6,6'-diphenylfulvene

Endpoint summary

Description of key information

Combining the results derived from:

a)    profiling results with OECD QSAR Toolbox v4.2,

b)    QSAR predictions from VEGA, Danish QSAR Database, and iSafeRat® Skin Sensitisation Pilot model

c)     And the structural alert results derived using Nexus DEREK v6.0.1

[cyclopenta-2,4 -dien-1 -ylidene(phenyl)methyl]benzene was predicted as non-sensitising to the skin.

Conclusions from individual models:

Profiling and chemical category approach results using the OECD QSAR Toolbox v4.2 suggests that the query substance is not a skin sensitiser.

Nexus DEREK v6.0.1 predicts the query substance as non-sensitiser to the skin.

iSafeRat® Skin Sensitisation Pilot Model predicts the query substance as non sensitiser to the skin because no structural alerts for skin sensitisation were triggered.

LeadScope model incorporated into the Danish QSAR Database predicts the query substance as non-sensitiser to the skin.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Reference 1

Endpoint:

skin sensitisation, other

Type of information:

(Q)SAR

Remarks:

Danish QSAR Database

Adequacy of study:

supporting study

Study period:

04-May-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

Remarks:

Results are reliable but no QPRF report was generated as model output

Justification for type of information:

1. SOFTWARE
Danish QSAR Database

2. MODEL
Models incorporated into Danish QSAR Database:
a) SciQSAR
b) Case Ultra
c) LeadScope

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
C1=CC=C(C=C1)C(=C2C=CC=C2)C3=CC=CC=C3

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
Please refer to the attached QMRF of this model for further information about how the model satisfies the five recommended OECD principles for QSARs.

5. APPLICABILITY DOMAIN
Please refer to the attached QMRF of this model for further information about how the model's applicability domain.

6. ADEQUACY OF THE RESULT
If the substance falls within the applicability domain of the model, the result is expected to be reliable.

Qualifier:

no guideline followed

Principles of method if other than guideline:

The skin sensitisation potential of the query substance was predicted using a battery of the following three different models incorporated into the tool:
a) SciQSAR
b) Case Ultra
c) LeadScope

GLP compliance:

no

Parameter:

other: Non sensitising to the skin

Remarks on result:

no indication of skin sensitisation based on QSAR/QSPR prediction

Model	Prediction for Skin Sensitisation
SciQSAR	Inconclusive (outside the applicability domain)
Leadscope	Non sensitiser (inside the applicability domain)
CASE Ultra	Skin Sensitiser (outside the applicability domain)

As per the results from Danish QSAR Database, only LeadScope was able to provide a reliable prediction as the query substance falls within its applicability domain. Results generated using CASE Ultra and SciQSAR models were therefore not considered further in this report. As the substance falls outside the domain for 2 out of 3 QSAR models, the battery prediction using this tool was considered as inconclusive.

Interpretation of results:

other: non-sensitising to the skin

Conclusions:

LeadScope model incorporated into the Danish QSAR Database predicts [cyclopenta-2,4-dien-1-ylidene(phenyl)methyl]benzene as non-sensitising to the skin.

Executive summary:

LeadScope model incorporated into the Danish QSAR Database predicts [cyclopenta-2,4 -dien-1 -ylidene(phenyl)methyl]benzene as non-sensitising to the skin. The predictions from SciQSAR and Case Ultra were not reliable as the query substance falls outside their applicability domains.

Reference 2

Endpoint:

skin sensitisation, other

Remarks:

QSAR prediction

Type of information:

(Q)SAR

Remarks:

QSAR prediction derived using iSafeRat Skin Sensitisation Pilot model

Adequacy of study:

weight of evidence

Study period:

04-May-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

Remarks:

The result is expected to be reliable however no QMRF or QPRF reports are provided as model output.

Justification for type of information:

1. SOFTWARE
iSafeRat v1.7

2. MODEL (incl. version number)
iSafeRat Skin Sensitisation Pilot model v1.0

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
C1=CC=C(C=C1)C(=C2C=CC=C2)C3=CC=CC=C3

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
The pilot model triggers structural alerts for skin sensitisation for the query substance. No QMRF is available as the model is in its beta version.

5. APPLICABILITY DOMAIN
No QMRF is available currently for this model.

6. ADEQUACY OF THE RESULT
If no structural alerts are triggered, the query substance is expected to be non-sensitising to the skin.

Qualifier:

no guideline followed

Principles of method if other than guideline:

KREATiS is currently validating its High Accuracy QSAR to predict Skin Sensitisation. In the meantime, KREATiS has made available a Pilot model which could identify several structural alerts in a chemical structure for skin sensitisation. If no structural alerts are triggered, the pilot model classifies the substance as non sensitiser to the skin.

GLP compliance:

no

Remarks:

QSAR prediction

Parameter:

other: Non-sensitising to the skin

Remarks on result:

no indication of skin sensitisation based on QSAR/QSPR prediction

No structural alerts were triggered using iSafeRat Skin Sensitisation Pilot model. Therefore, [cyclopenta-2,4 -dien-1-ylidene(phenyl)methyl]benzene was predicted as non sensitising to the skin.

Interpretation of results:

other: Non-sensitising to the skin

Conclusions:

iSafeRat Skin Sensitisation Pilot Model predicts [cyclopenta-2,4 -dien-1 -ylidene(phenyl)methyl]benzene as non sensitiser to the skin because no structural alerts for skin sensitisation were triggered.

Executive summary:

iSafeRat® Skin Sensitisation Pilot Model predicts [cyclopenta-2,4 -dien-1 -ylidene(phenyl)methyl]benzene as non sensitiser to the skin because no structural alerts for skin sensitisation were triggered.

Reference 3

Endpoint:

skin sensitisation, other

Remarks:

QSAR prediction based on structural alert system applied using Nexus DEREK v6.0.1

Type of information:

(Q)SAR

Remarks:

Structural alert system using Nexus DEREK v6.0.1

Adequacy of study:

key study

Study period:

03-May-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

Remarks:

Prediction report and QMRF are available. However, no QPRF was generated as model output.

Justification for type of information:

1. SOFTWARE
Nexus DEREK

2. MODEL (incl. version number)
Nexus DEREK v6.0.1

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
C1=CC=C(C=C1)C(=C2C=CC=C2)C3=CC=CC=C3

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
Please refer to the attached QMRF of this model for further information about how the model satisfies the five recommended OECD principles for QSARs.

5. APPLICABILITY DOMAIN
Please refer to the attached QMRF of this model for further information about the model's applicability domain (based on structural alerts)

6. ADEQUACY OF THE RESULT
If no structural alerts are triggered and if no misclassified features were identified in the chemical structure, the query substance can be considered as non-sensitising to the skin.

Qualifier:

no guideline followed

Principles of method if other than guideline:

DEREK predicts the skin sensitisation potential of a substance based on the triggered structural alerts for this endpoint. If the substance is a sensitiser, DEREK provides the EC3 value. The attached prediction report generated with this tool also provides detailed information about each triggered alert.

GLP compliance:

no

Remarks:

QSAR prediction

Parameter:

other: Non-sensitising in mammal

Remarks on result:

no indication of skin sensitisation based on QSAR/QSPR prediction

The query structure did not match any structural alerts for skin sensitisation with Nexus DEREK therefore it was predicted as Non-sensitiser in mammal. Please refer to the attached prediction for the reasoning summary for this endpoint result.

Interpretation of results:

other: Non-sensitising to the skin

Remarks:

QSAR prediction based on structural alerts

Conclusions:

[cyclopenta-2,4-dien-1-ylidene(phenyl)methyl]benzene did not match any structural alerts for skin sensitisation with Nexus DEREK therefore it was predicted as Non-sensitiser in mammal.

Executive summary:

[cyclopenta-2,4 -dien-1 -ylidene(phenyl)methyl]benzene did not match any structural alerts for skin sensitisation with Nexus DEREK therefore it was predicted as Non-sensitiser in mammal.

Reference 4

Endpoint:

skin sensitisation, other

Remarks:

Profiling results using OECD QSAR Toolbox v4.2

Type of information:

(Q)SAR

Remarks:

Profiling results were generated by applying Skin Sensitisation profilers incorporated into the OECD QSAR Toolbox v4.2

Adequacy of study:

supporting study

Study period:

04-May-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

Remarks:

Reliable results, however no report was provided as output with the model. No QMRF and QPRF may be necessary as only profilers were applied and no QSAR result was generated.

Justification for type of information:

1. SOFTWARE
OECD QSAR Toolbox

2. MODEL (incl. version number)
OECD QSAR Toolbox v4.2

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
C1=CC=C(C=C1)C(=C2C=CC=C2)C3=CC=CC=C3

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
Skin sensitisation relevant profilers incorporated into the OECD QSAR Toolbox were applied. Further information about each profiler can be found in the help file of the OECD QSAR Toolbox v4.2 (see attached).

5. APPLICABILITY DOMAIN
Please refer to the help file of the OECD QSAR Toolbox v4.2 for further information (see attached).

6. ADEQUACY OF THE RESULT
Profiling results provided a list of structural alerts triggered for the query substance for the skin sensitisation endpoint. If no alerts are triggered, the substance is predicted as non-sensitiser. It is better to use the profiling results in combination with the results derived with other QSAR models to derive a consensus/battery result.

Qualifier:

no guideline followed

Principles of method if other than guideline:

Skn Sensitisation relevant profilers integrated into the OECD QSAR Toolbox v4.2 were applied on the query substance. If no structural alerts were triggered for the qeury substance with any of the profilers, the substance is predicted as non-sensitiser to the skin.

List of profilers applied:
Protein binding potency GSH
Protein binding potency Cys (DPRA 13%)
Protein binding by OASIS
Protein binding by OECD
Protein binding potency Lys (DPRA 13%)
Keratinocyte gene expression
Protein binding alerts for skin sensitization by OASIS
Protein binding alerts for skin sensitization according to GHS
Respiratory sensitisation
Protein Binding Potency h-CLAT

GLP compliance:

no

Remarks:

QSAR result

Parameter:

other: Non-sensitiser to the skin

Remarks on result:

no indication of skin sensitisation based on QSAR/QSPR prediction

OECD QSAR Toolbox v4.2 Profilers for Skin Sensitisation (results for diphenylfulvene)
Profilers
General Mechanistic
Protein binding potency GSH	Not possible to classify according to these rules (GSH)
Protein binding potency Cys (DPRA 13%)	DPRA less than 9% (DPRA 13%) >> No protein binding alert
Protein binding by OASIS	No alert found
Protein binding by OECD	No alert found
Protein binding potency Lys (DPRA 13%)	DPRA less than 9% (DPRA 13%) >> No protein binding alert
Endpoint Specific
Keratinocyte gene expression	Not possible to classify according to these rules
Protein binding alerts for skin sensitization by OASIS	No alert found
Protein binding alerts for skin sensitization according to GHS	No alert found
Respiratory sensitisation	No alert found
Protein Binding Potency h-CLAT	No alert found

None of the skin sensitisation profilers in the OECD QSAR Toolbox v4.2 triggered any structural alerts for skin sensitisation. OECD QSAR Toolbox v4.2 also provides the possibility to get a better understanding of the skin sensitisation potential of a substance via the Skin Sensitisation AOP approach integrated into its interface. However, since no protein binding alerts were triggered for the query substance, the AOP approach wasn’t investigated any further.

The OECD QSAR Toolbox also includes a Skin metabolism simulator to identify potential metabolites for the query substance. Using this metabolism simulator, the following single metabolite was identified for diphenylfulvene. None of the skin sensitisation profilers in the OECD QSAR Toolbox v4.2 triggered any structural alerts for skin sensitisation also for this metabolite.

Interpretation of results:

other: [cyclopenta-2,4-dien-1-ylidene(phenyl)methyl]benzene is predicted as non-sensitiser to the skin based on the profiling results generated using OECD QSAR Toolbox v4.2

Conclusions:

As per the profiling results, the [cyclopenta-2,4-dien-1-ylidene(phenyl)methyl]benzene will be predicted as non-sensitising to the skin.

Executive summary:

None of the skin sensitisation profilers in the OECD QSAR Toolbox v4.2 triggered any structural alerts for skin sensitisation for [cyclopenta-2,4-dien-1-ylidene(phenyl)methyl]benzene.

OECD QSAR Toolbox v4.2 provides the possibility to get a better understanding of the skin sensitisation potential of a substance via the Skin Sensitisation AOP approach integrated into its interface. However, since no protein binding alerts were triggered for the [cyclopenta-2,4-dien-1-ylidene(phenyl)methyl]benzene, the AOP approach wasn’t investigated any further.

One metabolite was identified using the Skin metabolism simulator incorporated into the OECD QSAR Toolbox v4.2. No structural alerts were triggered for this metabolite (please refer to the attached in silico study report for further information).

As per the profiling results, the [cyclopenta-2,4 -dien-1 -ylidene(phenyl)methyl]benzene will be predicted as non-sensitising to the skin.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)