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Short-term toxicity to aquatic invertebrates

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Endpoint:
short-term toxicity to aquatic invertebrates
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
Reliability:
3 (not reliable)
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:
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 Daphnia acute toxicity
Dependent variable Daphnia Magna LC50 (48 hour), -log(mol/L).
3.2 Algorithm (OECD Principle 2)
Model or submodel name 48-hour Daphnia Magna LC50 Model (DEMETRA) within VEGA 1.1.4
Model version 1.0.4
Reference to QMRF There is no QMRF available. Information to the VEGA models can be found at vega-qsar.eu
Predicted values (model result) 10.93 mg/L
Predicted values (comments) -log(mol/L): 3.91. According to VEGA’s evaluation scheme, the prediction may be not reliable.
Input for prediction Smiles
Descriptor values Not provided by the software
3.3 Applicability domain (OECD Principle 3)
Domains
i. According to VEGA’s evaluation scheme the predicted compound is outside the Applicability Domain of the model
ii. One fragment of the query structure has not been found in the compounds of the training set
iii. Not applicable since statistical model
Structural analogues (for details, it is referred to the software printout)
i. CAS: 79-09-4, propionic acid
ii. CAS: 34375-28-5, 2-(N-hydroxy-N-methyl-amino)ethanol
iii. CAS: 144-49-0, fluoroacetic acid
iv. CAS: 7747-35-5, oxazolidine-E
Consideration on structural analogues
With 72%, the average similarity of the four most similar analogues in the training set to the query structure may be considered high. However, the most similar structure is an ester and a surfactant, the second an aliphatic amine and the third contains a halogen, all suggesting a different mode of action. Similarity is therefore considered low. Predicted and experimental values of the four most similar structures vary by
a factor of up to 4.2 which is below a default factor of 10 often used in traditional risk assessment of environmental chemicals to compensate for uncertainties*. Hence accuracy between predicted and actual value is considered acceptable.
3.4 The uncertainty of the prediction (OECD principle 4)
Low similarity and a fragment of the query structure not found in the compounds of the training set indicate uncertainty and suggest the query structure to be 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 Acute toxicity to daphnia endpoint for providing information on aquatic pelagic toxicity.
4.2 Approach for regulatory interpretation of the model result Unit conversion provided by the software.
4.3 Outcome There is no confidence in the prediction because of low similarity and the query structure out of the applicability domain.
4.4 Conclusion The prediction is not considered reliable.

*Stedeford, T.; Zhao, Q.J.; Dourson, M.L.; Banasik, M.; Hsu, C.H. The application of non-default uncertainty factors in the US EPA’s Integrated Risk Information System (IRIS). Part I: UFL, UFS, and “Other uncertainty factors”. J. Environ. Sci. Heal. C 2007, 25, 245–279.
Qualifier:
no guideline followed
Principles of method if other than guideline:
- Principle of test: QSAR prediciton of Acute toxicity to daphnia
- Short description of test conditions: n/a
- Parameters analysed / observed: LC50
Duration:
48 h
Dose descriptor:
LC50
Effect conc.:
10.39 mg/L

DEMETRA

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 Daphnia acute toxicity

Dependent variable Daphnia Magna LC50 (48 hour), -log(mol/L).

3.2 Algorithm (OECD Principle 2)

Model or submodel name 48-hour Daphnia Magna LC50 Model (DEMETRA) within VEGA 1.1.4

Model version 1.0.4

Reference to QMRF There is no QMRF available. Information to the VEGA models can be found at vega-qsar.eu

Predicted values (model result) 10.93 mg/L

Predicted values (comments) -log(mol/L): 3.91. According to VEGA’s evaluation scheme, the prediction may be not reliable.

Input for prediction Smiles

Descriptor values Not provided by the software

3.3 Applicability domain (OECD Principle 3)

Domains

i. According to VEGA’s evaluation scheme the predicted compound is outside the Applicability Domain of the model

ii. One fragment of the query structure has not been found in the compounds of the training set

iii. Not applicable since statistical model

Structural analogues (for details, it is referred to the software printout)

i. CAS: 79-09-4, propionic acid

ii. CAS: 34375-28-5, 2-(N-hydroxy-N-methyl-amino)ethanol

iii. CAS: 144-49-0, fluoroacetic acid

iv. CAS: 7747-35-5, oxazolidine-E

Consideration on structural analogues

With 72%, the average similarity of the four most similar analogues in the training set to the query structure may be considered high. However, the most similar structure is an ester and a surfactant, the second an aliphatic amine and the third contains a halogen, all suggesting a different mode of action. Similarity is therefore considered low. Predicted and experimental values of the four most similar structures vary by

a factor of up to 4.2 which is below a default factor of 10 often used in traditional risk assessment of environmental chemicals to compensate for uncertainties*. Hence accuracy between predicted and actual value is considered acceptable.

3.4 The uncertainty of the prediction (OECD principle 4)

Low similarity and a fragment of the query structure not found in the compounds of the training set indicate uncertainty and suggest the query structure to be 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 Acute toxicity to daphnia endpoint for providing information on aquatic pelagic toxicity.

4.2 Approach for regulatory interpretation of the model result Unit conversion provided by the software.

4.3 Outcome There is no confidence in the prediction because of low similarity and the query structure out of the applicability domain.

4.4 Conclusion The prediction is not considered reliable.

*Stedeford, T.; Zhao, Q.J.; Dourson, M.L.; Banasik, M.; Hsu, C.H. The application of non-default uncertainty factors in the US EPA’s Integrated Risk Information System (IRIS). Part I: UFL, UFS, and “Other uncertainty factors”. J. Environ. Sci. Heal. C 2007, 25, 245–279.

Conclusions:
There is no confidence in the prediction because of low similarity and the query structure out of the applicability domain.
The prediction is not considered reliable
Endpoint:
short-term toxicity to aquatic invertebrates
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:
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 (ISO) 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 Dapnia acute toxicity (48 hour LC50)
Dependent variable Log 48-h LC50 (mmol/L)
3.2 Algorithm (OECD Principle 2)
Model or submodel name DAPHNIA 48-h LC50 and submodel SAR Neutral Organics
Model version ECOSAR v1.11 and submodel SAR Neutral Organics 5/2012
Reference to QMRF There is no QMRF available. Information to ECOSAR models
can be found at https://www.epa.gov/chemicalresearch/toxicity-estimation-software-tool-test. For information similar to those provided in the QMRF it is also referred to section Interpreting ECOSAR QSAR.
Predicted values (model result) Class Neutral organics: 1407.862 mg/L
Predicted values (comments) -
Input for prediction Smiles
Calculated descriptor values Experimental water solubility, 1.E06 mg/L, and predicted log Kow, 0.223
3.3 Applicability domain (OECD Principle 3)
Domains
i. The predicted compound is in the Applicability Domain of the models log Kow< 5.
ii. Structure belongs to class neutral organic
iii. SAR based on structural classes
Structural analogues ECOSAR does not provide information on structural analogues due to the nature of the regression algorithm.
Neutral organics: Model equation based on n= 98 + 31 structures
Consideration on structural analogues
Not applicable, see above.
3.4 The uncertainty of the prediction (OECD principle 4)
The coefficient of determination, R2 = 0.7704, suggests moderate confidence.
3.5 The chemical and biological mechanisms according to the model underpinning the predicted result (OECD principle 5) SAR based on structural classes

4 Adequacy (Optional)
4.1 Regulatory purpose Acute toxicity to daphnia endpoint for providing information on aquatic pelagic toxicity.
4.2 Approach for regulatory interpretation of the model result Unit conversion provided by the software.
4.3 Outcome The prediction suggests an LC50 of 1407.862 mg/L but there is only moderate confidence in the prediction.
4.4 Conclusion The prediction is considered to be of moderate reliability and will be used together with other QSARs in a weight of evidence conclusion.
Qualifier:
no guideline followed
Principles of method if other than guideline:
- Principle of test: QSAR prediciton of Acute toxicity to daphnia
- Short description of test conditions: n/a
- Parameters analysed / observed: LC50
Duration:
48 h
Dose descriptor:
LC50
Effect conc.:
1 407.862 mg/L

ECOSAR

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 (ISO) 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 Dapnia acute toxicity (48 hour LC50)

Dependent variable Log 48-h LC50 (mmol/L)

3.2 Algorithm (OECD Principle 2)

Model or submodel name DAPHNIA 48-h LC50 and submodel SAR Neutral Organics

Model version ECOSAR v1.11 and submodel SAR Neutral Organics 5/2012

Reference to QMRF There is no QMRF available. Information to ECOSAR models

can be found at https://www.epa.gov/chemicalresearch/toxicity-estimation-software-tool-test. For information similar to those provided in the QMRF it is also referred to section Interpreting ECOSAR QSAR.

Predicted values (model result) Class Neutral organics: 1407.862 mg/L

Predicted values (comments) -

Input for prediction Smiles

Calculated descriptor values Experimental water solubility, 1.E06 mg/L, and predicted log Kow, 0.223

3.3 Applicability domain (OECD Principle 3)

Domains

i. The predicted compound is in the Applicability Domain of the models log Kow< 5.

ii. Structure belongs to class neutral organic

iii. SAR based on structural classes

Structural analogues ECOSAR does not provide information on structural analogues due to the nature of the regression algorithm.

Neutral organics: Model equation based on n= 98 + 31 structures

Consideration on structural analogues

Not applicable, see above.

3.4 The uncertainty of the prediction (OECD principle 4)

The coefficient of determination, R2 = 0.7704, suggests moderate confidence.

3.5 The chemical and biological mechanisms according to the model underpinning the predicted result (OECD principle 5) SAR based on structural classes

4 Adequacy (Optional)

4.1 Regulatory purpose Acute toxicity to daphnia endpoint for providing information on aquatic pelagic toxicity.

4.2 Approach for regulatory interpretation of the model result Unit conversion provided by the software.

4.3 Outcome The prediction suggests an LC50 of 1407.862 mg/L but there is only moderate confidence in the prediction.

4.4 Conclusion The prediction is considered to be of moderate reliability and will be used together with other QSARs in a weight of evidence conclusion.

Conclusions:
The prediction suggests an LC50 of 1407.862 mg/L but there is only moderate confidence in the prediction.
The prediction is considered to be of moderate reliability and will be used together with other QSARs in a weight of evidence conclusion.
Endpoint:
short-term toxicity to aquatic invertebrates
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 Daphnia magna LC50 (48 hr) -Log10(mol/L)
Dependent variable Daphnia magna LC50 (48 hr) -Log10(mol/L)
3.2 Algorithm (OECD Principle 2)
Model or submodel name US EPA T.E.S.T Daphnia magna LC50 (48 hr) - Consensus method
Model version 4.2
Reference to QMRF There is no QMRF available and provided by US EPA, respectively.
Predicted values (model result) LC50 = 576.80 mg/L
Predicted values (comments) Unit conversion provided by the software
Input for prediction Smiles
Descriptor values Not provided
3.3 Applicability domain (OECD Principle 3)
Domains
i. Query structure is within the domain of the model
ii. One descriptor of the clustering method is out of range, while in all other methods no violation was obtained.
iii. Considerations on the mechanism domain are not applicable since statistical model
Structural analogues (training set)
i. CAS 109-87-5: dimethoxymethane
ii. CAS 141-78-6: ethyl acetate
iii. CAS 107-98-2: 1-Methoxy-2-hydroxypropane
iv. CAS 105-37-3: Ethyl propionate
Consideration on structural analogues
With 88% the average similarity of the four most similar structures in the training set to the query structure is considered high. Only one structure was predicted, while prediction for the others failed. In addition, the MAE of the prediction with the training set is greater than for the prediction with entire set, thus accuracy is considered low. The predicted result of the query structure agrees with the experimental results of the most similar structures when omitting less lipophilic 1-Methoxy-2-hydroxypropane. Hence concordance can be considered high.
3.4 The uncertainty of the prediction (OECD principle 4)
High similarity and concordance suggest confidence, but low accuracy indicate uncertainty. In addition, prediction of the most similar structures failed.
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 Acute toxicity to daphnia endpoint for providing information on aquatic pelagic toxicity.
4.2 Approach for regulatory interpretation of the model result
Unit conversion provided by the software.
4.3 Outcome The prediction suggests an LC50 of 576.80 mg/L but there is only low confidence in the prediction.
4.4 Conclusion The prediction is considered to be low reliability and may be used together with other QSARs in a weight of evidence conclusion.

*Stedeford, T.; Zhao, Q.J.; Dourson, M.L.; Banasik, M.; Hsu, C.H. The application of non-default uncertainty factors in the US EPA’s Integrated Risk Information System (IRIS). Part I: UFL, UFS, and “Other uncertainty factors”. J. Environ. Sci.
Heal. C 2007, 25, 245–279.
Qualifier:
no guideline followed
Principles of method if other than guideline:
- Principle of test: QSAR prediciton of Acute toxicity to daphnia
- Short description of test conditions: n/a
- Parameters analysed / observed: EC50
Duration:
48 h
Dose descriptor:
LC50
Effect conc.:
576.8 mg/L

T.E.S.T.

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 Daphnia magna LC50 (48 hr) -Log10(mol/L)

Dependent variable Daphnia magna LC50 (48 hr) -Log10(mol/L)

3.2 Algorithm (OECD Principle 2)

Model or submodel name US EPA T.E.S.T Daphnia magna LC50 (48 hr) - Consensus method

Model version 4.2

Reference to QMRF There is no QMRF available and provided by US EPA, respectively.

Predicted values (model result) LC50 = 576.80 mg/L

Predicted values (comments) Unit conversion provided by the software

Input for prediction Smiles

Descriptor values Not provided

3.3 Applicability domain (OECD Principle 3)

Domains

i. Query structure is within the domain of the model

ii. One descriptor of the clustering method is out of range, while in all other methods no violation was obtained.

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

Structural analogues (training set)

i. CAS 109-87-5: dimethoxymethane

ii. CAS 141-78-6: ethyl acetate

iii. CAS 107-98-2: 1-Methoxy-2-hydroxypropane

iv. CAS 105-37-3: Ethyl propionate

Consideration on structural analogues

With 88% the average similarity of the four most similar structures in the training set to the query structure is considered high. Only one structure was predicted, while prediction for the others failed. In addition, the MAE of the prediction with the training set is greater than for the prediction with entire set, thus accuracy is considered low. The predicted result of the query structure agrees with the experimental results of the most similar structures when omitting less lipophilic 1-Methoxy-2-hydroxypropane. Hence concordance can be considered high.

3.4 The uncertainty of the prediction (OECD principle 4)

High similarity and concordance suggest confidence, but low accuracy indicate uncertainty. In addition, prediction of the most similar structures failed.

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 Acute toxicity to daphnia endpoint for providing information on aquatic pelagic toxicity.

4.2 Approach for regulatory interpretation of the model result

Unit conversion provided by the software.

4.3 Outcome The prediction suggests an LC50 of 576.80 mg/L but there is only low confidence in the prediction.

4.4 Conclusion The prediction is considered to be low reliability and may be used together with other QSARs in a weight of evidence conclusion.

*Stedeford, T.; Zhao, Q.J.; Dourson, M.L.; Banasik, M.; Hsu, C.H. The application of non-default uncertainty factors in the US EPA’s Integrated Risk Information System (IRIS). Part I: UFL, UFS, and “Other uncertainty factors”. J. Environ. Sci.

Heal. C 2007, 25, 245–279.

Conclusions:
The prediction suggests an LC50 of 576.80 mg/L but there is only low confidence in the prediction.
The prediction is considered to be low reliability and may be used together with other QSARs in a weight of evidence conclusion.
Endpoint:
short-term toxicity to aquatic invertebrates
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
Acute toxicity to daphnia (LC50; EC50: fathead minnow) of 1,1-dimethoxyethane was predicted to be 1780 mg/L. The prediction is based on trend analysis with 195 data points and the statistics suggests confidence in the prediction.
Qualifier:
no guideline followed
Principles of method if other than guideline:
- Principle of test: QSAR prediciton of Acute toxicity to daphnia
- Short description of test conditions: n/a
- Parameters analysed / observed: EC50
Duration:
48 h
Dose descriptor:
LC50
Effect conc.:
1 780 mg/L
Conclusions:
Acute toxicity to daphnia (LC50; EC50: fathead minnow) of 1,1-dimethoxyethane was predicted to be 1780 mg/L. The prediction is based on trend analysis with 195 data points and the statistics suggests confidence in the prediction
Endpoint:
short-term toxicity to aquatic invertebrates
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
Reliability:
3 (not reliable)
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:
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 (ISO) dimethyl acetal
CAS
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 Short-term toxicity to daphnia (immobilisation)
Dependent variable pEC50 = -log(EC50) [mol/L]
3.2 Algorithm (OECD Principle 2)
Model or submodel name Biovia toxicity prediction model – acute fish toxicity
Model version Biovia Discovery Studio v4.5
Reference to QMRF The corresponding QMRF BIOVIA toxicity prediction model
– acute fish toxicity is available from JRC QSAR Model Database (https://qsardb.jrc.ec.europa.eu/qmrf; ID: Q17-31- 0047)
Predicted values (model result) 30.275 mg/L
Predicted values (comments) Unit conversion provided by software
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
Number of aromatic rings in the structure 0
The polar surface area over the molecule 0.142
Number of rings in the structure 0
Number of fragments in the structure 1
The polar solvent accessible surface area 28.7127
ECFP_6: Unitless Extended-connectivity fingerprint with a maximum bond length of 6 Not provided
FCFP_6 Unitless Functional class-extended fingerprint with maximum bond length of 6 Not provided
MDL Public Keys Unitless Fingerprint comprised of features defined in the MDL Public Keys Not provided
3.3 Applicability domain (OECD Principle 3)
Domains
i. All properties and OPS components are within expected ranges.
ii. Two fingerprint features of the query compound have not been found in the compounds of the training set
iii. Considerations on the mechanism domain are not applicable since statistical model.
Structural analogues
i. Propanoic acid; methyl ester
ii. Ethyl acetate
iii. Propanoic acid; ethyl ester
iv. Chloroacetic acid; ethyl ester
Consideration on structural analogues
The average structural distance between 1,1-dimethoxyethane and the four most similar structures in the training set is 0.45. They are all esters with low log Kow’s and water solubilities comparable to the query structure. Similarity is therefore considered high. Predicted and actual value of the most similar structures vary by a factor of up 36.8 which is well above a default factor of 10 often used in traditional risk assessment of environmental chemicals to compensate for uncertainties*. Accuracy is therefore considered poor. The predicted value for 1,1-dimethoxyethane disagrees with the experimental values of two out of four structures provided, thus indicating low concordance.
3.4 The uncertainty of the prediction (OECD principle 4)
High similarity but poor accuracy and low concordance, and two fragments of the query structure not found in the compounds of the training set indicate uncertainty and the structure to be out of the domain of the model.
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 Acute toxicity to daphnia endpoint for providing information on aquatic pelagic toxicity
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 an LC50 of 30.275 mg/L but there is no confidence in the prediction.
4.4 Conclusion This prediction is not considered reliable.

*Stedeford, T.; Zhao, Q.J.; Dourson, M.L.; Banasik, M.; Hsu, C.H. The application of non-default uncertainty factors in the US EPA’s Integrated Risk Information System (IRIS). Part I: UFL, UFS, and “Other uncertainty factors”. J. Environ. Sci. Heal. C 2007, 25, 245–279.
Qualifier:
no guideline followed
Principles of method if other than guideline:
- Principle of test: QSAR prediciton of Acute toxicity to daphnia
- Short description of test conditions: n/a
- Parameters analysed / observed: EC50
Duration:
48 h
Dose descriptor:
LC50
Effect conc.:
30.275 mg/L

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 (ISO) dimethyl acetal

CAS

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 Short-term toxicity to daphnia (immobilisation)

Dependent variable pEC50 = -log(EC50) [mol/L]

3.2 Algorithm (OECD Principle 2)

Model or submodel name Biovia toxicity prediction model – acute fish toxicity

Model version Biovia Discovery Studio v4.5

Reference to QMRF The corresponding QMRF BIOVIA toxicity prediction model

– acute fish toxicity is available from JRC QSAR Model Database (https://qsardb.jrc.ec.europa.eu/qmrf; ID: Q17-31- 0047)

Predicted values (model result) 30.275 mg/L

Predicted values (comments) Unit conversion provided by software

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

Number of aromatic rings in the structure 0

The polar surface area over the molecule 0.142

Number of rings in the structure 0

Number of fragments in the structure 1

The polar solvent accessible surface area 28.7127

ECFP_6: Unitless Extended-connectivity fingerprint with a maximum bond length of 6 Not provided

FCFP_6 Unitless Functional class-extended fingerprint with maximum bond length of 6 Not provided

MDL Public Keys Unitless Fingerprint comprised of features defined in the MDL Public Keys Not provided

3.3 Applicability domain (OECD Principle 3)

Domains

i. All properties and OPS components are within expected ranges.

ii. Two fingerprint features of the query compound have not been found in the compounds of the training set

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

Structural analogues

i. Propanoic acid; methyl ester

ii. Ethyl acetate

iii. Propanoic acid; ethyl ester

iv. Chloroacetic acid; ethyl ester

Consideration on structural analogues

The average structural distance between 1,1-dimethoxyethane and the four most similar structures in the training set is 0.45. They are all esters with low log Kow’s and water solubilities comparable to the query structure. Similarity is therefore considered high. Predicted and actual value of the most similar structures vary by a factor of up 36.8 which is well above a default factor of 10 often used in traditional risk assessment of environmental chemicals to compensate for uncertainties*. Accuracy is therefore considered poor. The predicted value for 1,1-dimethoxyethane disagrees with the experimental values of two out of four structures provided, thus indicating low concordance.

3.4 The uncertainty of the prediction (OECD principle 4)

High similarity but poor accuracy and low concordance, and two fragments of the query structure not found in the compounds of the training set indicate uncertainty and the structure to be out of the domain of the model.

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 Acute toxicity to daphnia endpoint for providing information on aquatic pelagic toxicity

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 an LC50 of 30.275 mg/L but there is no confidence in the prediction.

4.4 Conclusion This prediction is not considered reliable.

*Stedeford, T.; Zhao, Q.J.; Dourson, M.L.; Banasik, M.; Hsu, C.H. The application of non-default uncertainty factors in the US EPA’s Integrated Risk Information System (IRIS). Part I: UFL, UFS, and “Other uncertainty factors”. J. Environ. Sci. Heal. C 2007, 25, 245–279.

Conclusions:
The prediction suggests an LC50 of 30.275 mg/L but there is no confidence in the prediction.
This prediction is not considered reliable.

Description of key information

Acute Daphnia Toxicity

Predicted EC/LC50`s for acute daphnia toxicity of 1, 1-dimethoxyethane range between 10.93 and 1780 mg/L (Table 3). Only one prediction is considered reliable, two are considered to be of moderate and low reliability respectively, and two are not reliable.

The prediction by TOPKAT is characterised by poor accuracy in the prediction of the most similar structures in training set, which are all esters with low log Kow’s and water solubilities comparable to 1,1-dimethoxyethane. Moreover, the predicted EC50 for 1,1-dimethoxyethane does not agree with the experimental results of these structures, and two fingerprints of 1,1 - dimethoxyethane have not been found in the compounds of the training set. 1,1 - dimethoxyethane is therefore considered out of the model’s applicability domain and the prediction not considered reliable.

An overall low accuracy in the prediction of similar structures and in particular the failure of predicting three out of the four most similar structures indicate low confidence in the prediction by TEST.

Although 1,1-dimethoxyethane is in the applicability domain of the ECOSAR SAR class neutral organics, a coefficient of determination, r2, of 0.7704 suggests only moderate predictive accuracy of the model and the prediction is therefore considered to be of moderate reliability.

The DEMETRA prediction is not considered reliable since 1,1-dimethoxyethane is out of the model’s applicability domain. Moreover, the most similar structures in training set are an aliphatic amine, an acetic acid with a halogen and a surfactant, all with a different mode of action.

Trend analysis with OECD Toolbox was performed using standardised workflow for aquatic toxicity, invertebrates (EC50, LC50 at 48h), which provided 196 data points from neutral organic compounds, with the same profiling result as 1,1-dimethoxyethane (for details on profiling and categorisation, see QPRF and software printout). Only test results from daphnia magna were selected. The model statistics indicate confidence and the prediction is considered reliable.

Prediction results of acute daphnia toxicity of 1,1-dimethoxyethane

Model

Daphnia toxicity EC/LC50[mg/L], 48h

Reliability

TOPKAT

30.28

not reliable

US EPA T.E.S.T:

576.80

low

ECOSAR

1407.86

moderate

DEMETRA*

10.93

not reliable

OECD Toolbox

1780.00

reliable

Excluding the results from predictions not considered reliable and considered to be of low reliability respectively, and using the geometric mean of the predictions by OECD Toolbox and ECOSAR results in an EC/LC50 of 1593.93 mg/L. The geometric mean of 1593.93 mg/L does not conflict with the EC50 value of structurally similar acetal dimethoxymethane and may therefore substantiate the predictions. Taking additionally into account the small differences in terms of water solubility and log Kow there is an argument for a weight of evidence that 1,1-dimethoxyethane does not qualify for classification.

Key value for chemical safety assessment

EC50/LC50 for freshwater invertebrates:
1 593.93 mg/L

Additional information