Registration Dossier

Administrative data

Description of key information

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin sensitisation, other
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
results derived from a valid (Q)SAR model, but not (completely) falling into its applicability domain, with adequate and reliable documentation / justification
Justification for type of information:
CAESAR (VEGA)
1 Substance
1.1 CAS number 534-15-6
1.2 EC number 208-589-8
1.3 Chemical name
IUPAC 1,1-dimethoxyethane
Other Dimethyl acetal
Other
1.4 Structural formula

1.5 Structure codes
SMILES COC(C)OC
InChI 1S/C4H10O2/c1-4(5-2)6-3/h4H,1-3H3
Other
Stereochemical features Not applicable

2 General Information
2.1 Date of QPRF 29 May 2018
2.2 Author and contact details Dr. Stefan Pudenz, Envigo CRS Switzerland Ltd.,
Rheinstrasse 74, 4414 Füllinsdorf, Switzerland,
Email: stefan.pudenz@envigo.com

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) Non-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. According to CAESARs evaluation scheme the predicted compound could be outside the applicability domain of the model.
ii. One fragment of the query structure only infrequently found in the compounds of the training set.
iii. Considerations on the mechanism domain are not applicable since statistical model.
Structural analogues i. CAS: 57-55-6
ii. CAS: 140-88-5
iii. CAS: 2426-08-6
iv. CAS: 67-63-0

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.
3.4 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.
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 out of the applicability domain of the model and there is only low confidence in the prediction.

4.4 Conclusion 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.

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

1

Substance

 

 

 

1.1

CAS number

 

534-15-6

 

1.2

EC number

 

208-589-8

 

1.3

Chemical name

 

 

 

 

IUPAC

1,1-dimethoxyethane

 

 

 

Other

Dimethyl acetal

 

 

 

Other

 

 

1.4

Structural formula

 

 

 

 

 

 

1.5

Structure codes

 

 

 

 

 

SMILES

COC(C)OC

 

 

 

InChI

1S/C4H10O2/c1-4(5-2)6-3/h4H,1-3H3

 

 

 

Other

 

 

 

 

Stereochemical features

Not applicable

 

2

General Information

 

 

 

2.1

Date of QPRF

 

29 May 2018

 

2.2

Author and contact details

Dr. Stefan Pudenz, Envigo CRS Switzerland Ltd.,
Rheinstrasse 74, 4414 Füllinsdorf, Switzerland,
Email: stefan.pudenz@envigo.com

 

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)

Non-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.

According to CAESARs evaluation scheme the predicted compound could be outside the applicability domain of the model.

ii.

One fragment of the query structure only infrequently found in the compounds of the training set.

iii.

Considerations on the mechanism domain are not applicable since statistical model.

 

 

 

Structural analogues

i.

CAS: 57-55-6

ii.

CAS: 140-88-5

iii.

CAS: 2426-08-6

iv.

CAS: 67-63-0

 

 

 

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.

 

3.4

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.

 

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 out of the applicability domain of the model and there is only low confidence in the prediction.

 

 

 

 

4.4

Conclusion

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.

 

Interpretation of results:
GHS criteria not met
Conclusions:
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.
Endpoint:
skin sensitisation, other
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
results derived from a valid (Q)SAR model, but not (completely) falling into its applicability domain, with adequate and reliable documentation / justification
Justification for type of information:
1.SOFTWARE
QSAR Toolbox 4.2

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
COC(C)OC

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
see attached justificaiton

5. APPLICABILITY DOMAIN
see attached justification

6. ADEQUACY OF THE RESULT
There is evidence that 1,1-diemthoxyethane is not sensisitising. The structure is also considered with the domain, as water solubility and log kow of both structures are very similar. The prediction is considered reliable.
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:
There is evidence that 1,1-diemthoxyethane is not sensisitising. The structure is also considered with the domain, as water solubility and log kow of both structures are very similar. The prediction is considered reliable.
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 (Q)SAR model, with limited documentation / justification, but validity of model and reliability of prediction considered adequate based on a generally acknowledged source
Justification for type of information:
DEREK (skin sensitisation)
1 Substance
1.1 CAS number 534-15-6
1.2 EC number 208-589-8
1.3 Chemical name
IUPAC 1,1-dimethoxyethane
Other Dimethyl acetal
Other
1.4 Structural formula

1.5 Structure codes
SMILES COC(C)OC
InChI 1S/C4H10O2/c1-4(5-2)6-3/h4H,1-3H3
Other
Stereochemical features Not applicable

2 General Information
2.1 Date of QPRF 29 May 2018
2.2 Author and contact details Dr. Stefan Pudenz, Envigo CRS Switzerland Ltd.,
Rheinstrasse 74, 4414 Füllinsdorf, Switzerland,
Email: stefan.pudenz@envigo.com

3 Prediction
3.1 Endpoint (OECD Principle 1)
Endpoint Skin Sensitisation
Dependent variable Not applicable
3.2 Algorithm (OECD Principle 2)
Model or submodel name Skin sensitisation in mammal
Model version DEREK Nexus 6.0.1, Nexus: 2.2.1.
Knowledge Base: Derek KB 2018 1.1
Reference to QMRF The QMRF with the identifier Q13-34-36-315 is available from the JRC QMRF inventory (https://qsardb.jrc.ec.europa.eu/qmrf/).
Predicted values (model result) Alert matched: 424 Alkyl aldehyde 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 0.15
LogKp -3.16

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

Match with query compound:

Example Data Test data:
CAS Number: 101-48-1, (2,2-dimethoxyethyl)benzene; weak sensitiser (guinea pig, maximisation test)

CAS: 94354-60-6; ethylidene benzoacetate ; 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)

Consideration on structural analogues Example structures trigger the same alert as the query structure. There are all acetals but structurally very different to the query structure.
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. The predictive performance of this alert seems to be low as only few compounds in the data sets triggered this alert.
3.5 The chemical and biological mechanisms according to the model underpinning the predicted result (OECD principle 5)
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.

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. 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.

4.4 Conclusion The prediction is considered to be of low reliability.
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


DEREK (skin sensitisation)

1

Substance

 

 

 

1.1

CAS number

 

534-15-6

 

1.2

EC number

 

208-589-8

 

1.3

Chemical name

 

 

 

 

IUPAC

1,1-dimethoxyethane

 

 

 

Other

Dimethyl acetal

 

 

 

Other

 

 

1.4

Structural formula

 

 

 

 

 

 

1.5

Structure codes

 

 

 

 

 

SMILES

COC(C)OC

 

 

 

InChI

1S/C4H10O2/c1-4(5-2)6-3/h4H,1-3H3

 

 

 

Other

 

 

 

 

Stereochemical features

Not applicable

 

2

General Information

 

 

 

2.1

Date of QPRF

 

29 May 2018

 

2.2

Author and contact details

Dr. Stefan Pudenz, Envigo CRS Switzerland Ltd.,
Rheinstrasse 74, 4414 Füllinsdorf, Switzerland,
Email: stefan.pudenz@envigo.com

 

3

Prediction

 

 

 

3.1

Endpoint (OECD Principle 1)

 

 

 

 

Endpoint

Skin Sensitisation

 

 

 

Dependent variable

Not applicable

 

3.2

Algorithm (OECD Principle 2)

 

 

 

 

Model or submodel name

Skin sensitisation in mammal

 

 

 

Model version

DEREK Nexus 6.0.1, Nexus: 2.2.1.
Knowledge Base: Derek KB 2018 1.1

 

 

 

Reference to QMRF

The QMRF with the identifier Q13-34-36-315 is available from the JRC QMRF inventory (https://qsardb.jrc.ec.europa.eu/qmrf/).

 

 

 

Predicted values (model result)

Alert matched: 424 Alkyl aldehyde 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

0.15

LogKp

-3.16

 

3.3

Applicability domain (OECD Principle 3)

 

 

 

Domains

Alert description image:

Match with query compound:

 

 

 

 

Example Data

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)

 

 

Consideration on structural analogues

Example structures trigger the same alert as the query structure. There are all acetals but structurally very different to the query structure.

 

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. The predictive performance of this alert seems to be low as only few compounds in the data sets triggered this alert.

 

3.5

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

 

 

 

 

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.

 

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. 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.

 

 

 

 

 

4.4

Conclusion

The prediction is considered to be of low reliability.

Interpretation of results:
GHS criteria not met
Conclusions:
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.
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 (Q)SAR model, with limited documentation / justification, but validity of model and reliability of prediction considered adequate based on a generally acknowledged source
Justification for type of information:
DEREK (EC3, potency)
1 Substance
1.1 CAS number 534-15-6
1.2 EC number 208-589-8
1.3 Chemical name
IUPAC 1,1-dimethoxyethane
Other Dimethyl acetal
Other
1.4 Structural formula

1.5 Structure codes
SMILES COC(C)OC
InChI 1S/C4H10O2/c1-4(5-2)6-3/h4H,1-3H3
Other
Stereochemical features Not applicable

2 General Information
2.1 Date of QPRF 29 May 2018
2.2 Author and contact details Dr. Stefan Pudenz, Envigo CRS Switzerland Ltd.,
Rheinstrasse 74, 4414 Füllinsdorf, Switzerland,
Email: stefan.pudenz@envigo.com

3 Prediction
3.1 Endpoint (OECD Principle 1)
Endpoint EC3
Dependent variable Not applicable
3.2 Algorithm (OECD Principle 2)
Model or submodel name Derek EC3 Model
Model version 1.2.0
Reference to QMRF 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
Predicted values (model result) 23 % (weak sensitiser)
Predicted values (comments) Based on structures triggering alert: 424 Alkyl aldehyde precursor and similarity (based on fingerprints); 4/4 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 424 Alkyl aldehyde precursor and similarity (based on fingerprints); 4/4 compounds used in calculation.
Structural analogues
i.
LLNA EC3 % Median: non-sensitiser
Similarity: 35%
CAS 2495-37-6 Saflufenacil, CAS: 372137-35-4
ii.
LLNA EC3 % Median: 25% (weak sensitiser)
Similarity: 23% CAS 140-11-4 Budesonide, CAS: 51333-22-3
iii.
LLNA EC3 % Median: non-sensitiser
Similarity: 17% Methyl cinnamate Mometasone furoate, CAS: not available
iv.
LLNA EC3 % Median: 35% (weak sensitiser)
Similarity: 4.7%
Benzyl benzoate Tixocortol pivalate, CAS: not available

Consideration on structural analogues With an average value of 19.9% the structural similarity to the query structure is considered low.
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. 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.
3.5 The chemical and biological mechanisms according to the model underpinning the predicted result (OECD principle 5)
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.

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 the query structure to be a weak sensitiser, EC3 = 23%.

4.4 Conclusion 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.
Qualifier:
no guideline followed
Principles of method if other than guideline:
- Principle of test: QSAR prediciton of Skin senistisation
- Short description of test conditions: n/a
- Parameters analysed / observed: Skin senistisation
Parameter:
other: EC3
Value:
23
Remarks on result:
positive indication of skin sensitisation

DEREK (EC3, potency)

1

Substance

 

 

 

1.1

CAS number

 

534-15-6

 

1.2

EC number

 

208-589-8

 

1.3

Chemical name

 

 

 

 

IUPAC

1,1-dimethoxyethane

 

 

 

Other

Dimethyl acetal

 

 

 

Other

 

 

1.4

Structural formula

 

 

 

 

 

 

1.5

Structure codes

 

 

 

 

 

SMILES

COC(C)OC

 

 

 

InChI

1S/C4H10O2/c1-4(5-2)6-3/h4H,1-3H3

 

 

 

Other

 

 

 

 

Stereochemical features

Not applicable

 

2

General Information

 

 

 

2.1

Date of QPRF

 

29 May 2018

 

2.2

Author and contact details

Dr. Stefan Pudenz, Envigo CRS Switzerland Ltd.,
Rheinstrasse 74, 4414 Füllinsdorf, Switzerland,
Email: stefan.pudenz@envigo.com

 

3

Prediction

 

 

 

3.1

Endpoint (OECD Principle 1)

 

 

 

 

Endpoint

EC3

 

 

 

Dependent variable

Not applicable

 

3.2

Algorithm (OECD Principle 2)

 

 

 

 

Model or submodel name

Derek EC3 Model

 

 

 

Model version

1.2.0

 

 

 

Reference to QMRF

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

 

 

 

Predicted values (model result)

23 % (weak sensitiser)

 

 

 

Predicted values (comments)

Based on structures triggering alert: 424 Alkyl aldehyde precursor and similarity (based on fingerprints); 4/4 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 424 Alkyl aldehyde precursor and similarity (based on fingerprints); 4/4 compounds used in calculation.

 

Structural analogues

i.

 
LLNA EC3 % Median: non-sensitiser

Similarity: 35%

 

CAS 2495-37-6

Saflufenacil, CAS: 372137-35-4

ii.

LLNA EC3 % Median: 25% (weak sensitiser)

Similarity: 23%

CAS 140-11-4

Budesonide, CAS: 51333-22-3

iii.


LLNA EC3 % Median: non-sensitiser

Similarity: 17%

Methyl cinnamate

Mometasone furoate, CAS: not available

iv.


LLNA EC3 % Median: 35% (weak sensitiser)

Similarity: 4.7%

 

Benzyl benzoate

Tixocortol pivalate, CAS: not available

 

 

Consideration on structural analogues

With an average value of 19.9% the structural similarity to the query structure is considered low.

 

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. 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.

 

3.5

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

 

 

 

 

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.

 

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 the query structure to be a weak sensitiser, EC3 = 23%.

 

 

 

 

 

4.4

Conclusion

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.

Interpretation of results:
GHS criteria not met
Conclusions:
The prediction suggests the query structure to be a weak sensitiser, EC3 = 23%.
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.
Endpoint:
skin sensitisation, other
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
results derived from a valid (Q)SAR model, but not (completely) falling into its applicability domain, with adequate and reliable documentation / justification
Justification for type of information:
1 Substance
1.1 CAS number 534-15-6
1.2 EC number 208-589-8
1.3 Chemical name
IUPAC 1,1-dimethoxyethane
Other Dimethyl acetal
Other
1.4 Structural formula

1.5 Structure codes
SMILES COC(C)OC
InChI 1S/C4H10O2/c1-4(5-2)6-3/h4H,1-3H3
Other
Stereochemical features Not applicable

2 General Information
2.1 Date of QPRF 29 May 2018
2.2 Author and contact details Dr. Stefan Pudenz, Envigo CRS Switzerland Ltd.,
Rheinstrasse 74, 4414 Füllinsdorf, Switzerland,
Email: stefan.pudenz@envigo.com

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 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.
Predicted values (model result) Sensitiser
Predicted values (comments) 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.
Input for prediction Smiles
Calculated descriptor values Descriptor Value
LogP 0.079
Molecular weight (g/mol) 90.121
Number of hydrogen bond donors 0
Number of hydrogen bond acceptors 2
Number of rotatable bonds in the molecule 2
The fraction of polar surface area over the total molecular surface area 0.142
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. Methyl methacrylate
ii. Acetone
iii. 2-Methoxyethanol acetate
iv. Butyl acetate Tixocortol pivalate,

Consideration on structural analogues 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.
3.4 The uncertainty of the prediction (OECD principle 4)
Uncertainty is indicated due to moderate similarity, low concordance, moderate accuracy and a Bayesian score just above the cut-off value.
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 moderate similarity and accuracy, low concordance and a Bayesian score just above the cut-off value, there is only low confidence in the prediction.

4.4 Conclusion 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.

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

TOPKAT

1

Substance

 

 

1.1

CAS number

 

534-15-6

1.2

EC number

 

208-589-8

1.3

Chemical name

IUPAC

1,1-dimethoxyethane

 

 

 

Other

Dimethyl acetal

 

 

 

Other

 

 

1.4

Structural formula

 

 

1.5

Structure codes

 

 

 

 

 

SMILES

COC(C)OC

 

 

 

InChI

1S/C4H10O2/c1-4(5-2)6-3/h4H,1-3H3

 

 

 

Other

 

 

 

 

Stereochemical features

Not applicable

2

General Information

 

 

 

2.1

Date of QPRF

 

29 May 2018

 

2.2

Author and contact details

Dr. Stefan Pudenz, Envigo CRS Switzerland Ltd.,
Rheinstrasse 74, 4414 Füllinsdorf, Switzerland,
Email: stefan.pudenz@envigo.com

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 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.

Predicted values (model result)

Sensitiser

Predicted values (comments)

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.

 

 

 

Input for prediction

Smiles

 

 

 

Calculated descriptor values

Descriptor

Value

LogP

0.079

Molecular weight (g/mol)

90.121

Number of hydrogen bond donors

0

Number of hydrogen bond acceptors

2

Number of rotatable bonds in the molecule

2

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

0.142

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.

Methyl methacrylate

ii.

Acetone

iii.

2-Methoxyethanol acetate

iv.

Butyl acetate

Consideration on structural analogues

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.

 

3.4

The uncertainty of the prediction (OECD principle 4)

 

Uncertainty is indicated due to moderate similarity, low concordance, moderate accuracy and a Bayesian score just above the cut-off value.

 

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 moderate similarity and accuracy, low concordance and a Bayesian score just above the cut-off value, there is only low confidence in the prediction.

 

4.4

Conclusion

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.

 

Interpretation of results:
GHS criteria not met
Conclusions:
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.
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.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

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.

Justification for classification or non-classification

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.