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EC number: 208-589-8 | CAS number: 534-15-6
Date of QPRF
29 May 2018
Author and contact details
Dr. Stefan Pudenz, Envigo CRS Switzerland Ltd.,Rheinstrasse 74, 4414 Füllinsdorf, Switzerland,Email: firstname.lastname@example.org
Endpoint (OECD Principle 1)
Skin Sensitisation (None vs Sensitiser)
Classification as sensitiser or non-sensitiser
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
Reference to QMRF
Predicted values (model result)
Predicted values (comments)
According to VEGA's evaluation scheme the structure is a sensitizer but the result may be not reliable.
Input for prediction
Applicability domain (OECD Principle 3)
According to CAESARs evaluation scheme the predicted compound could be outside the applicability domain of the model.
One fragment of the query structure only infrequently found in the compounds of the training set.
Considerations on the mechanism domain are not applicable since statistical model.
Consideration on structural analogues
With 75% the average similarity of the four most structurally similar analogues to the query structure may be considered high. Two out of four structures are sensitiser, thus indicating only moderate concordance with the query structure. The two sensitising structures (epoxide and ester) do trigger a protein binding alert for skin sensitisation (OASIS profiler in Toolbox), while the query does not trigger an alert. This may suggest a different mode of action of the two structures. In addition, not any of the similar structures is an acetal. Similarity is therefore considered low. Accuracy is high as all four structure were predicted correctly.
The uncertainty of the prediction (OECD principle 4)
Uncertainty is indicated by moderate concordance and low similarity. The query structure is out of the model’s applicability domain.
The chemical and biological mechanisms according to the model underpinning the predicted result (OECD principle 5)
Not applicable since statistical model
Skin sensitisation endpoint for assessing the skin sensitisation potential with in vitro and in silico methods according to ECHA Guidance, Chapter R.7a, 2016.
Approach for regulatory interpretation of the model result
Result is directly applicable since no conversion of the result is required.
The query structure is out of the applicability domain of the model and there is only low confidence in the prediction.
The prediction is considered to be of low reliability and may be used together with predictions from other models in a weight of evidence conclusion.
Skin sensitisation in mammal
DEREK Nexus 6.0.1, Nexus: 2.2.1.Knowledge Base: Derek KB 2018 1.1
The QMRF with the identifier Q13-34-36-315 is available from the JRC QMRF inventory (https://qsardb.jrc.ec.europa.eu/qmrf/).
Alert matched: 424 Alkyl aldehyde precursor
Skin sensitisation in mammal is PLAUSIBLE (The weight of evidence supports the proposition)
Calculated descriptor values
Alert description image:
Match with query compound:
Test data:CAS Number: 101-48-1, (2,2-dimethoxyethyl)benzene; weak sensitiser (guinea pig, maximisation test)
CAS: 94354-60-6; ethylidenebenzoacetate; weak sensitiser (guinea pig, single injection adjuvant test)
CAS Number: 94354-68-4; ethylidene heptanoate acetate; moderate sensitiser (guinea pig, single injection adjuvant test)
CAS Number: 58567-11-6; (ethoxymethoxy)cyclododecane, weak sensitiser (LLNA)
Example structures trigger the same alert as the query structure. There are all acetals but structurally very different to the query structure.
Skin sensitisation in mammal is PLAUSIBLE, i.e. The weight of evidence supports the proposition. The predictive performance of this alert seems to be low as only few compounds in the data sets triggered this alert.
Potential mechanism: Pre hapten producing an electrophile with Schiff base forming potential. The mechanism of skin sensitisation activity of alkyl aldehyde precursors is dependent on hydrolysis to the corresponding aldehyde. This aldehyde then undergoes Schiff base formation with nucleophilic groups present in the skin.The scope of this alert has been defined to include acetal compounds which can hydrolyse to alkyl aldehydes.
Skin sensitisation in mammal is PLAUSIBLE. Although the Alert has been defined to include acetal compounds which can hydrolyse to alkyl aldehydes, it is considered unlikely that hydrolysis occurs under basic (skin) conditions. The TIMES skin metabolism simulator predicted hydrolytic products only under acid conditions, which are considered unlikely in skin.
The prediction is considered to be of low reliability.
Derek EC3 Model
The QMRF for skin sensitisation alert with the identifier Q13-34-36-315 is available from the JRC QMRF inventory (https://qsardb.jrc.ec.europa.eu/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
23 % (weak sensitiser)
Based on structures triggering alert: 424 Alkyl aldehyde precursor and similarity (based on fingerprints); 4/4 compounds used in calculation.
Alert and fingerprints used for selecting analogues
Based on structures triggering alert 424 Alkyl aldehyde precursor and similarity (based on fingerprints); 4/4 compounds used in calculation.
LLNA EC3 % Median: non-sensitiser
Saflufenacil, CAS: 372137-35-4
LLNA EC3 % Median: 25% (weak sensitiser)
Budesonide, CAS: 51333-22-3
LLNA EC3 % Median: non-sensitiser
Mometasone furoate, CAS: not available
LLNA EC3 % Median: 35% (weak sensitiser)
Tixocortol pivalate, CAS: not available
With an average value of 19.9% the structural similarity to the query structure is considered low.
DEREK assessment: Skin sensitisation in mammal is PLAUSIBLE, i.e. The weight of evidence supports the proposition. The predictive power of this alert is considered low and indicates uncertainty. In addition, similarity of the structures used for read-across is also low.
Skin sensitisation endpoint for assessing the skin sensitisation potency with in silico methods according to ECHA Guidance, Chapter R.7a, 2016.
The prediction suggests the query structure to be a weak sensitiser, EC3 = 23%.
Toxicity Prediction (Extensible)Toxicity Prediction (Extensible) Skin sensitisation (None vs Sensitiser)
The corresponding QMRF with the identifier Q17-46-0042 is available at https://qsardb.jrc.ec.europa.eu/qmrf/. The original data set was extended with 56 additional compounds from the Envigo database.
A Bayesian score of -0.03 just above the best split of -1.115 suggest uncertainty in the prediction, whereas a probability of 0.74 suggest a positive result in an experimental assay.
Molecular weight (g/mol)
Number of hydrogen bond donors
Number of hydrogen bond acceptors
Number of rotatable bonds in the molecule
The fraction of polar surface area over the total molecular surface area
FCFP_12: Unit functional class extended-connectivity atom type fingerprint with a maximum length of 12 bonds
All properties and OPS components are within expected ranges
All fingerprint features of the query molecule are found in the training set.
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)
With 0.52, the average distance of the four analogues to the query structure is considered moderate. Three out of four structures are non-sensitiser, thus indicating low concordance with the predicted result of query structure. Accuracy between predicted and actual result is moderate as one analogue was predicted false-positively.
Uncertainty is indicated due to moderate similarity, low concordance, moderate accuracy and a Bayesian score just above the cut-off value.
Due to moderate similarity and accuracy, low concordance and a Bayesian score just above the cut-off value, there is only low confidence in the prediction.
QSAR assessment inconclusive no available information available via read across. Substance not excluded from Annex VII criteria for to waive the endpoint, therefore in vitro studies proposed.
As the exclusion criteria for testing according to ECHA are not met, testing of 1,1-dimethoxyethane should be performed. Although there is evidence from the (Q)SAR study that 1,1-dimethoxyethane is likely to be not sensitising, the TIMES metabolism simulator and DEREK suggest 1,1-dimethoxyethane to be acting as pre/pro-hapten. Confirmatory testing of the parent substance in the DPRA is therefore proposed. In case of a positive outcome 1,1-dimethoxyethane can be classified as sensitiser, while a negative outcome requires further testing with the h-CLAT. In the case of a negative result classification is non sensitiser is proposed.
In the case of a positive result, it should be noted that currently, there is no standardized way to conclude on skin sensitising potency using results of these tests. Therefore, if a positive result is obtained, and if there are no other data allowing a conclusion on classification (i.e. whether classification as Category 1A is required) then testing in vivo, i.e. LLNA would be required to determine skin sensitizing potency and conclude on classification.
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