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Partition coefficient

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Endpoint:
partition coefficient
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
Study period:
2016
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
Ester tetrasodium salt: Oc1c(N=Nc5ccc(cc5)S(=O)(=O)CCOS(=O)(=O)O[Na])c(cc2cc(cc(Nc3nc(CL)nc(Nc4ccc(cc4)S(=O)(=O)CCOS(=O)(=O)O[Na])n3)c12)S(=O)(=O)O[Na])S(=O)(=O)O[Na]

Ester free acid: Oc1c(N=Nc5ccc(cc5)S(=O)(=O)CCOS(O)(=O)=O)c(cc2cc(cc(Nc3nc(CL)nc(Nc4ccc(cc4)S(=O)(=O)CCOS(O)(=O)=O)n3)c12)S(O)(=O)=O)S(O)(=O)=O

Vinyl trisodium salt: Oc5c2c(Nc3nc(Nc4ccc(cc4)S(=O)(=O)C=C)nc(CL)n3)cc(cc2cc(c5N=Nc1ccc(cc1)S(=O)(=O)CCOS(=O)(=O)O[Na])S(=O)(=O)O[Na])S(=O)(=O)O[Na]

Vinyl free acid:
Oc5c2c(Nc3nc(Nc4ccc(cc4)S(=O)(=O)C=C)nc(CL)n3)cc(cc2cc(c5N=Nc1ccc(cc1)S(=O)(=O)CCOS(O)(=O)=O)S(O)(=O)=O)S(O)(=O)=O


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
Type:
log Pow
Partition coefficient:
-2.97
Temp.:
25 °C
Remarks on result:
other: ester tetrasodium salt
Type:
log Pow
Partition coefficient:
-5.34
Temp.:
25 °C
Remarks on result:
other: ester free acid
Type:
log Pow
Partition coefficient:
-1.77
Temp.:
25 °C
Remarks on result:
other: vinyl trisodium salt
Type:
log Pow
Partition coefficient:
-1.67
Temp.:
25 °C
Remarks on result:
other: vinyl free acid
Conclusions:
Partition coefficient
log Kow: -2.97 at 25°C (ester tetrasodium salt)
log Kow: -5.34 at 25°C (ester free acid)
log Kow: -1.77 at 25°C (vinyl trisodium salt)
log Kow (mean) < - 2.9
log Kow: -1.67 at 25°C (vinyl free acid)
log Kow (mean) < -2.9
Executive summary:

Log Kow (version 1.68 estimate):

log Kow: -2.97 at 25°C (ester tetrasodium salt)

log Kow: -5.34 at 25°C (ester free acid)

log Kow: -1.77 at 25°C (vinyl trisodium salt)

log Kow: -1.67 at 25°C (vinyl free acid)

log Kow (mean) < -2.9

Endpoint:
partition coefficient
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
10 August 1989 to 19 September 1989
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
documentation insufficient for assessment
Remarks:
The study was conducted according to a revised test guidance in compliance with GLP, and therefore from a technical point of view reliable. However the HPLC test method (OECD 117) is not suitable for very good water soluble stubstances with a log Kow <0, as only log Kow values between 0 and 6 (up to 10) can be determined by this method. For log Kow values < 0, the shake flask method (OECD 107) would be the appropriate method. The result of this study is therefore not taken into consideration for risk assessment.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 117 (Partition Coefficient (n-octanol / water), HPLC Method)
Principles of method if other than guideline:
The investigation was carried out according to „revised test guideline" following Forschungsbericht (research report) 106 02 054 (FhG-Schmallenberg, im Auftrage des Umweltbundesamtes). The HPLC method is based on the correlation between the retention of substances on a reverse phase and the n-octanol/water partition coefficient. Due to a high water solubility and a low fat solubility a low value for the log Kow can be expected.
GLP compliance:
yes
Type of method:
HPLC method
Partition coefficient type:
octanol-water
Analytical method:
high-performance liquid chromatography
Type:
log Pow
Partition coefficient:
<= 0.2
Temp.:
40 °C
Remarks on result:
other: pH not tested
Details on results:
The test substance wasn't retarded under the given conditions which was initially the opinion of the testing laboratory. The determination leads to the following result: log P <= 0.2.
Conclusions:
The determination leads to the following result: log Kow <= 0.2.
Executive summary:

The determination leads to the following result: log Kow <= 0.2. The results are not indicative of the substance to be bioaccumulative.

Description of key information

Log Kow (version 1.68 estimate):

log Kow: -2.97 at 25°C (ester tetrasodium salt)

log Kow: -5.34 at 25°C (ester free acid)

log Kow: -1.77 at 25°C (vinyl trisodium salt)

log Kow: -1.67 at 25°C (vinyl free acid)

log Kow (mean) < -2.9 at 25 °C

Key value for chemical safety assessment

Additional information

Log Kow (version 1.68 estimate):

log Kow: -2.97 at 25°C (ester tetrasodium salt)

log Kow: -5.34 at 25°C (ester free acid)

log Kow: -1.77 at 25°C (vinyl trisodium salt)

log Kow: -1.67 at 25°C (vinyl free acid)

log Kow (mean) < -2.9 at 25 °C

A study to determine the partition coefficient was carried out in 1989 according to „revised test guideline" following Forschungsbericht (research report) 106 02 054 (FhG-Schmallenberg, im Auftrage des Umweltbundesamtes) similar to OECD 117. However the HPLC test method is not suitable for very good water soluble stubstances with a log Kow <0, as only log Kow values between 0 and 6 (up to 10) can be determined by this method. For log Kow values < 0, the shake flask method (OECD 107) would be the appropriate method. The result of this study (log Kow <= 0.2) is therefore not taken into consideration for risk assessment.