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Partition coefficient

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Endpoint:
partition coefficient
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2016
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Guideline study performed under GLP. Relevant validity criteria were met with acceptable amendment to allow for partition coefficient screening beyond the traditional guideline range.
Remarks:
Specific constitutents with Log P < 3.0 were reviewed by the applicant, separately.
Qualifier:
according to
Guideline:
EU Method A.8 (Partition Coefficient)
Deviations:
no
Qualifier:
according to
Guideline:
OECD Guideline 117 (Partition Coefficient (n-octanol / water), HPLC Method)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 830.7570 (Partition Coefficient, n-octanol / H2O, Estimation by Liquid Chromatography)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Remarks:
inspected: September 2015; signature: November 2015
Type of method:
HPLC method
Remarks:
using UPLC system
Partition coefficient type:
octanol-water
Analytical method:
liquid chromatography
photometric method
other: UPLC
Type:
log Pow
Partition coefficient:
7.1
Temp.:
35 °C
pH:
7
Remarks on result:
other: Refers to constituents 1 and 2

HPLC method

The results of the HPLC method are given in the Table 2 methanol/buffer pH 7 and Table 3 acetonitrile/buffer pH 7 as mobile phase, respectively.

 

methanol/buffer pH 7: The calibration curve of the log k’ of the reference substances as function of log Pow had an regression line represented by the equation: log k’ = 0.295 ´ log Pow – 0.644 (r = 0.998, n = 14)

acetonitrile/buffer pH 7: The calibration curve of the log k’ of the reference substances as function of log Pow had an regression line represented by the equation: k’ = 0.217 ´ log Pow – 0.524 (r = 0.995, n = 14).

 

Table 2. Pow of the substance - methanol/buffer pH 7

Substance

tr,1
[min]

tr,2
[min]

mean tr
(n=2)

log Pow

Pow

Formamide (t0)

0.598

0.598

0.598

 

 

 

 

 

 

 

 

1,4-Dichlorobenzene

1.918

1.925

1.922

3.4

 

Biphenyl

2.574

2.585

2.580

4.0

 

1,2,4-Trichlorobenzene

2.958

2.970

2.964

4.2

 

Dibenzyl

4.282

4.301

4.292

4.8

 

Triphenylamine

7.826

7.859

7.843

5.7

 

4,4’-DDT

11.151

11.201

11.176

6.5

 

Benzo[ghi]perylene

18.152

18.238

18.195

7.2

 

 

 

 

 

 

 

Peak1

0.934

0.933

0.934

1.3 #1

2.2´10^1

Peak2

16.684

16.693

16.689

7.0

1.1´10^7

Peak3

17.585

17.593

17.589

7.1

1.3´10^7

 

 

 

 

 

 

#1: Estimated value , calculated by extrapolation of the calibration curve.

 

Table 3. Pow of the substance - acetonitrile/buffer pH 7

Substance

tr,1
[min]

tr,2
[min]

mean tr
(n=2)

log Pow

Pow

Formamide (t0)

0.553

0.553

0.553

 

 

 

 

 

 

 

 

1,4-Dichlorobenzene

1.496

1.496

1.496

3.4

 

Biphenyl

1.678

1.678

1.678

4.0

 

1,2,4-Trichlorobenzene

1.995

1.994

1.995

4.2

 

Dibenzyl

2.262

2.259

2.261

4.8

 

Triphenylamine

3.700

3.694

3.697

5.7

 

4,4’-DDT

4.741

4.742

4.742

6.5

 

Benzo[ghi]perylene

6.586

6.586

6.586

7.2

 

 

 

 

 

 

 

Peak1

0.855

0.856

0.856

1.2 #1

1.6´10^1

Peak2

5.970

5.971

5.971

7.0

9.3´10^6

 

 

 

 

 

 

#1: Estimated value , calculated by extrapolation of the calibration curve.

 

Comments: The substance possesses constituents with weak basic functional groups although at pH 7 the substance is considered to be typically in a non-ionised form of the substance. Therefore on this basis the HPLC test was conducted with appropriate buffer to pH 7.0. Additional buffers were deemed unnecessary.

Conclusions:
The partition coefficient of the test substance was determined to be log Pow = 7.1 at 35 °C and pH 7.0 with oxydipropanol constituents beyond the guideline range Log P < 0 (zero).
Executive summary:

The n-octanol-water partition coefficient was determined using the HPLC method of EU Method A.8, OECD Method 117 and OPPTS 830.7570. The partition coefficient of the substance was determined to be log Pow = 7.1 at 35 °C and neutral pH. Applicant assessment indicates the oxydipropanol constituent is beyond the range of the HPLC method (calculated Log P = -0.64, US EPA, KOWWIN v1.68). Peak 1 is one of two known hydrolysis degradation products which has limit values of: Log P = 2.85 (measured and predicted). The main constituents have log P > 6.0 and were measured by a scientifically acceptable amendment to the OECD TG 117 guideline by interpolation using benzo[ghi]perylene (Log P = 7.2).

Endpoint:
partition coefficient
Type of information:
(Q)SAR
Adequacy of study:
key study
Study period:
2017
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
EPISUITE v4.1
2. MODEL (incl. version number)
KOWWIN v1.68 - November 2012 (model publication)
3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
See attached QPRF attached: ‘QPRF Title: Reaction mass of methyl 2-[[(E)-(2,4-dimethylcyclohex-3-en-1-ylidene)methyl]amino]benzoate and methyl 2-[[(Z)-(2,4-dimethylcyclohex-3-en-1-ylidene)methyl]amino]benzoate and oxydipropanol using the model KOWWIN v1.68 for the endpoint: Partition Coefficient (Log Kow)’ version 1.0; 30 May 2017 which has been newly compiled.
4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
QMRF named ‘QMRF Title: KOWWIN v1.68 : n-Octanol/Water Partition Coefficient (Log Kow)’ version 1.01, 01 September 2015
5. APPLICABILITY DOMAIN
See ‘any other information on results incl. tables’.
6. ADEQUACY OF THE RESULT
See ‘any other information on results incl. tables’ and ‘overall remarks, attachments’. The results are adequate when taken under consideration of REACH Regulation (EC) 1907/2006 in a weight of evidence.
Guideline:
other:
Version / remarks:
REACH Guidance on QSARs R.6, May/July 2008
Principles of method if other than guideline:
- Software tool(s) used including version: EPISUITE v4.1
- Model(s) used: KOWWIN v1.68
- Model description: 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 1.01; 01 September 2015. There has been no model updates in the intervening period since the QMRF was prepared.
The model applies the following methodology to generate predictions: Fragment based (group contribution) QSAR; based on multivariate 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:
1. Shake Flask method (OECD TG 107)
2. HPLC method (OECD TG 117)
3. 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.
- Justification of QSAR prediction: Supporting information within weight of evidence due to test item properties and guideline method limitations.
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.
Type:
log Pow
Partition coefficient:
-0.64
Temp.:
25 °C
pH:
7
Remarks on result:
other: Oxydipropanol
Type:
log Pow
Partition coefficient:
2.26
Temp.:
25 °C
pH:
7
Remarks on result:
other: hydrolysis product 1
Type:
log Pow
Partition coefficient:
2.85
Temp.:
25 °C
pH:
7
Remarks on result:
other: hydrolysis product 2
Type:
log Pow
Partition coefficient:
6.23
Temp.:
25 °C
pH:
7
Remarks on result:
other: constituent 1 and 2

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 methyl 2-[[(E)-(2,4-dimethylcyclohex-3-en-1-ylidene)methyl]amino]benzoate and methyl 2-[[(Z)-(2,4-dimethylcyclohex-3-en-1-ylidene)methyl]amino]benzoate and oxydipropanol using the model KOWWIN v1.68 for the endpoint: Partition Coefficient (Log Kow)’ version 1.0; 30 May 2017 which has been newly compiled.

The range of constituents Log Kow was: -0.64 to 6.23

Oxydipropanol: Log Kow = -0.64 ;

Hydrolysis Product 1: 2.26 , experimental Log P: 1.88, Hansch, C et al. (1995)

Hydrolysis Product 2: 2.85

Constituent 1 and 2: 6.23

The majority of constituents had log Kow = 6.23. All hydrolytic degradants and other constituents have predictions for log Kow < 4.0.

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 1.01, 01 September 2015 – section 5; indicates the substance (constituents):

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

(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).

It is however acknowledged that above Log P 6.0 to 7.0 there is lower numbers of substances in the training set although significant numbers of substances in the validation set. Above Log P 8.0 the model should be treated with additional caution. It is also acknowledged for the secondary amine constituents there are limited number of amine analogues within the training set. Which would improve the prediction. There is very good correlation between predictions and measured values on the ECHA REACH dissemination portal (checked 30 May 2017) for measured values of Log P for the hydrolysis products and oxydipropanol.

 

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 ACF 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.

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

KOWWIN v1.68 (model publication: November 2012)

Log Kow range (all constituents): -0.64 to 6.23

Value represents range of Log P for impurities and hydrolysis degradation products and is based on a combination of measured and experimental reference citations.

Value also represents range for all constituents including model predictions.

 

Summary of individual predictions:

Oxidipropanol: Log Kow = -0.64 ;

Hydrolysis Product 1: 2.26 , experimental Log P: 1.88, Hansch, C et al. (1995)

Hydrolysis Product 2: 2.85

Constituent 1 and 2: 6.23

 

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:
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 7.8 the study does not need to be conducted if the test cannot be performed (e.g. the substance decomposes). A calculated value for log P as well as details of the calculation method shall be provided. The test substance has been demonstrated to be hydrolytically unstable. The applicant confirms that Log P determination according to OECD TG 117 HPLC method was attempted however evidence of on-column degradation (hydrolysis) was observed. The applicant adapts the information by providing an endpoint study record for hydrolysis in conjunction to HPLC measurement of specific constituents with log P > 4.0 along with calculated values for log P. Testing according to the Flask Method OECD TG 107 or Slow Stirring Methods OECD TG 123 is inapplicable due to instability and physical properties of the test item. According to ECHA Guidance on Information Requirements and Chemical Safety Assessment (Chapter R.7a: Endpoint Specific Guidance, R.7.1.8.4, December 2016) the study does not need to be conducted.

Description of key information

Weight of evidence: Log Kow (all constituents) range: -0.64 to 7.1 at 25 °C and pH 7, 2017

Log Kow constituents at 25 °C:

Oxydipropanol: -0.64

Hydrolysis Product 1 / Impurity 1: 2.26

Hydrolysis Product 2 / Impurity 2: 2.85

Constituent 1 and 2 (isomers): 7.1

The above constituents are indicated by a combination of predicted (log Kow < 4.0) and measured (Log Kow > 4.0) methods in a weight of evidence approach.

Key value for chemical safety assessment

Additional information

In accordance with REACH Regulation (EC) No. 1907/2006 Annex VII, column 2 section 7.8 the study does not need to be conducted if the test cannot be performed (e.g. the substance decomposes). A calculated value for log P as well as details of the calculation method shall be provided. The test substance has been demonstrated to be hydrolytically unstable. The applicant confirms that Log P determination according to OECD TG 117 HPLC method was attempted however evidence of on-column degradation (hydrolysis) was observed. The applicant adapts the information by providing an endpoint study record for hydrolysis in conjunction to HPLC measurement of specific constituents with log P > 4.0 along with calculated values for log P. Testing according to the Flask Method OECD 107 or Slow Stirring Methods OECD TG 123 is inapplicable due to instability and physical properties of the test item. According to ECHA Guidance on Information Requirements and Chemical Safety Assessment (Chapter R.7a: Endpoint Specific Guidance, R.7.1.8.4, December 2016) the study does not need to be conducted.

 

Weight of evidence: Log Kow (all constituents) range: -0.64 to 7.1 at 25 °C and pH 7, 2017

Log Kow constituents at 25 °C:

Oxydipropanol: -0.64 (QSAR Prediction)

Hydrolysis Product 1 / Impurity 1: 2.26 (QSAR Prediction)

Hydrolysis Product 2 / Impurity 2: 2.85 (QSAR Prediction)

Constituent 1 and 2 (isomers): 7.1 (Measured)

The above constituents are indicated by a combination of predicted (log Kow < 4.0) and measured (Log Kow > 4.0) methods in a weight of evidence approach and using expert judgement.

 

References for further information:

1. QMRF Title: KOWWIN v1.68 : n-Octanol/Water Partition Coefficient (Log Kow) : version 1.01, 01 September 2015

2. QPRF Title: Reaction mass of methyl 2-[[(E)-(2,4-dimethylcyclohex-3-en-1-ylidene)methyl]amino]benzoate and methyl 2-[[(Z)-(2,4-dimethylcyclohex-3-en-1-ylidene)methyl]amino]benzoate and oxydipropanol using the model KOWWIN v1.68 for the endpoint: Partition Coefficient (Log Kow) : version 1.0, 30 May 2017

3. Experimental Study: Anon., OECD TG 117, 2016