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Water solubility

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

water solubility

Type of information:

(Q)SAR

Adequacy of study:

key study

Study period:

25 May, 2021

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: Water Solubility Program (WATERNT v1.01) subprogram in EPISUITE v4.11.
2. MODEL (incl. version number): EPISUITE version 4.11 was released in September, 2012. WATERNT v1.01 was released in September, 2010.
3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL: O=C(OCCCCCCCCCCOC(=O)C(=C)C)C(=C)C
4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
- Defined endpoint: Water solubility
Unambiguous algorithm: The predicted water solubility value is calculated through the following equation:
log WS (moles/ L) = ∑fjnj + ∑cjnj+0.24922
where fj is the coefficient for each atom/fragment), cj is the coefficient for each correction factor, and ni is the number of times the atom/fragment (and correction factor) occurs in the test species.
- Defined domain of applicability: WATERNT v1.01 predicts water solubility of a given test chemical based on the functional groups which are part of that given test chemical’s structure. The log WS is calculated as the summation of the atom fragment constants of individual chemical functionalities (fj). The contribution of individual chemical functionality to the overall log WS is corrected according to a corresponding coefficient correction (cj) for a given atom type or chemical functionality. The summation of these atom fragment constants and associated correction factors is representative of the overall log WS. The log WS value is then exponentiated to obtain the final water solubility. The predictive capacity of WATERNT is limited to chemical functionalities which are contained in the reference data set and therefore only test chemicals which fall in that domain are accurately estimated. WATERNT v1.01 accurately estimates test chemical which contain most commonly occurring aliphatic and aromatic chemical functional groups. Inorganics, organometallics, and boron containing species are generally outside the predictive domain of WATERNT v1.01

Training set parameters:
Molecular weight range: 30.30 D – 627.62 D
Average molecular weight: 187.73
Solubility range (mg/L): 0.0000004 mg/L – miscible
Solubility range (log moles/L): -12.0605 – 1.3561

- Appropriate measures of goodness-of-fit and robustness and predictivity: The WATERNT has 1128 compounds in the training set, and 4636 compounds in the validation set. From the log-log plot of predicted and experimental Wsol (mole/L) of the training set (1128 compounds), the correlation coefficient is 0.940, the standard deviation is 0.537, and the absolute mean error is 0.355. From the log-log plot of predicted and experimental Wsol (mole/L) of the validation set (4636 compounds), the correlation coefficient is 0.815, the standard deviation is 1.045, and the absolute mean error is 0.795.
- Mechanistic interpretation: The mechanistic basis for this QSAR is the specific chemical functional groups behave a certain way in water. These fragments impart solubility characteristics on the given chemical and this is a constant. These constants have been calculated for a wide variety of functional groups and provide a basis by which to predict the water solubility may be predicted for a chemical which contains functional groups from the training set. The individual mechanisms of this dissolution will vary between different chemical species and functional groups.
5. APPLICABILITY DOMAIN
- Descriptor domain: The total number of modelled fragments are not overrepresented in the structure. The total number of each modelled fragment within the substance is less than the maximum number of occurrence of that fragment in a single structure within the model training or validation sets.
- Structural and mechanistic domains: The parametric domain includes chemicals with molecular weight of 30.30 D – 627.62 D and log solubility (log moles/L) of -12.0605 – 1.3561 (Water solubility from 4E-07 mg/L to miscible). The molecular weight and
predicted water solubility for 1,10-decanediyl bismethacrylate are within the parametric range of the model. In addition, the structure modelled does not contain any unidentified fragments, and there is complete coverage of the structure by the molecule descriptors. The test substance is therefore within the applicability domain of this QSAR model.

- Similarity with analogues in the training set: Structural analogues used by this QSAR in the prediction of the water solubility of the target substance are located in the supporting information provided with the software. The exact list of chemicals used to determine fragment coefficients and structure corrections are not available for each fragment type. Among the structural analogues identified by hand, there are 15 in the training and validation sets which contain acrylate functional group and these are
used to determine prediction uncertainty. Data for four additional analogues were extracted from public databases for uncertainty analysis. Statistical variation of the 19 pairs of experimental and predicted water solubility values indicate that there is a correlation coefficient (r^2) of 0.964, a standard deviation of 0.321, and an absolute mean error of 0.255.
- Other considerations (as appropriate)
6. ADEQUACY OF THE RESULT
In aquatic systems chemicals may dissolve and will therefore be bioavailable to aquatic organisms. The water solubility is representative of a chemicals tendency to dissolve in an aqueous phase. The water solubility is a basis by which to assess a chemicals potential for aquatic bioavailability.

Qualifier:

according to guideline

Guideline:

other: Guidance on information requirements and chemical safety assessment: Chapter R.6:QSARs

Deviations:

no

Principles of method if other than guideline:

- Software tool(s) used including version: Episuite 4.11
- Model(s) used: WATERNT v1.01
- Model description: see field 'Attached justification'

GLP compliance:

no

Remarks:

QSAR model

Type of method:

other: calculation method (fragments) WATERNT v1.01 as implemented through EPI Suite v4.11

Specific details on test material used for the study:

Molecular formula: C18H30O4 (molecular weight,310.44)
Smile: O=C(OCCCCCCCCCCOC(=O)C(=C)C)C(=C)C

Key result

Water solubility:

0.156 mg/L

Conc. based on:

test mat.

Temp.:

25 °C

Remarks on result:

other: pH not in model output

Details on results:

Nineteen structural analogues which contain acrylate functional groups are used to determine prediction uncertainty.Statistical variation of the 19 pairs of experimental and predicted water solubility values indicate that there is a correlation coefficient (r^2) of 0.964, a standard deviation of 0.321, and an absolute mean error of 0.255 (See table 1).

Table 1. The predicted and experiment log Water sol. (mole/L) of analogous and target compounds

CAS	Exp. Water sol. (mg/L)	Exp. Log Water sol. (moles/L)	Est. Log Water sol. (moles/L)	Error
96-33-3	4.94E+04	-0.2412	-0.3398	-0.0986
140-88-5	1.50E+04	-0.8244	-0.8768	-0.0524
80-62-6	1.50E+04	-0.8244	-0.6611	0.1633
818-61-1	1.00E+06	0.9351	0.5087	-0.4264
97-63-2	5.40E+03	-1.3251	-1.1981	0.1270
868-77-9	1.00E+05	-0.1144	0.1874	0.3018
999-61-1	1.00E+06	0.8856	0.1959	-0.6897
141-32-2	2.00E+03	-1.8068	-1.9508	-0.1440
106-63-8	1.80E+03	-1.8525	-1.7266	0.1259
97-86-9	1.30E+03	-2.0390	-2.0479	-0.0089
97-88-1	8.00E+02	-2.2498	-2.2721	-0.0223
585-07-9	1.00E+03	-2.1529	-1.881	0.2719
103-11-7	1.00E+02	-3.2655	-3.8747	-0.6092
109-16-0	3.60E+03	-1.9006	-1.6017	0.2989
3290-92-4	1.30E+01	-4.4155	-4.5645	-0.1490
2499-95-8*	5.74E+01	-3.4349	-3.0249	0.4100
42928-85-8*	1.34E+01	-4.1400	-3.8747	0.2653
44914-03-6*	3.16E+02	-2.6532	-2.2636	0.3896
688-84-6*	3.10E+00	-4.8060	-4.5254	0.2810
Target compound
6701-13-9			-6.299

*from public data source

Conclusions:

1,10-Decanediyl bismethacrylate is a constituent of MDP. 1,10-Decanediyl bismethacrylate has an estimated water solubility of 0.156 mg/L at 25 °C using WATERNT v1.01as implemented through EPISuite v4.11.

Executive summary:

1,10-Decanediyl bismethacrylate is a constituent of MDP. The water solubility of 1,10-decanediyl bismethacrylate was estimated to be 0.156 mg/L using the WATERNT v1.01 QSAR as implemented through EPI Suite v4.11. The software is an accepted, valid model for estimation of water solubility. The structure of 1,10-decanediyl bismethacrylate is within the parametric domain of the model (molecular weight, maximum number of structural fragments per structure, predicted water solubility). The use of this QSAR to predict water solubility for this substance was determined to be applicable and reliable based on representation of analogous substances within the training set and performance statistics (a correlation coefficient (r^2) of 0.964, a standard deviation of 0.321, and an absolute mean error of 0.255) derived from a comparison of experimental and estimated water solubility values for 19 representative analogous substances.

This study is classified as an acceptable QSAR and satisfies the requirements for water solubility study. It is pertinent to the potential of MDP for aquatic bioavailability.

Reference 2

Endpoint:

water solubility

Type of information:

(Q)SAR

Adequacy of study:

key study

Study period:

04 June 2021

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 : ACD/Labs v.12.00

2. MODEL (incl. version number) : ACD/Solubility DB v.12.00

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

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL

- Defined endpoint: Water solubility which is defined in the model as the logarithm of a compound concentration in a saturated solution in pure water, log Sw (mol/L).
- Unambiguous algorithm: ACD/Labs is proprietary commercial software. The general method for calculating water solubilities is described in the publisher's QMRF. The model uses Global linear baseline QSAR + local similarity based corrections. The global QSAR was developed using linear regression by partial least squares (PLS) in combination with a bootstrapping technique. This method implies random compound sampling from the initial training set, i.e. generation of new “training sub-sets”. Each of the sampled sub-sets is of the same size as the initial training set, however, the random manner of their population results in some compounds being selected more than once, others being omitted. This procedure is performed 100 times and an independent PLS model is derived for every sub-set. Each of those PLS models is based on 2D fragmental descriptors: log Sw = SUM[i=1..n](ai*fi) + c
where fi is the number of occurences of the i-th fragment in a molecule, ai - its statistical coefficient, and c - intercept.
- Defined domain of applicability: The software predictions are based on a set of 6807 discrete chemicals with 377 fragment descriptors. The software database contains 6807 chemicals in the entire dataset with log Sw of -12.79 to 2.06. The predicted log Sw for 10-methacryloyl-oxy-decylphosphate is within the parametric range of the model. The structure modelled does not contain any unidentified fragments and there is complete coverage of the structure by the molecule descriptors. The test substance is therefore within the applicability domain of this QSAR model.
- Appropriate measures of goodness-of-fit and robustness and predictivity: The model dataset contains 4764 compounds in the training set and 2043 compounds in validation sets. For validation, the developers defined a reliability index (RI) to determine applicability of the model to members of the set, where all substances have RI >0.3 were defined as within the applicability domain. There are 4608 (96.7%) of the training set compounds that fall within the applicability domain of the model, with correlation coefficient (R²) = 0.865, the standard deviation (Std. Dev.) = 0.782. There are 1989 (97.4%) of the validation set compounds that fall within the applicability domain of the model, with R² = 0.847, Std. Dev. = 0.815.
- Mechanistic interpretation: The only mechanistic consideration utilized in model building is the use of a linear regression method (PLS) and the fragmental descriptors. In other words it is assumed that the final predicted value is composed of a linear combination of all the contributions of structural moieties making up the test molecule.

5. APPLICABILITY DOMAIN
- Descriptor domain: The model uses a molecular fragment approach with 377 specific defined fragments. The specific fragments and their associated coefficients are proprietary to the model and most are not publicly available.
- Structural and mechanistic domains: The software database contains 6807 chemicals in the entire dataset with log Sw of -12.79 to 2.06, with standard deviation of 1.92. The predicted log Sw for 10-methacryloyl-oxy-decylphosphate is within the parametric range of the model. The structure modelled does not contain any unidentified fragments and there is complete coverage of the structure by the molecule descriptors. The test substance is therefore within the applicability domain of this QSAR model.
- Similarity with analogues in the training set: The list of the structural or compositional analogues used by this QSAR in the prediction of the water solubility, log Sw are proprietary information.
- Other considerations (as appropriate):

6. ADEQUACY OF THE RESULT
In aquatic systems chemicals may dissolve and will therefore be bioavailable to aquatic organisms. The water solubility is representative of a chemicals tendency to dissolve in an aqueous phase. The water solubility is a key variable used in every analysis of fate, degradation, transport and bioavailability.

Qualifier:

according to guideline

Guideline:

other: Guidance on information requirements and chemical safety assessment: Chapter R.6: QSARs

Deviations:

no

Principles of method if other than guideline:

-Software tool(s) used including version: ACD/Labs
- Model(s) used: ACD/Solubility DB v.12.00 .
- Model description: see field 'Attached justification'
- Justification of QSAR prediction: see field 'Attached justification'

GLP compliance:

no

Remarks:

QSAR

Type of method:

other: QSAR

Specific details on test material used for the study:

Molecular formula: C14H27O6P1 (molecular weight,322. 34)
Smile: CC(=C)C(=O)OCCCCCCCCCCOP(=O)(O)O

Water solubility:

113 000 mg/L

Conc. based on:

test mat.

pH:

5

Remarks on result:

other: Temperature not in model output

Key result

Water solubility:

1 000 000 mg/L

Conc. based on:

test mat.

pH:

7

Remarks on result:

other: Temperature not in model output

Water solubility:

1 000 000 mg/L

Conc. based on:

test mat.

pH:

9

Remarks on result:

other: Temperature not in model output

Details on results:

10-Methacryloyl-oxy-decylphosphate has estimated pKa values of 1.95 and 6.46, it will be present as monoanions and dianions in environmental pH 5 – 9. Its water solubility changes as a function of pH. The estimated water solubility is 1.13E+05 mg/L (at pH 5) and 1E+06 mg/L (at pH 7 and pH 9).
The intrinsic solubility is the solubility of the un-ionized form in pure water in the absence of acid or alkali. The predicted intrinsic solubility log (S, mol/L) is -3.39 mol/L (131 mg/L) for 10-methacryloyl-oxy-decylphosphate in un-ionized form.
Predicted water solubility in pure water at pH 2.67 is 2.6E-3 mole/L (838 mg/L).

Conclusions:

10-Methacryloyl-oxy-decylphosphate is a constituent of MDP. The estimated water solubility for 10-methacryloyl-oxy-decylphosphate is 1.13E+05 mg/L (at pH 5) and 1E+06 mg/L (at pH 7 and pH 9) using ACD/ Solubility DB as implemented through ACD/Labs v.12.00.

Executive summary:

10-Methacryloyl-oxy-decylphosphate is a constituent of MDP. The water solubility of 10-methacryloyl-oxy-decylphosphate was estimated using ACD/ solubility DB as implemented through ACD/Labs v.12.00.

The software is an accepted, valid model for estimation of water solubility. The software database contains 6807 chemicals in the entire dataset with log Sw (mole/L) of -12.79 to 2.06. The predicted log Sw for 10-methacryloyl-oxy-decylphosphate is within the parametric range of the model. The structure modelled does not contain any unidentified fragments, and there is complete coverage of the structure by the molecule descriptors. The use of this QSAR to predict water solubility for this substance was determined to be applicable and reliable.

10-Methacryloyl-oxy-decylphosphate has estimated pKa values of 1.95 and 6.46, it will be present as monoanions and dianions in environmental pH 5 – 9. The predicted water solubility of 1.13E+05 mg/L (at pH 5) and 1.0E+06 mg/L (at pH 7 and pH 9), indicates that the test substance is considered water soluble and may partition into aqueous phases and therefore is anticipated to be bioavailable to aquatic organisms.

This study is classified as an acceptable QSAR and satisfies the requirements for water solubility study. It is pertinent to the fate, degradation, transport and bioavailability of MDP. The model results are considered reliable with restrictions and may be used for risk analysis, classification and labelling, and PBT analysis.

Description of key information

MDP consists of two main constituents. The constituent 1,10-decanediyl bismethacrylate has an estimated water solubility of 0.156 mg/L at 25 °C. The constituent 10-methacryloyl-oxy-decylphosphate has an estimated water solubility of 1.0E+06 mg/L at pH 7.

Additional information

MDP consists of two main constituents: 1,10-decanediyl bismethacrylate and 10-methacryloyl-oxydecylphosphate. Each constituent was modeled separately using different modeling software.

1,10-Decanediyl bismethacrylate is a neutral compound at environmental pH, water solubility is modeled using WATERNTv1.01 QSAR as implemented through EPI Suite v4.11 since the software is an accepted, valid model for estimate water solubility of neutral compound. The water solubility of 1,10-decanediyl bismethacrylate was estimated to be 0.156 mg/L at 25 °C. 1,10-Decanediyl bismethacrylate is within the applicability domain of the model. The results are therefore reliable with restriction (Klimsch 2) and a key study.

10-Methacryloyl-oxy-decylphosphate has estimated pKa values of 1.95 and 6.46, it will be present as monoanions and dianions in environmental pH 5 – 9, thus water solubility is modeled using ACD/ solubility DB as implemented through ACD/Labs v.12.00, since the software is an accepted, valid model for estimate water solubility of ionic compound. The predicted range of water solubility is 1.13E+05 mg/L (at pH 5) and 1E+06 mg/L (at pH 7 and pH 9). 10-Methacryloyl-oxy-decylphosphate is within the applicability domain of the model. The results are therefore reliable with restriction (Klimsch 2) and a key study.

Both studies are classified as acceptable QSARs and satisfy the requirement for water solubility. They are pertinent to the fate of MDP and may be used for risk analysis, classification, and labelling, and PBT analysis.