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Description of key information

Neryl acetate is predicted as weak sensitiser to the skin (predicted LLNA EC3%: 15) using Derek Nexus v5.0.2.

Neryl acetate is predicted as skin sensitiser using the VEGA skin sensitisation model (CAESAR).

Based on the results obtained with the OECD QSAR Toolbox, neryl acetate and several of its potential metabolites are associated with multiple structural alerts for protein binding, making them as potential skin sensitisers.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin sensitisation, other
Remarks:
QSAR model
Type of information:
(Q)SAR
Adequacy of study:
key study
Study period:
16/08/2017
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:
Nexus v2.1.1

2. MODEL:
Derek Nexus v5.0.2

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


4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL:
See attached QMRF

5. APPLICABILITY DOMAIN:
See attached prediction report

6. ADEQUACY OF THE RESULT:
See attached prediction report
Reference:
Composition 0
Composition 0
Composition 0
Composition 0
Qualifier:
no guideline required
Principles of method if other than guideline:
Derek Nexus is a proprietary, rule-based expert system for the prediction of toxicity. Its knowledge base is composed of alerts, examples and reasoning rules which may each contribute to the predictions made by the system. Each alert in Derek describes a chemical substructure believed to be responsible for inducing a specific toxicological outcome (often referred to as a toxicophore). Alerts are derived by experts, using toxicological data and information regarding the biological mechanism of action. Where relevant, metabolism data may be incorporated into an alert, enabling the prediction of compounds which are not directly toxicity but are metabolised to an active species. The derivation of each alert is described in the alert comments along with supporting references and example compounds where possible. By reporting this information to the user, Derek provides highly transparent predictions. The use of structural alerts for the prediction of toxicity is both widely understood and the subject of many publications. Derek Nexus makes predictions for and against toxicity through reasoning. For the endpoint of skin sensitisation, predictions for toxicity decrease in confidence in the following order: certain> probable>plausible>equivocal. Predictions against toxicity increase in confidence in the following order: doubted
GLP compliance:
no
Test material information:
Composition 1
Specific details on test material used for the study:
not applicable
Key result
Parameter:
other: EC3% (predicted)
Value:
15
Other effects / acceptance of results:
Reasoning summary:
Prediction strength: EQUIVOCAL
Alert matched: 712 Terpenoid
Please refer to the attached prediction report for further details about this alert.

Interpretation of results:
Category 1B (indication of skin sensitising potential) based on GHS criteria
Conclusions:
Neryl acetate is predicted as weak sensitiser to the skin (predicted LLNA EC3% : 15) using Derek Nexus v5.0.2.
The prediction is based on the triggered structured alert for terpenoids.
The prediction strength is Equivocal.
Executive summary:

Based on the derived prediction using Derek Nexus v5.0.2, neryl acetate is predicted as weak sensitiser to the skin with a predicted LLNA EC3 of 15% and a prediction strength as Equivocal. This substance triggered a skin sensitisation alert for terpenoids.

Therefore, neryl acetate is classified as skin sensitiser category 1B according to CLP Regulation (EC) No 1272/2008 and UN GHS.

Endpoint:
skin sensitisation, other
Remarks:
QSAR model
Type of information:
(Q)SAR
Adequacy of study:
supporting study
Study period:
16/08/2017
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:
OECD QSAR Toolbox v3.4

2. MODEL:
Multiple profilers relevant to Skin Sensitisation incorporated into this tool were applied.

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

4. Additional information
Please refer to the attached table as PDF file to refer to the structural alerts triggered by neryl acetate and its metabolites.
Qualifier:
no guideline followed
Version / remarks:
Protein binding is one of the crucial events of the Skin Sensitisation AOP. Protein binding profilers provide indication about the skin sensitisation potential of the substance.
Principles of method if other than guideline:
Protein binding by OASIS v1.4:
The protein binding alerts have been developed by industry consortia involving ExxonMobil, Procter&Gamble, Unilever, Research Institute for Fragrance Materials (RIFM), Dow and Danish National Food Institute with the Laboratory of Mathematical Chemistry Bourgas and the partnership of Dr D.Roberts, as a part of the TIMES model to predict skin sensitisation.
Under the scope of a research agreement signed in 2007 with Professor Mekenyan (OASIS - LMC), L'Oreal contributed to the assessment and refinement of chemical categories provided in the QSAR Toolbox. The scope of the profiler is to investigate presence of alerts within target molecules responsible for interaction with proteins. The list of 101 structural alerts has been separated into 11 mechanistic domains. Each of the mechanistic domains has been separated into more than 2 mechanistic alerts. The profiling result outcome assigns a target to the corresponding structural alert, mechanistic alerts and domain.

Protein binding by OECD:
The Protein binding by OECD profiler was developed by an analysis of direct acting structural alerts based on theoretical organic chemistry (the profiler does not contain metabolically / abiotically activated structural alerts). The alert compilations were analysed in order to place the information contained within the literature into a mechanistic chemistry framework. This mechanistic chemistry can be used as the basis for chemical category formation when utilising the Protein binding by OECD profiler. Within each of the five mechanistic domains related structural alerts have been grouped based on the presence of a common reactivity site into so-called mechanistic alerts. Chemical category formation can be carried out at either the mechanistic alert or structural alert level using this profiler. The protein binding by OECD profiler contains 16 mechanistic alerts covering 52 structural alerts. These data are supported by mechanistic chemistry and references to the scientific literature (the meta data).

Protein binding potency:
This profiler is developed on the base of empirical data for thiol reactivity expressed by the in chemico RC50 value. Data are obtained by measuring target chemical covalent binding with the thiol group of glutathione (GSH). The structural alerts for protein binding are extracted from about 400 chemicals comprised within GSH Experimental RC50. All the chemicals have two common electrophilic mechanisms of interaction with GSH – interaction via SN2 and interaction via Michael addition (MA) mechanism.
The profiler contains 49 MA and 46 SN2 categories. The set of 95 structural alerts are separated into five potency categories: Extremely, Highly, Moderately, Slightly reactive and Suspect. Classification of potency categories is as follows: extremely reactive (RC50 < 0.099mmol/L); highly reactive (RC50 = 0.100 – 0.990mmol/L); moderately reactive (RC50 = 1.000 – 15.000mmol/L); slightly reactive (RC50 = 16.000 – 70.000mmol/L); suspect (RC50 = 71.000 – 135.000).
The profiling results outcome assigns a target to the corresponding potency category based on matched structural criteria.

Protein binding alerts for skin sensitization by OASIS v1.4
The protein binding alerts have been developed by industry consortia involving ExxonMobil, Procter&Gamble, Unilever, Research Institute for Fragrance Materials (RIFM), Dow and Danish National Food Institute with the Laboratory of Mathematical Chemistry Bourgas and the partnership of Dr D.Roberts, as a part of the TIMES model to predict skin sensitisation.
The scope of this profiler is to investigate the presence of alerts within the target molecules responsible for interaction with proteins and especially with skin proteins. This profiler accounts for incapability of some chemicals having an alert to interact with skin due to electronic and steric factors. This is explicitly defined by inhibition masks associated with some alerts. The list of 100 structural alerts has been separated into 11 mechanistic domains. Each of the mechanistic domains has been separated into more than 2 mechanistic alerts. The profiling result outcome assigns a target to the corresponding structural alert, mechanistic alerts and domain.

Reference: The information about the profilers was retrieved from the OECD QSAR Toolbox v3.4.
GLP compliance:
no
Test material information:
Composition 1
Other effects / acceptance of results:
The results derived from the profiling using OECD QSAR Toolbox for Skin Sensitisation endpoint suggests that the parent compound (neryl acetate) and several of its metabolites (identified using auto-oxidation and skin metabolism simulators) are associated with multiple structural alerts for Skin Sensitisation. This indicates that neryl acetate and its metabolites have the potential for protein binding, and therefore making them potential candidates for skin sensitisation. The structural alert results are listed in the attached table. Neryl acetate was associated with the following two structural alerts:
a) Activated alkyl esters and thioesters
b) Allyl acetates and related chemicals

Please refer to the attached table for structural alerts for all the metabolites of neryl acetate.
Regarding the acceptance of results, the structural alerts are specific to protein binding potential of chemicals. These profilers doesn't provide a final result for skin sensitisation potential, however the parent compound and its metabolites that triggered the protein binding alerts are considered as potential skin sensitisers as protein binding is a crucial event in the sensitisation AOP.
Interpretation of results:
Category 1 (skin sensitising) based on GHS criteria
Conclusions:
Based on the results obtained with the OECD QSAR Toolbox, neryl acetate and several of its potential metabolites are associated with multiple structural alerts for protein binding, making them as potential skin sensitisers.
Executive summary:

OECD QSAR Toolbox v3.4 was used to perform profiling for skin sensitisation on neryl acetate by applying the four profilers incorporated into the tool for protein binding. Additionally, these profilers were also applied on all the metabolites identified for neryl acetate using auto-oxidation and skin metabolism simulators. Profiling results suggest that both neryl acetate and several of its metabolites are associated with multiple alerts for protein binding, therefore indicating them as potential skin sensitisers.

Endpoint:
skin sensitisation, other
Remarks:
QSAR model
Type of information:
(Q)SAR
Adequacy of study:
supporting study
Study period:
16/08/2017
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:
VEGA in silico platform v1.1.4

2. MODEL:
VEGA Skin Sensitisation model (CAESAR) 2.1.6

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


4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL:
See attached article

5. APPLICABILITY DOMAIN:
See attached prediction report

6. ADEQUACY OF THE RESULT:
See attached prediction report
Reference:
Composition 0
Qualifier:
no guideline required
Principles of method if other than guideline:
To address the skin sensitization issue, two complementary approaches were investigated in the CAESAR Platform:
a) A global approach aimed at developing a classifier to discriminate sensitizers vs non sensitizers.
b) A local approach that investigated a mechanistic based category formation coupled with a read-across approach within each category.

The CAESAR model for skin sensitization was developed using Adaptive Fuzzy Partition (AFP) – AFP was used to develop classification models implementing a fuzzy partition algorithm. It models relations between molecular descriptors and chemical activities by dynamically dividing the descriptor space into a set of fuzzy partitioned subspaces. The aim of this algorithm is to select the descriptor and the cut position that allow to get the maximal difference between the two fuzzy rule scores generated by the new subspaces. The score is determined by the weighted average of the chemical activity values in an active subspace A and in its neighbouring subspaces.

A complementary approach was developed to enable potential mechanisms of toxic action to be assigned to chemicals thought to be capable of skin sensitisation. This approach was based on the work of Aptula and Roberts [2] who had previously suggested that for a chemical to be a skin sensitiser it must be capable (either directly or after some abiotic or metabolic transformation) of one of five electrophilic-nucleophilic reactions. The approach undertaken was to devise SMARTS patterns capable of identifying the electrophilic mechanisms previously assigned to the 210 Gerberick LLNA dataset [3]. The 44 chemical TIMES-SS LLNA data, in which each chemical has also had a mechanism of action assigned to it by the same authors [4] was then used to validate the applicability of the SMARTS patterns.

Reference: http://www.caesar-project.eu/index.php?page=results§ion=endpoint&ne=2
GLP compliance:
no
Test material information:
Composition 1
Key result
Parameter:
other:
Remarks:
QSAR model
Run / experiment:
Prediction: Skin Sensitiser (realible result)
Other effects / acceptance of results:
Prediction is Sensitizer, the result appears reliable as the substance is within the applicability domain of the model.
Please refer to the applicability domain information provided in the attached predictionr report.

Please refer to the attached prediction report for further information about the prediction result for neryl acetate, list of most similar compounds found in the training set, parameters used for evaluating the reliability in prediction.

Interpretation of results:
Category 1 (skin sensitising) based on GHS criteria
Conclusions:
Neryl acetate is predicted as skin sensitiser using the VEGA skin sensitisation model (CAESAR). Neryl acetate falls within the applicability domain of the model.
Executive summary:

Neryl acetate was predicted, with a good reliability, as skin sensitiser using the VEGA Skin Sensitisation model (CAESAR v2.1.6). Neryl acetate falls within the applicability domain of the model.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (sensitising)
Additional information:

Based on the derived prediction using Derek Nexus v5.0.2, neryl acetate is predicted as weak sensitiser to the skin with a predicted LLNA EC3 of 15% and a prediction strength as Equivocal. This substance triggered a skin sensitisation alert for terpenoids. This result was confrmed with two other predictions: VEGA Skin Sensitisation model and OECD QSAR Toolbox.

Neryl acetate was predicted, with a good reliability, as skin sensitiser using the VEGA Skin Sensitisation model (CAESAR v2.1.6). Neryl acetate falls within the applicability domain of the model.

OECD QSAR Toolbox v3.4 was used to perform profiling for skin sensitisation on neryl acetate by applying the four profilers incorporated into the tool for protein binding. Additionally, these profilers were also applied on all the metabolites identified for neryl acetate using auto-oxidation and skin metabolism simulators. Profiling results suggest that both neryl acetate and several of its metabolites are associated with multiple alerts for protein binding, therefore indicating them as potential skin sensitisers.

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

Neryl acetate is predicted as weak sensitiser to the skin (predicted LLNA EC3% : 15) using Derek Nexus v5.0.2.

Therefore, neryl acetate is classified as skin sensitiser category 1B according to CLP Regulation (EC) No 1272/2008 and UN GHS.

This classification is confimed by the results obtained with the VEGA skin sensitisation model and the OECD QSAR Toolbox.