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Partition coefficient

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Endpoint:
partition coefficient
Data waiving:
study technically not feasible
Justification for data waiving:
other:
Justification for type of information:
The substance is a complex mixture, which contains a large number of constituents, which are mostly unkown but which have different solubility (often low solubility) and volatility. In addition its physical state leads to difficulties for physico-chemical testing: It is described as orange-brown to red-brown flowable viscous liquid to pasty.

A GLP study has been conducted on an analogue substance, according to OECD 117 showing a non reliable result (the major peak of the test item detected with a logKow < 0.3 while the substance is mainly insoluble in water) (see disregarded study on labdanum resinoid(ethanol)).
In addition a feasibility studies conducted on other natural complex substances showed that this method is difficult to applicate for this kind of substances due to the very low response of the test items with the HPLC detectors tested (Diode Array Detector and Mass Spectrometry). Another strategy based on the application of the OECD 123 method and the quantification of the test item in both octanol and water phases by a GC-FID analytical method was considered. However, this approach does not allow to detect the totality of the test item constituents and was not considered as appropriate to define a range of logKow for the whole substance.
Finally the standard tests for partition coefficient endpoint are intended for single substances and are not appropriate for such complex substances because of the limited knowledge of composition and the physical state of the substance.
Reason / purpose:
data waiving: supporting information
Endpoint:
partition coefficient
Type of information:
(Q)SAR
Adequacy of study:
supporting study
Study period:
run on 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 limited documentation / justification
Justification for type of information:
QSAR prediction : The values obtained on known constituents of the substance are not experimental results, however the QSAR model is recommended by the ECHA guidance document on information requirements, is well documented with regard to validation parameters according to OECD principles. Moreover, the constituents of the substance are fully characterised towards the applicability domain.
Reason / purpose:
reference to other study
Principles of method if other than guideline:
QSAR estimation
Partition coefficient type:
octanol-water
Type:
log Pow
Partition coefficient:
>= -0.14 - <= 9.63
Remarks on result:
other: Temperature and pH not provided (QSAR estimation)
Remarks:
Range of logKow estimated on a the known constituents of the substance

Temperature and pH values are not considered in this model.

The estimation is based on the non-ionised form of the molecule.

No Experimental Value Adjustment was made.

The molecular weight of the constituents are between 46,07 and 340,59 g/mol, hence within the estimation domain of the validation set (27.03 -991.15 g/mol), all the functional groups are included in the list of descriptors, and, the occurence of each fragment is below or very closed to the maximum number in the training/validation sets (Appendix D), such as:

    Training Set Validation Set
Fragment Descriptor & Correction Factor Descriptor Coef Max Number Max Number
-CH3 [aliphatic carbon] 0,5473 13 1401 20 7413
-CH2-   [aliphatic carbon] 0,4911 18 1083 28 7051
-CH   [aliphatic carbon] 0,3614 16 460 23 3864
 =CH- or =C<  [olefinc carbon] 0,3836 10 239 10 1847
-COOH   [acid, aliphatic attach]  -0,6895 3 126 3 672
-tert Carbon [3 or more carbon attach] 0,2676 4 130 8 1381
Fused aliphatic ring unit correction  -0,3421 8 41 8 684
-OH   [hydroxy, aliphatic attach] -1,4086 6 187 9 1525
Aromatic carbon 0,294 24 1790 30 8792
-C(=O)O [ester, aliphatic attach] -0,9505 3 113 6 1178
-C(=O)- [carbonyl, aliphatic attach] -1,5586 2 54 2 241
 =CH2 [olefinic carbon] 0,5184 2 50 4 235
Conclusions:
Log Kow of known constituents of the substance, representing a limited fraction of the composition, were estimated to be between -0.14 and 9.63 (estimated by QSAR)
Executive summary:

The partition coefficient of the known constituents of the substance were estimated using the recommended QSAR model KOWWIN v1.68, based on Atom/Fragment Contribution (AFC) method. The constituents of the test item were within the applicability domain (MW, descriptors).

This range of logKow was estimated between -0.14 and 9.63, with a standard deviation provided by the model of 0.48.

Endpoint:
partition coefficient
Type of information:
experimental study
Adequacy of study:
disregarded due to major methodological deficiencies
Study period:
06-11 March 2014
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
significant methodological deficiencies
Justification for type of information:
A study has been conducted according to OECD 117 leading to a non reliable result (logKow < 0.3 while the substance is mainly insoluble in water) and showing that the conventional standard tests for partition coefficient endpoint are intended for single substances and are not appropriate for such complex substances because of the limited knowledge of composition and the physical state of the substance.
Qualifier:
according to
Guideline:
OECD Guideline 117 (Partition Coefficient (n-octanol / water), HPLC Method)
Version / remarks:
2004
Deviations:
no
Qualifier:
according to
Guideline:
EU Method A.8 (Partition Coefficient - HPLC Method)
Version / remarks:
2008
Deviations:
no
Principles of method if other than guideline:
not applicable
GLP compliance:
yes (incl. certificate)
Remarks:
inspected on 29 and 30 November 2010 / signed on 11 April 2011
Type of method:
HPLC method
Partition coefficient type:
octanol-water
Type:
log Pow
Partition coefficient:
< 0.3
Temp.:
25 °C
pH:
ca. 6
Remarks on result:
not determinable because of methodological limitations
Remarks:
Assuming that the test item consists mainly of one peak, calculation of logKow, mean and standard deviation of the major component of test item was not possible because the retention time of measurements lay below the retention time of thiourea. So the log POW of the test item is stated as < 0.3.

Results:

Reference item:

For each reference item, the retention times, the calculated capacity factors K, logK and log Kow were presented in the following table:

Compound Mean Retention Time (min) K log K log POW
Thiourea 1,482 0    
2-Butanone 1,981 0,3369 -0.4726 0.30
Benzylalcohol 2,407 0,6241 -0.2047 1.10
Acetophenone 3,016 1,0355 0.0152 1.70
Nitrobenzene 3,645 1,4599 0.1643 1.90
Benzene 5,286 2,567 0.4094 2.10
Toluene 8,596 4,8008 0.6813 2.70
Naphthalene 12,367 7,346 0.8660 3.60

Dead time is 1.482 ± 0.002 minutes, with RSD 0.1%.

The RSD of the retention times of the reference items lay all below 0.5 %.

Equation of the regression:

log k = 0.4399 * log POW – 0.6337 with a coefficient of determination r2 = 0.9616

Test item:

Retention Times Test Item

Measurement

RT 1

RT 2

RT 3

 

min.

min.

min.

Measurement 1

1.365

1.936

5.412

Measurement 2

1.36

1.946

5.405

Measurement 3

1.361

1.930

5.407

Mean

1.362

1.937

5.408

Standard Deviation

0.003

0.008

0.004

 

Areas Test Item

Measurement

Area

Peak 1

Rel.
1

Area

Peak 2

Rel.
2

Area

Peak 3

Rel. Area
Peak 3

 

mAU*min

%

mAU*min

%

mAU*min

%

Measurement 1

17.4385

95.64

0.2898

1.59

0.1424

0.78

Measurement 2

17.4690

94.60

0.3843

2.08

0.1925

1.04

Measurement 3

17.3221

94.25

0.4228

2.30

0.1481

0.81

Mean

17.4099

94.83

0.3656

1.99

0.1610

0.88

Standard Deviation

0.45%

0.76%

18.73%

18.31%

17.05%

16.48%

As peaks 2 and 3, showed a relative area < 5%, they were considered as minor peaks.

The calculated values are presented in the following table:

Capacity Factor, log Capacity Factor, log POWTest Item Peaks

Peak

Measurement No.

K

log K

log POW

1

1

-0.0788

Not calculable*

Not calculable*

2

-0.0822

Not calculable*

Not calculable*

3

-0.0815

Not calculable*

Not calculable*

Mean

 

Not calculable*

Not calculable*

Stand. Dev.

 

Not calculable*

Not calculable*

2

1

0.3065

-0.5136

0.273

2

0.3132

-0.5041

0.295

3

0.3024

-0.5194

0.260

Mean

 

 

0.276

Stand. Dev.

 

 

0.017

3

1

2.6522

0.4236

2.403

2

2.6475

0.4228

2.402

3

2.6489

0.4231

2.402

Mean

 

 

2.402

Stand. Dev.

 

 

0.001

*As the retention time of peak 1 lies below the retention time of thiourea, the log POWof peak 1 is not calculable.

 

log POWwas calculated from the capacity factor as follows:

 

log POW= (log K + 0.6337) / 0.4399

Executive summary:

The partition coefficient of the test substance was measured according to the OECD 117/EU A8 guideline, HPLC method. The system was calibrated with seven different references substances.

The measurements of the test item solution were very reproducible ( very small variations in the retention times of reference items and test item) and correlation log K/Log POW is good (r² = 0.9616).

Nevertheless, the log POW of the major peak of test item was not calculable, because during the measurements its retention time lies below the retention time of thiourea and thus not within the range of log Kows of the reference items. The corresponding log Kow is stated as < 0.3 (log POW of 2-Butanone, the reference item with the lowest log POW).

Description of key information

No range of logKow representative of the test item can be determined (neither with an experimental approach nor with an estimation approach)

Key value for chemical safety assessment

Additional information

The substance is a complex mixture, which contains a large number of constituents, which are mostly unkown but which have different solubility (often low solubility) and volatility. In addition its physical state leads to difficulties for physico-chemical testing: It is described as orange-brown to red-brown flowable viscous liquid to pasty. For such complex substances, the standard tests for partition coefficient endpoint are considered as not appropriate because of the limited knowledge of composition and the physical state of the substance. That is why the test has been waived.

In addition calculated values were provided on known constituents of the substance. However, only a range of logKow on a limited part of the composition of the substance can be calculated using QSAR estimations.

Therefore it is considered that no range logKow representative of the whole test item can be determined (neither with an experimental approach nor with an estimation approach).