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Toxicological information

Skin sensitisation

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Administrative data

Endpoint:
skin sensitisation, other
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:
DEREK (EC3, potency)
1 Substance
1.1 CAS number 6408-50-0
1.2 EC number 229-059-2
1.3 Chemical name 1-(methylamino)-4-[(3-methylphenyl)amino]anthraquinone
IUPAC 1-(methylamino)-4-[(3-methylphenyl)amino]anthraquinone
Other HSB-2651
Other
1.4 Structural formula

1.5 Structure codes
SMILES CNc3ccc(Nc1cccc(C)c1)c4c(=O)c2ccccc2c(=O)c34
InChI InChI=1S/C22H18N2O2/c1-13-6-5-7-14(12-13)24-18-11-10-17(23-2)19-20(18)22(26)16-9-4-3-8-15(16)21(19)25/h3-12,23-24H,1-2H3
Other
Stereochemical features Not applicable

2 General Information
2.1 Date of QPRF 29 March 2018
2.2 Author and contact details Jamie Marshall, Envigo, Shardlow Business Park
London Road, Shardlow, Derbyshire, DE72 2GD
Email: jamie.marshall@envigo.com

3 Prediction
3.1 Endpoint (OECD Principle 1)
Endpoint EC3
Dependent variable Not applicable
3.2 Algorithm (OECD Principle 2)
Model or submodel name Derek EC3 Model
Model version 1.0.6
Reference to QMRF The QMRF for skin sensitisation alert with the identifier Q13-34-36-315 is available from the JRC QMRF inventory (http://qsardb.jrc.it/qmrf/). No QMRF for the EC3 model available. Further details can be obtained from https://www.lhasalimited.org/products/EC3-predictions-for-skin-sensitisation.htm
Predicted values (model result) 0.77 % (strong sensitiser)
Predicted values (comments) Based on structures triggering Alert 837 Ortho or para amino- or hydroxy-aniline: 10/27 compounds used in calculation.
Input for prediction Smiles
Calculated descriptor values Alert and fingerprints used for selecting analogues
3.3 Applicability domain (OECD Principle 3)
Domains Based on structures triggering Alert 837 Ortho or para amino- or hydroxy-aniline: 10/27 compounds used in calculation
Structural analogues i. LLNA EC3 % Median: 0.60% (strong sensitiser), Similarity: 32%
CAS 2495-37-6 Saflufenacil, CAS: 372137-35-4
ii. LLNA EC3 % Median: 0.90% (strong sensitiser), Similarity: 31%
CAS 140-11-4 Budesonide, CAS: 51333-22-3
iii. LLNA EC3 % Median: 0.57% (strong sensitiser), Similarity: 29%
Methyl cinnamate Mometasone furoate, CAS: not available
iv. LLNA EC3 % Median: 5.9% (moderate sensitiser), similarity: 27%
Benzyl benzoate Tixocortol pivalate, CAS: not available

Consideration on structural analogues Structural similarity between the four most similar structures and the query structure (30%) is considered poor.
The lack of similarity however is due to the analogues being chosen for their similarity to the para-aminoaniline moiety in the molecule. All the substances are ortho or para substituted anilines which, as explained above, are the anticipated autoxidation products of the substance and thus their similarity is to those substances rather than the parent compound itself. Thus while this similarity value is poor, it should not necessarily lead to the conclusion of discounting this result.
3.4 The uncertainty of the prediction (OECD principle 4)
DEREK assessment: Skin sensitisation in mammal is PLAUSIBLE, i.e. The weight of evidence supports the proposition.
3.5 The chemical and biological mechanisms according to the model underpinning the predicted result (OECD principle 5)
Hapten, binding to epidermal proteins via a range of reactive intermediates, ethier radical cations or Michael acceptors [Aptula et al]
This alert describes skin sensitisation of anilines substituted with hydroxyl or amino groups in ortho or para positions.
A range of reactive intermediates and oligomeric derivatives able to bind to epidermal proteins, have been proposed. The presence of an amino or hydroxy group in the para (or ortho) position to the aniline moiety makes this chemical class very effective at stabilising free radicals. Enzymatic or autoxidation of ortho and para amino or hydroxy substituted anilines lead to the formation of Wurster salt radical cations, quinone diimines and/or quinoneimines. Wurster salt-type intermediates are reactive, for example, at the exocyclic nitrogen while quinone diimine and quinoneimines are Michael acceptors..

4 Adequacy (Optional)
4.1 Regulatory purpose Skin sensitisation endpoint for assessing the skin sensitisation potency with in silico methods according to ECHA Guidance, Chapter R.7a, 2016.

4.2 Approach for regulatory interpretation of the model result
Result is directly applicable since no conversion of the result is required.

4.3 Outcome Using the average of the lowest values as reported for each structure in the DEREK report results in a conservative EC3 of 0.77 %.

4.4 Conclusion The prediction is considered reliable and will be used together with predictions from other models in a weight of evidence conclusion.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2018

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
- Principle of test: QSAR prediciton of Skin senistisation
- Short description of test conditions: n/a
- Parameters analysed / observed: Skin senistisation

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Details on test material:
Identification: 1-(methylamino)-4-[(3-methylphenyl)amino] anthraquinone
Physical state/Appearance: dark red powder
Batch: 702W01
Purity: 99.4%
Expiry Date: 08 February 2020
Storage Conditions: room temperature in the dark
Intended use/Application: industrial chemical

Results and discussion

In vitro / in chemico

Results
Parameter:
other: Prediciton
Run / experiment:
EC3 = 0.77%
Remarks on result:
positive indication of skin sensitisation

Any other information on results incl. tables


DEREK (EC3, potency)

1

Substance

 

 

 

1.1

CAS number

 

6408-50-0

 

1.2

EC number

 

229-059-2

 

1.3

Chemical name

 

1-(methylamino)-4-[(3-methylphenyl)amino]anthraquinone

 

 

 

IUPAC

1-(methylamino)-4-[(3-methylphenyl)amino]anthraquinone

 

 

 

Other

HSB-2651

 

 

 

Other

 

 

1.4

Structural formula

 

 

 

 

 

 

 

1.5

Structure codes

 

 

 

 

 

SMILES

CNc3ccc(Nc1cccc(C)c1)c4c(=O)c2ccccc2c(=O)c34

 

 

 

InChI

InChI=1S/C22H18N2O2/c1-13-6-5-7-14(12-13)24-18-11-10-17(23-2)19-20(18)22(26)16-9-4-3-8-15(16)21(19)25/h3-12,23-24H,1-2H3

 

 

 

Other

 

 

 

 

Stereochemical features

Not applicable

 

2

General Information

 

 

 

2.1

Date of QPRF

 

29 March 2018

 

2.2

Author and contact details

Jamie Marshall, Envigo, Shardlow Business Park

London Road, Shardlow, Derbyshire, DE72 2GD

Email: jamie.marshall@envigo.com

 

3

Prediction

 

 

 

3.1

Endpoint (OECD Principle 1)

 

 

 

 

Endpoint

EC3

 

 

 

Dependent variable

Not applicable

 

3.2

Algorithm (OECD Principle 2)

 

 

 

 

Model or submodel name

Derek EC3 Model

 

 

 

Model version

1.0.6

 

 

 

Reference to QMRF

The QMRF for skin sensitisation alert with the identifier Q13-34-36-315 is available from the JRC QMRF inventory (http://qsardb.jrc.it/qmrf/). No QMRF for the EC3 model available. Further details can be obtained from https://www.lhasalimited.org/products/EC3-predictions-for-skin-sensitisation.htm

 

 

 

Predicted values (model result)

0.77 % (strong sensitiser)

 

 

 

Predicted values (comments)

Based on structures triggering Alert 837 Ortho or para amino- or hydroxy-aniline: 10/27 compounds used in calculation.

 

 

 

Input for prediction

Smiles

 

 

 

Calculated descriptor values

Alert and fingerprints used for selecting analogues

 

3.3

Applicability domain (OECD Principle 3)

 

 

 

Domains

Based on structures triggering Alert 837 Ortho or para amino- or hydroxy-aniline: 10/27 compounds used in calculation

 

 

 

Structural analogues

i.

LLNA EC3 % Median: 0.60% (strong sensitiser), Similarity: 32%

CAS 2495-37-6

Saflufenacil, CAS: 372137-35-4

ii.

LLNA EC3 % Median: 0.90% (strong sensitiser), Similarity: 31%

CAS 140-11-4

Budesonide, CAS: 51333-22-3

iii.

LLNA EC3 % Median:    0.57% (strong sensitiser), Similarity: 29%

Methyl cinnamate

Mometasone furoate, CAS: not available

iv.

LLNA EC3 % Median: 5.9% (moderate sensitiser), similarity: 27%

Benzyl benzoate

Tixocortol pivalate, CAS: not available

 

 

 

Consideration on structural analogues

Structural similarity between the four most similar structures and the query structure (30%) is considered poor.

The lack of similarity however is due to the analogues being chosen for their similarity to the para-aminoaniline moiety in the molecule. All the substances are ortho or para substituted anilines which, as explained above, are the anticipated autoxidation products of the substance and thus their similarity is to those substances rather than the parent compound itself. Thus while this similarity value is poor, it should not necessarily lead to the conclusion of discounting this result.

 

3.4

The uncertainty of the prediction (OECD principle 4)

 

 

 

 

DEREK assessment: Skin sensitisation in mammal is PLAUSIBLE, i.e. The weight of evidence supports the proposition.

 

3.5

The chemical and biological mechanisms according to the model underpinning the predicted result (OECD principle 5)

 

 

 

 

Hapten, binding to epidermal proteins via a range of reactive intermediates, ethier radical cations or Michael acceptors [Aptula et al]

This alert describes skin sensitisation of anilines substituted with hydroxyl or amino groups in ortho or para positions.

A range of reactive intermediates and oligomeric derivatives able to bind to epidermal proteins, have been proposed. The presence of an amino or hydroxy group in the para (or ortho) position to the aniline moiety makes this chemical class very effective at stabilising free radicals. Enzymatic or autoxidation of ortho and para amino or hydroxy substituted anilines lead to the formation of Wurster salt radical cations, quinone diimines and/or quinoneimines. Wurster salt-type intermediates are reactive, for example, at the exocyclic nitrogen while quinone diimine and quinoneimines are Michael acceptors..

 

4

Adequacy (Optional)

 

 

 

4.1

Regulatory purpose

Skin sensitisation endpoint for assessing the skin sensitisation potency with in silico methods according to ECHA Guidance, Chapter R.7a, 2016.

 

 

 

 

 

4.2

Approach for regulatory interpretation of the model result

 

 

 

Result is directly applicable since no conversion of the result is required.

 

 

 

 

 

4.3

Outcome

Using the average of the lowest values as reported for each structure in the DEREK report results in a conservative EC3 of 0.77 %.

 

 

 

 

 

4.4

Conclusion

The prediction is considered reliable and will be used together with predictions from other models in a weight of evidence conclusion.

Applicant's summary and conclusion

Interpretation of results:
Category 1A (indication of significant skin sensitising potential) based on GHS criteria
Conclusions:
Using the average of the lowest values as reported for each structure in the DEREK report results in a conservative EC3 of 0.77 %.
The prediction is considered reliable and will be used together with predictions from other models in a weight of evidence conclusion.