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Dissociation constant

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Endpoint:
dissociation constant
Data waiving:
study technically not feasible
Justification for data waiving:
other:
Endpoint:
dissociation constant
Type of information:
calculation (if not (Q)SAR)
Adequacy of study:
disregarded due to major methodological deficiencies
Study period:
Testing was conducted between 15 June 2011 and 20 December 2011.
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: Estimation of the dissociation constants was made by relevant computer-based estimation software.
Qualifier:
no guideline followed
Principles of method if other than guideline:
Testing was not possible according to Method 112 of the DECO Guidelines for Testing of chemicals, 12 May 1981 since the test item contained multiple overlapping dissociation constants. Therefore, estimation of the dissociation constants was made by relevant computer-based estimation software.

The estimation was performed using Advanced Chemistry Development I-Lab Web Service (ACD I-Lab 2.0).
GLP compliance:
no
Dissociating properties:
yes
pKa:
0.42 - 6.31
Remarks on result:
other: Functional Group P-OH groups (systematic ionisation of the first and then second hydroxyl group on each of the four phosphate groups)
pKa:
9.76 - 9.85
Remarks on result:
other: Tertiary amine group

                

The test item was considered to be a complex mixture. The dissociation constants for the main constituent have been estimated. Dissociation constant estimations were as follows:

Functional Group

Dissociation Constant

P-OH groups
(systematic ionisation of the first and then second hydroxyl group on each of the four phosphate groups)

6.31 ± 0.3
6.31 ± 0.3
5.77 ± 0.3
5.77 ± 0.3
0.88 ± 0.14
0.87 ± 0.14
0.42 ± 0.14
0.42 ± 0.14

Tertiary amine group

9.85 ± 0.5
9.76 ± 0.5

Conclusions:
No determination was possible according to Method 112 of the OECD Guidelines for Testing of Chemicals, 12 May 1981, due the presenceof overlapping dissociation constants. Estimates of dissociation constants were obtained using computer based estimation software, ACD/I-Lab v2.0. The following dissociation constants were obtained.



Functional Group Dissociation Constant
P-OH groups
(systematic ionisation of the first
and then second hydroxyl group
on each of the four phosphate groups) 6.31 ± 0.3
6.31 ± 0.3
5.77 ± 0.3
5.77 ± 0.3
0.88 ± 0.14
0.87 ± 0.14
0.42 ± 0.14
0.42 ± 0.14

Tertiary amine group 9.85 ± 0.5
9.76 ± 0.5
Executive summary:

No determination was possible according to Method 112 of the OECD Guidelines for Testing of Chemicals, 12 May 1981, due the presence of overlapping dissociation constants. Estimates of dissociation constants were obtained using computer based estimation software, ACD/I-Lab v2.0. The following dissociation constants were obtained.

Functional Group

Dissociation Constant

P-OH groups
(systematic ionisation of the first and then second hydroxyl group on each of the four phosphate groups)

6.31 ± 0.3
6.31 ± 0.3
5.77 ± 0.3
5.77 ± 0.3
0.88 ± 0.14
0.87 ± 0.14
0.42 ± 0.14
0.42 ± 0.14

Tertiary amine group

9.85 ± 0.5
9.76 ± 0.5

From these results, it can be determined that the test item would always be ionised at environmentally relevant pH's.

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
SPARC Automated Reasoning Caclulator v6.0


2. MODEL (incl. version number)
SPARC - pKa


3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
Please refer to attached justification.


4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
Please refer to attached justification.


5. APPLICABILITY DOMAIN
Please refer to attached justification.


6. ADEQUACY OF THE RESULT
Please refer to attached justification.
Qualifier:
according to
Guideline:
other: ECHA's Guidance on information requirements and chemical safety assessment Chapter R.6: QSARs and grouping of chemicals
Version / remarks:
May 2008
Principles of method if other than guideline:
- Software tool(s) used including version:
SPARC Automated Reasoning Caclulator v6.0


- Model(s) used:
SPARC - pKa


- Model description: see field 'Justification for non-standard information', 'Attached justification' and/or 'Cross-reference'
Please refer to attached justification.


- Justification of QSAR prediction: see field 'Justification for type of information', 'Attached justification' and/or 'Cross-reference'
Please refer to attached justification.
GLP compliance:
no
Specific details on test material used for the study:
SMILES notation:
Please refer to attached QPRF.
Dissociating properties:
yes
pKa:
>= 2.19 - <= 7.93
Temp.:
20 °C
Remarks on result:
other: Functional Group P-OH groups
Remarks:
(systematic ionisation of the first and then second hydroxyl group on each of the four phosphate groups of each identified constituent)
pKa:
>= 1.97 - <= 2.45
Temp.:
20 °C
Remarks on result:
other: Tertiary amine group
Remarks:
(systematic ionisation of the first and then second tertiary amine group on each identified constituent)

Ionisation Type

Estimated pKa – Component A

Estimated pKa – Component B

Estimated pKa – Component C

Estimated pKa – Component D

P-OH (1stionisation):

2.19

2.19

2.19

2.19

P-OH (2ndionisation):

7.62

7.62

7.62

7.62

P-OH (3rdionisation):

2.49

2.49

2.49

2.49

P-OH (4thionisation):

7.92

7.92

7.92

7.92

P-OH (5thionisation):

2.20

2.19

2.19

2.19

P-OH (6thionisation):

7.63

7.62

7.62

7.62

P-OH (7thionisation):

2.50

2.49

2.49

2.49

P-OH (8thionisation):

7.93

7.92

7.92

7.92

3oamine (1stionisation):

2.45

2.43

2.43

2.43

3oamine (2ndionisation):

1.97

2.37

2.42

2.43

Conclusions:
A pKa range of 2.19 - 7.93 was predicted for hydroxy groups and a pKa range of 1.97 - 2.45 was predicted for tertiary amine groups.
Executive summary:

(Q)SAR –  The Acid Dissociation Constant (pKa) of the test item was estimated using a procedure designed to be compatible with ECHA's Guidance on information requirements and chemical safety assessment Chapter R.6: QSARs and grouping of chemicals (May 2008).

SMILES notations were derived for the non-salified form of each identified constituent.  The SMILES notation for a constituent was entered into the pKa module of SPARC Automated Reasoning Calculator (v6.0) and the model was run.  This was repeated systematically for each ionisation site (hydroxy groups and tertiary amines) on a given constituent. Each identified constituent was assessed to see if they fell within the model’s applicability domain.  It was concluded that the (non-salified form) each constituent was within the domain of SPARC.  As such the results of these estimations can be considered to be reliable given the limits of the model.

A pKa range of 2.19 - 7.93 was predicted for hydroxy groups and a pKa range of 1.97 - 2.45 was predicted for tertiary amine groups (both predictions are made at 20 ℃).  These values were predicted for non-salified forms of test item constituents due to limitations of the model.

Description of key information

Acid Dissociation Constant (pKa): pKa = 2.19 - 7.93 (hydroxy groups, at 20 ℃) and pKa = 1.97 - 2.45 (tertiary amines, at 20 ℃); ECHA's Guidance on information requirements and chemical safety assessment Chapter R.6: QSARs and grouping of chemicals (May 2008)

Key value for chemical safety assessment

Additional information

Two sets of predictive data are presented in relation to the acid dissociation constant of the test item.

(Q)SAR (SPARC) –  The Acid Dissociation Constant (pKa) of the test item was estimated using a procedure designed to be compatible with ECHA's Guidance on information requirements and chemical safety assessment Chapter R.6: QSARs and grouping of chemicals (May 2008).

SMILES notations were derived for the non-salified form of each identified constituent.  The SMILES notation for a constituent was entered into the pKa module of SPARC Automated Reasoning Calculator (v6.0) and the model was run.  This was repeated systematically for each ionisation site (hydroxy groups and tertiary amines) on a given constituent. Each identified constituent was assessed to see if they fell within the model’s applicability domain.  It was concluded that the (non-salified form) each constituent was within the domain of SPARC.  As such the results of these estimations can be considered to be reliable given the limits of the model.

A pKa range of 2.19 - 7.93 was predicted for hydroxy groups and a pKa range of 1.97 - 2.45 was predicted for tertiary amine groups (both predictions are made at 20 ℃).  These values were predicted for non-salified forms of test item constituents due to limitations of the model.

(Q)SAR (ACD I-Lab 2.0) –  The Acid Dissociation Constant (pKa) of the test item was initially predicted using Advanced Chemistry Development I-Lab Web Service (ACD I-Lab 2.0) as part of a previous submission.  Subsequently this prediction has been disregarded due to major methodological deficiencies.  Insufficient supporting information was reported for this prediction.

OECD 112 –  Determination of the Acid Dissociation Constant (pKa) of the test item was deemed to be not experimentally determinable due to multiple overlapping dissociation constants.