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Partition coefficient

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Endpoint:
partition coefficient
Type of information:
(Q)SAR
Adequacy of study:
key study
Study period:
2015
Reliability:
2 (reliable with restrictions)
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)
KOWWIN v1.68
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: KOWWIN v1.68 : n-Octanol/Water Partition Coefficient (Log Kow)’ version 1.02; date: 01 September 2015; updated 24 January 2018.

5. APPLICABILITY DOMAIN
Information provided within the QPRF attached: ‘QPRF Title: 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 KOWWIN v1.68 for the endpoint: Partition Coefficient (Log Kow))’ 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 (see below).
To address the information requirement for REACH Regulation (EC) 1907/2006: Annex VII – Section 7.8 (Partition Coefficient) and contribute to the assessment for Classification and Labelling: part 4 Environmental Hazards; under CLP Regulation (EC) 1272/2008 as amended. Provision of measured experimental log Kow for all constituents has been determined as not technically possible under guideline OECD TG 117 HPLC method. It is also potentially not possible by other methods such as OECD TG 123 slow stir method due to the high log Kow predicted and the limitations of the methods that may be employed. Therefore, in accordance with the tonnage driven information requirements: the calculated method for log Kow 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: KOWWIN v1.68 : n-Octanol/Water Partition Coefficient (Log Kow)’ 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 Log Kow values in the training set and validation set were measured using one or more methods equivalent or similar to the following guidelines:
- Shake Flask method (OECD TG 107)
- HPLC method (OECD TG 117)
- Slow Stirring method (OECD TG 123)
Plus relevant EU (1992 as amended) and US EPA OPPTS (1982 as amended) and ASTM (1993) methods may be also used where appropriate.
A full list of experimental Log Kow reference citations is provided in the KOWWIN help menu with additional reference citations.
Partition coefficient type:
octanol-water
Type:
log Pow
Partition coefficient:
ca. 3.85
Temp.:
25 °C
pH:
ca. 7
Remarks on result:
other: Value represents the Log P for constituent 1
Type:
log Pow
Partition coefficient:
>= 9.64 - <= 9.77
Temp.:
25 °C
pH:
ca. 7
Remarks on result:
other: Value represents range of Log P for constituents 2 and 3

1. Defined Endpoint:

QMRF 1. Physical Chemical Properties

QMRF 1.6. Octanol-water partition coefficient (Kow)

Reference to type of model used and description of results:

KOWWIN v1.68; 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: 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 KOWWIN v1.68 for the endpoint: Partition Coefficient (Log Kow))’ version 1.0; 01 September 2015.

 

The range of constituents log Kow was: 3.85 to 9.77

Constituent 1 had log Kow = 3.85 (experimental reference within the prediction model validation set). Constituents 2 and 3 have predictions for log Kow = 9.77 and 9.64 respectively.

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: KOWWIN v1.68 : n-Octanol/Water Partition Coefficient (Log Kow)’ version 1.02 – section 5:

Indicates the substance (constituents):

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

(ii) No constituents 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).

It was however acknowledged, that predictions for log Kow > 8.0 need to be treated with additional caution due to the limited number of substances with measured values in that range in the validation set.

 

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 = 2447 ; correlation coef (r2) = 0.982 ; standard deviation = 0.217 ; absolute deviation = 0.159 and avg Molecular Weight = 199.98

The model has been externally validated on a set of 10,946 substances and the following statistics and coefficients of determination are presented:

Total Validation Set Statistics: number in dataset = 10946 ; correlation coef (r2) = 0.943 ; standard deviation = 0.479 ; absolute deviation = 0.356 ; avg Molecular Weight = 258.98

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 KOWWIN v1.68 run in standalone mode allows Log Kow 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 extensively validated externally (using > 10,000) substances with a correlation coefficient (r2) = 0.943. 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. Expert review of the data on relevant structural analogues in the validation dataset indicate that in general they over predict log Kow compared to measured data. 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 relevant structural analogues: with corresponding structural features and in the same Mw range (180 – 200) which indicate that log Kow < 4.0 is supported for this constituent. The discrepancy between prediction and experimental reference it was felt could be due to non-optimised measured data in the OECD TG 117 guideline within the dataset in this range of log Kow. In so far as poor selection of reference substances and optimisation of the method could yield erroneous results > 4.0. As previously mentioned, the model tends to over predict log Kow as indicated in the present substance predictions comparison with analogues.

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

KOWWIN v1.68 (model publication: November 2012)

Log Kow range (all constituents): 3.85 and 9.64 to 9.77

Constituent 1: 3.85 (experimental reference within the prediction model validation set)

Constituents 2 and 3: 9.64 to 9.77

 

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 or risk assessment of the substance as indicated in REACH Regulation (EC) 1907/2006: Annex XI Section 1.3. The assessment indicates that the prediction is suitable for the regulatory conclusion in accordance with the tonnage driven information requirements specifically when combined with further information available such as environmental toxicity and environmental fate testing.

Endpoint:
partition coefficient
Data waiving:
study technically not feasible
Justification for data waiving:
other:
Justification for type of information:
JUSTIFICATION FOR DATA WAIVING
In accordance with REACH Regulation (EC) 1907/2006 Annex XI, section 2: the study is technically not possible in that the substance possesses constituents outside the applicable range for guideline tests. Such as OECD TG 117 HPLC method (0.0 > Log P < 6.0) and OECD TG 123 slow stirring method adapted to OECD, 2003 (limit for hydrophobic substances: log P < 8.3). The applicant completed the OECD TG 117 and confirmed the test method inapplicability. A calculated value for log P meeting the requirements of REACH Regulation (EC) 1907/2006 Annex XI, section 1.3 is provided. The applicant adapts the information requirement by providing a calculated value for log P. According to ECHA Guidance on Information Requirements and Chemical Safety Assessment (Chapter R.7a: Endpoint Specific Guidance, R.7.1.8.4, July 2017) the study does not need to be conducted. Further testing for partition coefficient is not justified.
Endpoint:
partition coefficient
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; supporting information provided. Not all constituents were within the test guideline calibration range. Choice of reference substances was not optimal for determining the Log P of specific constituents less than 4.0 screening criteria. Only one reference substance had log P < 4.0 leading to poor calibration in this range.
Qualifier:
according to guideline
Guideline:
EU Method A.8 (Partition Coefficient)
Deviations:
no
Qualifier:
according to guideline
Guideline:
OECD Guideline 117 (Partition Coefficient (n-octanol / water), HPLC Method)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
inspected: November 2011; signature: March 2012
Type of method:
HPLC method
Partition coefficient type:
octanol-water
Analytical method:
high-performance liquid chromatography
Type:
log Pow
Partition coefficient:
4.11
Temp.:
30 °C
pH:
5.5
Remarks on result:
other: Constituent 1; mean log Pow

Preliminary test

A preliminary assessment of the partition coefficient was made based by the KOWWIN calculation method (Epiwin® v3.10, Microsoft Windows c/William Meylan, 1990 -2000) using the structure of the test material.

Log Pow estimate: 4.29 (constituent 1)

Definitive test

Calibration

The retention times, capacity factors (k) and log Pow values for the reference standards are shown in the following tables:

Table 1

Standard

Tr1

Tr2

Tr3

Tr4

Tr5

Tr mean

K

Log K

Log Pow

 

2.92

2.92

2.92

2.92

2.92

2.92

0.00

-

-

Isopropylbenzene

5.24

5.24

5.24

5.24

5.24

5.24

0.79

-0.100

3.70

Biphenyl

6.66

6.66

6.66

6.66

6.66

6.66

1.28

0.107

4.00

n-Butylbenzene

7.09

7.09

7.09

7.09

7.09

7.09

1.43

0.155

4.50

2,6-diphenylpyridine

8.66

8.66

8.66

8.66

8.66

8.66

1.97

0.294

4.90

Triphenylamine

11.95

11.96

11.95

11.95

11.96

11.95

3.09

0.490

5.70

DDT

12.65

12.65

12.65

12.65

12.65

12.65

3.33

0.523

6.50

The retention times, capacity factors and log Pow values determined for the sample are shown in the following table:

Standard

Tr1

Tr2

Tr3

Tr4

Tr5

Tr mean

K

Log K

Log Pow

To

2.92

2.92

2.92

2.92

2.92

2.92

0.00

-

-

Constituent 1

6.28

6.29

6.29

6.29

6.29

6.29

1.153

0.062

4.11

 

 

 

 

 

 

 

 

 

 

* constituent 2 and 3 did not elute

Conclusions:
The partition coefficient of the test substance could not be determined as not all constituents eluted within the calibration range. Constituent 1 was determined to be log Pow = 4.11 at 30 °C and pH 5.5. Constituents 2 and 3 were outside the calibration range.
Executive summary:

The n-octanol-water partition coefficient was evaluated using the HPLC method of EU Method A.8 and OECD Method TG 117 under GLP. The partition coefficient of the test substance could not be fully determined since not all constituents eluted within the calibration range. Constituent 1 was determined to have log Pow = 4.11 at 30 °C and pH 5.5. Applicant reassessment of the data indicates this constituent is poorly calibrated for due to choice of reference substances. Comparison with calculated values (KOWWIN v1.67) presented within the study report and apparent consistency between HPLC result (log P = 4.11) and the calculated value (log P = 4.29) did not consider that the constituent was present as an experimental literature value within the model dataset. Constituent 2 and 3 had calculated log P = 9.77 and 9.64, respectively.

Description of key information

Log Kow (range): ≥ 3.85 (constituent 1) to ≤ 9.77 (constituents 2 and 3) at 25 °C; ca. pH 7, QSAR Prediction - KOWWIN v1.68; EpiSuite 4.11 - US EPA, 2015

Key value for chemical safety assessment

Additional information

QSAR Predictions KOWWIN v1.68 model, 2015 - Log Kow range (all constituents): ≥3.85 to ≤9.77, at 25 °C and ca. pH 7

Constituent 1: 3.85 (experimental reference within the prediction model validation set)

Constituents 2 and 3: 9.64 to 9.77

References for further information:

1. QMRF Title: KOWWIN v1.68 : n-Octanol/Water Partition Coefficient (Log Kow); version 1.02, dated: 01-09-2015; updated: 24-01-2018

2. QPRF Title: 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 KOWWIN v1.68 for the endpoint: Partition Coefficient (Log Kow); version 1.0, dated: 01-09-2015

 

Disregarded study, EU Method A.8, 2013: The n-octanol-water partition coefficient was evaluated using the HPLC method of EU Method A.8 and OECD Method TG 117 under GLP. The partition coefficient of the test substance could not be fully determined since not all constituents eluted within the calibration range. Constituent 1 was determined to have log Pow = 4.11 at 30 °C and pH 5.5. Applicant reassessment of the data indicates this constituent is poorly calibrated for due to choice of reference substances. Comparison with calculated values (KOWWIN v1.67) presented within the study report and apparent consistency between HPLC result (log P = 4.11) and the calculated value (log P = 4.29) did not consider that the constituent was present as an experimental literature value within the model dataset. Constituent 2 and 3 had calculated log P = 9.64 and 9.77, respectively.

 

In accordance with REACH Regulation (EC) 1907/2006 Annex XI, section 2: the study is technically not possible in that the substance possesses constituents outside the applicable range for guideline tests. Such as OECD TG 117 HPLC method (0.0 > Log P < 6.0) and OECD TG 123 slow stirring method adapted to OECD, 2003 (limit for hydrophobic substances: log P < 8.3). The applicant completed the OECD TG 117 and confirmed the test method inapplicability. A calculated value for log P meeting the requirements of REACH Regulation (EC) 1907/2006 Annex XI, section 1.3 is provided. The applicant adapts the information requirement by providing a calculated value for log P. According to ECHA Guidance on Information Requirements and Chemical Safety Assessment (Chapter R.7a: Endpoint Specific Guidance, R.7.1.8.4, July 2017) the study does not need to be conducted. Further testing for partition coefficient is not justified.