Reaction mass of (3E)-4-(2,6,6-trimethylcyclohex-2-en-1-yl)but-3-en-2-one and 4-(dodecylsulfanyl)-4-(2,6,6-trimethylcyclohex-1-en-1-yl)butan-2-one and 4-(dodecylsulfanyl)-4-(2,6,6-trimethylcyclohex-2-en-1-yl)butan-2-one

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:

2015

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)
WATERNT v1.01
September 2010 (model development); November 2012 (model publication)

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
The SMILES and input parameters plus the predicted values are provided within the QPRF attached: ‘QPRF Title: Substance: Reaction mass of (3E)-4-(2,6,6-trimethylcyclohex-2-en-1-yl)but-3-en-2-one and 4-(dodecylsulfanyl)-4-(2,6,6-trimethylcyclohex-1-en-1-yl)butan-2-one and 4-(dodecylsulfanyl)-4-(2,6,6-trimethylcyclohex-2-en-1-yl)butan-2-one using the model WATERNT v1.01 for the endpoint: Water Solubility’ version 1.0; 01 September 2015.

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
Full details of the method are provided in the attached QMRF named ‘QMRF Title: WATERNT v1.01 : Water Solubility’ version 1.02; 01 September 2015 updated: 24 January 2018.

5. APPLICABILITY DOMAIN
Information provided within the QPRF attached: ‘QPRF Title: Substance: Reaction mass of (3E)-4-(2,6,6-trimethylcyclohex-2-en-1-yl)but-3-en-2-one and 4-(dodecylsulfanyl)-4-(2,6,6-trimethylcyclohex-1-en-1-yl)butan-2-one and 4-(dodecylsulfanyl)-4-(2,6,6-trimethylcyclohex-2-en-1-yl)butan-2-one using the model WATERNT v1.01 for the endpoint: Water Solubility’ version 1.0; 01 September 2015.

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 prediction is fit for regulatory purpose. The prediction is adequate as To address the information requirement for REACH Regulation (EC) 1907/2006: Annex VII – Section 7.7 (Water Solubility) and contribute to the assessment for Classification and Labelling: part 4 Environmental Hazards; under CLP Regulation (EC) 1272/2008 as amended. Provision of measured water solubility data for all constituents has been determined as not technically possible under relevant guidelines OECD TG 105 guideline methods or using reasonable adaptations thereof. Since predicted solubility are significantly below 0.001 mg/L for specific constituents. Therefore, in accordance with the tonnage driven information requirements: the calculated method for water solubility has been adopted.

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 attached QMRF named ‘QMRF Title: WATERNT v1.01 : Water Solubility’ version 1.02; date: 01 September 2015; updated 24 January 2018.
- The model applies the following methodology to generate predictions:
Fragment based (group contribution) 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 water solubility reference citations is provided in the WATERNT help menu with additional reference citations.

Water solubility:

106 mg/L

Temp.:

25 °C

pH:

ca. 7

Remarks on result:

other: Value represents the water solubility for constituent 1

Water solubility:

>= 0 - <= 0 mg/L

Temp.:

25 °C

pH:

ca. 7

Remarks on result:

other: Value represents range water solubility for constituents 2 and 3

Water solubility:

>= -9.869 - <= -9.671 other: moles/L

Temp.:

25 °C

pH:

ca. 7

Remarks on result:

other: Value represents range water solubility (moles/L) for constituents 2 and 3; values are negative as they are logarithm-base10 values of water solubility (moles/L)

1. Defined Endpoint:

QMRF 1. Physical Chemical Properties

QMRF 1.3. Water Solubility

Reference to type of model used and description of results:

WATERNT v1.01; 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 (3E)-4-(2,6,6-trimethylcyclohex-2-en-1-yl)but-3-en-2-one and 4-(dodecylsulfanyl)-4-(2,6,6-trimethylcyclohex-1-en-1-yl)butan-2-one and 4-(dodecylsulfanyl)-4-(2,6,6-trimethylcyclohex-2-en-1-yl)butan-2-one using the model WATERNT v1.01 for the endpoint: Water Solubility’ version 1.02, date: 01 September 2015 ; updated 24 January 2018.

The range of constituents water solubility was: 0.0000533 – 106.0 mg/L

Constituent 1 had water solubility: 106 mg/L; > 100-1000 mg/L ('moderately soluble' band); this is based on experimental reference within the prediction model validation set. Constituent 2 and 3 had water solubility < 0.1 mg/L ('insoluble' band).

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 ‘QMRF Title: WATERNT v1.01 : Water Solubility’ version 1.02 – section 5:

Indicates the substance (constituents):

(i) All constituents fall within the Molecular Weight and Water Solubility (mol/L) training set domain ranges (noting that predictions log WSOL < -8.0 should be treated with additional caution).

(ii) No substances have functional groups or features not in the training set of the model and/or for which no fragment constants and correction factors available. No constituents contain multiple fragment instances than the maximum of the training set (see QMRF title section 9.3 for more information).

 

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 = 1128 ; correlation coef (r2) = 0.940 ; standard deviation = 0.537 ; avg Molecular Weight = 187.74

The model has been externally validated on a set of 4636 substances and the following statistics and coefficients of determination are presented:

Total Validation Set Statistics: number in dataset = 4636 ; correlation coef (r2) = 0.815 ; standard deviation = 1.045 ; avg Molecular Weight = 227.52

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 model correlates thermodynamic relationships of surrogates to chemical activity. The WATERNT run in standalone mode allows water solubility to be estimated based on measured values of analogues within the training set (if available). Then the model applies by adding/subtracting fragment constants and correction factors from the measured value. This therefore improves prediction since calculations are based on structural differences between target and analogue. The model domain ideally has at least one or more structurally similar substances to target substances on which to then apply AFC methodology. Whilst there appears to be no direct analogues within the training set. The model has been has been validated externally (using > 4000) substances with a correlation coefficient (r2) = 0.815. 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. Model predictivity could be improved by the assignment of additional substances into the training set. Inclusion of additional structural fragments and expansion of sub-structure correction factors and related rules. In addition, rules for stereochemical effects could feasibly improve modelling. Constituent 1 was present within the validation set as an experimental reference. This result was by expert assessment preferentially selected over the model prediction for this constituent; supported by reliable measured data which was available to the applicant on other structural analogues: with corresponding structural features and in the same Mw range (180 – 200) which indicate that the water solubility can be reasonably expected to be in the 100-1000 mg/L (‘moderately soluble’ band). This was supported by parallel model predictions and measured values which indicated that Partition Coefficient (log Kow) < 4.0 was supported for these analogues.

Conclusions:

Interpretation of results:
other: Substance consists of constituents within two bands of solubility:
i. insoluble to ii. moderately soluble
Water Solubility range (all known constituents): 0.0000533 mg/L (insoluble) to 106 mg/L (moderately soluble) at 25 °C and ca. pH 7

Executive summary:

WATERNT (model publication: November 2012)

Water Solubility range (all constituents): 0.0000533 – 106.0 mg/L at 25 °C and ca. pH 7

<= 0.01 mg/L (insoluble) to 100-1000 mg/L (moderately soluble)

Constituent 1: 106 mg/L (experimental reference within the prediction model validation set)

Constituents 2 and 3: 0.0000533 to 0.0000841 mg/L 

 

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 as supporting information for the Classification and Labelling or risk assessment of the substance as indicated in REACH Regulation (EC) 1907/2006: Annex XI Section 1.3.

Reference 2

Endpoint:

water solubility

Data waiving:

other justification

Justification for data waiving:

other:

Justification for type of information:

JUSTIFICATION FOR DATA WAIVING
In accordance with REACH Regulation (EC) No. 1907/2006 Annex VII, column 2 section 7.7 the study does not need to be conducted if the substance appears ‘insoluble’ in water, a limit test up to the detection limit of the analytical method shall be performed. The applicant completed testing consistent with OECD TG 105 guideline of the water solubility up to the analytical limit of the method employed. There are constituents present with water solubility below the guideline applicability range (< 0.001 mg/L). The applicant adapts the information requirement by providing a calculated value for water solubility for the constituents in accordance with REACH Annex XI, section 1.3. According to ECHA Guidance on Information Requirements and Chemical Safety Assessment (Chapter R.7a: Endpoint Specific Guidance, R.7.1.7.4, July 2017) the study does not need to be conducted. Further testing for water solubility is not justified.

Reference 3

Endpoint:

water solubility

Type of information:

experimental study

Adequacy of study:

disregarded due to major methodological deficiencies

Study period:

2013

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Guideline study performed under GLP; since the substance is a multi-constituent (complex) substance consisting of water soluble and insoluble substances (range of solubilities > x 1000 difference). Water solubility of soluble components were only just above the limit of detection utilised. The study utilised only a limited number of loading rates; did not include a slow-stirring adaptation or an equilibration time determination.

Qualifier:

according to guideline

Guideline:

EU Method A.6 (Water Solubility)

Deviations:

no

Qualifier:

according to guideline

Guideline:

OECD Guideline 105 (Water Solubility)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

inspected: November 2011; signature: March 2012

Type of method:

flask method

Water solubility:

< 33 mg/L

Temp.:

20 °C

pH:

7

Remarks on result:

other: Determination of A/B/C: 20°C at 72 hours

Conclusions:

Interpretation of results : slightly soluble (0.1-100 mg/L)
The test substance water solubility was determined to be < 33 mg/L or the limit of detection of the test system employed at 20.0 ± 0.5 °C.

Executive summary:

The water solubility of the substance was determined using the flask method according to EU Method A.6 and OECD Method 105 under GLP. The test substance water solubility was determined to be < 33 mg/L or the limit of detection of the test system employed at 20.0 ± 0.5 °C. Applicant assessment of the data indicates: that at a mean loading rate 5.77 g/L and under conditions consistent with OECD TG 105 that the water solubility of the test substance cannot be determined < 33 mg/L.

Description of key information

Water Solubility range (all constituents): ≥ 0.0000533 mg/L (constituents 2 and 3) to ≤ 106.0 mg/L (constituent 1) at 25 °C and ca. pH 7, QSAR Prediction - WATERNT v1.01; EpiSuite 4.11 - US EPA, 2015

Additional information

QSAR Predictions WATERNT v1.01 model, 2015 - Water Solubility range (all known constituents): 0.0000533 mg/L (insoluble) to 106 mg/L (moderately soluble) at 25 °C and ca. pH 7

Constituent 1: 106 mg/L (experimental reference within the prediction model validation set)

Constituents 2 and 3: 0.0000533 to 0.0000841 mg/L

 

References for further information:

1. QMRF Title: WATERNT v1.01 : Water Solubility; version 1.02, dated: 01-09-2015 updated: 24-01-2018

2. QPRF Title: Substance: Reaction mass of (3E)-4-(2,6,6-trimethylcyclohex-2-en-1-yl)but-3-en-2-one and 4-(dodecylsulfanyl)-4-(2,6,6-trimethylcyclohex-1-en-1-yl)butan-2-one and 4-(dodecylsulfanyl)-4-(2,6,6-trimethylcyclohex-2-en-1-yl)butan-2-one using the model WATERNT v1.01 for the endpoint: Water Solubility; version 1.0, dated: 01-09-2015

 

Disregarded study, EU Method A.6, 2013: The water solubility of the substance was determined using the flask method according to EU Method A.6 and OECD Method 105 under GLP. The test substance water solubility was determined to be < 33 mg/L or the limit of detection of the test system employed at 20.0 ± 0.5 °C.. Expert assessment indicates that under the conditions of the study, the test substance soluble components could not be detected above 33 mg/L. However, only a single loading rate was utilised and/or there was an absence of an examination of equilibration within the study. The use of filtration may be leading to an under estimation of the soluble constituents within the study.

 

In accordance with REACH Regulation (EC) No. 1907/2006 Annex VII, column 2 section 7.7 the study does not need to be conducted if the substance appears ‘insoluble’ in water, a limit test up to the detection limit of the analytical method shall be performed. The applicant completed testing consistent with OECD TG 105 guideline of the water solubility up to the analytical limit of the method employed. There are constituents present with water solubility below the guideline applicability range (< 0.001 mg/L). The applicant adapts the information requirement by providing a calculated value for water solubility for the constituents in accordance with REACH Annex XI, section 1.3. According to ECHA Guidance on Information Requirements and Chemical Safety Assessment (Chapter R.7a: Endpoint Specific Guidance, R.7.1.7.4, July 2017) the study does not need to be conducted. Further testing for water solubility is not justified.