Hexadecanedioic acid

Dissociation constant

Administrative data

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 (Q)SAR model, with limited documentation / justification, but validity of model and reliability of prediction considered adequate based on a generally acknowledged source

Justification for type of information:

1. SOFTWARE
ACD/Percepta (Advanced Chemistry Development, Inc., Pharma Algorithms, Inc.)

2. MODEL (incl. version number)
ACD/Percepta pKa GALAS (2017).
ACD/pKa module calculates accurate acid-base ionization constants (pKa values) under 25°C and zero ionic strength in aqueous solutions. Each calculation is provided with its 95% confidence interval and, when available, literature references. 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). More in detail, ACD/pKa calculates: i) apparent dissociation constants (approximate and exact) for organic and some inorganic chemical compounds (based on the choice of the dominating ionic form in the system at the equilibrium state) under the standard conditions (25°C and zero ionic strength); ii) microscopic ionization constant for the specific ionic forms which could be present in an equilibrium system; iii) single pKa values for all possible dissociation centers when the rest of the molecule is considered neutral.
ACD/pKa GALAS model provides an estimation of ionization constants using the GALAS (Global, Adjusted Locally According to Similarity) methodology. GALAS method for pKa prediction is a multi-step procedure involving estimation of pKa microconstants for all possible ionization centers in the hypothetical state of an uncharged molecule ("fundamental microconstants"), with numerous corrections to these initial pKa values according to the chemical environment of the reaction center, and calculation of charge influences of ionized groups to neighbouring ionization centers. This module also provides graphical/tabular representation of the obtained predictions in the form of pH dependency of net molecular charge, distribution of protonation states and the average charge of each ionization centre.

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
Name Hexadecanedioic acid
IUPAC Name hexadecanedioic acid
CAS No. 505-54-4
SMILES O=C(O)CCCCCCCCCCCCCCC(=O)O
Molecular Formula C16H30O4
Molecular Weight 286.4070 g/mol

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
Applicability Domain (AD): Detailed structural and/or response limits of the applicability domain are not defined.
-descriptor domain: not applicable.
-structural fragment domain: not applicable.

Structural analogues: No structural analogues are provided by ACD/Percepta.
Prediction uncertainty & reliability: The accuracy of pKa calculations is based on the confidence interval at 95% (pKa +/- Err). In the case of the target Hexadecanedioic acid, moderately reliable pKa predictions of 4.6 and 5.2 were derived, considering an error estimation equal to ±0.4.
Adequacy: The pKa prediction was assessed as adequate for regulatory purposes (Klimisch 2 – results derived from a valid QSAR model, with limited documentation/justification, but validity of model and reliability of prediction considered adequate based on a generally acknowledged source).

5. APPLICABILITY DOMAIN
Applicability Domain (AD): Detailed structural and/or response limits of the applicability domain are not defined.
-descriptor domain: not applicable.
-structural fragment domain: not applicable.

6. ADEQUACY OF THE RESULT
The pKa prediction was assessed as adequate for regulatory purposes (Klimisch 2 – results derived from a valid QSAR model, with limited documentation/justification, but validity of model and reliability of prediction considered adequate based on a generally acknowledged source).

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Report date:

2018

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

The acid dissociation constant (pKa) of the target compound Hexadecanedioic acid was estimated by using ACD/Percepta pKa GALAS. ACD/Percepta pKa GALAS (ACD/pKa GALAS) module estimates pKa based on the GALAS methodology, a multi-step procedure involving estimation of pKa microconstants for all possible ionization centers in the hypothetical state of an uncharged molecule, with numerous corrections to these initial pKa values according to the chemical environment of the reaction center, and calculation of charge influences of ionized groups to neighbouring ionization centers.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Hexadecanedioic acid

EC Number:

208-013-5

EC Name:

Hexadecanedioic acid

Cas Number:

505-54-4

Molecular formula:

C16H30O4

IUPAC Name:

hexadecanedioic acid

Results and discussion

Dissociating properties:

yes

Dissociation constant

Dissociation constant 1

pKa:

4.6

Remarks on result:

other: temeprature not measured as it is a QSAR prediction

Dissociation constant 2

pKa:

5.2

Remarks on result:

other: temeprature not measured as it is a QSAR prediction

Any other information on results incl. tables

Strongest acid pKa value equal to 4.6 ± 0.4, due to the dissociation of the first carboxylic acid group; the second carboxylic group has a pKa value of 5.2 ± 0.4. Although the molecule is symmetrical (i.e., the two carboxylic groups have an identical chemical environment), the different pKa values are due to the influence of the first dissociated centre on the second dissociation event. The two terminal carboxylic acid groups of the target molecule are illustrated in Figure 4.1.

No base pKa was calculated for the target compound, due to the absence of basic groups. The three main protonation states of the target compound (PS1, PS2 and PS3) are illustrated in Figure 4.2, while a graphical representation of the obtained pKa prediction in the form of pH dependency of net molecular charge is provided in Figure 4.3.

The predicted pKa values indicate that the target compound will dissociate at environmentally-relevant pH values; this may affect key physico-chemical properties (e.g., partition coefficients and water solubility), bioavailability and toxicity.

Applicant's summary and conclusion

Conclusions:

This study was designed to generate in silico (non-testing) data of pKa by means of QSAR (Quantitative Structure-Activity Relationship) methodology for Hexadecanedioic acid (CAS No. 505-54-4) to be used for its hazard assessment.
ACD/Percepta was employed for the prediction of pKa, which calculated acid pKa values equal to 4.6 ± 0.4 (strongest pKa) and 5.2 ± 0.4, based on the identification of two dissociating groups (i.e., terminal carboxylic acid groups). The pKa prediction was assessed as moderately reliable and adequate for regulatory purposes.