monoesters of C16 and C18 (branched and linear) fatty acids with decan-1-ol

Endpoint summary

Description of key information

(Q)SAR: not sensitising

In vivo (LLNA, GPMT): not sensitising (read-across)

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Reference 1

Endpoint:

skin sensitisation: in vivo (LLNA)

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Justification for type of information:

refer to analogue justification provided in IUCLID section 13

Reason / purpose for cross-reference:

read-across source

Key result

Parameter:

SI

Value:

1.2

Test group / Remarks:

25%

Remarks on result:

other: Source: 3687-46-5

Key result

Parameter:

SI

Value:

2

Test group / Remarks:

50%

Remarks on result:

other: Source: 3687-46-5

Key result

Parameter:

SI

Value:

2.1

Test group / Remarks:

100%

Remarks on result:

other: Source: 3687-46-5

Interpretation of results:

other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No. 1272/2008

Conclusions:

Based on the results of the LLNA with the source substance CAS 3687-46-5 no skin sensitising properties were determined. As explained in the analogue justification, this result is considered to be valid also for the target substance.

Reference 2

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Justification for type of information:

refer to analogue justification provided in IUCLID section 13

Reason / purpose for cross-reference:

read-across source

Key result

Reading:

1st reading

Hours after challenge:

24

Group:

negative control

Dose level:

undiluted

No. with + reactions:

0

Total no. in group:

5

Remarks on result:

other: Source 93803-87-3

Key result

Reading:

1st reading

Hours after challenge:

24

Group:

test chemical

Dose level:

undiluted

No. with + reactions:

0

Total no. in group:

10

Remarks on result:

other: Source 93803-87-3

Key result

Reading:

2nd reading

Hours after challenge:

48

Group:

negative control

Dose level:

undiluted

No. with + reactions:

0

Total no. in group:

5

Remarks on result:

other: Source 93803-87-3

Key result

Reading:

2nd reading

Hours after challenge:

48

Group:

test chemical

Dose level:

undiluted

No. with + reactions:

0

Total no. in group:

10

Remarks on result:

other: Source 93803-87-3

Key result

Group:

positive control

Remarks on result:

positive indication of skin sensitisation

Interpretation of results:

other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No 1272/2008.

Conclusions:

Based on the results of the GPMT with the source substance CAS 93803-87-3 no skin sensitising properties were determined. As explained in the analogue justification, this result is considered to be valid also for the target substance.

Reference 3

Endpoint:

skin sensitisation, other

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model, but not (completely) falling into its applicability domain, and documentation / justification is limited

Justification for type of information:

CAESAR (VEGA)
1 Substance
1.1 CAS number 84605-08-3
1.2 EC number 306-448-6
1.3 Chemical name
IUPAC Decyl 16-methylheptadecanoate
Other Heptadecanoic acid, 16-methyl-, decyl ester
Other Decyl isostearate
1.4 Structural formula

1.5 Structure codes
SMILES CCCCCCCCCCOC(=O)CCCCCCCCCCCCCCC(C)C
InChI InChI=1S/C28H56O2/c1-4-5-6-7-8-17-20-23-26-30-28(29)25-22-19-16-14-12-10-9-11-13-15-18-21-24-27(2)3/h27H,4-26H2,1-3H3
Other
Stereochemical features N/A

2 General Information
2.1 Date of QPRF 09 March 2018
2.2 Author and contact details Envigo, Shardlow Business Park London Road, Shardlow, Derbyshire, DE72 2GD

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 may be not reliable.
Input for prediction Smiles
Descriptor values Not provided
3.3 Applicability domain (OECD Principle 3)
Domains i. The predicted compound is into the Applicability Domain of the model.
ii. Strongly similar compounds with known experimental value in the training set have been found.
iii. Accuracy of prediction for similar molecules found in the training set is good.
iv. Similar molecules found in the training set have experimental values that agree with the predicted
value.
v. Descriptors for this compound have values inside the descriptor range of the compounds of the
training set.
vi. All atom centered fragment of the compound have been found in the compounds of the training
set.
Structural analogues i. Isopropyl myristate
ii. 4,4-dimethyl-2-nonadecyl-4,5-dihydro-1,3-oxazol-5-one
iii. 2-heptadecyl-4,4-dimethyl-4,5-dihydro-1,3-oxazol-5-one
iv. 4,4-Dimethyl-2-pentadecyl-1,3-oxazol-5(4H)-one

Consideration on structural analogues With 86.6% the average similarity of the four most structurally similar analogues to the query structure is considered high. All four of the structures are sensitizers, thus indicating high concordance with the query structure. Three of the four structures trigger an alert from the OASIS protein binding profiler for skin sensitisation in OECD Toolbox, whereas the target molecule does not show any alerts in the profiling. Furthermore, the metabolism predictions for these molecules show different pathways and again no alerts for the query structure. It is therefore assumed to be likely that mode of action followed by the three oxazolone structures is not relatable to the target compound.

3.4 The uncertainty of the prediction (OECD principle 4)
The models own statistics indicate high reliability in the prediction, with high similarity, recognition of all compound fragments in the training set, good concordance of results with measured data etc. However it is clear to the assessor that the nearest molecules in the dataset used for the prediction have considerably different properties and functional groups to the target compound.
An assessment of these differences using the profilers in the OECD QSAR Toolbox identifies alerts for the oxazolone containing structures compared with the target structure. Furthermore assessment of the predicted metabolism of these compounds has shown different routes to breakdown products again which the target molecule does not display any alerts for.
This indicates uncertainty in the results from the model.
The Isopropyl myristate is also predicted to be sensitising.
The Data matrix with this information in has been included in the printouts section below for reference.

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 The query structure is within the applicability domain of the model, and the prediction is made with good statistics, however due to concerns regarding the mode of action displayed by the similar structures in the training set, there is some uncertainty in the result.

4.4 Conclusion The prediction is not considered reliable and will not be considered 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

Remarks on result:

positive indication of skin sensitisation

CAESAR (VEGA)
1	Substance
	1.1	CAS number			84605-08-3
	1.2	EC number			306-448-6
	1.3	Chemical name
			IUPAC		Decyl 16-methylheptadecanoate
			Other		Heptadecanoic acid, 16-methyl-, decyl ester
			Other		Decyl isostearate
	1.4	Structural formula
	1.5	Structure codes
			SMILES		CCCCCCCCCCOC(=O)CCCCCCCCCCCCCCC(C)C
			InChI		InChI=1S/C28H56O2/c1-4-5-6-7-8-17-20-23-26-30-28(29)25-22-19-16-14-12-10-9-11-13-15-18-21-24-27(2)3/h27H,4-26H2,1-3H3
			Other
			Stereochemical features		N/A
2	General Information
	2.1	Date of QPRF			09 March 2018
	2.2	Author and contact details			Envigo, Shardlow Business Park, London Road, Shardlow, Derbyshire, DE72 2GD
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 may be not reliable.
			Input for prediction		Smiles
			Descriptor values		Not provided
	3.3	Applicability domain (OECD Principle 3)
			Domains		i.	The predicted compound is into the Applicability Domain of the model.
					ii.	Strongly similar compounds with known experimental value in the training set have been found.
					iii.	Accuracy of prediction for similar molecules found in the training set is good.
					iv.	Similar molecules found in the training set have experimental values that agree with the predicted value.
					v.	Descriptors for this compound have values inside the descriptor range of the compounds of the training set.
					vi.	All atom centered fragment of the compound have been found in the compounds of the training set.
			Structural analogues		i. Isopropyl myristate ii. 4,4-dimethyl-2-nonadecyl-4,5-dihydro-1,3-oxazol-5-one iii. 2-heptadecyl-4,4-dimethyl-4,5-dihydro-1,3-oxazol-5-one iv. 4,4-Dimethyl-2-pentadecyl-1,3-oxazol-5(4H)-one
			Consideration on structural analogues		With 86.6% the average similarity of the four most structurally similar analogues to the query structure is considered high. All four of the structures are sensitizers, thus indicating high concordance with the query structure. Three of the four structures trigger an alert from the OASIS protein binding profiler for skin sensitisation in OECD Toolbox, whereas the target molecule does not show any alerts in the profiling. Furthermore, the metabolism predictions for these molecules show different pathways and again no alerts for the query structure. It is therefore assumed to be likely that mode of action followed by the three oxazolone structures is not relatable to the target compound.
	3.4	The uncertainty of the prediction (OECD principle 4)
					The models own statistics indicate high reliability in the prediction, with high similarity, recognition of all compound fragments in the training set, good concordance of results with measured data etc. However it is clear to the assessor that the nearest molecules in the dataset used for the prediction have considerably different properties and functional groups to the target compound. An assessment of these differences using the profilers in the OECD QSAR Toolbox identifies alerts for the oxazolone containing structures compared with the target structure. Furthermore assessment of the predicted metabolism of these compounds has shown different routes to breakdown products again which the target molecule does not display any alerts for. This indicates uncertainty in the results from the model. The Isopropyl myristate is also predicted to be sensitising. The Data matrix with this information in has been included in the printouts section below for reference.
	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			The query structure is within the applicability domain of the model, and the prediction is made with good statistics, however due to concerns regarding the mode of action displayed by the similar structures in the training set, there is some uncertainty in the result.
	4.4	Conclusion			The prediction is not considered reliable and will not be considered with predictions from other models in a weight of evidence conclusion.

Interpretation of results:

GHS criteria not met

Conclusions:

The query structure is within the applicability domain of the model, and the prediction is made with good statistics, however due to concerns regarding the mode of action displayed by the similar structures in the training set, there is some uncertainty in the result.

The prediction is not considered reliable and will not be considered with predictions from other models in a weight of evidence conclusion.

Reference 4

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 limited documentation / justification

Justification for type of information:

DEREK (skin sensitisation)
1 Substance
1.1 CAS number 84605-08-3
1.2 EC number 306-448-6
1.3 Chemical name
IUPAC Decyl 16-methylheptadecanoate
Other Heptadecanoic acid, 16-methyl-, decyl ester
Other Decyl isostearate
1.4 Structural formula

1.5 Structure codes
SMILES CCCCCCCCCCOC(=O)CCCCCCCCCCCCCCC(C)C
InChI InChI=1S/C28H56O2/c1-4-5-6-7-8-17-20-23-26-30-28(29)25-22-19-16-14-12-10-9-11-13-15-18-21-24-27(2)3/h27H,4-26H2,1-3H3
Other
Stereochemical features N/A

2 General Information
2.1 Date of QPRF 09 March 2018
2.2 Author and contact details Envigo, Shardlow Business Park, London Road, Shardlow, Derbyshire, DE72 2GD

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) Skin sensitisation in mammal is NON-SENSITISER
Predicted values (comments) No misclassified or unclassified features
Input for prediction Smiles
Calculated descriptor values Descriptor Value
LogP 12.0
LogKp 3.21

3.3 Applicability domain (OECD Principle 3)
Domains No structural alerts or examples for skin sensitisation Structure does not contain any unclassified or misclassified features
Therefore no Domain is available to report
Structural analogues N/A
Consideration on structural analogues N/A.
3.4 The uncertainty of the prediction (OECD principle 4)
The software has not identified any substructures within the compound that match its database of alerts. While some confidence can be placed in the softwares prediction, this result alone should not be considered conclusive on its own. The uncertainty of the prediction cannot be directly measured/assessed as no statistics are reported by the model.
3.5 The chemical and biological mechanisms according to the model underpinning the predicted result (OECD principle 5)
The query structure does not match any structural alerts or examples for skin sensitisation in Derek. Additionally, the query structure does not contain any unclassified or misclassified features and is consequently predicted to be a non-sensitiser.

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 Non-sensitiser

4.4 Conclusion Non-sensitiser, no misclassified or unclassified features
The query structure does not match any structural alerts or examples for skin sensitisation in Derek. Additionally, the query structure does not contain any unclassified or misclassified features.

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:

no indication of skin sensitisation

DEREK (skin sensitisation)
	1	Substance
		1.1	CAS number			84605-08-3
		1.2	EC number			306-448-6
		1.3	Chemical name
				IUPAC		Decyl 16-methylheptadecanoate
				Other		Heptadecanoic acid, 16-methyl-, decyl ester
				Other		Decyl isostearate
		1.4	Structural formula
		1.5	Structure codes
				SMILES		CCCCCCCCCCOC(=O)CCCCCCCCCCCCCCC(C)C
				InChI		InChI=1S/C28H56O2/c1-4-5-6-7-8-17-20-23-26-30-28(29)25-22-19-16-14-12-10-9-11-13-15-18-21-24-27(2)3/h27H,4-26H2,1-3H3
				Other
				Stereochemical features		N/A
	2	General Information
		2.1	Date of QPRF			09 March 2018
		2.2	Author and contact details			Envigo, Shardlow Business Park, London Road, Shardlow, Derbyshire, DE72 2GD
	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)		Skin sensitisation in mammal is NON-SENSITISER
				Predicted values (comments)		No misclassified or unclassified features
				Input for prediction		Smiles
				Calculated descriptor values		Descriptor Value LogP 12.0 LogKp 3.21
		3.3	Applicability domain (OECD Principle 3)
				Domains		No structural alerts or examples for skin sensitisation Structure does not contain any unclassified or misclassified features Therefore no Domain is available to report
				Structural analogues		N/A
				Consideration on structural analogues		N/A.
		3.4	The uncertainty of the prediction (OECD principle 4)
						The software has not identified any substructures within the compound that match its database of alerts. While some confidence can be placed in the softwares prediction, this result alone should not be considered conclusive on its own. The uncertainty of the prediction cannot be directly measured/assessed as no statistics are reported by the model.
		3.5	The chemical and biological mechanisms according to the model underpinning the predicted result (OECD principle 5)
						The query structure does not match any structural alerts or examples for skin sensitisation in Derek. Additionally, the query structure does not contain any unclassified or misclassified features and is consequently predicted to be a non-sensitiser.
	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			Non-sensitiser
		4.4	Conclusion			Non-sensitiser, no misclassified or unclassified features The query structure does not match any structural alerts or examples for skin sensitisation in Derek. Additionally, the query structure does not contain any unclassified or misclassified features.

Interpretation of results:

GHS criteria not met

Conclusions:

The software has not identified any substructures within the compound that match its database of alerts. While some confidence can be placed in the softwares prediction, this result alone should not be considered conclusive on its own. The uncertainty of the prediction cannot be directly measured/assessed as no statistics are reported by the model.
Non-sensitiser, no misclassified or unclassified features
The query structure does not match any structural alerts or examples for skin sensitisation in Derek. Additionally, the query structure does not contain any unclassified or misclassified features.

Reference 5

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 limited documentation / justification

Justification for type of information:

1. SOFTWARE
QSAR Toolbox 4.2

2. MODEL (incl. version number)
QSAR Toolbox 4.2
Database version: 4.2
TPRF v4.2

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

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]
Prediction is considered to be reliable since the nearest neighbours are of high (>70%) similarity to the target, and while the mechanism is ill defined, there is concordance within the categoryy substances which provides some confidence in the prediction.

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:

no indication of skin sensitisation

Interpretation of results:

GHS criteria not met

Conclusions:

Initially categorised by the esters category from ECOSAR, then further subcategorised using maximal data by substance type, Protein binding alerts for skin sensitization by oasis, Protein binding alerts for skin sensitization by oasis accounting autoxidation simulator, Protein binding alerts for skin sensitization by oasis accounting skin metabolism simulator, keratinocyte gene expression and finally structural similarity to 70%.

The profilers for the compounds and the metabolites show no alerts for sensitisation, and all but one compound in the category has negative study data. The one outlier is a long chain cyclic compound and is thus considered dissimilar to the rest of the group, it is also the furthest away in the prediction space due to its predicted partition coefficient being much lower than the rest of the category. Therefore there is concordance within the remaining category substances which provides some confidence in the prediction. Due to this and the high similarity between category members and profile alerts, it is considered that the prediction is reliable.

Reference 6

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 84605-08-3
1.2 EC number 306-448-6
1.3 Chemical name
IUPAC Decyl 16-methylheptadecanoate
Other Heptadecanoic acid, 16-methyl-, decyl ester
Other Decyl isostearate
1.4 Structural formula

1.5 Structure codes
SMILES CCCCCCCCCCOC(=O)CCCCCCCCCCCCCCC(C)C
InChI InChI=1S/C28H56O2/c1-4-5-6-7-8-17-20-23-26-30-28(29)25-22-19-16-14-12-10-9-11-13-15-18-21-24-27(2)3/h27H,4-26H2,1-3H3
Other
Stereochemical features N/A

2 General Information
2.1 Date of QPRF 09 March 2018
2.2 Author and contact details Envigo, Shardlow Business Park, London Road, Shardlow, Derbyshire, DE72 2GD

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) Non-Sensitizer
Predicted values (comments) A Bayesian score of -25.6 being well below the best split of -1.075 and a probability of 0.00 suggest confidence in the prediction.
Input for prediction Smiles
Caclulated descriptor values Descriptor Value
LogP 11.392
Molecular weight (g/mol) 424.743
Number of hydrogen bond donors 0
Number of hydrogen bond acceptors 2
Number of rotatable bonds in the molecule 0
The fraction of polar surface area over the total molecular surface area 0.049
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. OPS PC1 out of range. Value: -10.826. Training min, max, SD, explained variance: -9.801, 6.4075, 3.314, 0.1320.
ii. 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. Isodecyl oleate
ii. Ethyl hexyl palmitate
iii. Isostearyl neopentanoate
iv. Dilauryl thiodipropionate

Consideration on structural analogues With 0.58 the average distance of the four analogues to the query structure is considered poor. All four structures are non-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

Remarks on result:

no indication of skin sensitisation

TOPKAT
1	Substance
	1.1	CAS number			84605-08-3
	1.2	EC number			306-448-6
	1.3	Chemical name
			IUPAC		Decyl 16-methylheptadecanoate
			Other		Heptadecanoic acid, 16-methyl-, decyl ester
			Other		Decyl isostearate
	1.4	Structural formula
	1.5	Structure codes
			SMILES		CCCCCCCCCCOC(=O)CCCCCCCCCCCCCCC(C)C
			InChI		InChI=1S/C28H56O2/c1-4-5-6-7-8-17-20-23-26-30-28(29)25-22-19-16-14-12-10-9-11-13-15-18-21-24-27(2)3/h27H,4-26H2,1-3H3
			Other
			Stereochemical features		N/A
2	General Information
	2.1	Date of QPRF			09 March 2018
	2.2	Author and contact details			Envigo, Shardlow Business Park, London Road, Shardlow, Derbyshire, DE72 2GD
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)		Non-Sensitizer
			Predicted values (comments)		A Bayesian score of -25.6 being well below the best split of -1.075 and a probability of 0.00 suggest confidence in the prediction.
			Input for prediction		Smiles
			Caclulated descriptor values		Descriptor Value LogP 11.392 Molecular weight (g/mol) 424.743 Number of hydrogen bond donors 0 Number of hydrogen bond acceptors 2 Number of rotatable bonds in the molecule 0 The fraction of polar surface area over the total molecular surface area 0.049 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.	OPS PC1 out of range. Value: -10.826. Training min, max, SD, explained variance: -9.801, 6.4075, 3.314, 0.1320.
					ii.	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. Isodecyl oleate   ii. Ethyl hexyl palmitate   iii. Isostearyl neopentanoate   iv. Dilauryl thiodipropionate
			Consideration on structural analogues		With 0.58 the average distance of the four analogues to the query structure is considered poor. All four structures are non-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:

GHS criteria not met

Conclusions:

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

Endpoint conclusion:

no adverse effect observed (not sensitising)

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information:

Justification for read-across

There are no in vitro or in vivo data on the skin sensitisation potential of : Monoesters of C16 and C18 (branched and linear) fatty acids with decan-1-ol. The assessment was therefore performed as a weight-of-evidence approach based on QSAR modelling performed with the target substance and studies performed with analogue (source) substances as part of a read across approach, which is in accordance with Regulation (EC) No. 1907/2006, Annex XI, 1.5. For each specific endpoint the source substance(s) structurally closest to the target substance is/are chosen for read-across, with due regard to the requirements of adequacy and reliability of the available data. Structural similarities and similarities in properties and/or activities of the source and target substance are the basis of read-across. A detailed justification for the analogue read-across approach is provided in the technical dossier (see IUCLID Section 13).

QSAR prediction

CAS 84605-08-3

TOPKAT, DEREK, and OECD Toolbox predicted decyl isooctadecanoate be non-sensitising, the statistics related to these predictions suggest these results are reliable. The results obtained from the Danish QSAR Database were conclusive, with all results proposed to be negative for skin sensitisation, and also all within the applicability domain of the respective models. 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 CAESAR (VEGA) model identified the substance as sensitising, this was however discounted as the conclusion is based on compounds which were dissimilar to the target chemical, specifically in terms of functional groups. The three compounds were oxazolones which would possess different properties to the target. This was confirmed by running profilers through OECD QSAR Toolbox on the compounds to identify any alerts related not only to the compounds, but their potential metabolites (in case of pre/pro haptens). It was identified that these values were different to those of the target molecule and thus as the hypothesis was supported by this evidence, the result of the CAESAR modle was discounted.

The negative 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. Furthermore, the four compounds were included into a category with the target compound in OECD QSAR Toolbox and their similarity compared using the Dice atom paired fragments method commonly used in this software. The result indicated an average similarity of 72%, therefore the similarity could be considered moderate as opposed to poor, affording further confidence in the prediction. It was concluded that the model would be considered as part of the overall weight of evidence.

 

The DEREK skin sensitisation module indicated the query structure does not match any structural alerts or examples for skin sensitisation in Derek. Additionally, the query structure does not contain any unclassified or misclassified features and is consequently predicted to be a non-sensitiser.by the software. The uncertainty of the prediction cannot be directly measured/assessed as no statistics are reported by the model. The result will be used as part of the weight of evidence.

Prediction with OECD Toolbox was performed first via the automatic workflow, then manually amended after the workflow failed to conclude a result for skin sensitisation. Decyl isostearate did not trigger an alert by any of the skin sensitisation profilers and so the automatic workflow selected the ECOSAR profiler as a starting point, this was then subcategorised using maximal data by substance type, Protein binding alerts for skin sensitization by oasis, Protein binding alerts for skin sensitization by oasis accounting autoxidation simulator, Protein binding alerts for skin sensitization by oasis accounting skin metabolism simulator, keratinocyte gene expression, but the automated work flow could not conclude on a suitable grouping. At this point the prediction was manually further subcategorised by structural similarity to 70%. The resulting category are a group of similar substances to the target molecule which show the same predicted autoxidation and skin metabolism pathway and all carry negative study data, which can be seen from the resultant data matrix. There is high similarity of the substances to the query structure, high concordance of results within the category. As such the result is considered to be reliable.

 

Table 1: Prediction results

Model	Prediction result	Reliability
TOPKAT extended	Non-sensitising	High
TOPKAT non extended	Non-sensitising	High
DEREK	Non-sensitising	Moderate
OECD Toolbox	Non-sensitising	Moderate
CAESAR (VEGA)	Sensitising	Discounted
Toxtree	No alerts identified	Not applicable
Danish (Q)SAR Database	Non-Sensitising	Moderate

 

There is evidence that : Monoesters of C16 and C18 (branched and linear) fatty acids with decan-1-ol is not classified as a skin sensitizer.

From the predictions with OECD Toolbox, DEREK, and TOPKAT, the models were in concordance, identifying no alerts on the structure or its metabolites. In addition, the Danish QSAR database and Toxtree are also in agreement with these results.

The CAESAR model in Vega drew a conclusion from its assessment that the target substance was nearest to several oxazolone compounds which were classified as sensitizers. As discussed above and below, these compounds are dissimilar to the target in terms of functional groups, and the identified alerts for these compounds are different to that of the target substance when assessed in the QSAR Toolbox. Furthermore, the identified metabolism products from these compounds differ entirely to the target substances metabolites and pathways, it was determined that this prediction was not appropriate and it was discounted from the conclusion.

Therefore the identified conclusions from OECD QSAR Toolbox, US EPA TEST, and DEREK NEXUS were considered valid, and in concordance, providing a weight of evidence proposing that the substance should be considered not classified for skin sensitisation.

In vivo data

CAS 3687-46-5

An in vivo skin sensitisation study (Local Lymph Node Assay, LLNA) was performed with decyl oleate (CAS 3687-46-5) according to OECD guideline 429 and under GLP conditions (Notox, 2010). Five female CBA/J mice per dose were treated with 0, 25, 50 and 100% of the test substance in acetone/olive oil. The test substance formulations or the vehicle were applied epicutaneously onto the dorsal part of each ear (25 µL/ear) for three consecutive days. All mice were sacrificed three days after the last treatment (on Day 6) and the weight of the lymph nodes was determined. The cell proliferation of pooled lymph nodes from individual animals was measured as 3H-methyl thymidine incorporation and determined by beta-scintillation counting. The stimulation indices were 1.0, 1.2, 2.0 and 2.1 for the control, 25, 50 and 100% groups, respectively. The SI slightly increased with the dose level, but the increase was not statistically significant. Positive and vehicle controls were valid. An EC3 value of the test substance could not be calculated, as all stimulation indices were <3. Based on the study results, the test substance was not skin sensitising.

CAS 93803-87-3

A Guinea pig maximisation test (GPMT) was performed with 2-octyldodecyl isooctadecanoate (CAS 93803-87-3) under GLP conditions and according to OECD guideline 406 (Notox, 1998). Ten test and 5 control Himalayan guinea pigs were induced intradermally with undiluted test substance on both sides of the spine with and without Freud's complete adjuvant. On Day 7, the animals were treated with 10% sodium dodecyl sulfate to induce mild skin irritation. On Day 8, a 48-hour epicutaneous induction treatment with the undiluted test substance was performed under semi-occlusive conditions. On Day 22, the challenge treatment was performed by topical application of the test substance at 100% (right flank) and a blank patch (left flank) to all animals for 24 hours, under semi-occlusive conditions. Skin reactions were evaluated 24 and 48 hours after the challenge application. During the study, no test substance-related clinical signs and no effects on body weight gain were observed. 8 hours after intradermal induction, slight to severe erythema was noted at all of the sites injected with FCA/water and FCA/test substance in 10/10 treated and 5/5 control animals. 4/5 control animals also exhibited necrosis at the FCA/test substance injection site. In 3/10 treated animals slight to well-defined erythema was observed at the injection site of the test substance. Following the topical induction, severe erythema and scabs were observed at the test site in 3/10 treated animals. A further 4/10 (in total 7/10) treated and 4/5 control animals exhibited only scabs. No skin reactions were observed after the challenge treatment in any of the animals of the test and control groups. The results of the reliability check carried out at regular intervals were positive, confirming the reliability of the assay. Based on the results, the test substance had no sensitising effect in guinea pigs under the experimental conditions.

Overall conclusion for skin sensitisation

The QSAR predictions (OECD Toolbox, TOPKAT, DEREK, CAESAR) did not predict skin sensitising properties of decyl isostearate. No sensitising potential was seen in experimental studies in mice (LLNA) and guinea pigs (GPMT) performed with source substances. Based on the available information, : Monoesters of C16 and C18 (branched and linear) fatty acids with decan-1-ol is not expected to be skin sensitising.

Justification for classification or non-classification

According to Article 13 of Regulation (EC) No. 1907/2006 "General Requirements for Generation of Information on Intrinsic Properties of substances", information on intrinsic properties of substances may be generated by means other than tests e.g. from information from structurally related substances (grouping or read-across), provided that conditions set out in Annex XI are met. Annex XI, "General rules for adaptation of this standard testing regime set out in Annexes VII to X” states that “substances whose physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity may be considered as a group, or ‘category’ of substances. This avoids the need to test every substance for every endpoint". Since the analogue concept is applied to : Monoesters of C16 and C18 (branched and linear) fatty acids with decan-1-ol data will be generated from data for reference source substance(s) to avoid unnecessary animal testing. Additionally, once the analogue read-across concept is applied, substances will be classified and labelled on this basis.

Therefore, based on the analogue read-across approach, the available data on skin sensitisation do not meet the classification criteria according to Regulation (EC) No. 1272/2008 and are therefore conclusive but not sufficient for classification.