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Partition coefficient

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Reference
Endpoint:
partition coefficient
Type of information:
(Q)SAR
Adequacy of study:
key study
Study period:
23 August 2016
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
1. SOFTWARE


EPIsuite 4.1 2012

2. MODEL (incl. version number)

KOWWIN 1.68

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL

Clc1ccccc1C(Cl)(Cl)Cl

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL

- Defined endpoint:
octanol water partiton coeffcient
- Unambiguous algorithm: yes, the algorithm
is based on an atom/fragment contribution method
The  log P  = Σ(fini ) + Σ(cjnj ) + 0.229 where 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); 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) and 0.229 is the linear equation constant.

- Defined domain of applicability:
Currently there is no universally accepted definition of model domain.  However, users may wish to consider the possibility that log P estimates are less accurate for compounds outside the MW range of the training set compounds, and/or that have more instances of a given fragment than the maximum for all training set compounds.  It is also possible that a compound may have a functional group(s) or other structural features not represented in the training set, and for which no fragment coefficient was developed.  These points should be taken into consideration when interpreting model results.

- Appropriate measures of goodness-of-fit and robustness and predictivity:
The training set statistics are as follows:
  number in dataset      = 2447
  correlation coef (r2)  = 0.982
  standard deviation     = 0.217
  absolute deviation     = 0.159
  avg Molecular Weight   = 199.98

The training set estimation error shows >95% of estimates are within 0.5 of the measured values of the training set
Training Set Estimation Error:
within <= 0.10  -  45.0%
within <= 0.20  -  72.5%
within <= 0.40  -  92.4%
within <= 0.50  -  96.4%
within <= 0.60  -  98.2%

KOWWIN has been tested on an external validation dataset of 10,946 compounds (compounds not included in the training set).  The validation set includes a diverse selection of chemical structures that rigorously test the predictive accuracy of any model.  It contains many chemicals that are similar in structure to chemicals in the training set, but also many chemicals that are different from and structurally more complex than chemicals in the training set.

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

Validation Set Estimation Error:
within <= 0.20  -  39.6%
within <= 0.40  -  66.0%
within <= 0.50  -  75.6%
within <= 0.60  -  82.5%
within <= 0.80  -  91.6%
within <= 1.00  -  95.6%
within <= 1.20  -  97.7%
within <= 1.50  -  99.1%

- Mechanistic interpretation:
nort relevant for intrinsic pysical properties of substances

5. APPLICABILITY DOMAIN

- Descriptor domain:
The substances falls within the molecular weight range of the training and validation datasets, close to the mean MW of both sets. The substance only contains molecular fragments contained in the model training set.
- Structural and mechanistic domains:


Log Kow(version 1.68 estimate): 6.13

SMILES : CC(C)(C)OC(=O)C(C)(C)ON=C(C(=O)NC1C2SCC(=C(N2C1(=O))C(=O)(O))Cn3(H)cc
ccc3)c4csc(n4)NC(c5ccccc5)(c6ccccc6)c7ccccc7
CHEM :
MOL FOR: C45 H46 N6 O7 S2
MOL WT : 847.02
-------+-----+--------------------------------------------+---------+--------
TYPE| NUM | LOGKOW FRAGMENT DESCRIPTION| COEFF| VALUE
-------+-----+--------------------------------------------+---------+--------
Frag | 5 | -CH3 [aliphatic carbon] | 0.5473 | 2.7365
Frag | 2 | -CH2- [aliphatic carbon] | 0.4911 | 0.9822
Frag | 2 | -CH [aliphatic carbon] | 0.3614 | 0.7228
Frag | 1 | C [aliphatic carbon - No H, not tert] | 0.9723 | 0.9723
Frag | 2 | =CH- or =C< [olefinc carbon] | 0.3836 | 0.7672
Frag | 1 | -NH- [aliphatic attach] |-1.4962 | -1.4962
Frag | 1 | -N< [aliphatic attach] |-1.8323 | -1.8323
Frag | 26 | Aromatic Carbon | 0.2940 | 7.6440
Frag | 1 | -N [aliphatic N, one aromatic attach] |-0.9170 | -0.9170
Frag | 1 | -COOH [acid, aliphatic attach] |-0.6895 | -0.6895
Frag | 1 | Aromatic Sulfur | 0.4082 | 0.4082
Frag | 1 | -C(=O)O [ester, aliphatic attach] |-0.9505 | -0.9505
Frag | 2 | -C(=O)N [aliphatic attach] |-0.5236 | -1.0472
Frag | 1 | -S- [aliphatic attach] |-0.4045 | -0.4045
Frag | 1 | -O-N [oxygen, nitrogen attach] | 0.2352 | 0.2352
Frag | 1 | Aromatic Nitrogen [5-member ring] |-0.5262 | -0.5262
Frag | 3 | -tert Carbon [3 or more carbon attach] | 0.2676 | 0.8028
Frag | 1 | -N=C [aliphatic attach] |-0.0010 | -0.0010
Frag | 1 | Aromatic nitrogen [+5 valence; H attach] |-4.5000 | -4.5000
Factor| 1 | Pyridine ring (non-fused) correction |-0.1621 | -0.1621
Factor| 1 | >N-C(-S-)-C-{O,N,CO} correction | 0.8370 | 0.8370
Factor| 1 | C-C(=O)N-C-COOH structure correction | 0.4193 | 0.4193
Factor| 1 | Ring Reaction: amino-type thiazole | 0.7500 | 0.7500
Factor| 1 | aromatic-C-N-aromatic correction |-0.3000 | -0.3000
Factor| 1 | Reaction: nitrogen[+5] / polar group | 1.2500 | 1.2500
Factor| 1 | aliph-C=N-O-carbon(aliphat) [iminoxy] cor.|-1.9000 | -1.9000
Factor| 1 | -C(=O)-C=N-O- structure correction | 2.1000**| 2.1000
Const | | Equation Constant | | 0.2290
-------+-----+--------------------------------------------+---------+--------
NOTE | | An estimated coefficient (**) used |
-------+-----+--------------------------------------------+---------+--------
Log Kow = 6.1300

Experimental Database Structure Match:
Name : N,N'-DIMETHYLACETAMIDE
CAS Num : 000127-19-5
Exp Log P: -0.77
Exp Ref : HANSCH,C ET AL. (1995)

SMILES : CN(C)C(=O)(C)
CHEM :
MOL FOR: C4 H9 N1 O1
MOL WT : 87.12
-------+-----+--------------------------------------------+---------+--------
TYPE | NUM | LOGKOW FRAGMENT DESCRIPTION | COEFF | VALUE
-------+-----+--------------------------------------------+---------+--------
Frag | 3 | -CH3 [aliphatic carbon] | 0.5473 | 1.6419
Frag | 1 | -N< [aliphatic attach] |-1.8323 | -1.8323
Frag | 1 | -C(=O)N [aliphatic attach] |-0.5236 | -0.5236
Const | | Equation Constant | | 0.2290
-------+-----+--------------------------------------------+---------+--------
Log Kow = -0.4850


- Similarity with analogues in the training set:
The substance only contains molecular fragments contained in the model training set.


6. ADEQUACY OF THE RESULT
The result can be considered adequate for risk assessment purposes as the prediction and model fulfil the OECD principlesfor QSAR.
Qualifier:
according to
Guideline:
OECD Guideline 107 (Partition Coefficient (n-octanol / water), Shake Flask Method)
Qualifier:
according to
Guideline:
EU Method A.8 (Partition Coefficient - Shake Flask Method)
Deviations:
yes
Remarks:
A calculation method was applied because the partition coefficient could not be determined experimentally due to the substance being practically insoluble to water
Principles of method if other than guideline:
Prediction software (KOWWIN v1.68) was used, according to the test guidance, because the test material was found to be insoluble in water and therefore formal testing was not possible.
GLP compliance:
no
Type of method:
other: Use of prediction software (KOWWIN v1.68)
Partition coefficient type:
octanol-water
Analytical method:
other: Not applicable; prediction software was used instead
Key result
Type:
log Pow
Partition coefficient:
ca. 6.13
Remarks on result:
other: predicted by KOWWIN
Details on results:
Formal aqueous solubility was estimated as < 0.3mg/L. This solubility was found to be below the detection limit of the analytical determination method developed to quantify the amount of sample in the aqueous phase. Therefore it is not possible to conduct EC A.8 Partition Coefficient analysis by the shake flask method. In accordance with the test guidance the partition coefficient was estimated using prediction software (KOWWIN v1.68). The prediction software uses SMILES input to calculate the Partition Coefficient.
Conclusions:
The logKow of the substance was estimated to be 6.13 using prediction software (KOWWIN v1.68) because the substance is insoluble in water.
Executive summary:

Formal aqueous solubility was estimated as < 0.3mg/L. This solubility was found to be below the detection limit of the analytical determination method developed to quantify the amount of sample in the aqueous phase. Therefore it is not possible to conduct EC A.8 Partition Coefficient analysis  by the shake flask method. In accordance with the test guidance the partition coefficient was estimated using prediction software (KOWWIN v1.68). The prediction software uses SMILES input to calculate the Partition Coefficient.

The logKow for the substance was calculated to be 6.13

Description of key information

Formal aqueous solubility was estimated as < 0.3mg/L. This solubility was found to be below the detection limit of the analytical determination method developed to quantify the amount of sample in the aqueous phase. Therefore it is not possible to conduct EC A.8 Partition Coefficient analysis  by the shake flask method. In accordance with the test guidance the partition coefficient was estimated using prediction software (KOWWIN v1.68). The prediction software uses SMILES input to calculate the Partition Coefficient.

The logKow for the substance was calculated to be 6.13

Key value for chemical safety assessment

Log Kow (Log Pow):
6.13
at the temperature of:
20 °C

Additional information