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Water solubility

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Reference
Endpoint:
water solubility
Type of information:
(Q)SAR
Adequacy of study:
key study
Study period:
2018
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
Estimation Programme Interface (EPI) Suite programme for Microsoft Windows v4.11
Contact EPISuite:
U.S. Environmental Protection Agency
1200 Pennsylvania Ave.
N.W. (Mail Code 7406M)
Washington, DC 20460

2. MODEL (incl. version number)
WSKOWWIN v1.42
September 2010 (model development); November 2012 (model publication)

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
See QPRF attached: ‘QPRF Title: Substance: Reaction products of 2-hydroxyethyl methacrylate and diphosphorous pentoxide and water using the model WSKOWWIN v1.42 for the endpoint: Water Solubility’ version 1.01; dated 30 May 2018

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
Full details of the method are provided in the attached QMRF named ‘QMRF Title: WSKOWWIN v1.42 and parallel model WATERNT v1.01: Water Solubility’ version 1.01; date: 01 April 2018; updated 30 May 2018.

5. APPLICABILITY DOMAIN
See ‘any other information on results incl. tables’.
See attached QPRF attached: ‘QPRF Title: Substance: Reaction products of 2-hydroxyethyl methacrylate and diphosphorous pentoxide and water using the model WSKOWWIN v1.42 for the endpoint: Water Solubility’ version 1.01; dated 30 May 2018

6. ADEQUACY OF THE RESULT
1) QSAR model is scientifically valid. 2) The substance falls within the applicability domain of the QSAR model. 3) The results are adequate when taken under consideration of REACH Regulation (EC) 1907/2006 in a weight of evidence.
Guideline:
other: REACH Guidance on QSARs R.6, May/July 2008
Principles of method if other than guideline:
Full details of the method are provided in the QMRF named ‘QMRF Title: WSKOWWIN v1.42 and parallel model WATERNT v1.01: Water Solubility’ version 1.01; date: 01 April 2018; updated 30 May 2018.
- The model applies the following methodology to generate predictions:
WSKOWWIN: physical-property correlation QSAR; based on multiple linear-regression modelling
- The model and the training and validation sets are published by US Environmental Protection Agency (USA).
The experimental Water Solubility values in the training set and validation set were measured using one or more methods equivalent or similar to the following guidelines:
- Flask or column elution methods (OECD TG 105)
- Slow Stirring methods (modified OECD TG 105) according to methods similar to those described by Letinksi and coworkers: Slow-stir water solubility measurements of selected alcohols and diesters”, Chemosphere, 48, 257 – 265 (2000).
Plus relevant EU and US EPA OPPTS methods may be also used where appropriate.
A full list of experimental Log Kow reference citations is provided in the WSKOWWIN help menu with additional reference citations.
- Justification of QSAR prediction: The result should be considered in relation to corresponding information presented and in accordance with the tonnage driven information requirements of REACH Regulation (EC) 1907/2006 in a weight of evidence.
Specifically, the assessment is presented to assess the solubility of known constituents of the assessment is presented to assess the solubility of known constituents of the complex: Unknown or Variable composition, Complex reaction products or Biological Materials (UVCB) substance using the n-octanol/water partition coefficient data as an input parameter that yields results by expert judgement that are consistent with the weight of evidence. That substance consists of constituents in the slightly soluble (1 – 100 mg/L) to miscible (> 1000 mg/L) range.
There is evidence the substance may be presented in representative blocks under the ‘block method’ of environmental risk assessment, given their comparable chemistries and physico-chemical properties. Specifically, the substance consists of blocks of constituents of Log Kow < 4.0 and specific solubility ranging from: slightly soluble (1 – 100 mg/L) to miscible (> 1000 mg/L). Typically, ≥ 95%wt of the mass balance of the UVCB substance is expected to be: essentially miscible (> 1000 mg/L). Which is consistent with the weight of evidence for the chemical class.
Specific details on test material used for the study:
Detailed information on the 'test material identity' is provided in the attached QSAR Prediction Reporting Format (QPRF) document including information on individual constituents.
Water solubility:
24.73 mg/L
Conc. based on:
other:
Temp.:
25 °C
pH:
7
Remarks on result:
other: solubility: Block 1 constituents
Water solubility:
>= 1 124 - <= 137 000 mg/L
Conc. based on:
other:
Temp.:
25 °C
pH:
7
Remarks on result:
other: solubility: Block 2 constituents
Water solubility:
>= 11 200 - <= 539 000 mg/L
Temp.:
25 °C
pH:
7
Remarks on result:
other: solubility: Block 3 constituents

1. Defined Endpoint:

QMRF 1. Physical Chemical Properties

QMRF 1.3. Water Solubility

Reference to type of model used and description of results:

WSKOWWIN v1.42; integrated within the Estimation Programme Interface (EPI) Suite programme for Microsoft Windows v4.11; September 2010 (model development); November 2012 (model publication)

 

2. Description of results and assessment of reliability of the prediction:

The predicted values are provided within the QPRF attached: ‘QPRF Title: Substance: Reaction products of 2-hydroxyethyl methacrylate and diphosphorous pentoxide and water using the model WSKOWWIN v1.42 for the endpoint: Water Solubility’ version 1.01; dated 30 May 2018

 

The range of main constituents was: WSOL = 24.73 to 539000 mg/L, respectively. In three blocks.

The substance consists of constituents in the slightly soluble (1 – 100 mg/L) to soluble (> 1000 mg/L) range.

The mass %wt majority of substances are soluble (> 1000 mg/L)

 

Table 1.0: Structural formula and inputs (SMILES) and Log Kow (if appropriate) with Water Solubility output of the substance

Note: All predictions are at 25 °C and ca. pH 7.0

Number

Constituent Name (IUPAC)

MW

Water Solubility

(WATERNT)

/ mg/L

Log Kow (measured or predicted KOWWIN v1.68)

Water Solubility (WSKOW)

/ mg/L

1

phosphoric acid

97.9952

1000000

-0.7699

5.39 x10^5

2

2-(dimethylphosphoryl)ethyl 2-methylbutanoate

206.222

9.76 x10^5

0.6535

11200

3

2-hydroxyethyl methacrylate

130.1418

Measured:

1.00 x10^5

CITI, (1992)

 

2.00 x10^5

Measured:

0.47

Hansch, (1995)

 

0.3014

Measured:

1.00 x10^5

CITI, (1992)

 

1.18 x10^5

4

2-hydroxyethyl 2-hydroxy-2-methylpropanoate

148.158

1000000

-0.7879

3.64 x10^5

5

{2-[(2-methylprop-2-enoyl)oxy]ethoxy}phosphonic acid

210.1217

3.42 x10^5

0.2199

25200

6

bis({1-[(2-methylprop-2-enoyl)oxy]ethoxy})phosphinic acid

322.2482

56993

1.0627

1124

7

2-{[bis({2-[(2-methylprop-2-enoyl)oxy]ethoxy})phosphoryl]oxy}ethyl 2-methylprop-2-enoate

434.378

1058.8

2.1995

24.73

8

{[hydroxy({2-[(2-methylprop-2-enoyl)oxy]ethoxy})phosphoryl]oxy}phosphonic acid

290.101

1000000

-0.7490

61130

9

{[hydroxy({[hydroxy({2-[(2-methylprop-2-enoyl)oxy]ethoxy})phosphoryl]oxy})phosphoryl]oxy}phosphonic acid

370.079

1000000

-1.7179

1.37 x10^5

 

It is noted by the applicant there is no universally acknowledged applicability domain for the model. However, assessment of the substance within the applicability domains recommended by the developers is documented within the corresponding QMRF named ‘WSKOWWIN v1.42 and parallel model WATERNT v1.01: Water Solubility’ version 1.01; date: 01 April 2018; updated 30 May 2018 – section 5; indicates the substance (constituents):

(i) All constituents fall within the Molecular Weight range domain

(> 27.03 AND < 627.62 g/mol)

(ii) All constituents fall within the Log Kow range domain

(> -3.89 AND < 8.27)

(iiI) All constituents fall within the Water Solubility range domain

(> 0.0000004 mg/L – to miscible)

(iv) TThe substance has functional groups for which no correction factor was developed. Specifically, assessment of the WSKOWWIN training and validation sets indicates that the test item constituents have functional groups or features (phosphates, phosphonate and polyphosphate esters substances or equivalents) for which no fragment constants and correction factors are available. However, expert assessment of US EPA (1994), Title: Upgrade of the PCGEMS Water Solubility Method (document: SRC-TR-94_009) indicates there are several or more phosphates, phosphonate and polyphosphate esters substances or equivalents present in the model training set used to derive the regression equation. This means that the constituents should be considered ‘in domain’. Constituent 1 is considered by the programme as ‘inorganic’ and therefore outside the training set domain and should be used with caution. However, the prediction is comparable to literature data which essentially indicates that the water solubility of phosphoric acid is > 850 g/L (ECHA, 2018) or is ‘miscible’. Expert judgement for all constituents would indicate that the predictions appear adequate for all structures. The model can be extrapolated to substances outside the MW-Log Kow and/or fragments domains (see QMRF title section 9.3 and US EPA (1994), document: SRC-TR-94_009, for more information which is available through the model help-system file by reference to an internet address where the documents may be downloaded).

(v) There is no overt mechanistic basis for the model. The WSKOWWIN model is based on the thermodynamic relationship between surrogate physicochemical properties (Log Kow and MP), chemical structure and their chemical activity (Water Solubility). Including within this specific model correlation between physico-chemistry and the measured water solubility along with sub-structure correction factors.

 

3. Uncertainty of the prediction and mechanistic domain:

The training set of the model has the following statistics and coefficients of determination:

Total Training Set Statistics: number in dataset (MW only) = 1450 ; correlation coef (r2) = 0.934 ; standard deviation = 0.585 ; average deviation = 0.442

Total Training Set Statistics: number in dataset (MW and MW) = 1450 ; correlation coef (r2) = 0.970 ; standard deviation = 0.409 ; average deviation = 0.313

The model has been externally validated. The relevant coefficients of determination for the external validation set of (i) 85 substances (Log Kow measured) and (ii) 817 (MP measured, no measured Log Kow) and the following statistics and coefficients of determination are presented:

Total Validation Set Statistics (i) 85 substances: number in dataset = 85 ; correlation coef (r2) = 0.865 ; standard deviation = 0.961 ; average deviation = 0.714

Total Validation Set Statistics (ii) 817substances: ; number in dataset = 817 ; correlation coef (r2) = 0.902 ; standard deviation = 0.615 ; average deviation = 0.480

Data for the training set are available via external validation (see attached QMRF prepared by the applicant for full citations).

There is no overt mechanistic basis for the model. The WSKOWWIN model is based on the thermodynamic relationship between surrogate physicochemical properties (Log Kow and MP), chemical structure and their chemical activity (Water Solubility). Including within this specific model correlation between physico-chemistry and the measured water solubility along with sub-structure correction factors. In order to improve the model additional substances could be added to the model training set with further measured experimental Log Kow and MP data. Additional substances not presently represented with substructure corrections could be introduced. Whilst there appears to be no direct analogues within the training set the model has been has been validated externally (using > 800) substances with a correlation coefficient (r2) = 0.902. The model is non-proprietary and the training sets and validation sets can be downloaded from the internet. A summary of this information is presented by the applicant.

Conclusions:
The results are adequate for the for the regulatory purpose.
Executive summary:

WSKOWWIN v1.42 (model publication: November 2012)

The range of main constituents was: WSOL = 24.73 to 539000 mg/L, respectively. In three blocks.

The substance consists of constituents in the slightly soluble (1 – 100 mg/L) to soluble (> 1000 mg/L) range.

The mass %wt majority of substances are soluble (> 1000 mg/L)

 

There is evidence the substance may be presented in representative blocks under the ‘block method’ of environmental risk assessment, given their comparable chemistries and physico-chemical properties. Specifically, the substance consists of blocks of constituents of Log Kow < 4.0 and specific solubility ranging from: slightly soluble (1 – 100 mg/L) to miscible (> 1000 mg/L). Typically, ≥ 95%wt of the mass balance of the UVCB substance is expected to be: essentially miscible (> 1000 mg/L). Which is consistent with the weight of evidence for the chemical class.

 

Adequacy of assessment of the (Q)SAR results.

1) QSAR model is scientifically valid. 2) The substance falls within the applicability domain of the QSAR model. 3) The prediction is fit for regulatory purpose (see below).

The prediction is adequate for the Classification and Labelling and/or risk assessment of the substance as indicated in REACH Regulation (EC) 1907/2006: Annex XI Section 1.3. The assessment is presented to assess the solubility of known constituents of the complex: Unknown or Variable composition, Complex reaction products or Biological Materials (UVCB) substance using the n-octanol/water partition coefficient data as an input parameter that yields results by expert judgement that are consistent with the weight of evidence. That substance consists of constituents in the slightly soluble (1 – 100 mg/L) to miscible (> 1000 mg/L) range.

Description of key information

Water Solubility (range): 24.73 to 539000 mg/L in three blocks, at 25 °C; ca. pH 7, QSAR Prediction - WSKOWWIN v1.42, 2018

The substance consists of constituents in the slightly soluble (1 – 100 mg/L) to soluble (> 1000 mg/L) range.

The mass %wt majority of substances are soluble (> 1000 mg/L).

 

The key value for chemical safety assessment is determined at 539000 mg/L, the highest water solubility value, corresponding to the worst case scenario.

Key value for chemical safety assessment

Water solubility:
539 000 mg/L
at the temperature of:
25 °C

Additional information

QSAR Predictions WSKOWWIN v1.42 model, 2018 –

The range of main constituents was: WSOL = 24.73 to 539000 mg/L, respectively. In three blocks.

The substance consists of constituents in the slightly soluble (1 – 100 mg/L) to soluble (> 1000 mg/L) range.

The mass %wt majority of substances are soluble (> 1000 mg/L)

 

There is evidence the substance may be presented in representative blocks under the ‘block method’ of environmental risk assessment, given their comparable chemistries and physico-chemical properties. Specifically, the substance consists of blocks of constituents of Log Kow < 4.0 and specific solubility ranging from: slightly soluble (1 – 100 mg/L) to miscible (> 1000 mg/L). Typically, ≥ 95%wt of the mass balance of the UVCB substance is expected to be: essentially miscible (> 1000 mg/L). Which is consistent with the weight of evidence for the chemical class.

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