2-{3-[(4-amino-2-methylpyrimidin-5-yl)methyl]-4-methyl-1,3-thiazol-3-ium-5-yl}ethyl hydrogen phosphate

Partition coefficient

Link to relevant study record(s)

Reference

Endpoint:

partition coefficient

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

20 Sep - 27 Sep 2016

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Remarks:

log POW could not be determined by the flask method nor by the computerized calculation. Only an estimation by using a visual value for n-octanol solubility was applicable.

Qualifier:

according to guideline

Guideline:

OECD Guideline 107 (Partition Coefficient (n-octanol / water), Shake Flask Method)

Qualifier:

according to guideline

Guideline:

EU Method A.8 (Partition Coefficient - Shake Flask Method)

GLP compliance:

no

Type of method:

calculation method (fragments)

Partition coefficient type:

octanol-water

Specific details on test material used for the study:

Storage conditions: Ambient temperature (10 to 30 °C)

Analytical method:

high-performance liquid chromatography

Type:

log Pow

Partition coefficient:

< -3.1

Temp.:

20 °C

Remarks on result:

other: pH not measured

Results
Table 1 – Preliminary visual estimation of n-octanol solubility

Test item amount [mg]	Added volume of n-octanol [mL]	Total volume of n-octanol [mL]	Stirring time [h]	Appearance of mixture
2.1	10	10	2	Not dissolved
10.5			~ 18

 

The solubility of the test item in n-octanol was: c_s^n-octanol< 210 mg/L.

Calculation of Partition Coefficient from Preliminary Test
The calculation was done with the result of the preliminary estimation of water solubility determined in the study reference 4.8 -1, i.e. c_s^water= 286 g/L and the c_s^n-octanol value above.

It was calculated to be: log P_OW< -3.1

Using KOWWIN, the calculated value was 0.9. The test item is an inner salt and contains groups that are not taken into account in the calculation, thus this value is not conclusive.
Due to the calculations the partition coefficient was determined based on the ratio of the individual solubilities the test item in water and octanol. The individual octanol solubility was determined using the flask method.

Determination of solubility in n-octanol – Flask Method
The n-octanol solubility was calculated from the measured and unrounded concentration values (not from the rounded values given in table 2).

Table 2 – n-octanol Solubility Experiments of the Test Item

Experiment	24 h experiment	48 h experiment	72 h experiment	Blank experiment (72 h)
Test item amount [mg]	55.4	53.8	55.0	--
Octanol amount [mL]	50
Stirring time at 30 °C [h]	24	48	72	72
Dilution factor	12.5
Measured concentration [mg/L]	0.952 0.956	1.197 1.201	0.794 0.809	-- --
Mean concentration [mg/L]	0.954	1.199	0.801	--
n-octanol solubility [g/L]	0.012	0.015	0.010	--

 

Chromatograms of test item experiments showed several peaks. It was assumed that the test item reacted under the test conditions and so no result can be given for the test item n-octanol solubility at 20 °C.

Calculation of Partition Coefficient from Individual Solubilities
According to the HPLC chromatogram, a reaction product was detected after the shake flask experiment. Therefore, the experimental value for log P_OWwas considered.

No individual n-octanol solubility was available, only a preliminary one. To obtain an approximate value for the partition coefficient, a calculation from the water solubility test (study reference 4.8 -1) and the value from the preliminary estimation was carried out, yielding a log P_OW< -3.1

A KOWWIN calculation was also done.

Conclusion
The test item is an inner salt (betain). After stirring the n-octanol flask, an additional peak appeared in the chromatogram. Thus it is assumed the test item reacts under the test conditions and that the flask method might not be applicable.

Calculation programs such as KOWWIN generate theoretical values of log P_OW, but this program was mainly designed for organic compounds that usually show no reaction under the test conditions. Therefore, the calculation with KOWWIN might not be applicable.

From a scientific point, no reliable log P_OWcan be determined, neither by the flask method nor by the computerized calculation. Only an estimation by using a visual value for n-octanol solubility seems to be applicable and gives a rough value of: log P_OW< -3.1.

Description of key information

Log Pow could not be determined by the flask method nor by the computerized calculation. Only an estimation using a visual value for n-octanol solubility was applicable. Consequently, the experimental result of log Pow < -3.1 is not fully reliable.

Three QSAR estimations were done using VEGA 1.1.3, ALogP v1.0.0; MLog P v.1.0.0 and EPI Suite v4.11, KOWWIN v1.68. The predicted partition coefficient results were as follows:

MLogP: log Pow = 0.39

ALogP: log Pow = -1.16

EPI Suite, KOWWIN: log Pow = -1.86

Key value for chemical safety assessment

Log Kow (Log Pow):

0.39

Additional information

The key result given as log Pow < 0.39 is used in a weight of evidence approach (QSAR using the software VEGA 1.1.3, MLog P v.1.0.0).

It was chosen as it is the highest estimated log Pow value, thus it is reported as a worst case scenario.