Reaction mass of potassium;sodium;2-[bis[2-[bis(carboxymethyl)amino]ethyl]amino]acetate;copper and potassium;sodium;2-[2-[bis(carboxymethyl)amino]ethyl-(2-hydroxyethyl)amino]acetate;copper

Partition coefficient

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

partition coefficient

Data waiving:

study technically not feasible

Justification for data waiving:

the study does not need to be conducted because the substance does not dissolve in water or in octanol

Justification for type of information:

The reaction mixture of CuDTPa and CuHEEDTA is very polar and therefore dissolves very well in water but not in octanol.

Reference 2

Endpoint:

partition coefficient

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

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 : EPIWEB 4.1

2. MODEL (incl. version number) : Kowwin v1.68

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL :
C(=O)(CN(CC(=O)O[Na])CCN1CC(=O)O[Cu]OC(=O)CN(CC(=O)O[Na])CC1)O[Na]

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
[Explain how the model fulfils the OECD principles for (Q)SAR model validation. Consider attaching the QMRF or providing a link]
- Defined endpoint: Log Octanol-Water Partition Coefficient

- Unambiguous algorithm:
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.

- Defined domain of applicability:
The intended application domain is organic chemicals. Inorganic and organometallic chemicals are generally outside the domain.

- Appropriate measures of goodness-of-fit and robustness and predictivity:
Training Set Statistics:
  number in dataset      = 2447
  correlation coef (r2)  = 0.982
  standard deviation     = 0.217
  absolute deviation     = 0.159
  avg Molecular Weight   = 199.98
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

- Mechanistic interpretation:
See methodology

5. APPLICABILITY DOMAIN
[Explain how the substance falls within the applicability domain of the model]
- Descriptor domain:
CuDTPA (MW = 520.83) falls within the molecular weight range of the compounds in the training set (i.e. between 18 and 720).
- Structural and mechanistic domains:
See attached graph
- Similarity with analogues in the training set:
not provided
- Other considerations (as appropriate):
none

6. ADEQUACY OF THE RESULT
[Explain how the prediction fits the purpose of classification and labelling and/or risk assessment]
The logKow prediction is used to predict the fate of the substance in the environment.

Guideline:

other: REACH Guidance on QSARs R.6

Principles of method if other than guideline:

Meylan, W.M. and P.H. Howard. 1995. Atom/fragment contribution method for estimating octanol-water partition coefficients. J. Pharm. Sci. 84: 83-92

Specific details on test material used for the study:

SMILES: C(=O)(CN(CC(=O)O[Na])CCN1CC(=O)O[Cu]OC(=O)CN(CC(=O)O[Na])CC1)O[Na]

Type:

log Pow

Partition coefficient:

-13.5

Remarks on result:

other: Calculation

Conclusions:

The logKow as estimated by Kowwin v1.68 for CuDTPA was -13.5.

Reference 3

Endpoint:

partition coefficient

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

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 : EPIWEB 4.1

2. MODEL (incl. version number) : Kowwin v1.68

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL :
C1(=O)CN(CC(=O)O[Na])CCN(CCO[Na])CC(=O)O[Cu]O1

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
[Explain how the model fulfils the OECD principles for (Q)SAR model validation. Consider attaching the QMRF or providing a link]
- Defined endpoint: Log Octanol-Water Partition Coefficient

- Unambiguous algorithm:
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.

- Defined domain of applicability:
The intended application domain is organic chemicals. Inorganic and organometallic chemicals are generally outside the domain.

- Appropriate measures of goodness-of-fit and robustness and predictivity:
Training Set Statistics:
  number in dataset      = 2447
  correlation coef (r2)  = 0.982
  standard deviation     = 0.217
  absolute deviation     = 0.159
  avg Molecular Weight   = 199.98
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

- Mechanistic interpretation:
See methodology

5. APPLICABILITY DOMAIN
[Explain how the substance falls within the applicability domain of the model]
- Descriptor domain:
CuHEEDTA (MW = 383.76) falls within the molecular weight range of the compounds in the training set (i.e. between 18 and 720).
- Structural and mechanistic domains:
See attached figure
- Similarity with analogues in the training set:
not provided
- Other considerations (as appropriate):
none

6. ADEQUACY OF THE RESULT
[Explain how the prediction fits the purpose of classification and labelling and/or risk assessment]
The logKow prediction is used to predict the fate of the substance in the environment.

Guideline:

other: REACH Guidance on QSARs R.6

Principles of method if other than guideline:

Meylan, W.M. and P.H. Howard. 1995. Atom/fragment contribution method for estimating octanol-water partition coefficients. J. Pharm. Sci. 84: 83-92

Specific details on test material used for the study:

SMILES: C1(=O)CN(CC(=O)O[Na])CCN(CCO[Na])CC(=O)O[Cu]O1

Type:

log Pow

Partition coefficient:

-11.16

Remarks on result:

other: Calculation

Conclusions:

The logKow as estimated by Kowwin v1.68 for CuHEEDTA was -11.16.

Description of key information

The log Kow cannot be determined experimentally because of the low solubility of the metal chelate in octanol. Therefore, calculated values of the constituents are provided.

The calculated log Kow of CuDTPA and CuHEEDTA are very low: -13.5 and -11.16 for CuDTPA and CuHEEDTA, respectively. Taking into account the typical composition of Reaction mixture of CuDTPA and CuHEEDTA, the average logKow is estimated at -12.33

Key value for chemical safety assessment

Log Kow (Log Pow):

-12.33