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Water solubility

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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 mass of (9E)-9-undecenal and (9Z)-9-undecenal and undec-10-enal using the model WSKOWWIN v1.42 for the endpoint: Water Solubility’ version 1.0; 01 April 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 1.0; date: 01 April 2018.

5. APPLICABILITY DOMAIN
See ‘any other information on results incl. tables’.
See attached QPRF attached: ‘QPRF Title: Substance: Reaction mass of (9E)-9-undecenal and (9Z)-9-undecenal and undec-10-enal using the model WSKOWWIN v1.42 for the endpoint: Water Solubility’ version 1.0; 01 April 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 1.0; date: 01 April 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 substance is presented to assess the solubility of known constituents of the multi-constituent substance using high reliability 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) range.
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:
14.7 mg/L
Conc. based on:
other:
Temp.:
25 °C
pH:
7
Remarks on result:
other: solubility: Constituent 3
Water solubility:
17.21 mg/L
Conc. based on:
other:
Temp.:
25 °C
pH:
7
Remarks on result:
other: solubility: Constituent 1 and Constituent 2

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 mass of (9E)-9-undecenal and (9Z)-9-undecenal and undec-10-enal using the model WSKOWWIN v1.42 for the endpoint: Water Solubility’ version 1.0; 01 April 2018

The range of main constituents was: WSOL = 14.70 to 17.21 mg/L, respectively.

The other identified constituents were: WSOL = 34.93 mg/L

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

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 1.0; date: 01 April 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) The substance has functional groups for which there are no functional groups for which a correction factor was developed. Specifically, assessment of the WSKOWWIN training and validation sets indicates that the test item constituent substances have functional groups or features (aldehyde, aliphatic) 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 at least ten (10) aldehydes, aliphatic and cyclic in the model training set used to derive the regression equation. This means that the constituents should be considered ‘in domain’. No constituents contain multiple fragment instances than the maximum of the training set (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.

See QPRF section 3.3 and QMRF sections 5.1 and 9.3 for more information.

The model can be used to extrapolate on substances out of domain, by expert judgement with additional caution.

 

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 is: WSOL = 14.70 to 17.21 mg/L, respectively.

The other identified constituents are: WSOL = 34.93 mg/L

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

Adequacy of the QSAR:

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.

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.

Endpoint:
water solubility
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2014
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Guideline study performed under GLP. The method for CMC determination utilises multiple test item loadings. The estimate of water solubility reported will be reliable with acknowledgement of the uncertainties associated with multi constituent substances and; substances which have a low degree of solubility as shown in the reference data for OECD TG 105 method.
Qualifier:
according to
Guideline:
other: ISO 4311: Anionic and non-ionic surface active agents — Determination of the critical micellization concentration — Method by measuring surface tension with a plate, stirrup or ring
Deviations:
no
GLP compliance:
yes (incl. certificate)
Remarks:
inspected March 2013; signature: May 2013
Type of method:
other: Anionic and non-ionic surface active agents — Determination of the critical micellization concentration
Water solubility:
3 mg/L
Temp.:
20 °C
pH:
7
Remarks on result:
other: at 20± 0.5 °C; in double distilled water (pH 7); estimated based on visual observations of solutions completely dissolving

Table 1. test solutions of the study:

Code

Nominal concentration [mg/l]

Test substance completely dissolved

 

 

 

CMC_0.5

0.5

Yes

CMC_1

1

Yes

CMC_1_a

1

Yes

CMC_2

2

Yes

CMC_4

4

No

CMC_6

6

No

CMC_7

7

No

CMC_8

8

No

CMC_10

10

No #1

CMC_100

1*102

No

CMC_1000

1*103

No

CMC_10000

1*104

No

 

 

 

#1 Since the surface tension of CMC_1 was 73.2 mN/m, the surface tension of CMC_10 was also measured despite the fact that it was not completely in solution.

 

 

Table2 Mean results for solutions

Measurement

at 20°C±0.5°C

Surface tension
[mN/m]

Mean #1

mean multiplied by
Φb (i.e. 1.02) and Harkins-Jordan corrected value

 

 

 

Test solution CMC_0.5 mg/l (day 2)

71.7

73.1

Test solution CMC_1 mg/l (day 1)

73.9

73.2

Test solution CMC_1_a mg/l (day 2)

72.5

74.0

Test solution CMC_2 mg/l (day 2)

72.5

74.0

Test solution CMC_10 mg/l (day 1)

68.0

66.9

 

 

 

# 1: Mean calculated, after equilibrium was reached.

 

From the CMC experiments it was concluded the test substance has only a very low water solubility. Below (and even slightly above) the water solubility the measured surface tension is only marginally lower than that of pure water. Therefore it is not possible to determine to critical micelle concentration of the test substance. Based on the visual experiments, where a solution at 2 mg/l was completely dissolved whereas a solution at 4 mg/l was not completely dissolved, it was concluded that the water solubility is 3 mg/l (i.e. the closest approximation between a completely dissolved and supersaturated solution).

Conclusions:
Interpretation of results (migrated information): slightly soluble (0.1-100 mg/L)The test substance water solubility was determined to be 3 mg/l of solution at 20.0 °C. The substance is not surface active based on measurements of surface tension at different concentrations in a Critical Micelle Concentration (CMC) determination under ISO 4311. The CMC could not be determined.
Executive summary:

The critical micelle concentration of the substance was examined using an ISO 4311 method for anionic and non-ionic surface active agents using a plate, stirrup or ring methodology. From the experiments it was concluded the test substance has only a very low water solubility. Below (and even slightly above) the water solubility the measured surface tension is only marginally lower than that of pure water. Therefore it is not possible to determine to critical micelle concentration of the test substance. Based on the visual experiments, where a solution at 2 mg/L was completely dissolved whereas a solution at 4 mg/L was not completely dissolved, it was concluded that the water solubility is 3 mg/l (i.e. the closest approximation between a completely dissolved and supersaturated solution). The water solubility of the substance is considered to be 3 mg/L of solution at 20.0 °C and at approximately pH = 7.0.

Description of key information

Water Solubility range (all main constituents): ≥ 14.7 mg/L (constituent 3) to ≤ 17.21 mg/L (constituent 1 and 2) at 25 °C and ca. pH 7, QSAR Prediction – WSKOWWIN v1.42; EpiSuite 4.11 - US EPA, 2018

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

Key value for chemical safety assessment

Water solubility:
3 mg/L
at the temperature of:
20 °C

Additional information

QSAR Predictions WSKOWWIN v1.42 model, 2018 - Water Solubility range (all main constituents): 14.7 mg/L to 17.21 mg/L (slightly soluble) at 25 °C and ca. pH 7

Constituent 3: 14.21 mg/L

Constituents 1 and 2: 17.21 mg/L

The other identified minor constituents were: WSOL = 34.93 mg/L

 

References for further information:

1. QMRF Title: WSKOWWIN v1.42 and parallel model WATERNT v1.01: Water Solubility, version 1.0; date: 01 April 2018.

2. QPRF Title: Substance: Reaction mass of (9E)-9-undecenal and (9Z)-9-undecenal and undec-10-enal using the model WSKOWWIN v1.42 for the endpoint: Water Solubility, version 1.0; 01 April 2018.

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 substance is presented to assess the solubility of known constituents of the multi-constituent substance using high reliability 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) range.

ISO 4311, 2014 - The critical micelle concentration of the substance was examined using an ISO 4311 method for anionic and non-ionic surface active agents using a plate, stirrup or ring methodology. From the experiments it was concluded the test substance has only a very low water solubility. Below (and even slightly above) the water solubility the measured surface tension is only marginally lower than that of pure water. Therefore it is not possible to determine to critical micelle concentration of the test substance. Based on the visual experiments, where a solution at 2 mg/L was completely dissolved whereas a solution at 4 mg/L was not completely dissolved, it was concluded that the water solubility is 3 mg/l (i.e. the closest approximation between a completely dissolved and supersaturated solution). The water solubility of the substance is considered to be 3 mg/L of solution at 20.0 °C and at approximately pH = 7.0.