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Dissociation constant

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Endpoint:
dissociation constant
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
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
Remarks:
The functional groups (reaction centres) of this chemical substance were within the domain of applicability for the SPARC model. Similar molecules were used in the training set and the validation set. SPARC is one of the recommended models for the estimation of pKa identified in ECHA Guidance on Information Requirements.
Justification for type of information:
QSAR prediction: migrated from IUCLID 5.6
Guideline:
other:
Version / remarks:
ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.6: QSARs and Grouping of Chemicals. May 2008.
Principles of method if other than guideline:
(Q)SAR - SPARC
Specific details on test material used for the study:
SMILES: C1N(C)CN(C)CN1C
Dissociating properties:
yes
No.:
#1
pKa:
ca. 9.5
Temp.:
25 °C
Remarks on result:
other: QSAR Predicted Value
Conclusions:
SPARC estimated the macro pKa to be 9.5.
Executive summary:

Accurate values for the pKa of hexahydro-1,3,5 -trimethyl-1,3,5 -triazine were difficult to determine using classic experimental methodology due to hydrolysis at low pH. Structural modelling provided an overall pKa pf 9.5.

Endpoint:
dissociation constant
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
Not reported
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
significant methodological deficiencies
Remarks:
The effect of hydrolysis of hexahydro-1,3,5-trimethyl-1,3,5-triazine is suspected to have interfered with the titration results.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 112 (Dissociation Constants in Water)
GLP compliance:
no
Dissociating properties:
yes
No.:
#1
pKa:
ca. 7.1
Temp.:
20 °C
Remarks on result:
other: Titration (Methodology 1)
No.:
#1
pKa:
8.69
Temp.:
20 °C
Remarks on result:
other: Molar Solution (Methodology 2)

Methodology (1)

Titration method: pKa = 7.1

Methodology (2)

pKa estimate from molar solutions:

Sample 1 pKa = 8.54

Sample 2 pKa = 8.39

The SPARCs model prediction for the first ionisation of MMA Tz gives a value of pKa = 9.5

The dilution method above gives a value of 8.69 which is approximately half an order of magnitude below the SPARCS model and magnitude ~ 1.5 above the titrimetric determination.

This result adds weight to the hypothesis of facile hydrolysis of the parent triazine in dilute aqueous solution (assuming the SPARC model is accurate).

Plotting both pKa values as a function of concentration and extrapolating to zero concentration (infinite dilution) gives a value of pKa = 8.69

Conclusions:
Compared to the SPARC models the unhydrolysed value is lower than predicted but much nearer than the titrimetric value. This supports the theory of hydrolysis of this molecule in the “real world” situation. The true value must lie between 7 and 9 and would allow a conclusion to support an assertion that the pKa is not within physiological relevance (i.e. >6).

Description of key information

pKa = 7 - 9, OECD 112, Mountford (2010)

pKa = 8.5, SPARC, Hargreaves (2010)

Key value for chemical safety assessment

pKa at 20°C:
8.5

Additional information

Accurate values for the pKa for hexahydro-1,3,5-trimethyl-1,3,5-triazine were difficult to determine using classic experimental methodology due to hydrolysis at low pH. Using the titration method, pKa was estimated to be 7.1. Structural modelling provided an overall pKa of 9.5 and pKa estimated from the pH of molar solutions was estimated to be 8.69. Based on a weight-of-evidence approach, the pKa of hexahydro-1,3,5-trimethyl-1,3,5-triazine is between 7-9.5, with typical values being approximately 8.5.

There are considerable differences between the modelled and laboratory results for pKa. This is possibly due to interferences in the method, caused by the hydrolysis of hexahydro-1,3,5 -trimethyl-1,3,5 -triazine at low pH and the formation of methylmethylenimine (N-methylmethanimine). Using identical modelling procedures to those used for hexahydro-1,3,5 -trimethyl-1,3,5 -triazine, the pKa of methylmethylenemine was estimated to be 6.91, which is close to that obtained using the titration method.

To investigate the pKa further with minimal interference from methylmethyleneimine, pKa of hexahydro-1,3,5 -trimethyl-1,3,5 -triazine was estimated from the pH of solution with a known molar concentration. This exercise was conducted twice for hexahydro-1,3,5 -trimethyl-1,3,5 -triazine at molar solutions of 0.10 and 0.202, pH was measured as 10.77 and 10.85 respectively. From these solutions, pKa was estimated to be 8.54 and 8.39. Plotting both pKa values as a function of concentration and extrapolation to zero concentration (infinite dilution) gives a value pKa = 8.69.