Benzyl acrylate

Endpoint summary

Description of key information

The prediction of the skin sensitisation potential of BZA (CAS 2495-35-4) was performed with BIOVIA Discovery Studio (TOPKAT) 4.5, VEGA NIC 1.1.4 (CAESAR), OECD QSAR Toolbox 4.0, Toxtree 2.6.13 and DEREK Nexus 5.0.2. In addition, results from the Danish QSAR Database were also considered in this assessment. The TOPKAT model for skin sensitisation was extended by including data from the Envigo database. In addition, three structurally similar analogues triggering the same protein binding alert for skin sensitisation (OASIS v1.4 in OECD Toolbox) as BZA were also included in the training set. For details on the three analogues, it is referred to the data matrix of category members used for read-across with OECD Toolbox.

The prediction results for BZA are detailed in the QSAR prediction reporting formats (QPRFs). Reliability indices are assigned to each prediction and which are based on considerations of similar structures in the training set, prediction statistics and the applicability domain. For details, it is referred to the QPRFs. 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:

All models predicted BZA to be a sensitiser. The predictions with TOPKAT, CAESAR and the results taken from Danish QSAR database are considered to of moderate reliability, while there is high confidence in the predictions with OECD Toolbox and DEREK. Mechanistic reasoning of both predictions is based on the ability of interacting with skin proteins via a Michael addition mechanism and S_N2 reaction at the sp³carbon atom, respectively. The same mechanisms were identified by Toxtree and thus substantiating the predictions with OECD Toolbox and DEREK.

The OECD Toolbox skin metabolism simulator calculated two metabolites for BZA, but not any triggered a protein binding alert for skin sensitisation. An additional risk of skin sensitising properties due to formation of metabolites can therefore be excluded.

With all predictions indicating sensitising properties and a mechanistic reasoning substantiated by three models there is an argument for a weight of evidence that BZA is likely to be skin sensitising.

For skin sensitisation potency estimation, EC3 values were predicted with DEREK and OECD Toolbox. OECD Toolbox predicted an EC3 of 19.5% based on three analogues triggering the same protein binding alert (Michael addition) and belonging to the same chemical category as BZA (acrylate). Since BZA also alerted possible interaction with skin proteins via S_N2 reaction at the sp³carbon atom another prediction with one category member triggering both protein binding mechanisms (see, Toolbox data matrix – EC3 with CAS 103-41-3) was performed. Here, the EC3 value was predicted to be 18.4% and thus substantiating an EC3 of > 10%.

DEREK predicted an EC3 of 3.6% based on 12 compounds with structural similarities between 24 and 31% and of which nine are weak sensitiser, two are moderate sensitiser and one is a strong sensitiser. All weak sensitiser are acrylates. The strong sensitiser is dimethyl fumarate and the moderate sensitiser are diethyl fumarate and 2-hydroxyethyl acrylate. The water solubility of these substances indicate that partition from stratum into epidermis is likely to be notably higher when compared to BZA, thus suggesting that their use in the calculation of the LLNA EC3 for BZA is mechanistically not justified.

There is only moderate confidence in the predictions of EC3 with DEREK and OECD as they are characterised by uncertainties such as a large confidence range and category members with only low to moderate structural similarity. It is however not expected that the mode of action of the category member used for the predictions is different to the query structure as their majority and BZA are both acrylate, which are known to be weak sensitiser. Uncertainty may be still indicated by three category members used in the DEREK prediction, of which two are moderate sensitiser and one is a strong sensitiser. Their water solubilities and log K_ow suggest however higher partition from stratum into epidermis when compared to BZA. In terms of water solubility, log K_ow and molecular weight the most similar acrylate is butyl acrylate with an EC3 of 24.4%. With almost the same log K_ow but less water solubility it is not expected that BZA has a higher partition from stratum to epidermis and thus to bind covalently with skin proteins to form the immunogenic complex. With all these considerations, there is an argument for a weight of evidence that BZA is very likely to have an LLNA EC3 value > 2% and thus a moderate sensitiser. It is therefore proposed to classify BZA as moderate sensitiser (Cat 1b) according to CLP.

Prediction results:

Model	Prediction result	Reliability (model statistics)
TOPKAT	sensitising	moderate
CAESAR (VEGA)	sensitising	moderate
OECD Toolbox	sensitising (EC3 = 19.5%)	reliable moderate
DEREK	sensitising (EC3 = 3.6%)	reliable moderate
Toxtree	alerts for Michael acceptor & SN2	not applicable
Danish (Q)SAR Database	sensitising	moderate (only two out of three models positive, all within AD^1))

¹⁾AD: applicability domain

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:

CAESAR (VEGA)

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:

CAESAR (VEGA)
1 Substance
1.1 CAS number 2495-35-4
1.2 EC number 219-673-9
1.3 Chemical name
IUPAC 2-Propenoic acid, phenylmethyl ester
Other Benzyl acrylate
Other BZA
1.4 Structural formula

1.5 Structure codes
SMILES C=CC(=O)OCc1ccccc1
InChI 1S/C10H10O2/c1-2-10(11)12-8-9-6-4-3-5-7-9/h2-7H,1,8H2
Other
Stereochemical features Not applicable

2 General Information
2.1 Date of QPRF 26 March 2018
2.2 Author: Envigo CRS Switzerland Ltd., Rheinstrasse 74, 4414 Füllinsdorf, Switzerland,


3 Prediction
3.1 Endpoint (OECD Principle 1)
Endpoint Skin Sensitisation (None vs Sensitiser)
Dependent variable Classification as sensitiser or non-sensitiser
3.2 Algorithm (OECD Principle 2)
Model or submodel name Extension of the original CAESAR model for skin sensitisation (None vs Sensitiser) within VEGA 1.1.4
Model version 2.1.6
Reference to QMRF Not available
Predicted values (model result) Sensitiser
Predicted values (comments) According to VEGA's evaluation scheme the structure is a sensitizer, but the result shows some critical aspects, which require to be checked.
Input for prediction Smiles
Descriptor values Not provided
3.3 Applicability domain (OECD Principle 3)
Domains i. Predicted compound could be outside the applicability domain of the model.
ii. One infrequent fragments found.
iii. Considerations on the mechanism domain are not applicable since statistical model.
Structural analogues i. CAS: 17369-59-4
ii. CAS: 120-51-4
iii. CAS: 94-09-7
iv. CAS: 94-13-3

Consideration on structural analogues With 85.6%, the average similarity of the four most structurally similar analogues to the query structure is considered high. Two out of four structures are non-sensitisers thus indicating only moderate concordance with the query structure. Accuracy between predicted and actual result is moderate as only three out of were predicted correctly.
3.4 The uncertainty of the prediction (OECD principle 4)
Moderate concordance and accuracy indicate uncertainty.
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 There is evidence that the query structure is skin sensitising though the prediction is characterised by some uncertainties.

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 prediction of Skin sensitisation
- Parameters analysed / observed: Skin sensitisation

Run / experiment:

other: QSAR prediction - CAESAR (VEGA)

Parameter:

other: Prediction result

Remarks on result:

other: sensitising

CAESAR (VEGA)
1	Substance
	1.1	CAS number			2495-35-4
	1.2	EC number			219-673-9
	1.3	Chemical name
			IUPAC		2-Propenoic acid, phenylmethyl ester
			Other		Benzyl acrylate
			Other		BZA
	1.4	Structural formula
	1.5	Structure codes
			SMILES		C=CC(=O)OCc1ccccc1
			InChI		1S/C10H10O2/c1-2-10(11)12-8-9-6-4-3-5-7-9/h2-7H,1,8H2
			Other
			Stereochemical features		Not applicable
2	General Information
	2.1	Date of QPRF			26 March 2018
	2.2	Author and contact details			Envigo CRS Switzerland Ltd., Rheinstrasse 74, 4414 Füllinsdorf, Switzerland,
3	Prediction
	3.1	Endpoint (OECD Principle 1)
			Endpoint		Skin Sensitisation (None vs Sensitiser)
			Dependent variable		Classification as sensitiser or non-sensitiser
	3.2	Algorithm (OECD Principle 2)
			Model or submodel name		Extension of the original CAESAR model for skin sensitisation (None vs Sensitiser) within VEGA 1.1.4
			Model version		2.1.6
			Reference to QMRF		Not available
			Predicted values (model result)		Sensitiser
			Predicted values (comments)		According to VEGA's evaluation scheme the structure is a sensitizer, but the result shows some critical aspects, which require to be checked.
			Input for prediction		Smiles
			Descriptor values		Not provided
	3.3	Applicability domain (OECD Principle 3)
			Domains		i.	Predicted compound could be outside the applicability domain of the model.
					ii.	One infrequent fragments found.
					iii.	Considerations on the mechanism domain are not applicable since statistical model.
			Structural analogues		i. CAS: 17369-59-4 ii. CAS: 120-51-4 iii. CAS: 94-09-7 iv. CAS: 94-13-3
			Consideration on structural analogues		With 85.6%, the average similarity of the four most structurally similar analogues to the query structure is considered high. Two out of four structures are non-sensitisers thus indicating only moderate concordance with the query structure. Accuracy between predicted and actual result is moderate as only three out of were predicted correctly.
	3.4	The uncertainty of the prediction (OECD principle 4)
					Moderate concordance and accuracy indicate uncertainty.
	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			There is evidence that the query structure is skin sensitising though the prediction is characterised by some uncertainties.
	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:

other: CAESAR (VEGA) prediction result: Sensitising

Conclusions:

There is evidence that the query structure is skin sensitising though the prediction is characterised by some uncertainties.
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.

Reference 2

Endpoint:

skin sensitisation, other

Type of information:

(Q)SAR

Remarks:

DEREK

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:

BZA – DEREK (skin sensitisation)
1 Substance
1.1 CAS number 2495-35-4
1.2 EC number 219-673-9
1.3 Chemical name
IUPAC 2-Propenoic acid, phenylmethyl ester
Other Benzyl acrylate
Other BZA
1.4 Structural formula

1.5 Structure codes
SMILES C=CC(=O)OCc1ccccc1
InChI 1S/C10H10O2/c1-2-10(11)12-8-9-6-4-3-5-7-9/h2-7H,1,8H2
Other
Stereochemical features Not applicable

2 General Information
2.1 Date of QPRF 26 March 2018
2.2 Author: Envigo CRS Switzerland Ltd., Rheinstrasse 74, 4414 Füllinsdorf, Switzerland,

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: 481 alpha,beta-Unsaturated ester or precursor
Predicted values (comments) Skin sensitisation in mammal is PLAUSIBLE (The weight of evidence supports the proposition)
Input for prediction Smiles
Calculated descriptor values Descriptor Value
LogP 2.302
LogKp -1.88

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

Match with query compound:



Structural analogues Test data:
2-hydroxyethyl acrylate; strong sensitiser (guinea pig, maximisation test)

CAS Number: 818-61-1

-[[[(4-chlorophenyl)sulfonyl]oxy]methyl]-5,5-dimethyldihydro-2(3H)-furanone; positive (guinea pig, single injection adjuvant test)

CAS Number: 154750-28-4
3-(bromomethyl)-5,5-dimethyldihydro-2(3H)-furanone; positive (guinea pig, single injection adjuvant test)

CAS Number: 154750-20-6
5,5-dimethyl-3-(thiocyanatomethyl)dihydro-2(3H)-furanone, positive (guinea pig, single injection adjuvant test)

CAS Number: 154750-32-0

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)
This alert describes the skin sensitisation of alpha,beta-unsaturated esters and precursors which interact with skin proteins via a Michael addition mechanism [Ashby et al]. By analogy with beta-disubstituted alpha,beta-unsaturated ketones, beta-disubstituted alpha,beta-unsaturated esters are less susceptible to Michael addition and are therefore excluded from the scope of the current alert.

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 DEREK alert is substantiated by skin sensitisation alerts based on Michael addition mechanism triggered in OECD Toolbox and Toxtree.

4.4 Conclusion The prediction is considered reliable, thus it cannot be excluded that BZA is a skin sensitiser.

Qualifier:

no guideline followed

Principles of method if other than guideline:

- Principle of test:
QSAR prediction of Skin sensitisation
- Parameters analysed / observed: Skin sensitisation

Run / experiment:

other: QSAR prediction - DEREK

Parameter:

other: Prediction result

Remarks on result:

other: sensitising

BZA – DEREK (skin sensitisation)
1	Substance
	1.1	CAS number			2495-35-4
	1.2	EC number			219-673-9
	1.3	Chemical name
			IUPAC		2-Propenoic acid, phenylmethyl ester
			Other		Benzyl acrylate
			Other		BZA
	1.4	Structural formula
	1.5	Structure codes
			SMILES		C=CC(=O)OCc1ccccc1
			InChI		1S/C10H10O2/c1-2-10(11)12-8-9-6-4-3-5-7-9/h2-7H,1,8H2
			Other
			Stereochemical features		Not applicable
2	General Information
	2.1	Date of QPRF			26 march 2018
	2.2	Author and contact details			Envigo CRS Switzerland Ltd., Rheinstrasse 74, 4414 Füllinsdorf, Switzerland,
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: 481 alpha,beta-Unsaturated ester or precursor
			Predicted values (comments)		Skin sensitisation in mammal is PLAUSIBLE (The weight of evidence supports the proposition)
			Input for prediction		Smiles
			Calculated descriptor values		Descriptor Value LogP 2.302 LogKp -1.88
	3.3	Applicability domain (OECD Principle 3)
			Domains		Alert description image: Match with query compound:
			Structural analogues		Test data: 2-hydroxyethyl acrylate; strong sensitiser (guinea pig, maximisation test) CAS Number: 818-61-1   -[[[(4-chlorophenyl)sulfonyl]oxy]methyl]-5,5-dimethyldihydro-2(3H)-furanone; positive (guinea pig, single injection adjuvant test) CAS Number: 154750-28-4 3-(bromomethyl)-5,5-dimethyldihydro-2(3H)-furanone; positive (guinea pig, single injection adjuvant test) CAS Number: 154750-20-6 5,5-dimethyl-3-(thiocyanatomethyl)dihydro-2(3H)-furanone, positive (guinea pig, single injection adjuvant test) CAS Number: 154750-32-0
			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)
					This alert describes the skin sensitisation of alpha,beta-unsaturated esters and precursors which interact with skin proteins via a Michael addition mechanism [Ashby et al]. By analogy with beta-disubstituted alpha,beta-unsaturated ketones, beta-disubstituted alpha,beta-unsaturated esters are less susceptible to Michael addition and are therefore excluded from the scope of the current alert.
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 DEREK alert is substantiated by skin sensitisation alerts based on Michael addition mechanism triggered in OECD Toolbox and Toxtree.
	4.4	Conclusion			The prediction is considered reliable, thus it cannot be excluded that BZA is a skin sensitiser.

BZA – DEREK (EC3, potency)
1	Substance
	1.1	CAS number			2495-35-4
	1.2	EC number			219-673-9
	1.3	Chemical name
			IUPAC		2-Propenoic acid, phenylmethyl ester
			Other		Benzyl acrylate
			Other		BZA
	1.4	Structural formula
	1.5	Structure codes
			SMILES		C=CC(=O)OCc1ccccc1
			InChI		1S/C10H10O2/c1-2-10(11)12-8-9-6-4-3-5-7-9/h2-7H,1,8H2
			Other
			Stereochemical features		Not applicable
2	General Information
	2.1	Date of QPRF			26 March 2018
	2.2	Author and contact details			Envigo CRS Switzerland Ltd., Rheinstrasse 74, 4414 Füllinsdorf, Switzerland,
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)		3.6 % (moderate sensitiser)
			Predicted values (comments)		Based on structures triggering alert 481 alpha,beta-Unsaturated ester or precursor similarity and similarity (based on fingerprints) ≥ 25%: 12/25 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 481 alpha,beta-Unsaturated ester or precursor similarity and similarity (based on fingerprints) ≥ 25%: 12/25 compounds used in calculation
			Structural analogues		i.   LLNA EC3 % Median:     33% (weak sensitiser) Similarity:           31% CAS 2495-37-6 Saflufenacil, CAS: 372137-35-4 ii. LLNA EC3 % Median:     1.4% (moderate sensitiser) Similarity:           29% CAS 140-11-4 Budesonide, CAS: 51333-22-3 iii. LLNA EC3 % Median:     20% (weak sensitiser) Similarity:           28% Methyl cinnamate Mometasone furoate, CAS: not available iv. LLNA EC3 % Median:     24% (weak sensitiser) Similarity:           28% Benzyl benzoate Tixocortol pivalate, CAS: not available
			Consideration on structural analogues		Structural similarity to the query structure is considered low, however at least the four most similar structures have the methyl acrylate.
	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)
					This alert describes the skin sensitisation of alpha,beta-unsaturated esters and precursors, which interact with skin proteins via a Michael addition mechanism [Ashby et al]. By analogy with beta-disubstituted alpha,beta-unsaturated ketones, beta-disubstituted alpha,beta-unsaturated esters are less susceptible to Michael addition and are therefore excluded from the scope of the current alert.
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			The prediction suggests BZA to be a moderate sensitiser.
	4.4	Conclusion			The prediction is considered to be moderately reliable and will be used together with predictions from other models in a weight of evidence conclusion.

Interpretation of results:

other: DEREK prediction: sensitising

Conclusions:

The prediction suggests BZA to be a moderate sensitiser.
The prediction is considered to be moderately reliable and will be used together with predictions from other models in a weight of evidence conclusion.

Reference 3

Endpoint:

skin sensitisation, other

Type of information:

(Q)SAR

Remarks:

OECD Toolbox

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
QSAR Toolbox 4.0

2. MODEL (incl. version number)
QSAR Toolbox 4.0
Database version: 4.0/3.4


3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
C=CC(=O)OCc1ccccc1

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 justification

6. ADEQUACY OF THE RESULT
Reliable (see attached).

Qualifier:

no guideline followed

Principles of method if other than guideline:

- Principle of test:
QSAR prediciton of Skin senistisation
- Parameters analysed / observed: Skin senistisation

Run / experiment:

other: QSAR prediction - OECD Toolbox

Parameter:

other: Prediction result

Remarks on result:

other: sensitising

Model	Prediction result	Reliability (model statistics)
OECD Toolbox	sensitising (EC3 = 19.5%)	reliable moderate

Interpretation of results:

other: Toolbox prediction: Sensitising.

Reference 4

Endpoint:

skin sensitisation, other

Type of information:

(Q)SAR

Remarks:

TOPKAT

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 2495-35-4
1.2 EC number 219-673-9
1.3 Chemical name
IUPAC 2-Propenoic acid, phenylmethyl ester
Other Benzyl acrylate
Other BZA
1.4 Structural formula

1.5 Structure codes
SMILES C=CC(=O)OCc1ccccc1
InChI 1S/C10H10O2/c1-2-10(11)12-8-9-6-4-3-5-7-9/h2-7H,1,8H2
Other
Stereochemical features Not applicable

2 General Information
2.1 Date of QPRF 26 March 2018
2.2 Author Envigo CRS Switzerland Ltd., Rheinstrasse 74, 4414 Füllinsdorf, Switzerland,


3 Prediction
3.1 Endpoint (OECD Principle 1)
Endpoint Skin Sensitisation (None vs Sensitiser)
Dependent variable Classification as sensitiser or non-sensitiser
3.2 Algorithm (OECD Principle 2)
Model or submodel name Toxicity Prediction (Extensible)Toxicity Prediction (Extensible) Skin sensitisation (None vs Sensitiser)
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 29 additional compounds from the Envigo database.
Predicted values (model result) Sensitiser
Predicted values (comments) A Bayesian score of 4.18 being well above the best split of -1.07 and a probability of 0.92 indicating high confidence in the prediction.
Input for prediction Smiles
Caclulated descriptor values Descriptor Value
LogP 2.302
Molecular weight (g/mol) 162.185
Number of hydrogen bond donors 0
Number of hydrogen bond acceptors 2
Number of rotatable bonds in the molecule 4
The fraction of polar surface area over the total molecular surface area 0.146
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. CAS 2495-37-6 Saflufenacil, CAS: 372137-35-4
ii. CAS 140-11-4 Budesonide, CAS: 51333-22-3
iii. Methyl cinnamate Mometasone furoate, CAS: not available
iv. Benzyl benzoate Tixocortol pivalate, CAS: not available

Consideration on structural analogues With 66% the average similarity of the four analogues to the query structure is considered moderate. Three out of four structures are sensitisers, thus indicating moderate concordance with the predicted result of query structure. Accuracy between predicted and actual result is moderate as only three out of four analogues were predicted correctly.
3.4 The uncertainty of the prediction (OECD principle 4)
Uncertainty may be indicated due to moderate similarity, concordabce and accuracy (see, above). Significant prediction statistics may however compensate for this uncertainty.
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 There is evidence that the query structure is skin sensitising. The prediction is characterised by significant statistics (p value, Bayesian score, enrichment), but only moderate concordance, accuracy and similarity with regard to similar structures.

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 prediction of Skin sensitisation
- Parameters analysed / observed: Skin sensitisation

Run / experiment:

other: QSAR prediction - TOPKAT

Parameter:

other: Prediction result

Remarks on result:

other: sensitising

TOPKAT
1	Substance
	1.1	CAS number			2495-35-4
	1.2	EC number			219-673-9
	1.3	Chemical name
			IUPAC		2-Propenoic acid, phenylmethyl ester
			Other		Benzyl acrylate
			Other		BZA
	1.4	Structural formula
	1.5	Structure codes
			SMILES		C=CC(=O)OCc1ccccc1
			InChI		1S/C10H10O2/c1-2-10(11)12-8-9-6-4-3-5-7-9/h2-7H,1,8H2
			Other
			Stereochemical features		Not applicable
2	General Information
	2.1	Date of QPRF			26 March 2018
	2.2	Author and contact details			Envigo CRS Switzerland Ltd., Rheinstrasse 74, 4414 Füllinsdorf, Switzerland,
3	Prediction
	3.1	Endpoint (OECD Principle 1)
			Endpoint		Skin Sensitisation (None vs Sensitiser)
			Dependent variable		Classification as sensitiser or non-sensitiser
	3.2	Algorithm (OECD Principle 2)
			Model or submodel name		Toxicity Prediction (Extensible)Toxicity Prediction (Extensible) Skin sensitisation (None vs Sensitiser)
			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 29 additional compounds from the Envigo database.
			Predicted values (model result)		Sensitiser
			Predicted values (comments)		A Bayesian score of 4.18 being well above the best split of -1.07 and a probability of 0.92 indicating high confidence in the prediction.
			Input for prediction		Smiles
			Caclulated descriptor values		Descriptor Value LogP 2.302 Molecular weight (g/mol) 162.185 Number of hydrogen bond donors 0 Number of hydrogen bond acceptors 2 Number of rotatable bonds in the molecule 4 The fraction of polar surface area over the total molecular surface area 0.146 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. CAS 2495-37-6 Saflufenacil, CAS: 372137-35-4 ii. CAS 140-11-4 Budesonide, CAS: 51333-22-3 iii. Methyl cinnamate Mometasone furoate, CAS: not available iv. Benzyl benzoate Tixocortol pivalate, CAS: not available
			Consideration on structural analogues		With 66% the average similarity of the four analogues to the query structure is considered moderate. Three out of four structures are sensitisers, thus indicating moderate concordance with the predicted result of query structure. Accuracy between predicted and actual result is moderate as only three out of four analogues were predicted correctly.
	3.4	The uncertainty of the prediction (OECD principle 4)
					Uncertainty may be indicated due to moderate similarity, concordabce and accuracy (see, above). Significant prediction statistics may however compensate for this uncertainty.
	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			There is evidence that the query structure is skin sensitising. The prediction is characterised by significant statistics (p value, Bayesian score, enrichment), but only moderate concordance, accuracy and similarity with regard to similar structures.
	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:

other: TOPKAT prediction result: Sensitising

Conclusions:

There is evidence that the query structure is skin sensitising. The prediction is characterised by significant statistics (p value, Bayesian score, enrichment), but only moderate concordance, accuracy and similarity with regard to similar structures.
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.

Reference 5

Endpoint:

skin sensitisation, other

Type of information:

(Q)SAR

Remarks:

Toxtree

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:

Toxtree
1 Substance
1.1 CAS number 2495-35-4
1.2 EC number 219-673-9
1.3 Chemical name
IUPAC 2-Propenoic acid, phenylmethyl ester
Other Benzyl acrylate
Other BZA
1.4 Structural formula

1.5 Structure codes
SMILES C=CC(=O)OCc1ccccc1
InChI 1S/C10H10O2/c1-2-10(11)12-8-9-6-4-3-5-7-9/h2-7H,1,8H2
Other
Stereochemical features Not applicable

2 General Information
2.1 Date of QPRF 26 March 2018
2.2 Author: Envigo CRS Switzerland Ltd., Rheinstrasse 74, 4414 Füllinsdorf, Switzerland,


3 Prediction
3.1 Endpoint (OECD Principle 1)
Endpoint Grouping into skin sensitisation reactivity domain.
Dependent variable Not applicable
3.2 Algorithm (OECD Principle 2)
Model or submodel name Skin sensitisation reactivity domains in Toxtree
Model version 2.6.13
Reference to QMRF Not available. Reference: Enoch SJ, Madden JC, Cronin MT, Identification of mechanisms of toxic action for skin sensitisation using a SMARTS pattern based approach, SAR QSAR Environ Res. 2008;19(5-6): 555-78.
Predicted values (model result) Alerts for Michael acceptor and SN2 identified.
Predicted values (comments) Not applicable
Input for prediction Smiles
Descriptor values Not applicable
3.3 Applicability domain (OECD Principle 3)
Domains Not applicable. The applicability domain of each alert is defined by its modulating factors.
Structural analogues Not applicable
Consideration on structural analogues Not applicable
3.4 The uncertainty of the prediction (OECD principle 4)
Not applicable
3.5 The chemical and biological mechanisms according to the model underpinning the predicted result (OECD principle 5)
The alerts were derived from existing mechanistic knowledge, and not through data mining algorithms. No alerts were fired.

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 Alerts for Michael acceptor and SN2 were triggered by the query structure.

4.4 Conclusion The prediction 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 prediction of Skin sensitisation
- Parameters analysed / observed: Skin sensitisation

Run / experiment:

other: QSAR prediction - Toxtree

Parameter:

other: prediction

Remarks on result:

other: alerts for Michael acceptor & SN2

Toxtree
1	Substance
	1.1	CAS number			2495-35-4
	1.2	EC number			219-673-9
	1.3	Chemical name
			IUPAC		2-Propenoic acid, phenylmethyl ester
			Other		Benzyl acrylate
			Other		BZA
	1.4	Structural formula
	1.5	Structure codes
			SMILES		C=CC(=O)OCc1ccccc1
			InChI		1S/C10H10O2/c1-2-10(11)12-8-9-6-4-3-5-7-9/h2-7H,1,8H2
			Other
			Stereochemical features		Not applicable
2	General Information
	2.1	Date of QPRF			26 march 2018
	2.2	Author and contact details			Envigo CRS Switzerland Ltd., Rheinstrasse 74, 4414 Füllinsdorf, Switzerland,
3	Prediction
	3.1	Endpoint (OECD Principle 1)
			Endpoint		Grouping into skin sensitisation reactivity domain.
			Dependent variable		Not applicable
	3.2	Algorithm (OECD Principle 2)
			Model or submodel name		Skin sensitisation reactivity domains in Toxtree
			Model version		2.6.13
			Reference to QMRF		Not available. Reference: Enoch SJ, Madden JC, Cronin MT, Identification of mechanisms of toxic action for skin sensitisation using a SMARTS pattern based approach, SAR QSAR Environ Res. 2008;19(5-6): 555-78.
			Predicted values (model result)		Alerts for Michael acceptor and SN2 identified.
			Predicted values (comments)		Not applicable
			Input for prediction		Smiles
			Descriptor values		Not applicable
	3.3	Applicability domain (OECD Principle 3)
			Domains		Not applicable. The applicability domain of each alert is defined by its modulating factors.
			Structural analogues		Not applicable
			Consideration on structural analogues		Not applicable
	3.4	The uncertainty of the prediction (OECD principle 4)
					Not applicable
	3.5	The chemical and biological mechanisms according to the model underpinning the predicted result (OECD principle 5)
					The alerts were derived from existing mechanistic knowledge, and not through data mining algorithms. No alerts were fired.
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			Alerts for Michael acceptor and SN2 were triggered by the query structure.
	4.4	Conclusion			The prediction will be used together with predictions from other models in a weight of evidence conclusion.

Interpretation of results:

other: Toxtree prediction: alerts for sensitisation

Conclusions:

Alerts for Michael acceptor and SN2 were triggered by the query structure.
The prediction will be used together with predictions from other models in a weight of evidence conclusion.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (sensitising)

Additional information:

Appraisal of available data and testing strategy:

BZA is a colourless liquid with low molecular weight (162.19 g/mol) and with a predicted logKowand water solubility of 2.44 (log Kow) and 583 mg/L, respectively. Its lipophilicity suggest dermal penetration, while the low water solubility may indicate only low dermal uptake.

Available information on corrosivity and sensitisation:

Envigo study 1834102 confirms that BZA is skin irritant, while Envigo study 1834101 reveals that the substance is not corrosive.

Screening of databases such as ChemIDplus, Chemspider, Toxnet, US EPA did not reveal additional information on skin sensitization properties of BZA.

An analogue search with OECD Toolbox revealed several acrylates with some potential to cause skin sensitization: butyl acrylate (BA), ethyl acrylate (EA), methyl acrylate (MA) and benzyl methacrylate (BMA). In addition, EC3 values of BA, EA and MA range between 11 and 28%, thus suggesting weak sensitisation of BZA. Benzyl cinnamate, which triggered the same protein binding mechanism as BZA in OECD Toolbox (Michael addition and S_N2reaction at a sp³carbon atom) is reported with an EC3 value of 18.4% and therefore may substantiate that BZA is a weak sensitiser. For details on identified analogues and QSAR predictions, refer to 'prediction and evaluation of the skin sensitisation potential of BZA, Ref No. NR92SK).

Acid/Base:

Information on pH is not yet available. It is however considered unlikely that pH will trigger ECHA’s exclusion criteria for testing.

Flammability:

With an auto-ignition temperature of 428 ± 5 °C it is not expected that the substance is spontaneously flammable in air at room temperature.

Applicability of in vitro studies:

BZA appears to be in domain for the three in vitro assays (OECD 442C, D &E).

As the exclusion criteria for testing according to ECHA are not met, testing of BZA can be performed. Study result on skin sensitisation from previous testing are not available. Results from QSARs and read across provide an argument for a weight of evidence that BZA is sensitising and has an LLNA EC3 of at least >2%,thus suggesting classification as moderate sensitiser (Cat 1b) according to CLP. It is therefore proposed to exclude in vitro testing and to submit the QSAR / read-across study to ECHA for proposing classification as moderate sensitiser (Cat1b).

Justification for classification or non-classification

Study result on skin sensitisation from previous testing are not available. Results from QSARs and read across provide an argument for a weight of evidence that BZA is sensitising and has an LLNA EC3 of at least >2%,thus suggesting classification as moderate sensitiser (Cat 1b) according to CLP.