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Physical & Chemical properties

Partition coefficient

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Endpoint:
partition coefficient
Type of information:
calculation (if not (Q)SAR)
Adequacy of study:
weight of evidence
Study period:
2018
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
accepted calculation method
Justification for type of information:
1. SOFTWARE
EpiSuite / KOWWIN v1.68

2. MODEL (incl. version number)
EpiSuite 4.1
KOWWIN v1.68

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
CAS : 40783-05-9

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
See attachment

5. APPLICABILITY DOMAIN
See attachment

6. ADEQUACY OF THE RESULT
See attachment
Principles of method if other than guideline:
KOWWIN uses a "fragment constant" methodology to predict log P.  In a "fragment constant" method, a structure is divided into fragments (atom or larger functional groups) and coefficient values of each fragment or group are summed together to yield the log P estimate.   KOWWIN’s methodology is known as an Atom/Fragment Contribution (AFC) method.  Coefficients for individual fragments and groups were derived by multiple regression of 2447 reliably measured log P values.  KOWWIN’s "reductionist" fragment constant methodology (i.e. derivation via multiple regression) differs from the "constructionist" fragment constant methodology of Hansch and Leo (1979) that is available in the CLOGP Program (Daylight, 1995).  See the Meylan and Howard (1995) journal article for a more complete description of KOWWIN’s methodology.

To estimate log P, KOWWIN initially separates a molecule into distinct atom/fragments.  In general, each non-hydrogen atom (e.g. carbon, nitrogen, oxygen, sulfur, etc.) in a structure is a "core" for a fragment; the exact fragment is determined by what is connected to the atom.  Several functional groups are treated as core "atoms"; these include carbonyl (C=O), thiocarbonyl (C=S), nitro (-NO2), nitrate (ONO2), cyano (-C/N), and isothiocyanate (-N=C=S).  Connections to each core "atom" are either general or specific; specific connections take precedence over general connections.  For example, aromatic carbon, aromatic oxygen and aromatic sulfur atoms have nothing but general connections; i.e., the fragment is the same no matter what is connected to the atom.  In contrast, there are 5 aromatic nitrogen fragments: (a) in a five-member ring, (b) in a six-member ring, (c) if the nitrogen is an oxide-type {i.e. pyridine oxide}, (d) if the nitrogen has a fused ring location {i.e. indolizine}, and (e) if the nitrogen has a +5 valence {i.e. N-methyl pyridinium iodide}; since the oxide-type is most specific, it takes precedence over the other four.  The aliphatic carbon atom is another example; it does not matter what is connected to -CH3, -CH2-, or -CH< , the  fragment is the same; however, an aliphatic carbon with no hydrogens has two possible fragments: (a) if there are four single bonds with 3 or more carbon connections and (b) any other not meeting the first criteria.

It became apparent, for various types of structures, that log P estimates made from atom/fragment values alone could or needed to be improved by inclusion of  substructures larger or more complex than "atoms"; hence, correction factors were added to the AFC method.  The term "correction factor" is appropriate because their values are derived from the differences between the log P estimates from atoms alone and the measured log P values.  The correction factors have two main groupings: first, factors involving aromatic ring substituent positions and second,  miscellaneous factors.  In general, the correction factors are values for various steric interactions, hydrogen-bondings, and effects from polar functional substructures.  Individual correction factors were selected through a tedious process of correlating the differences (between log P estimates from atom/fragments alone and measured log P values) with common substructures.

Two separate regression analyses were performed.  The first regression related log P to atom/fragments of compounds that do not require correction factors (i.e., compounds estimated adequately by fragments alone).  The general regression equation has the following form:

 log P  = Σ(fini ) +  b     (Equation 1)

where Σ(fini )  is the summation of fi (the coefficient for each atom/fragment) times ni (the number of times the atom/fragment occurs in the structure) and b  is the linear equation constant.  This initial regression used 1120 compounds of the 2447 compounds in the total training dataset.

The correction factors were then derived from a multiple linear regression that correlated differences between the experimental (expl) log P and the log P estimated by Equation 1 above with the correction factor descriptors.  This regression did not utilize an additional equation constant.  The equation for the second regression is:

 lop P (expl)  -  log P (eq 1)  = Σ(cjnj )       (Equation 1)

where Σ(cjnj )  is the summation of cj (the coefficient for each correction factor) times nj  (the number of times the correction factor occurs (or is applied) in the molecule).

 

Regression Results

Results of the two successive multiple regressions (first for atom/fragments and second for correction factors) yield the following general equation for estimating log P of any organic compound:

log P  = Σ(fini ) + Σ(cjnj ) + 0.229     (Equation 3)

(num = 2447,   r2 = 0.982,  std dev = 0.217,  mean error = 0.159)
Type of method:
calculation method (fragments)
Partition coefficient type:
octanol-water
Key result
Type:
log Pow
Partition coefficient:
8
Temp.:
25 °C
pH:
7.4
Remarks on result:
other: assumed values for modelling
Conclusions:
Log Kow = 8
Executive summary:

Log Kow (version 1.68 estimate): 8

Endpoint:
partition coefficient
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
May 11, 2017 - June 07, 2017
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
equivalent or similar to guideline
Guideline:
EU Method A.8 (Partition Coefficient - Shake Flask Method)
Deviations:
no
Principles of method if other than guideline:
OECD 105 flask methode
GLP compliance:
no
Type of method:
other: OECD 105 flask methode
Partition coefficient type:
octanol-water
Analytical method:
analysis (not specified)
Key result
Type:
log Pow
Partition coefficient:
< -0.1
Remarks on result:
other: no information on ph value

  Individual results

Preliminary visual estimation of the n-octanol solubility

Defined amounts of the test item were stirred with increasing volumes of n-octanol at room temperature and visually checked for any undissolved parts.

Table1: Results of the preliminary visual estimation of the n-octanol solubility

Amount of test item

/ mg

Added volume of n-octanol

/ mL

Total volume of n-octanol

/ mL

Stirring time

/ h

Appearance of mixture

3

10

10

1

not dissolved

90

100

2

not dissolved

According to this preliminary test the solubility of the test item in n-octanol was below 30 mg/L (without correction for the purity).

Calculation of the partition coefficient log POW from the preliminary test

The partition coefficient POW may be estimated from the saturation concentrations in n-octanol and water. The estimated partition coefficient was calculated with the water solubility data determined in project 20160631.03 (19.1 mg/L (± 1.1 mg/L)) and the data obtained. It was calculated to be: log POW < 0.2.

Also the program KOWWIN (part of EPI Suite) was used for calculating the log POW of the test item. The calculated value was 8.

Due to the calculations the partition coefficient was estimated based on the ratio of the solubilities in water and n-octanol. The n-octanol solubility was determined using the flask method.The shake flask method and the HPLC method were not applicable due to the estimated low log POW and due to the low solubilities in water and n-octanol. For pigments it is technically not feasible to measure an n-octanol-water partition coefficient by OECD 107. For such substances a ratio of the saturated water solubility (OECD 105) and saturated octanol solubility (no guideline currently available but based on the principles of OECD 105) is obtained[1].

Determination of the solubility in n-octanol: Flask method

The individual saturation solubility of the test item in n-octanol was performed within this study. After that, the partition coefficient was estimated based on the ratio of the test item solubility in n-octanol and water.

The flask method was performed. The data for the evaluation are given in Table2. The n-octanol solubility was calculated from the measured and unrounded concentration values and not from the rounded values given in Table2.

Table2: n-Octanol solubility experiments of the test item

Experiment

24 h experiment

48 h experiment

72 h experiment

blank

experiment (72 h)

Amount of test item / mg

20.2

17.5

16.8

--

Amount of octanol / mL

100

100

100

100

Stirring time at 30 °C / h

24

48

72

72

Measured concentration / mg Cl/kg

1

1

1

1

Measured concentration / mg Cl/L

1.2

1.2

1.2

1.2

n-Octanol solubility / mg/L

13.7

13.7

13.7

13.7

For n-octanol a density of 0.83 kg/L was used. The test item had a content of 8.8 % (w/w) chlorine according to the certificate of analysis. With this data the n-octanol solubility was calculated. The n-octanol solubility of the test item at 20 °C was determined to be below the result of the blank experiment: 14 mg/L.

Calculation of the partition coefficient log POW from the individual solubilities

In the project 20160631.03 the water solubility of the test item at 20 °C was determined to be 19.1 mg/L (± 1.1 mg/L). Within this project the n-octanol solubility of the test item at 20 °C was determined to be < 14 mg/L.

The partition coefficient POW of the test item was determined to be:  < 0.7

log POW < -0.1


[1]Guidance on Information Requirements and Chemical Safety Assessment Chapter R.7a: Endpoint specific guidance Version 4.1 – October 2015.

Executive summary:

The partition coefficient (n-octanol/water) of the test item was estimated based on the ratio of the individual solubilities of the test item in water and n-octanol. The solubilities were determined according to the flask method. The shake flask method and the HPLC method were not applicable due to the pigment properties of the test item.

It was found to be:

log POW < -0.1

Description of key information

The partition coefficient (n-octanol/water) of the test item was estimated based on the ratio of the individual solubilities of the test item in water and n-octanol. Although according the log Kow calculation, the correct method for determination of the partition coefficient would be HPLC, the solubilities were determined according to the flask method, as due to the insolubility of the test substance in water and organic solvents, no analytical method for the quantification of the test substance is available. The shake flask method was based on the value of dissolved TOC in water and the solubility in n-octanol by argentometric determination of the chlorine contained in the test item. The resulting solubility was below that of the blank value (14 mg/L). Thus the determined log Kow was < -0.1. As this result was not scientifically reasonable, and the water solubility contains not only the test item, but all impurities containing carbon, the partition coefficient of the test item was calculated with KOWWIN v1.68 included in EpiSuite 4.1.

It was calculated to be log Kow = 8

Key value for chemical safety assessment

Log Kow (Log Pow):
8
at the temperature of:
25 °C

Additional information