1,6-Hexandiammonium dihydroxide, N,N'-bis-(2-hydroxypropyl)-N,N,N',N'-tetramethyl

Partition coefficient

Link to relevant study record(s)

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

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).

Description of key information

Since the active component (C-Quart) cannot be isolated without decomposition and does not exist in a pure form, log Kow for the active component was estimated by QSAR. Log Kow is estimated to be -7.45 by the valid and well-documented KOWWIN model (v. 1.68).

Key value for chemical safety assessment

Log Kow (Log Pow):

-7.45

at the temperature of:

20 °C