Nonanoic acid

Dissociation constant

Link to relevant study record(s)

Reference

Endpoint:

dissociation constant

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

Justification for type of information
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
[Describe why the read-across can be performed (e.g. common functional group(s), common precursor(s)/breakdown product(s) or common mechanism(s) of action]
The target substance n-nonanoic acid differs from the source substance only regarding structural isomerism (same molecular weight). While the target is straight chain, the source substance 3,5,5-trimethylhexanoic acid has three methyl substituents on a straight chain C6 backbone. Both compounds share the carboxylic acid moiety responsible for the acidic character.
Acidic strength of carboxylic acids is influenced by inductive effects: substituents with electron donating effects result in weaker acids, i.e. larger pKa values. Inductive effects are effective only in close proximity to the carboxyl group (strongest effect at Cα). Because the Cα-position of the source substance is non-substituted, the branched structure of the source substance will have no relevant impact on the size of the pKa value.
Accordingly, given the high similarity of the target substance to the source substance (same sum formular), the rather low inductive effect of methyl substituents on the carboxylic acid moiety, and the closest and inductively most effective Cα-position non-substituted in the source substance, the experimental results obtained for the endpoint 'Dissociation constant' from the source substance will be reliable and relevant for the target substance n-nonanoic acid as well.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
[Provide here, if relevant, additional information to that included in the Test material section of the source and target records]
The source substance is a mono-constituent substance of high purity (99.1% (w) 3,5,5-trimethylhexanoic acid). Also, the target substance is mono-constituent and of high purity (>=95.5%). Accordingly, both, source as well as target must be considered of high purity and high molecular similarity (structural isomers).

3. ANALOGUE APPROACH JUSTIFICATION
[Summarise here based on available experimental data how these results verify that the read-across is justified]
As outlined under paragraph 1 above, acidic strength of carboxylic acids is influenced by inductive effects: substituents with electron donating effects, like methyl groups, result in weaker acids, i.e. larger pKa values. However, inductive effects are effective only in close proximity to the carboxyl group (strongest effect at Cα). Because the Cα-position of the source substance is non-substituted, the branched structure of the source substance will have no relevant impact on the size of the pKa value. This can be substantiated from the series formic acid (no Cα), acetic acid (non-substituted Cα), propionic acid (non-substituted Cα plus non-substituted Cß), and butyric acid non-substituted Cα plus methyl-substituted Cß) with the following respective pKa-values (Rev. 1): 3.77; 4.76; 4.88; 4.82. Concluding, pKa values are increasing up to propionic acid (non-substituted Cα plus non-substituted Cß), further substitution of Cß with a methyl group resulting in butyric acid however leaves the pKa unchanged within experimental accuracy. Likely, pentanoic and hexanoic acid have pKa-values of 4.84 and 4.86, respectively, corroborating the importance of methyl substitution close to Cα necessary for any relevant inductive effect impacting pKa. The experimentally determined pKa for the source substance 3,5,5-trimethylhexanoic acid of pKa 4.8 is in full conformity with the considerations given. Accordingly, there aren´t any reasons at all which indicated that the pKa for the target substance n-nonanoic acid would - if determined - deviate from the pKa of the source substance 3,5,5-trimethylhexanoic acid.

4. DATA MATRIX AND CONCLUSIONS
Elemental physico-chemical parameters are similar for both, source and target substance. Slight deviations are due to the branched structure of the source substance 3,5,5-trimethylhexanoic acid, prohibiting the close molecular alignment possible for linear carbohydrate chains and thus leading to lower intermolecular forces (van der Waals forces), which becomes especially evident in the significant difference of melting points. However, density and boiling point are only slightly lower, vapour pressure and water solubility only slightly higher compared to the target n-nonanoic acid (all data from the most recent registration dossiers of the submitter):

Melting point 3,5,5-trimethylhexanoic acid: -77 °C
Melting point n-nonanoic acid: 13 °C

Relative density 3,5,5-trimethylhexanoic acid: 0.8996
Relative density n-nonanoic acid: 0.9046

Boiling point 3,5,5-trimethylhexanoic acid: 236 °C
Boiling point n-nonanoic acid: 249 °C

Vapour pressure (20 °C) 3,5,5-trimethylhexanoic acid: 4.6 Pa
Vapour pressure (20 °C) n-nonanoic acid: 0.12 Pa

Water solubility (20 °C) 3,5,5-trimethylhexanoic acid: 0.7 g/L (pH 3.8)
Water solubility (20 °C) n-nonanoic acid: 0.27 g/L (pH 4.2)

Based on these similar physico-chemical properties and the considerations given under sections 1 through 3, the read-across from the result for the dissociation constant determined for the source substance 3,5,5-trimethylhexanoic acid to the target substance n-nonanoic acid is reliable and relevant.

References:
1) Jencks, W. P. and J. Regenstein , "Ionization Constants of Acids and Bases" , in Handbook of Biochemistry and Molecular Biology au. Roger L. Lundblad and Fiona M. Macdonald (Boca Raton: CRC Press, 21 Mai 2010 ), accessed 16 Okt 2020 , Routledge Handbooks Online.

Reason / purpose for cross-reference:

read-across source

Dissociating properties:

yes

No.:

#1

pKa:

4.74

Temp.:

20 °C

Remarks on result:

other: Run 1

No.:

#2

pKa:

4.96

Temp.:

20 °C

Remarks on result:

other: Run 2

No.:

#3

pKa:

4.84

Temp.:

20 °C

Remarks on result:

other: Run 3

No.:

#4

pKa:

4.8

Temp.:

20 °C

Remarks on result:

other: mean value of run 1 to 3

Conclusions:

pKa (OECD 112; titration method): 4.8 at 20°C, based on acidic functionality (Envigo, 2018)

Executive summary:

The study used as source investigated the dissociation constant of the source substance isononanoic acid (3,5,5-trimethylhexanoic acid). The study results of the source substance were considered applicable to the target substance. Justification and applicability of the read-across approach (structural analogue) is outlined in section "Justification for type of information" of this endpoint study record.

Result:

pKa (OECD 112; titration method): 4.8 at 20°C, based on acidic functionality (Envigo, 2018)

Description of key information

pKa (OECD 112; titration method): 4.8 at 20°C, based on acidic functionality (Envigo, 2018)

Key value for chemical safety assessment

pKa at 20°C:

4.8

Additional information

The study used as source investigated the dissociation constant of the source substance isononanoic acid (3,5,5-trimethylhexanoic acid).

The pKa for 3,5,5 -trimethyhexanoic acid was determined in a reliable study performed according to OECD 112 compliant with GLP, following the potentiometric titration method.

Three titration runs were performed, each consisting of at least 49 titration steps, with the following results:

Run 1: pKa 4.74 (20 +/- 1 °C)

Run 2: pKa 4.96 (20 +/- 1 °C)

Run 3: pKa 4.84 (20 +/- 1 °C)

In conclusion, iso-nonanoic acid (3,5,5 -trimethylhexanoic acid) was found to have a pKa (acidic functionality) value of 4.8 at 20ºC (mean value of three runs). The repeatability of ± 0.1 units satisfied the requirement of the test method.

The study results of the source substance were considered applicable to the target substance. Justification and applicability of the read-across approach (structural analogue) is outlined in section "Justification for type of information" of the respective IUCLID endpoint study record.