Registration Dossier

Administrative data

Description of key information

Introduction

The prediction of the skin sensitising potential of 1-(methylamino)-4-[(3-methylphenyl)amino]anthraquinone (CAS 6408-50-0) was performed with BIOVIA Discovery Studio (TOPKAT) 4 .5, VEGA NIC 1.1.4 (CAESAR), OECD QSAR Toolbox 4.1, and DEREK Nexus 5.0.2. In addition, results from the Danish QSAR Database and Toxtree 2.6.13 were also checked but not used in consideration in this assessment. The TOPKAT model for skin sensitisation was extended by including data from the Envigo database. The model statistics are reported in section Information to Extended TOPKAT Model.

The prediction results for 1-(methylamino)-4-[(3-methylphenyl)amino]anthraquinone are detailed in the (Q)SAR prediction reporting formats (QPRFs). Reliability indices are assigned to each prediction, and are based on considerations of similar structures in the training set, prediction statistics and the applicability domain. For further details are available in the QPRFs below.Toxtree is based on classification trees and does not provide such information and thus no reliability index is assigned. No QPRFs were prepared for the predictions taken from the Danish QSAR database. The results are presented in the software printout section together with the printouts of all other models applied.

Appraisal of (Q)SAR Modelling

TOPKAT, DEREK, CAESAR and OECD Toolbox predicted 1-(methylamino)-4-[(3-methylphenyl)amino]anthraquinone to be sensitising, and with the exception of CAESAR the statistics related to these predictions suggest these results are reliable. The results obtained from the Danish QSAR Database were inconclusive, with only one result that was within the applicability domain, the remaining three were all out of domain. As all predictions are positive and the mechanism highlighted by DEREK supports the similar structures in the TOPKAT and OECD Toolbox predictions, overall battery results is considered to be of good reliability.

The positive prediction by TOPKAT is characterised by some uncertainties with regard to the most similar structurers in the training set, thus indicating only moderate confidence in the prediction. Nevertheless, the prediction statistics (probability, enrichment, baysian score/best split difference, concordance of measured data and accuracy of predictions) were all high indicating some amount of confidence in the prediction. It was concluded that the model would be considered as part of the overall weight of evidence since three of the four similar molecules displayed some similarity to the suspected moiety highlighted by the DEREK assessment for the target molecule.

 

The DEREK skin sensitisation module indicated that the principal hapten for these compounds has been proposed to be a range of reactive intermediates and oligomeric derivatives such as Bandrowski's base (BB), able to bind to epidermal proteins [Basketter and Goodwin, Basketter and Liden, Lisi and Hansel, Pot et al]. 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. All can in principle bind to proteins of the skin, with or without prior oligomerisation, and thereby elicit sensitisation [Aptula et al].

 

Of the four most similar structures in CAESAR’s training set, only two are all sensitizers. One non sensitising substance is falsely predicted to be sensitising. They have an average structural similarity to the query structure of 76.2 % according to the software. Upon investigation using the OECD toolbox to profile the similar compounds, protein binding by OASIS with autoxidation simulation and skin metabolism simulation shows that the similar structures do now show the same mechanistic domain as the query structure (see, CAESAR data matrix). Uncertainty indicated by the absence of fragments not found in the compounds of the training set is considered low since the fragments identified do not trigger a protein binding alert for skin sensitisation in OECD Toolbox, therefore if this was considered the query structure could be concluded to be within the applicability domain of the model. Nevertheless, the poor concordance and prediction statistics, and clearly different mechanisms highlighted for the similar structures, means and the prediction is considered to be unreliable.

 

Prediction with OECD Toolbox was performed using the automated workflow for skin sensitisation. 1-(methylamino)-4-[(3-methylphenyl)amino]anthraquinone did not trigger an alert by any of the skin sensitisation profiler. Primary grouping with the Autoxidation simulator followed by sub-categorisations using (i) substance type, (ii) protein binding alerts for skin sensitisation by OASIS with autoxidation simulator, (iii) protein binding alerts for skin sensitisation by OASIS with skin metabolism simulator and (iv) structural similarity revealed five analogues, which are all skin sensitizer. The query structure is within the applicability domain of all subcategories but with a calculated log Kowof 6.47 out of the range of values of the analogues, ranging between 3.16 and 3.98. this might imply that the similar structures are better dermally adsorbed, this is similar to the experimentally determined value of >6.5 (Envigo HH02NX). When considering the water solubility of the compound in the prediction shows it differing to the nearest structures, while within the same region, it is an order of magnitude less soluble according to the predicted value. We can see however from the data matrix that the measured values of the substances are in fact much lower than the predictions which brings them in line with the target substance, which has been shown to have a measured solubility of <0.01 mg/L (ENVIGO HH02NX). Considering both of these sets of values, there is a possibility of the target substance displaying less potential for dermal absorption than the nearest neighbours. However when considering similarity in relation to solubility of the compounds it is therefore expected that these substances will show similar epidermal uptake via the stratum corneum, therefore it can be considered that the poor similarity demonstrated for the partition coefficient can be addressed by the similarity in water solubility. It is therefore proposed that 1-(methylamino)-4-[(3-methylphenyl)amino]anthraquinone is within the applicability domain of the model and the prediction is considered reliable.

As with the query structure, not any of the three analogues triggered an alert by the OASIS protein binding profiler for skin sensitisation, while the autoxidation simulator identified several metabolites triggering skin sensitisation alerts based on the presence of various Michael acceptors, derived from the p-phenylenediamine moiety, for all five analogues and the query structure (see, Toolbox data matrix). Pre haptens are therefore considered likely to be responsible for skin sensitisation of the analogues and also for 1-(methylamino)-4-[(3-methylphenyl)amino]anthraquinone. While the skin metabolism simulator suggests a possible route to similar derivatives, the DEREK prediction suggested that enzymatic oxidation may also lead to the formation of these Michael acceptor species, thus the substances may also be pro haptens.

 

Table1    Prediction results

Model

Prediction result

Reliability

TOPKAT extended

Sensitising

Moderate

TOPKAT non extended

Strong-Sensitizer

Moderate

DEREK

Sensitising

High

DEREK

EC3 = 0.77%

High

OECD Toolbox

(Automated workflow)

Sensitising

High

(outside domain)

CAESAR (VEGA)

Sensitising

Low

Toxtree

Alert for Michael Addition

Not applicable

Danish (Q)SAR Database

Sensitising

Low1)

1)Inconclusive as two out of three models reported were inconclusive, where 1-(methylamino)-4-[(3-methylphenyl)amino]anthraquinone was outside of the applicability domain of each model. Whereas the CASE Ultra prediction was Positive, and inside the applicability domain.

Conclusion

From the predictions with OECD Toolbox, DEREK, and TOPKAT, there is evidence that 1-(methylamino)-4-[(3-methylphenyl)amino]anthraquinone is skin sensitising. Both, the analogues used for read across with OECD Toolbox, and the most similar structures in the prediction with TOPKAT are all sensitizers. Also, in agreement with the query structure, these do not trigger a protein binding alert for skin sensitisation (OASIS profiler). However, DEREK andthe autooxidation metabolism simulator (in OECD Toolbox) identified autoxidation products triggering skin sensitisation alerts with the substances binding to epidermal proteins via a range of reactive intermediates, either radical cations or Michael acceptors formed from interactions around the p-phenylenediamine moiety. Most of the analogues identified in the Toolbox and TOPKAT all showed a similar potential mechanism in the derivatives of the
p-phenylenediamine moiety. It can therefore be concluded that pre haptens as identified in the DEREK assessment will most likely be responsible for skin sensitisation of1-(methylamino)-4-[(3-methylphenyl)amino]anthraquinone. Moreover, assessment of the EC3 prediction from DEREK and the non extended TOPKAT model shows that the substance will likely be a strong sensitizer, with an EC3 <2%. This would allow for a conclusion on classification for the substance as a category 1A skin sensitizer.

Skin Sens. 1A, H317: May cause allergic skin reaction

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Referenceopen allclose all

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


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.

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.
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 (skin sensitisation)
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 Skin Sensitisation
Dependent variable Not applicable
3.2 Algorithm (OECD Principle 2)
Model or submodel name Skin sensitisation in mammal
Model version DEREK Nexus 5.0.2, Nexus: 2.1.1.
Knowledge Base: Derek KB 2015 2.0, Version 2.0 from 28/01/2016
Reference to QMRF The QMRF with the identifier Q13-34-36-315 is available from the JRC QMRF inventory (http://qsardb.jrc.it/qmrf/).
Predicted values (model result) Alert matched: 456 Diaryl ketone
Alert matched: 837 Ortho or para amino- or hydroxy-aniline
Predicted values (comments) Photoallergenicity in mammal is PLAUSIBLE (The weight of evidence supports the proposition)
Skin sensitisation in mammal is PLAUSIBLE (The weight of evidence supports the proposition)
Input for prediction Smiles
Calculated descriptor values Descriptor Value
LogP 6.64
LogKp -0.09

3.3 Applicability domain (OECD Principle 3)
Domains Alert 456 description image:

Match with query compound (Alert 456):

Alert 837 description image:

Match with query compound (Alert 837):






Structural analogues Test data (Alert 456):
Ketoprofen; positive (human photopatch test, Photoallergenicity), CAS Number: 22071-15-4

Tiaprofenic acid; positive (human photopatch test, Photoallergenicity), CAS Number: 33005-95-7

suprofen; positive (human photopatch test, Photoallergenicity), CAS Number: 40828-46-4


Test data (Alert 837):
p-phenylenediamine; positive (GPMT, strong / LLNA, extreme / LLNA, strong / GMPT, extreme / HRIPT, positive), CAS Number: 106-50-3

2-aminodiphenylamine; positive (LLNA, strong), CAS Number: 534-85-0




p-methylaminophenol sulphate; positive (LLNA, strong / GPMT, strong / GPMT,extreme), CAS Number: 55-55-0

2-aminophenol; positive (LLNA, strong), CAS Number: 95-55-6

2-(2-amino-4-nitroanilino)ethanol (GPMT, strong), CAS Number: 56932-44-6


Consideration on structural analogues Results of test data are in concordance with predicted result.
3.4 The uncertainty of the prediction (OECD principle 4)
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 potential with in vitro and 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 Skin sensitisation in mammal is PLAUSIBLE. The predictive performance of this alert is considered to be high (for details, see software printout). DEREK alert is substantiated by skin sensitisation alerts “direct acylation involving anhydrides” and “acyl transfer agent identified”, triggered in OECD Toolbox and Toxtree, respectively.

4.4 Conclusion The prediction is considered reliable and the result will used together with other predictions in an argument for a weight of evidence conclusion.
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
Parameter:
other: Prediciton
Run / experiment:
Positive
Remarks on result:
positive indication of skin sensitisation

DEREK (skin sensitisation)

 

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

Skin Sensitisation

 

 

 

 

 

Dependent variable

Not applicable

 

 

 

3.2

Algorithm (OECD Principle 2)

 

 

 

 

 

 

Model or submodel name

Skin sensitisation in mammal

 

 

 

 

 

Model version

DEREK Nexus 5.0.2, Nexus: 2.1.1.
Knowledge Base: Derek KB 2015 2.0, Version 2.0 from 28/01/2016

 

 

 

 

 

Reference to QMRF

The QMRF with the identifier Q13-34-36-315 is available from the JRC QMRF inventory (http://qsardb.jrc.it/qmrf/).

 

 

 

 

 

Predicted values (model result)

Alert matched: 456 Diaryl ketone

Alert matched: 837 Ortho or para amino- or hydroxy-aniline

 

 

 

 

 

Predicted values (comments)

Photoallergenicity in mammal is PLAUSIBLE (The weight of evidence supports the proposition)

Skin sensitisation in mammal is PLAUSIBLE (The weight of evidence supports the proposition)

 

 

 

 

 

Input for prediction

Smiles

 

 

 

 

 

Calculated descriptor values

Descriptor

Value

LogP

6.64

LogKp

-0.09

 

 

 

3.3

Applicability domain (OECD Principle 3)

 

 

 

 

 

Domains

Alert 456 description image:

Match with query compound (Alert 456):

     

Alert 837 description image:

Match with query compound (Alert 837):

 

 

 

 

 

 

 

 

 

 

 

 

Structural analogues

Test data (Alert 456):
Ketoprofen; positive (human photopatch test, Photoallergenicity), CAS Number: 22071-15-4

Tiaprofenic acid; positive (human photopatch test, Photoallergenicity), CAS Number: 33005-95-7

suprofen; positive (human photopatch test, Photoallergenicity), CAS Number: 40828-46-4

 

Test data (Alert 837):

p-phenylenediamine; positive (GPMT, strong / LLNA, extreme / LLNA, strong / GMPT, extreme / HRIPT, positive), CAS Number: 106-50-3

2-aminodiphenylamine; positive (LLNA, strong), CAS Number: 534-85-0

 

 

 

p-methylaminophenol sulphate; positive (LLNA, strong / GPMT, strong / GPMT,extreme), CAS Number: 55-55-0

2-aminophenol; positive (LLNA, strong), CAS Number: 95-55-6

2-(2-amino-4-nitroanilino)ethanol (GPMT, strong), CAS Number: 56932-44-6

 

 

 

 

 

 

Consideration on structural analogues

Results of test data are in concordance with predicted result.

 

 

 

3.4

The uncertainty of the prediction (OECD principle 4)

 

 

 

 

 

 

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 potential with in vitro and 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

Skin sensitisation in mammal is PLAUSIBLE. The predictive performance of this alert is considered to be high (for details, see software printout). DEREK alert is substantiated by skin sensitisation alerts “direct acylation involving anhydrides” and “acyl transfer agent identified”, triggered in OECD Toolbox and Toxtree, respectively.

 

 

 

 

 

 

 

 

 

4.4

Conclusion

The prediction is considered reliable and the result will used together with other predictions in an argument for a weight of evidence conclusion.

 

Interpretation of results:
Category 1 (skin sensitising) based on GHS criteria
Conclusions:
The model predicts the substance to be positive for skin sensitisiation, the prediction is considered to reliable and will be used together with predictions from other models in a weight of evidence conclusion.
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:
TOPKAT
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 Skin Sensitisation (None vs Sensitiser)
Dependent variable Classification as sensitizer or non-sensitizer
3.2 Algorithm (OECD Principle 2)
Model or submodel name Toxicity Prediction (Extensible)Toxicity Prediction (Extensible) Skin sensitisation (None vs Sensitizer)
Model version 4.5
Reference to QMRF The corresponding QMRF with the identifier Q50-54-55-509 is available at http://qsardb.jrc.it/qmrf/index.jsp. The original data set was extended with 42 additional compounds from the Envigo database.
Predicted values (model result) Sensitiser
Predicted values (comments) A Bayesian score of 4.098 being above the best split of -1.092 and a probability of 0.93 suggest confidence in the prediction.
Input for prediction Smiles
Caclulated descriptor values Descriptor Value
LogP 4.653
Molecular weight (g/mol) 342.39052
Number of hydrogen bond donors 2
Number of hydrogen bond acceptors 4
Number of rotatable bonds in the molecule 3
The fraction of polar surface area over the total molecular surface area 0.171
FCFP_12: Unit functional class extended-connectivity atom type fingerprint with a maximum length of 12 bonds Not applicable

3.3 Applicability domain (OECD Principle 3)
Domains i. All properties and OPS components are within expected ranges
ii. All fingerprint features of the query molecule are found in the training set.
iii. Considerations on the mechanism domain are not applicable since the contributing FCFP_12 features of the model are selected purely on their Bayesian score (statistical model)
Structural analogues i. 10-Hydroxy-7-
isopropyltetradecahydrophenanthrene-1-
carboxylic acid
ii. Disperse yellow 3
iii. 1-Amino-4-methylaminoanthraquinon
e
iv. Disperse Blue 3

Consideration on structural analogues With 0.65 the average distance of the four analogues to the query structure is considered poor. All four structures are sensitizers, thus indicating high concordance with the predicted result of query structure. Accuracy between predicted and actual result is high as all four analogues were predicted correctly.
3.4 The uncertainty of the prediction (OECD principle 4)
Uncertainty is indicated due to poor similarity.
3.5 The chemical and biological mechanisms according to the model underpinning the predicted result (OECD principle 5)
Not applicable since statistical model

4 Adequacy (Optional)
4.1 Regulatory purpose Skin sensitisation endpoint for assessing the skin sensitisation potential with in vitro and 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 Due to poor similarity, some uncertainty can be concluded, however as all other prediction statistics are good, there is moderate confidence in the prediction.

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

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
Parameter:
other: Prediciton
Run / experiment:
Positive
Remarks on result:
positive indication of skin sensitisation

TOPKAT

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

Skin Sensitisation (None vs Sensitiser)

 

 

 

Dependent variable

Classification as sensitizer or non-sensitizer

 

3.2

Algorithm (OECD Principle 2)

 

 

 

 

Model or submodel name

Toxicity Prediction (Extensible)Toxicity Prediction (Extensible) Skin sensitisation (None vs Sensitizer)

 

 

 

Model version

4.5

 

 

 

Reference to QMRF

The corresponding QMRF with the identifier Q50-54-55-509 is available athttp://qsardb.jrc.it/qmrf/index.jsp. The original data set was extended with 42 additional compounds from the Envigo database.

 

 

 

Predicted values (model result)

Sensitiser

 

 

 

Predicted values (comments)

A Bayesian score of 4.098 being above the best split of -1.092 and a probability of 0.93 suggest confidence in the prediction.

 

 

 

Input for prediction

Smiles

 

 

 

Caclulated descriptor values

Descriptor

Value

LogP

4.653

Molecular weight (g/mol)

342.39052

Number of hydrogen bond donors

2

Number of hydrogen bond acceptors

4

Number of rotatable bonds in the molecule

3

The fraction of polar surface area over the total molecular surface area

0.171

FCFP_12: Unit functional class extended-connectivity atom type fingerprint with a maximum length of 12 bonds

Not applicable

 

3.3

Applicability domain (OECD Principle 3)

 

 

 

Domains

i.

All properties and OPS components are within expected ranges

ii.

All fingerprint features of the query molecule are found in the training set.

iii.

Considerations on the mechanism domain are not applicable since the contributing FCFP_12 features of the model are selected purely on their Bayesian score (statistical model)

 

 

 

Structural analogues

i.

10-Hydroxy-7-

isopropyltetradecahydrophenanthrene-1-

carboxylic acid

 

ii.

Disperse yellow 3

 

iii.

1-Amino-4-methylaminoanthraquinon

e

 

iv.

Disperse Blue 3

 

 

 

 

Consideration on structural analogues

With 0.65 the average distance of the four analogues to the query structure is considered poor. All four structures are sensitizers, thus indicating high concordance with the predicted result of query structure. Accuracy between predicted and actual result is high as all four analogues were predicted correctly.

 

3.4

The uncertainty of the prediction (OECD principle 4)

 

 

 

 

Uncertainty is indicated due to poor similarity.

 

3.5

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

 

 

 

 

Not applicable since statistical model

 

4

Adequacy (Optional)

 

 

 

4.1

Regulatory purpose

Skin sensitisation endpoint for assessing the skin sensitisation potential with in vitro and 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

Due to poor similarity, some uncertainty can be concluded, however as all other prediction statistics are good, there is moderate confidence in the prediction.

 

 

 

 

 

4.4

Conclusion

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

 

Interpretation of results:
Category 1 (skin sensitising) based on GHS criteria
Conclusions:
The model predicts the substance to be positive for skin sensitisiation, the prediction is considered to be of moderate reliability and will be used together with predictions from other models in a weight of evidence conclusion.
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, but not (completely) falling into its applicability domain, with adequate and reliable documentation / justification
Justification for type of information:
1. SOFTWARE
QSAR Toolbox 4.1

2. MODEL (incl. version number)
QSAR Toolbox 4.1
Database version: 4.1
TPRF v4.1

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
CNc1ccc(Nc2cccc(C)c2)c2C(=O)c3ccccc3C(=O)c12

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
[Explain how the model fulfils the OECD principles for (Q)SAR model validation. Consider attaching the QMRF or providing a link]
see attached justificaiton

5. APPLICABILITY DOMAIN
[Explain how the substance falls within the applicability domain of the model]
see attached ustification

6. ADEQUACY OF THE RESULT
[Explain how the prediction fits the purpose of classification and labelling and/or risk assessment]
There are issue swith the adequacy of this prediction due to the dissimilarity in predicted log kow values for the target and the similar structures meaning this criteria of the applicability domain is not fulfilled. While the predicted partition coefficient shows some dissimilarity to the 5 nearest neighbours, using water solubility as a descriptor instead we see a greater degree of correlation. The prediction was ultimately considered adequate to include in the weight of evidence.
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
Remarks on result:
positive indication of skin sensitisation
Interpretation of results:
GHS criteria not met
Conclusions:
The prediction suggests that 1-(methylamino)-4-[(3-methylphenyl)amino]anthraquinone is sensitising. The analogues used all follow the same mechanistic route, with Michael addition alerts following from resulting autoxidation products.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (sensitising)

Justification for classification or non-classification

From the predictions with OECD Toolbox, DEREK, and TOPKAT, there is evidence that 1-(methylamino)-4-[(3-methylphenyl)amino]anthraquinone is skin sensitising.

Assessment of the EC3 prediction from DEREK and the non extended TOPKAT model shows that the substance will likely be a strong sensitizer, with an EC3 <2%. This would allow for a conclusion on classification for the substance as a category 1A skin sensitizer.

Skin Sens. 1A, H317: May cause allergic skin reaction