4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl)-N-(2-ethyl-3-oxo-1,2-oxazolidin-4-yl)-2-methylbenzamide

Dissociation constant

Link to relevant study record(s)

Reference

Endpoint:

dissociation constant

Type of information:

experimental study

Adequacy of study:

key study

Study period:

29 Nov 2016

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 112 (Dissociation Constants in Water)

Version / remarks:

May 1981

GLP compliance:

yes (incl. QA statement)

Dissociating properties:

no

Remarks on result:

other: the test substance has no dissociation within the range pH 2 to pH 12

RESULT:

Both solutions prepared precipitated out of solution on the addition of the water, indicating that an aqueous sample solution concentration of 0.01 M could not be achieved even when using 50 % v/v co-solvent. In the absence of suitable solubility, titration of sample solutions at the required concentrations was not feasible.

On expert assessment of the functional groups present within the test substance structure, no dissociating functional groups were identified within the dissociation constant range of interest (2 to 12), which would permit dissociation of the test substance within the environmentally relevant pH range of 4 to 10. This conclusion was fully supported by computer estimation of the dissociation constants. Evaluation with the specialized predictive software Advanced Chemistry Development, Algorithm Version v12.1.0.50374, resulted in dissociation constant values below 0 for the acceptance of protons by the two amide groups and a dissociation constant value above 12 for the donation of the proton from the secondary amide group (actual value 12.43 ± 0.20). The solubility of the test substance in water was insufficient to allow dissolution of the test substance in water at a concentration of 0.01 M, considered optimal for the investigation of dissociation constants and also critical to allow evaluation of any functional groups down to a possible dissociation constant value of 2. As a result of this, it was intended to adapt the OECD Method 112 procedure both by increasing the sample solution concentration above that of half the water solubility of the test substance and also the proportion of co-solvent content in the sample solutions to compensate for this, correcting to the dissociation constant in pure water using the Yasuda-Shedlovsky extrapolation method. However, successful dissolution at the required concentration could not be achieved, even on using 50 % v/v co-solvent. The alternative experimental procedure suitable for low water soluble substances, the spectrophotometric method, was not suitable for this test substance. This was due to the spatial separation between the possible dissociating functional groups and the absorbing aromatic functional groups, especially for the tertiary amide functional group. Therefore absorbance properties of the test substance were not expected to be dependent on the degree of ionization and more critically, the absence of any changes in absorbance could not be taken as conclusive of the absence of dissociation.

Expert assessment of the test substance structure did not identify any potential dissociating functional groups within the dissociation constant range of interest (2 to 12), which would permit dissociation of the test substance within the environmentally relevant pH range of 4 to 10. This conclusion was fully supported by computer estimation of the dissociation constants. Evaluation with the specialized predictive software Advanced Chemistry Development, Algorithm Version v12.1.0.50374, resulted in dissociation constant values below 0 for the acceptance of protons by the two amide groups and a dissociation constant value above 12 for the donation of the proton from the secondary amide group (actual value 12.43 ± 0.20). Although experimental evaluation of this conclusion was also attempted, low solubility in aqueous media prevented successful completion of any titrations, even when using significant co-solvent concentrations. The alternative experimental procedure suitable for low water soluble substances, the spectrophotometric method, was not suitable for this test substance due to the spatial separation between the possible dissociating functional groups and the absorbing aromatic functional groups; especially for the tertiary amide functional group. Therefore absorbance properties of the test substance were not expected to be dependent on the degree of ionization and more critically, the absence of any changes in absorbance could not be taken as conclusive of the absence of dissociation.

Conclusions:

The test substance has no dissociation within the range pH 2 to pH 12.

Executive summary:

The study was performed to evaluate the dissociation constant of the test substance in water according to OECD TG 112 and in compliance with GLP. Expert assessment and an evaluation with the specialized predictive software lead to the conclusion that no dissociation was to be expected within the range pH 2 to pH 12.

Description of key information

No dissociation within the range of pH 2 - 12, OECD 112, test substance was prepared in methanol and dimethyl sulfoxide, spectrophotometer, O'Connor 2017.