GPMT assays for defined approaches (SS AW for DASS).

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
See “Test material information”.

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
See attached information on the model provided by the developer. Further information on the OECD criteria as outlined by the applicant is provided below under "Any other information of materials and methods incl. tables".

5. APPLICABILITY DOMAIN
See attached information and information as provided in "Any other information on results incl. tables".

6. ADEQUACY OF THE RESULT
See assessment of adequacy as outlined in the "Overall remarks, attachments" section.
Qualifier:
according to guideline
Guideline:
other: Protocol for OECD QSAR Toolbox predictions for DASS AW (Defined Approaches for Skin Sensitisation Automated Workflow)
Version / remarks:
14 June 2021
Principles of method if other than guideline:
- Software tool(s) used including version: OECD QSAR Toolbox 4.5 .
- Model(s) used: EC3 from LLNA or Skin sensitization from GPMT assays for defined approaches (SS AW for DASS).
Full reference and details can be found in:
Yordanova, D. et al (2019). Automated and standardized workflows in the OECD QSAR Toolbox. Computational Toxicology, 10, 89-104.
- Model description: see field 'Justification for non-standard information', 'Attached justification' and 'any other information on Material and methods'.
- Justification of QSAR prediction: see field 'Justification for type of information', 'Attached justification' and/or 'overall remarks'.
GLP compliance:
no
Parameter:
other: QSAR
Remarks on result:
no indication of skin sensitisation
Outcome of the prediction model:
other: no skin sensitisation potential predicted

The automated workflow for EC3 from LLNA or Skin sensitization from GPMT assays for defined approaches (SS AW for DASS) predicts the molecule as NEGATIVE (i.e. not skin sensitizer), based on read-across from 6 sources. For detailed information on the results, please refer to the prediction report and the data matrix provided as attached information.

Interpretation of results:
other: The result is negative for skin sensitization, based on read-across prediction (OECD QSAR Toolbox 4.5, DASS AW). The result may be used together with other in chemico/in vitro information in a weight-of-evidence approach.
Conclusions:
The skin sensitization potential is predicted as negative using OECD QSAR Toolbox 4.5 (DASS AW), based on read-across of 6 sources, of which 4 have negative experimental data. The target molecule falls within the applicability domain. The result may be used together with other in chemico/in vitro information in a weight-of-evidence approach.
Endpoint:
skin sensitisation, other
Remarks:
Automated workflow prediction for skin sensitization
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
results derived from a valid (Q)SAR model, but not (completely) falling into its applicability domain, with adequate and reliable documentation / justification
Remarks:
The target molecule is not fully compliant with the applicability domain of the model. However, this calculation is used in a weight of evidence approach, in accordance to the REACh Regulation (EC) No 1907/2006, Annex XI section 1.2. For more details see section `overall remarks, attachments´.
Justification for type of information:
1. SOFTWARE
OECD QSAR Toolbox v4.5.

2. MODEL (incl. version number)
EC3 from LLNA or Skin sensitization from GPMT assays for defined approaches (SS AW for DASS).

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
See “Test material information”.

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
See attached information on the model provided by the developer. Further information on the OECD criteria as outlined by the applicant is provided below under "Any other information of materials and methods incl. tables".

5. APPLICABILITY DOMAIN
See attached information and information as provided in "Any other information on results incl. tables".

6. ADEQUACY OF THE RESULT
See assessment of adequacy as outlined in the "Overall remarks, attachments" section.
Qualifier:
according to guideline
Guideline:
other: Protocol for OECD QSAR Toolbox predictions for DASS AW (Defined Approaches for Skin Sensitisation Automated Workflow)
Version / remarks:
14 June 2021
Principles of method if other than guideline:
- Software tool(s) used including version: OECD QSAR Toolbox 4.5 .
- Model(s) used: EC3 from LLNA or Skin sensitization from GPMT assays for defined approaches (SS AW for DASS).
Full reference and details can be found in:
Yordanova, D. et al (2019). Automated and standardized workflows in the OECD QSAR Toolbox. Computational Toxicology, 10, 89-104.
- Model description: see field 'Justification for non-standard information', 'Attached justification' and 'any other information on Material and methods'.
- Justification of QSAR prediction: see field 'Justification for type of information', 'Attached justification' and/or 'overall remarks'.
GLP compliance:
no
Parameter:
other: QSAR
Remarks on result:
no indication of skin sensitisation
Outcome of the prediction model:
other: no skin sensitisation potential predicted

The automated workflow for EC3 from LLNA or Skin sensitization from GPMT assays for defined approaches (SS AW for DASS) predicts the molecule as NEGATIVE (i.e. not skin sensitizer), based on read-across from 1 source. For detailed information on the results, please refer to the prediction report and the data matrix provided as attached information.

Interpretation of results:
other: The result is negative for skin sensitization, based on read-across prediction (OECD QSAR Toolbox 4.5, DASS AW). The result may be used together with other in chemico/in vitro information in a weight-of-evidence approach.
Conclusions:
The skin sensitization potential is predicted as negative using OECD QSAR Toolbox 4.5 (DASS AW), based on read-across of 1 source with negative experimental data and limited similarity. The target molecule does not fall within the applicability domain. The result may be used together with other in chemico/in vitro information in a weight-of-evidence approach.
Endpoint:
skin sensitisation, other
Remarks:
Automated workflow prediction for skin sensitization
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
results derived from a valid (Q)SAR model, but not (completely) falling into its applicability domain, with adequate and reliable documentation / justification
Remarks:
The target molecule is not fully compliant with the applicability domain of the model. However, this calculation is used in a weight of evidence approach, in accordance to the REACh Regulation (EC) No 1907/2006, Annex XI section 1.2. For more details see section `overall remarks, attachments´.
Justification for type of information:
1. SOFTWARE
OECD QSAR Toolbox v4.5.

2. MODEL (incl. version number)
EC3 from LLNA or Skin sensitization from GPMT assays for defined approaches (SS AW for DASS).

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
See “Test material information”.

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
See attached information on the model provided by the developer. Further information on the OECD criteria as outlined by the applicant is provided below under "Any other information of materials and methods incl. tables".

5. APPLICABILITY DOMAIN
See attached information and information as provided in "Any other information on results incl. tables".

6. ADEQUACY OF THE RESULT
See assessment of adequacy as outlined in the "Overall remarks, attachments" section.
Qualifier:
according to guideline
Guideline:
other: Protocol for OECD QSAR Toolbox predictions for DASS AW (Defined Approaches for Skin Sensitisation Automated Workflow)
Version / remarks:
14 June 2021
Principles of method if other than guideline:
- Software tool(s) used including version: OECD QSAR Toolbox 4.5 .
- Model(s) used: EC3 from LLNA or Skin sensitization from GPMT assays for defined approaches (SS AW for DASS).
Full reference and details can be found in:
Yordanova, D. et al (2019). Automated and standardized workflows in the OECD QSAR Toolbox. Computational Toxicology, 10, 89-104.
- Model description: see field 'Justification for non-standard information', 'Attached justification' and 'any other information on Material and methods'.
- Justification of QSAR prediction: see field 'Justification for type of information', 'Attached justification' and/or 'overall remarks'.
GLP compliance:
no
Parameter:
other: QSAR
Remarks on result:
no indication of skin sensitisation
Outcome of the prediction model:
other: no skin sensitisation potential predicted

The automated workflow for EC3 from LLNA or Skin sensitization from GPMT assays for defined approaches (SS AW for DASS) predicts the molecule as NEGATIVE (i.e. not skin sensitizer), based on read-across from 5 sources. For detailed information on the results, please refer to the prediction report and the data matrix provided as attached information.

Interpretation of results:
other: The result is negative for skin sensitization, based on read-across prediction (OECD QSAR Toolbox 4.5, DASS AW). The result may be used together with other in chemico/in vitro information in a weight-of-evidence approach.
Conclusions:
The skin sensitization potential is predicted as negative using OECD QSAR Toolbox 4.5 (DASS AW), based on read-across of 5 sources, of which 4 have negative experimental data. The target molecule does not fall within the applicability domain. The result may be used together with other in chemico/in vitro information in a weight-of-evidence approach.
Endpoint:
skin sensitisation, other
Remarks:
Automated workflow prediction for skin sensitization
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
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:
1. SOFTWARE
OECD QSAR Toolbox v4.5.

2. MODEL (incl. version number)
EC3 from LLNA or Skin sensitization from GPMT assays for defined approaches (SS AW for DASS).

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
See “Test material information”.

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
See attached information on the model provided by the developer. Further information on the OECD criteria as outlined by the applicant is provided below under "Any other information of materials and methods incl. tables".

5. APPLICABILITY DOMAIN
See attached information and information as provided in "Any other information on results incl. tables".

6. ADEQUACY OF THE RESULT
See assessment of adequacy as outlined in the "Overall remarks, attachments" section.
Qualifier:
according to guideline
Guideline:
other: Protocol for OECD QSAR Toolbox predictions for DASS AW (Defined Approaches for Skin Sensitisation Automated Workflow)
Version / remarks:
14 June 2021
Principles of method if other than guideline:
- Software tool(s) used including version: OECD QSAR Toolbox 4.5 .
- Model(s) used: EC3 from LLNA or Skin sensitization from GPMT assays for defined approaches (SS AW for DASS).
Full reference and details can be found in:
Yordanova, D. et al (2019). Automated and standardized workflows in the OECD QSAR Toolbox. Computational Toxicology, 10, 89-104.
- Model description: see field 'Justification for non-standard information', 'Attached justification' and 'any other information on Material and methods'.
- Justification of QSAR prediction: see field 'Justification for type of information', 'Attached justification' and/or 'overall remarks'.
GLP compliance:
no
Parameter:
other: QSAR
Remarks on result:
no indication of skin sensitisation
Outcome of the prediction model:
other: no skin sensitisation potential predicted

The automated workflow for EC3 from LLNA or Skin sensitization from GPMT assays for defined approaches (SS AW for DASS) predicts the molecule as NEGATIVE (i.e. not skin sensitizer), based on read-across from 5 sources. For detailed information on the results, please refer to the prediction report and the data matrix provided as attached information.

Interpretation of results:
other: The result is negative for skin sensitization, based on read-across prediction (OECD QSAR Toolbox 4.5, DASS AW). The result may be used together with other in chemico/in vitro information in a weight-of-evidence approach.
Conclusions:
The skin sensitization potential is predicted as negative using OECD QSAR Toolbox 4.5 (DASS AW), based on read-across of 5 sources with negative experimental data. The target molecule falls within the applicability domain. The result may be used together with other in chemico/in vitro information in a weight-of-evidence approach.
Endpoint:
skin sensitisation: in vitro
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
6 Jan - 12 Feb 2021
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 442D (In Vitro Skin Sensitisation: ARE-Nrf2 luciferase KeratinoSens™ test method)
Version / remarks:
adopted in 2018
Deviations:
yes
Remarks:
no historical control data range provided
GLP compliance:
yes
Type of study:
ARE-Nrf2 luciferase KeratinoSens™ test method
Details of test system:
Keratinoses transgenic cell line [442D]
Details on the study design:
TEST METHOD:
The in vitro KeratinoSens™ assay enables the detection of the skin sensitising potential of a test item by analysing the activation of keratinocytes. This activation step represents the second molecular key event of the adverse outcome pathway, which is the induction of cyto-protective signaling pathways in keratinocytes in response to electrophilic test chemicals. The KeratinoSens™ assay addresses the effect on the antioxidant response element (ARE) Nrf2-dependent pathway in the transgenic KeratinoSens™ cell line, which is an immortalised adherent cell line derived from HaCaT human keratinocytes, stably transfected with a selectable plasmid containing the luciferase gene under the transcriptional control of the Anti-oxidant Response Element (ARE) from a gene that is known to be up-regulated by contact sensitisers. The Nrf2-dependent induction of this reporter gene is analysed following exposure to test chemicals. Luminescence detection in the cell lysate after 48 ± 2 h of exposure at 37.0 ± 1.0 °C indicates luciferase induction and allows the discrimination between skin sensitisers and non-sensitisers. The method was adapted to animal product-free conditions by the testing laboratory. The Foetal Calf Serum was replaced by Human Serum in the protocol following adaptation of the cells, and porcine trypsin was replaced by non-animal recombinant trypsin (Trypzean).

PREPARATION OF TEST SOLUTIONS
- Preparation of the positive controls : The positive control was 8, 16, 32, 64 and 128 µM cinnamic aldehyde, prepared in the solvent 1% ethanol in cell culture medium.
- Preparation of the solvent, vehicle and negative controls: The solvent control was 1% ethanol in cell culture medium. No justification was given for the choice of solvent control.

DOSE RANGE FINDING ASSAY:
The solubility of the test item in ethanol was confirmed up to 40 mg/mL. Subsequent dilution in cell culture medium gave a top concentration of 400 µg/mL, which was selected as the highest concentration in the main test.

APPLICATION OF THE TEST CHEMICAL AND CONTROL SUBSTANCES
- Number of replicates : 3
- Number of repetitions: 4 runs were performed. Each run consisted of 3 x 96-well plates for luminescence (n = 9 overall) and 2 x 96-well plates for MTT (n = 6 overall).
- Test chemical concentrations : 0.195, 0.391, 0.781,1.563, 3.125, 6.25, 12.5, 25, 50, 100, 200 and 400 µg/mL
- Application procedure : Per plate, for the test substance a single application of 12 concentrations of the test item was applied in cell culture medium (dilution factor of 2) with a final concentration of ethanol of 1%. For the positive and solvent control, per plate a single application of 5 concentrations of the positive control was applied in cell culture medium (dilution factor of 2) with a final concentration of ethanol of 1% and a single application of culture medium with 1% ethanol was applied as the negative control (6 wells per plate). One well per plate was left empty (no cells).
- Exposure time : 48 ± 2 h

- Study evaluation and decision criteria used: A test item is considered positive using the KeratinoSens prediction model if the following conditions are met in 2 of 3 repetitions:
1) The IMAX is ≥ 1.5-fold and statistically significantly different as compared to the solvent (negative) control (as determined by a two-tailed, unpaired Student’s T-test).
2) The cellular viability is higher than 70% at the lowest concentration with induction of luciferase activity ≥ 1.5-fold (i.e. at the EC1.5 determining concentration). Test items that only induce the gene activity at cytotoxic levels are not rated positive, as in the case for some non-sensitising skin irritants.
3) The EC1.5 value is < 1000 µM or < 200 µg/mL for test items with no defined MW.
4) There is an apparent overall dose-response for luciferase induction (or a biphasic response).

- Description on study acceptance criteria : Test results are acceptable if:
1) The positive control (cinnamic aldehyde) produces positive results, i.e. the luciferase gene induction produced by this control is above the threshold of 1.5 in at least one of the tested concentrations and this induction is statistically significant compared to the solvent (negative) control (p < 0.05).
2) The lMAX and the EC1.5 for cinnamic aldehyde is calculated and meet either or both of the following targets:
a) Average induction in the three replicates for cinnamic aldehyde at 32 µM is within the test facility's historical range (currently 1.6 and 3)
b) EC1.5 value for cinnamic aldehyde is within the test facility's historical range (currently 6 µM and 39 µM).
Note: At least one of these criteria must be met, otherwise the run is discarded unless there is sufficient reason not to do this as determined by the Study Director. If only one criterion is met, it is recommended to check the dose-response curve of cinnamic aldehyde in order to decide on acceptability.
3) CV% of blank values < 20%.

SEEDING AND INCUBATION
One day prior to testing cells were harvested, and seeded at a density of 10000 cells/well in basic medium in conventional 96-well plates. One plate was used for the luciferase activity measurements, and one parallel replicate was used for the MTT cell viability assay. The cells were incubated overnight in the incubator.
- Seeding conditions: passage number 17, seeding density 10,000 cells per well.
- Incubation conditions : 24 h after seeding, the test and control items were applied and plates were incubated at 37 °C, 5% CO2, ≥ 95% relative humidity for 48 ± 2 h.

LUCIFERASE ACTIVITY MEASUREMENTS
The luciferase activity induction was measured. No further details were given.

DATA EVALUATION
- Cytotoxicity assessment: An MTT assay was performed to measure the cellular viability. No further details were given.
- Other: Test facility's Form F0056: “KeratinoSens data processing” v.3 was used to analyse data. This form is a Microsoft Excel workbook, validated in-house (Mar 2019) containing formulae to process the raw data as described in SOP L0057.
Vehicle / solvent control:
other: 1% ethanol in cell culture medium
Positive control:
cinnamic aldehyde [442D]
Positive control results:
Cinnamic aldehyde was tested in a concentration range of 8 - 128 µM. The induction at 128 µM was ≥ 2-fold in 4 of 5 runs and showed a dose-dependent increase.
Key result
Group:
test chemical
Run / experiment:
run/experiment 3
Parameter:
EC 1.5 [442D]
Value:
12.04 µg/mL
Cell viability:
IC30 = 154.04 µg/mL, IC50 = 167.45 µg/mL
Imax = 4.719 at 100 µg/mL
Vehicle controls validity:
valid
Negative controls validity:
not examined
Positive controls validity:
valid
Remarks on result:
positive indication of skin sensitisation
Key result
Group:
test chemical
Run / experiment:
other: run/experiment 4
Parameter:
EC 1.5 [442D]
Value:
8.16 µg/mL
Cell viability:
IC30 = 253.91 µg/mL, IC50 = 295.65 µg/mL
Imax = 4.927 at 100 µg/mL
Vehicle controls validity:
valid
Negative controls validity:
not examined
Positive controls validity:
valid
Remarks on result:
positive indication of skin sensitisation
Outcome of the prediction model:
positive [in vitro/in chemico]
Other effects / acceptance of results:
OTHER EFFECTS:
- Visible damage on test system: no

DEMONSTRATION OF TECHNICAL PROFICIENCY:
The testing laboratory showed technical proficiency by validation in-house (studies 14XC004, 15XC001, 16XCO04) using the 10 proficiency chemicals and 11 reference chemicals described in TG 442D.

ACCEPTANCE OF RESULTS:
- Acceptance criteria met for negative control: Yes, CV% < 20% for experiment 3 and 4 (mean CV%: 11.26%).
- Acceptance criteria met for positive control: 4 of 5 replicates showed > 1.5-fold induction in a dose-dependent manner. The average induction was 3.269 and therefore did not meet the acceptance criterium (1.6 - 3.0 at 32 µM). As the other acceptance criteria were met, the results were considered to be valid overall.
- Acceptance criteria met for variability between replicate measurements: Four experiments were performed because the variability (CV%) across the negative control wells in experiment 1 and 2 were greater than 20%. Therefore, experiment 1 (CV%: 52.69) and 2 (CV%: 35.71) were considered invalid and not used to determine the result for the test item. For experiment 3 and 4 the acceptance criteria were met (mean CV: 11.26%).
- Range of historical values if different from the ones specified in the test guideline: No historical control values were given in the study report. However, the results from the validation study were included.

Experiment 1

The test substance showed cytotoxicity, with an IC30 = 203.10 µg/mL and IC50 = 254.22 µg/mL. The Imax was 4.47 at 100 µg/mL and the EC1.5 was 15.06 µg/mL. However, the experiment was not considered to be valid as the variability across the negative control wells (CV%) was 52.69.

Experiment 2

The test substance showed cytotoxicity, with an IC30 = 287.63 µg/mL and IC50 = 317.19 µg/mL. The Imax was 2.83 at 100 µg/mL and the EC1.5 was 28.53 µg/mL. However, the experiment was not considered to be valid as the variability across the negative control wells (CV%) was 35.71.

Experiment 3

The Imax was 4.72 at 100 µg/mL and lead to an EC1.5 = 12.04 µg/mL. The test substance showed cytotoxicity, with an IC30 = 154.04 µg/mL and IC50 = 167.49 µg/mL. In this run the negative and positive control results met the acceptance criteria. As the results were considered to be valid, the overall outcome of the experiment was positive.

Experiment 4

The Imax was 4.72 at 100 µg/mL and the EC1.5 was 12.04 µg/mL. The test substance showed cytotoxicity, with an IC30 = 253.91 µg/mL and IC50 = 295.65 µg/mL. In this run, the negative and positive control results met the acceptance criteria. As the results were considered to be valid, the overall outcome of the experiment was positive.

Tables 1 - 4 with results are included in Attachment 1 under "Overall remarks, attachments".

Interpretation of results:
other: skin sensitising potential based on the key event “inflammatory response in keratinocytes”
Conclusions:
There is regulatory acceptance in the EU for the application of the KeratinoSens™ test method to address key event 2, keratinocyte activation, in the skin sensitisation Adverse Outcome Pathway. Under the conditions of the test, the test substance induces keratinocyte activation. The result is not conclusive with respect to the non-classification or classification as skin sensitiser of the test substance and therefore further evaluation and/or data generation is required.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (sensitising)
Additional information:

In vitro skin sensitisation assay

The skin sensitising properties of fatty acids, C6-18 (branched and linear) alkyl and hydrocarbons, C10-18, n-alkanes, branched alkanes, cycloalkanes, aromatics (EC No. 942-654-8) were assessed in a KeratinoSens™ assay according to OECD guideline 442D and under GLP conditions (XCellR8, 2021). The standard method was adapted to animal product-free conditions by the testing laboratory. Foetal Calf Serum was replaced by Human Serum in the protocol following adaptation of the cells, and porcine trypsin was replaced by non-animal recombinant trypsin (Trypzean). The positive control was 8 - 128 µM cinnamic aldehyde in 1% ethanol in cell culture medium, and the solvent control was 1% ethanol in cell culture medium. In all 4 experiments, 12 concentrations in the range 0.195 – 400 µg/mL were used. The highest concentration was determined in a solubility test prior to the main experiments. Per experiment 3 replicates were prepared. One day prior to testing cells were harvested, and seeded at a density of 10,000 cells/well in basic medium in conventional 96-well plates. One plate was used for the luciferase activity measurements, and one parallel replicate was used for the MTT cell viability assay. The cells were incubated overnight in the incubator. 24 h after seeding, the test and control substances were applied and plates were incubated at 37 °C, 5% CO2 and ≥ 95% relative humidity for 48 ± 2 h.

Experiment 1 and 2 were considered invalid as the variability across the negative control wells (CV%) was > 20% (52.69% and 35.71%, respectively).

In Experiment 3 the Imax was 4.72 at 100 µg/mL and lead to an EC1.5 = 12.04 µg/mL. The test substance showed cytotoxicity, with an IC30 = 154.04 µg/mL and IC50 = 167.49 µg/mL. In this run the negative and positive control results met the acceptance criteria. In Experiment 4 the Imax was 4.72 at 100 µg/mL and the EC1.5 was 12.04 µg/mL. The test substance showed cytotoxicity, with an IC30 = 253.91 µg/mL and IC50 = 295.65 µg/mL. In this run, the negative and positive control results met the acceptance criteria. As Experiment 3 and 4 were considered to be valid, the overall outcome of the experiment was positive, indicating the test substance has a skin sensitising potential. As the result was not conclusive with respect to the non-classification or classification as skin sensitiser of the test substance and therefore further evaluation and/or data generation is required.

OECD QSAR Toolbox prediction

Prediction of the skin sensitisation potential of fatty acids, C6-18 (branched and linear) alkyl and hydrocarbons, C10-18, n-alkanes, branched alkanes, cycloalkanes, aromatics (EC No. 942-654-8) was generated by the Automated Workflow for Defined Approaches for Skin Sensitisation implemented in the OECD QSAR Toolbox 4.5, to be used as in silico information source for the ITSv2 defined approach, as described in OECD guideline 497.

Since the substance is of UVCB nature, nine representative constituents of saponifiable and unsaponifiable material were selected for QSAR estimations: (9Z)-tetradec-9-enoic acid, octanoic acid, 10-ethylhexadecanoic acid, 9,12-dimethylhexadecanoic acid, 6-methylundecanoic acid, decane, octadec-1-ene, 8-methylhexadecane and dodecylcyclohexane.

(9Z)-tetradec-9-enoic acid was predicted as positive (i.e. skin sensitiser) based on read-across and the constituent falls into the applicability domain of the automated workflow.

Octanoic acid, 10-ethylhexadecanoic acid, 9,12-dimethylhexadecanoic acid, 6-methylundecanoic acid and decane were predicted as negative (i.e. not skin sensitisers) based on read-across, while 8-methylhexadecane was estimated as negative based on the profiling method. All these constituents fall into the applicability domain of the automated workflow.

Octadec-1-ene and dodecylcyclohexane were predicted as negative based on the read-across method, but they fall outside the applicability domain of the automated workflow. However, the experimental data of the closest analogues agree with the predictions of these constituents.

In conclusion, based on a worst-case approach, the substance fatty acids, C6-18 (branched and linear) alkyl and hydrocarbons, C10-18, n-alkanes, branched alkanes, cycloalkanes, aromatics (EC No. 942-654-8) was estimated to be a potential skin sensitiser and the results may be used in a weight-of-evidence approach together with other in chemico/in vitro assays to reach a conclusion regarding the skin sensitising potential of the test substance.

Conclusion regarding the skin sensitising potential

The result of the in vitro KeratinoSens™ assay was positive for fatty acids, C6-18 (branched and linear) alkyl and hydrocarbons, C10-18, n-alkanes, branched alkanes, cycloalkanes, aromatics (EC No. 942-654-8). In the OECD QSAR Toolbox prediction one of the nine main constituents was predicted to be a skin sensitiser, six were predicted to be negative and two (with a negative prediction) fell outside the applicability domain of the automated workflow. Applying a worst-case approach, the conclusion of the prediction was positive for skin sensitisation.

Although the data on skin sensitisation is not sufficient to cover the 3 key events listed as the standard data requirement in Column 1 of Annex VII of the REACH Regulation (EC) No. 1907/2006, it can be used in a worst-case approach for classification purposes. The available data indicate that fatty acids, C6-18 (branched and linear) alkyl and hydrocarbons, C10-18, n-alkanes, branched alkanes, cycloalkanes, aromatics (EC No. 942-654-8) is a skin sensitiser.

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

The available data on skin sensitisation of fatty acids, C6-18 (branched and linear) alkyl and hydrocarbons, C10-18, n-alkanes, branched alkanes, cycloalkanes, aromatics (EC No. 942-654-8) meet the criteria for classification as Skin Sens. 1 (H317) according to Regulation (EC) No. 1272/2008 (CLP).