Registration Dossier

Administrative data

Endpoint:
adsorption / desorption: screening
Data waiving:
other justification
Justification for data waiving:
the study does not need to be conducted because the substance has a low octanol water partition coefficient and the adsorption potential of this substance is related to this parameter
Cross-reference
Reason / purpose:
data waiving: supporting information
Reference
Endpoint:
partition coefficient
Type of information:
(Q)SAR
Adequacy of study:
key study
Study period:
November 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 adequate and reliable documentation / justification
Justification for type of information:
Testing of the active component (C-Quart) is impossible, since the active component cannot be isolated without decomposition and does not exist in a pure form. In addition, Commission Regulation (EC) No 440/2008 (test method A.8) states for ionisable substances that testing should only be performed on the non-ionised form. This is not meaningful in the present case, since C-Quart exists in an ionised form at any relevant pH (at least up to pH10). Finally, Commission Regulation (EC) No 440/2008 (test method A.8) states that the shake flask method is applicable to substances with a log Kow of -2 to 4, while the HPLC method is applicable to substances with a log Kow of 0 to 6. Since estimates indicated a log Kow < -2, none of the experimental approaches in EU test method A.8 appeared meaningful.
Therefore, several calculation/estimation approaches were applied in agreement with Regulation (EC) No 1907/2006 (Annex VII, column 2) and Commission Regulation (EC) No 440/2008 (test method A.8, Appendix 1) to derive a log Kow value for C-Quart.
Qualifier:
according to
Guideline:
other: EU Method A.8
Version / remarks:
Calculation/estimation methods are part of EU Method A.8, Appendix 1
Deviations:
not applicable
Principles of method if other than guideline:
Due to the limitations discussed above, log Kow was estimated using KOWWIN software (version 1.68) as implemented in U.S.EPA’s EpiSuite™. This model calculates log Kow based on the chemical fragments present in the molecule. KOWWIN represents a well-documented, peer-reviewed model for estimating log Kow and full model documentation is available in the help file of the software.
This documentation reports correlation coefficients (R2) of 0.982 and 0.943, respectively, for the training (N= 2 447) and the validation set (N=10 946). The standard deviations are reported to be 0.217 (training set) and 0.479 (validation set).


GLP compliance:
no
Type of method:
calculation method (fragments)
Partition coefficient type:
octanol-water
Specific details on test material used for the study:
Test material information refers to the active component, for which QSAR was applied.
SMILES protonated form: CC(O)C[N+](C)(C)CCCCCC[N+](C)(C)CC(C)O
SMILES used in EpiSuite™: CC(O)CN(C)(C)CCCCCCN(C)(C)CC(C)O
EpiSuite™ is unable to process protonated SMILES notations. Therefore, a transformed SMILES notation was entered, ensuring that the critical fragment (N 5+) is correctly identified.
Key result
Type:
log Pow
Partition coefficient:
-7.45
Temp.:
20 °C
pH:
1 - 10
Type:
log Pow
Partition coefficient:
-7.2
Temp.:
20 °C
pH:
1 - 10
Type:
log Pow
Partition coefficient:
-0.846
Temp.:
20 °C
pH:
1 - 10
Details on results:
Estimated values are given for an assumed test temperature of 20 °C and the pH range of 1-10, since the test substance exists in a ionised state at these pH values.

See below for details.

The following table shows the input and output of KOWWIN:

Log Kow (version 1.68 estimate): -7.45

SMILES: CC(O)CN(C)(C)CCCCCCN(C)(C)CC(C)O

MOL FOR: C16 H38 N2 O2

MOL WT : 290.49

 

TYPE

NUM

FRAGMENT

DESCRIPTION

COEFF

VALUE

Frag

6

-CH3

[aliphatic carbon]

0.5473

3.2838

Frag

8

-CH2

[aliphatic carbon]

0.4911

3.9288

Frag

2

-CH

[aliphatic carbon]

0.3614

0.7228

Frag

2

-OH

[hydroxy, aliphatic attach]

-1.4086

-2.8172

Frag

2

>N<

[+5 valence; single bonds;no H attach]

-6.6000

-13.2000

Factor

1

 

Multi-alcohol correction

0.4064

0.4064

Const

 

 

Equation Constant 

 

0.2290

 

 

 

 

Log Kow =

-7.4464

KOWWIN estimates a log Kow for C-Quart of -7.45. The KOWWIN output illustrates that the chemical structure does not correctly represent C-Quart with the two positively charged nitrogen atoms. KOWWIN is not able to properly represent the structural formula, but correctly identifies the fragment as ‘>N< +5’ without a hydrogen atom attached.

It is also obvious that this fragment is largely responsible for the low log Kow estimated. As is evident from the extract of the help file of KOWWIN (see below), this fragment was represented in the training set (14 substances) and the validation set (92 substances), as shown in the following table.

 

Frequency of occurrence of fragments in the training and validation sets of the KOWWIN model*

Fragment

Descriptor

Training Set

Validation Set

Max

Number

Max

Number

-CH3

[aliphatic carbon]

13

1 401

20

7 413

-CH2

[aliphatic carbon]

18

1 083

28

7 051

-CH

[aliphatic carbon]

16

460

23

3 864

-OH

[hydroxy, aliphatic attach]

6

187

9

1 525

>N<

[+5 valence; single bonds;no H attach]

1

14

1

92

* Max: Maximum number of the fragment that occurs in any individual substance; Number: Number of individual substances having the fragment in the dataset

 

While the >N< fragment is represented in the training and validation sets by an adequate number of substances, the maximum number of this fragment in any substance in both the training and validation set was 1. This introduces some uncertainty in the estimate for C-Quart, which contains two of these fragments.. If only one >N< fragment is counted, the log Kow would be -0.846.

Additional calculations using Chemaxon software identified a log P (identical to log Kow) of -7.2. The method used for calculating LogP in the Chemaxon software is also based on fragments with predefined values, with the final log P value being the sum of values for all fragments. The methodology and datasets are published in the literature[1].

Log D values (apparent log Kow at specified pH values) also identified a value of -7.2 at pH values up to at least 10. Further documentation on the software is available on Chemaxon’s website[2]. The examples described in this documentation include a quaternary ammonium compound.


References:

[1] Viswanadhan, V. N. et al.: J.Chem.Inf.Comput.Sci., 1989, 29, 3, 163-172; Klopman, G. et al.: J.Chem.Inf.Comput.Sci., 1994, 34, 752-781

[2] https://docs.chemaxon.com/display/docs/LogP+and+logD+calculations, accessed November 2017.

Conclusions:
Log Kow is estimated to be -7.45 by the valid and well-documented KOWWIN model (v. 1.68).
Executive summary:

Due to the nature of the substance, log Kow could not be determined experimentally. Log Kow was therefore estimated with KOWWIN (v. 1.68), a valid well-documented model. The log Kow is estimated by KOWWIN to be -7.45, a value supported by additional considerations.

Both the key value derived and supporting information show that log Kow is below the cut-off values for bioaccumulation in aquatic (log Kow > 4.5) or air-breathing organisms (log Kow > 2 (and log Koa > 5)) according to the ECHA Guidance on PBT/vPvB assessment (v. 3.0, June 2017).

Data source

Materials and methods

Results and discussion

Applicant's summary and conclusion