1,3,5-Triazine-2,4-diamine, N2-[(1R,2S)-2,3-dihydro-2,6-dimethyl-1H-inden-1-yl]-6-(1-fluoroethyl)-

Dissociation constant

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

dissociation constant

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP-Guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 112 (Dissociation Constants in Water)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 830.7370 (Dissociation constants in water)

Deviations:

no

Principles of method if other than guideline:

Spectrophotometric Method

GLP compliance:

yes (incl. QA statement)

Dissociating properties:

yes

No.:

#1

pKa:

3.56

Temp.:

22 °C

Remarks on result:

other: SD=0.02; T=22 °C +/- 5 °C

Experiment A was discarded due to the fact that the data of only 4 pH values were within the

range between 10 and 90 % ionization. According to the OECD guideline 112 a number of at least 5

valid data points are required.

Experiment B

 

Experiment	Volume and concentration of added NaOH	Volume and concentration of added HCl	Resulted pH value	Absorption	pKa
B1	-	-	6.09	0.013	4.91
B2	0.1 ml - 0.01 mol/L	-	6.34	0.015	5.70
B3	1.0 ml - 0.1 mol/L	-	11.00	0.014	10.15^4
B4(dm)	1.0 ml - 1.0 mol/L	-	12.02	0.012	^2
B5	-	0.1 ml - 0.01 mol/L	5.92	0.011	³
B6	-	0.3 ml - 0.1 mol/L	3.59	0.019	3.48
B7	-	0.4 ml - 0.1 mol/L	3.45	0.022	3.67
B8	-	0.5 ml - 0.1 mol/L	3.36	0.023	3.70
B9	-	0.6 ml - 0.1 mol/L	3.28	0.023	3.61
B10	-	0.8 ml - 0.1 mol/L	3.15	0.023	3.49
B11	-	1.0 ml - 0.1 mol/L	3.05	0.024	3.53
B12	-	2.0 ml - 0.1 mol/L	2.74	0.025	3.38
B13	-	2.0 ml - 1.0 mol/L	1.78	0.026	2.63
B14(di)	-	10.0 ml - 1.0 mol/L	1.11	0.028	^1
				Mean	3.81 ± 0.87

¹dissociated form²undissociated form³no evaluation possible⁴outlier

 

The pKa value for each determination was calculated as the average of the individual values for which the dissociated proportion was between 10% and 90%. Data points for which the dissociated proportion was outside this range were not used to calculate the final result.

To calculate the percentage of the ionized test item and the usable pH range the following equations were used:

pH range = pKa_mean± log 9

pH range = 3.81 ± 0.95 = pH 2.86 to pH 4.76

Applying this pH range (i.e. experiments B6 to B11) the mean pKa-value is resulting in

pKa = 3.58 (SD = 0.10)

Applying this pKa value again for the definition of the pH range the experiments B6 to B12 are selected for the calculation of the final result:

pH range = 3.58 ± 0.95 → pH = 2.63 to pH = 4.53

This is resulting in the final value pKa = 3.55 (SD = 0.12)

 

Experiment C

 

Experiment	Volume and concentration of added NaOH	Volume and concentration of added HCl	Resulted pH value	Absorption	pKa
C1	-	-	5.81	0.012	4.66
C2	0.1 ml - 0.01 mol/L	-	6.32	0.012	5.17
C3	1.0 ml - 0.1 mol/L	-	10.99	0.011	³
C4(dm)	1.0 ml -1.0 mol/L	-	12.02	0.011	²
C5	-	0.1 ml - 0.01 mol/L	5.82	0.012	4.67
C6	-	0.3 ml - 0.1 mol/L	3.68	0.019	3.74
C7	-	0.4 ml - 0.1 mol/L	3.48	0.020	3.66
C8	-	0.5 ml - 0.1 mol/L	3.37	0.021	3.67
C9	-	0.6 ml - 0.1 mol/L	3.27	0.020	3.45
C10	-	0.8 ml - 0.1 mol/L	3.15	0.021	3.45
C11	-	1.0 ml - 0.1 mol/L	3.04	0.022	3.48
C12	-	2.0 ml - 0.1 mol/L	2.74	0.023	3.34
C13	-	2.0 ml -1.0 mol/L	1.78	0.025	2.93
C14(di)	-	10.0 ml -1.0 mol/L	1.11	0.026	^1
				Mean	3.84±0.69

¹dissociated form²undissociated form³no evaluation possible⁴outlier

 

The pKa value for each determination was calculated as the average of the individual values for which the dissociated proportion was between 10% and 90%. Data points for which the dissociated proportion was outside this range were not used to calculate the final result.

To calculate the percentage of the ionized test item and the usable pH range the following equations were used:

pH range = pKa_mean± log 9

pH range = 3.84 ± 0.95 = pH 2.89 to pH 4.79

Applying this pH range (i.e. experiments C6 to C11) the mean pKa-value is resulting in

pKa = 3.57 (SD = 0.13)

Applying this pKa value again for the definition of the pH range the experiments C6 to C12 are selected for the calculation of the final result:

pH range = 3.57 ± 0.95 → pH = 2.62 to pH = 4.52

 

This is resulting in the final value pKa = 3.54(SD = 0.15)

Experiment C

 

Experiment	Volume and concentration of added NaOH	Volume and concentration of added HCl	Resulted pH value	Absorption	pKa
D1	-	-	5.54	0.009	³
D2	0.1 ml - 0.01 mol/L	-	5.66	0.009	³
D3	1.0 ml - 0.1 mol/L	-	11.00	0.009	²
D4(dm)	1.0 ml -1.0 mol/L	-	12.04	0.010	³
D5	-	0.1 ml - 0.01 mol/L	5.53	0.009	³
D6	-	0.3 ml - 0.1 mol/L	3.64	0.017	3.49
D7	-	0.4 ml - 0.1 mol/L	3.48	0.019	3.53
D8	-	0.5 ml - 0.1 mol/L	3.39	0.020	3.54
D9	-	0.6 ml - 0.1 mol/L	3.29	0.022	3.67
D10	-	0.8 ml - 0.1 mol/L	3.16	0.023	3.67
D11	-	1.0 ml - 0.1 mol/L	3.07	0.024	3.74
D12	-	2.0 ml - 0.1 mol/L	2.75	0.024	3.42
D13	-	2.0 ml -1.0 mol/L	1.78	0.026	2.98
D14(di)	-	10.0 ml -1.0 mol/L	1.12	0.027	^1
				Mean	3.51±0.24

¹dissociated form²undissociated form³no evaluation possible⁴outlier

 

The pKa value for each determination was calculated as the average of the individual values for which the dissociated proportion was between 10% and 90%. Data points for which the dissociated proportion was outside this range were not used to calculate the final result.

To calculate the percentage of the ionized test item and the usable pH range the following equations were used:

pH range = pKa_mean± log 9

pH range = 3.51 ± 0.95 = pH 2.56 to pH 4.46

Applying this pH range (i.e. experiments D6 to D12) the mean pKa-value is resulting in

pKa = 3.58 (SD = 0.12)

Reference 2

Endpoint:

dissociation constant

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP-Guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 112 (Dissociation Constants in Water)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 830.7370 (Dissociation constants in water)

Deviations:

no

Principles of method if other than guideline:

Spectrophotometric Method

GLP compliance:

yes (incl. QA statement)

Dissociating properties:

yes

No.:

#1

pKa:

3.51

Temp.:

22 °C

Remarks on result:

other: SD=0.05; T=22 °C +/- 5 °C

Three individual experiments were carried out measuring the pH dependency of the UV /spectra of the test item at room temperature (22°C ± 5°C).

Experiment A

 

Experiment	Volume and concentration of added NaOH	Volume and concentration of added HCl	Resulted pH value	Absorption	pKa
A1	-	-	6.18	0.0201	^3
A2	0.1 mL - 0.01 mol/L	-	6.61	0.0207	^3
A3	1.0 mL - 0.1 mol/L	-	10.81	0.0224	^3
A4(dm)	1.0 mL - 1.0 mol/L	-	11.85	0.0229	^2
A5	-	0.1 mL - 0.01 mol/L	5.89	0.0292	5.21
A6	-	0.3 mL - 0.1 mol/L	3.52	0.0400	3.46
A7	-	0.4 mL - 0.1 mol/L	3.42	0.0441	3.55
A8	-	0.5 mL - 0.1 mol/L	3.32	0.0448	3.49
A9	-	0.6 mL - 0.1 mol/L	3.25	0.0482	3.59
A10	-	0.8 mL - 0.1 mol/L	3.11	0.0483	3.46
A11	-	1.0 mL - 0.1 mol/L	3.02	0.0491	3.41
A12	-	2.0 mL - 0.1 mol/L	2.71	0.0537	3.42
A13	-	2.0 mL - 1.0 mol/L	1.72	0.0595	3.98
A14(di)	-	10.0 mL - 1.0 mol/L	1.06	0.0597	^1
				Mean	3.73±0.58

¹dissociated form        ²undissociated form    ³no evaluation possible

 

To calculate the percentage of the ionized test item and the usable pH range the following equations were used:

pH range = pKa_mean± log 9

pH range = 3.73 ± 0.95→pH 2.78 to pH 4.68

Applying this pH range (i.e. experiments A6 to A11) the mean pKa-value is resulting in

pKa = 3.49 (SD = 0.07)

Applying this pKa value again for the definition of the pH range the experiments A6 to A12 are selected for the calculation of the final result:

pH range = 3.49 ± 0.95 → pH = 2.54 to pH = 4.44

This is resulting in the final value pKa = 3.48(SD = 0.07)

 

Experiment B

 

Experiment	Volume and concentration of added NaOH	Volume and concentration of added HCl	Resulted pH value	Absorption	pKa
B1	-	-	6.27	0.0209	^3
B2	0.1 ml - 0.01 mol/L	-	6.65	0.0239	5.08
B3	1.0 ml - 0.1 mol/L	-	10.79	0.0344	10.48^4
B4(dm)	1.0 ml - 1.0 mol/L	-	11.86	0.0230	^2
B5	-	0.1 ml - 0.01 mol/L	6.20	0.0285	5.48
B6	-	0.3 ml - 0.1 mol/L	3.55	0.0403	3.55
B7	-	0.4 ml - 0.1 mol/L	3.42	0.0440	3.61
B8	-	0.5 ml - 0.1 mol/L	3.31	0.0442	3.51
B9	-	0.6 ml - 0.1 mol/L	3.24	0.0465	3.57
B10	-	0.8 ml - 0.1 mol/L	3.10	0.0480	3.52
B11	-	1.0 ml - 0.1 mol/L	3.00	0.0514	3.67
B12	-	2.0 ml - 0.1 mol/L	2.72	0.0527	3.51
B13	-	2.0 ml - 1.0 mol/L	1.74	0.0579	^3
B14(di)	-	10.0 ml - 1.0 mol/L	1.06	0.0575	^1
				Mean	3.94 ± 0.76

¹dissociated form²undissociated form³no evaluation possible⁴outlier

 

The pKa value for each determination was calculated as the average of the individual values for which the dissociated proportion was between 10% and 90%. Data points for which the dissociated proportion was outside this range were not used to calculate the final result.

To calculate the percentage of the ionized test item and the usable pH range the following equations were used:

pH range = pKa_mean± log 9

pH range = 3.94 ± 0.95 = pH 2.99 to pH 4.89

Applying this pH range (i.e. experiments B6 to B11) the mean pKa-value is resulting in

pKa = 3.57 (SD = 0.06)

Applying this pKa value again for the definition of the pH range the experiments B6 to B12 are selected for the calculation of the final result:

pH range = 3.57 ± 0.95 → pH = 2.62 to pH = 4.52

This is resulting in the final value pKa = 3.56(SD = 0.06)

 

Experiment C

 

Experiment	Volume and concentration of added NaOH	Volume and concentration of added HCl	Resulted pH value	Absorption	pKa
C1	-	-	6.22	0.0323	5.77
C2	0.1 ml - 0.01 mol/L	-	6.72	0.0255	5.59
C3	1.0 ml - 0.1 mol/L	-	10.79	0.0238	9.10^4
C4(dm)	1.0 ml -1.0 mol/L	-	11.83	0.0231	^2
C5	-	0.1 ml - 0.01 mol/L	5.92	0.0210	^3
C6	-	0.3 ml - 0.1 mol/L	3.56	0.0385	3.46
C7	-	0.4 ml - 0.1 mol/L	3.43	0.0407	3.43
C8	-	0.5 ml - 0.1 mol/L	3.32	0.0445	3.52
C9	-	0.6 ml - 0.1 mol/L	3.24	0.0458	3.51
C10	-	0.8 ml - 0.1 mol/L	3.09	0.0483	3.50
C11	-	1.0 ml - 0.1 mol/L	3.01	0.0492	3.48
C12	-	2.0 ml - 0.1 mol/L	2.71	0.0530	3.48
C13	-	2.0 ml -1.0 mol/L	1.73	0.0573	3.36
C14(di)	-	10.0 ml -1.0 mol/L	1.06	0.0581	^1
				Mean	3.91±0.94

¹dissociated form²undissociated form³no evaluation possible⁴outlier

 

The pKa value for each determination was calculated as the average of the individual values for which the dissociated proportion was between 10% and 90%. Data points for which the dissociated proportion was outside this range were not used to calculate the final result.

To calculate the percentage of the ionized test item and the usable pH range the following equations were used:

pH range = pKa_mean± log 9

pH range = 3.91 ± 0.95 = pH 2.96 to pH 4.86

Applying this pH range (i.e. experiments C6 to C11) the mean pKa-value is resulting in

pKa = 3.48 (SD = 0.03)

Applying this pKa value again for the definition of the pH range the experiments C6 to C12 are selected for the calculation of the final result:

pH range = 3.48 ± 0.95 → pH = 2.53 to pH = 4.43

 

This is resulting in the final value pKa = 3.48(SD = 0.03)

Description of key information

pKa= 3.51-3.56 at 22 °C +/- 5 °C

(OECD 112, Spectrophotometric Method)