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Dissociation constant

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Reference
Endpoint:
dissociation constant
Type of information:
(Q)SAR
Adequacy of study:
key study
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:
1. SOFTWARE
The dissociation constant (pKa), predicted using ACD/Percepta 14.0.0 (Build 2254).

2. MODEL (incl. version number)
ACD/pKa DB included in ACD/Percepta 14.0.0 (Build 2254, 16. Jul. 2013)

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
The typical structure formula was imported through ChemSketch included in ACD/Percepta 14.0.0 (Build 2254).

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL

a. Defined endpoint: Dissociation constant (pKa) in water

b. Explicit algorithm: The algorithm of ACD/pKa DB ia a type of linear free energy relationship (LFER). LFER is an empirical correlation between the standard free energies of reaction or activation for two series of reactions, both subjected to the same variation in reactant structures or reaction conditions. ACD/pKa DB utilizes the Hammett relationship for aromatic systems and the Taft relationship for aliphatic substances to estimate acid dissociation constant.
The algorithm of ACD/pKa DB is built upon extensive compilation of Hammett and Taft correlations empirically derived from studying ionization equilibriums in over 15,000 compounds. The properties of this approach give it excellent reliability within the space of well characterized chemical substances. In addition, two reference databased are available that offer quick look-up of published data – one contains > 31,000 experimental pKa values for approximately 16,000 compounds in aqueous solutions; the other provides experimental data for more than 2000 molecules in non-aqueous solvents.

c. Applicability domain: Due to the fragment-based approach of ACD/pKa DB, it is adequate when the fragments present in the molecule under study are present in the database. In addition there are two techniques to improve the pka calculation when the fragments are not available, i.e. system training and accuracy extender.

d. Statistics for goodness-of-fit: Each calculation from ACD/pKa DB is provided with its 95 % confidence interval and, when available, literature references with experimental results. The accuracy of calculations for simple structures is usually better than ± 0.2 pka units (for complex structrues it is better than ± 0.5 pKa units).

e. Predictivity – statistics obtained by external validation: The accuracy statistics for the three external validation sets are reported in the literature as following: Dataset 1: correlation coeff. (r^2) = 0.9823, dataset 2: correlation coeff. (r^2) = 0.9928, dataset 3: correlation coeff. (r^2) = 0.9902.

f. Limits of applicability: The ACD/algorithm will refuse to predict pKa values for structures which:
-contain more than 225 atoms (note that the program refuses to predict pKa values for some cyclic compounds having less than 255 atoms due to the fact that the program uses cyclic-breaking algorithm that increases the number of atoms)
-do not contain an ionization center
-contain atoms of non-typical valence
-contain atoms other than C, H, O, S, P, N, F, Cl, Br, I, Se, Si, Ge, Pb, Sn, As, B
-contain two or more fragments in one ionization center
-contain more than 20 ionization center
-contain d-block or f-block metal atoms
-contain textual abbreviations which cannot be transformed to structural fragments

5. APPLICABILITY DOMAIN
a. Domains:
i. Molecular weight: Not relevant.
ii. Structural fragment domain:
- The identified reaction centres have been found as fragments in the Internal Reaction Centres Database with experimental equations.
- The substance only contains 54 atoms, which is much less than the limit of ACD/pKa DB of 255.
- The substance contains two ionization centres, each with one fragment.
- The substance does not contain atoms, which are not accepted by ACD/pKa DB.
iii. Mechanism domain: No information available
iv. Metabolic domain, if relevant: Not relevant
b. Structural analogues: Not applicable
i. Considerations on structural analogues: Not applicable
c. The uncertainty of the prediction (OECD principle 4): The Substance is not highly complex and the rules applied for the substance appear appropriate. An individual uncertainty for the investigated substance is not available.d. The chemical and biological mechanisms according to the model underpinning the predicted result (OECD principle 5): No information available.

6. ADEQUACY OF THE RESULT
a. Regulatory purpose: The data may be used under any regulatory purpose.
b. Approach for regulatory interpretation of the model result: If no experimental data are available, the estimated value may be used to fill data gaps needed for hazard and risk assessment.
c. Outcome: The prediction of dissociation constant (pKa) yields a useful result for further evaluation.
d. Conclusion: The result is considered as useful for regulatory purposes.
Guideline:
other: REACH guidance on QSARs R.6, May 2008
Principles of method if other than guideline:
ACD 14.0.0 software program for estimating the dissociation constant (pKa) in water.The recommended method, “apparent constants, approximated”, was used for the estimation. The program was developed by Advanced Chemistry Development Inc.
90 Adelaide Street West, Toronto, Ontario, M5H 3V9, Canada (http://www.acdlabs.com); Copyright © 1997-2013; Build 2254, 16. Jul 2013
GLP compliance:
no
Dissociating properties:
yes
No.:
#1
pKa:
-1.8
Temp.:
25 °C
Remarks on result:
other: pka (base)
No.:
#2
pKa:
-2.8
Temp.:
25 °C
Remarks on result:
other: pka (base)

1. Defined endpoint: Dissociation constant (pKa) in water

2. Unambiguous algorithm: For Solvent Violet 36 the following fragment descriptors (parent compound) were identified as reaction centres: R-NH-R

3. Applicable domain: The identified reaction centers have been found as fragments in the Internal Reaction Centers Database with experimental equations. The substance only contains 44 atoms, which is much less than the limit of ACD/pKa DB of 255. The substance only contains two ionization centres with one fragment for each. The substance does not contain the atoms, what are not accepted by ACD/pKa DB. The fragment that occurs in the structure of Solvent Violet 36 applied by the program is verified by the user. The rules applied for the substance appears appropriate. An individual uncertainty for the investigated substance is not available.

4. Statistical characteristics: Each calculation from ACD/pKa DB is provided with its 95 % confidence interval and, when available, literature references with experimental results. The accuracy of calculations for simple structures is usually better than ±0.2 pKa units (for complex structures it is better than ±0.5 pKa units).

5. Mechanistic interpretation: The mechanistic basis of the model is the linear free energy relationship (LFER), which is an empirical correlation between the standard free energies of reaction or activation for two series of reactions, both subjected to the same variations in reactant structures or reaction conditions. As applied to the estimation of acid dissociation constants, the LFER is basically a substituent-effect approach.

6. Adequacy of prediction: The result for Solvent Violet 36 falls within the applicability domain described above and the estimation rulesapplied for the substance appears appropriate. Therefore the predicted value can be considered reliable yielding a useful result for further assessment.

Conclusions:
The dissociation constants for Solvent Violet 36 are estimated to be pKa1 (base) of -1.8 (Atom number: 6) and pKa2 of 2.8 (Atom number: 20).
Executive summary:

The dissociation constants of Solvent Violet 36 were estimated by ACD/pKa DB included in ACD/labs 7.00 Release. According to the estimated results, this substance presents mainly as non-ionic form under environmentally relevant pH 5 -9.

Description of key information

The dissociation constants for Solvent Violet 36 are estimated to be pKa1 (base) of -1.8 (Atom number: 6) and pKa2 of 2.8 (Atom number: 20).

Key value for chemical safety assessment

pKa at 20°C:
-1.8

Additional information

"Should read: pka at 25 °C"

The dissociation constants of Solvent Violet 36 were estimated by ACD/pKa DB included in ACD/labs 7.00 Release. According to the estimated results, this substance presents mainly as non-ionic form under environmentally relevant pH 5 -9.