2-ethylhexanoic acid, zirconium salt

Dissociation constant

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

dissociation constant

Remarks:

dissociation of salts into individual ions

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Qualifier:

no guideline followed

Principles of method if other than guideline:

zero-sink test that measures the dissociation of the metal carboxylate substance in two contrasting test media (low and neutral pH) based on the free metal ion concentration in the presence of a selective adsorbent that acts as a zero-sink for the metal cation

GLP compliance:

no

Dissociating properties:

yes

No.:

#1

Temp.:

20 °C

Remarks on result:

other: >=91% dissociation after 1h in simulated gastric fluid (pH 1.5)

No.:

#2

Temp.:

20 °C

Remarks on result:

other: 95±2% dissociation after 1h in simulated interstitial fluid (pH 7.4)

Simulated gastric fluid 

Solution composition

The measured metal concentration of the reference compound and MC in the gastric medium is given in Table 5. The percentage dissolved material of the metal arboxylate (MC) at 1 g MC/L is low (< 0.1% on average based on Zr), which means that the compound is highly insoluble in the gastric fluid. The solubility of the reference compound approaches the prepared concentration in the gastric fluid. 

Table 5 Measured total Zr concentration (C_Zr) dissolved during 12h in the simulated gastric fluid and percent solubility (f_sol) ± standard deviation. The nominal concentrations are the expected concentrations in solution based on the metal content of the compound and using the weighted mass of the compounds and volume of stock solution used to prepare the test solutions. 

	Measured	Nominal
Compound	CZr	CZr	fsol
	μM	μM	%
Reference salt
ZrOCl2.8H2O	9.99 ± 3.45	11.2	89 ± 31
	605 ± 70	548	110 ± 13
MC
(C8H15O2)2Zr	1.67 ± 0.10	2105	<0.1

Free metal ion concentration measurement 

For the reference salt (ZrOCl₂.8H₂O) the Zr concentration in solution decreased to < 2% of the initial concentration after 1h due to sorption of the metal on the resin (Table 6). The measured Zr concentration in diluted test solutions is below the quantification limit (LOQ) of the ICP-MS analysis for some test samples. The concentration in solution is the free metal in equilibrium with the resin. Binding of Zr to the resin is instantaneous since almost no differences are observed between measurements at 1h, 6h and 24h. 

The initial Zr concentration of the MC after 12h dissolution in gastric medium, but before addition of the zero sink resin is below the concentration of the lowest reference. The Zr concentration in solution of the MC decreased to about 10% of the initial concentration after 1h due to sorption of Zr on the resin. The MC undergoes a dissociation reaction and exists in equilibrium with its dissociation products. The dissociated metal reacts with the resin. The metal concentration in solution of the MC is thus, in theory, the free metal in equilibrium with the zero-sink and undissociated MC. The free ion concentration is calculated from the reference compounds and is after 1h ≥0.03 μM Zr. This is close to the total measured Zr concentration in solution of 0.17 μM Zr. After 1h, the calculated dissociated fraction of metal carboxylate is thus ≥ 91%. Therefore, this test indicates that the MC dissociates fully and instantaneously (< 1h) in the test media representing gastric fluid. The dissociated fraction remained constant in time. 

Table 6 Measured Zr concentration in solution at the start (C_Zr,i) and after equilibration (C_Zr,e) and concentration sorbed on the zero sink (C_Zr,s) ± standard deviation at different time points for the reference salts and the MC dissolved in the gastric medium. For the MC, the equilibrium free metal concentration CZr is calculated from the reference compounds and used to calculate the dissociated fraction (f_diss). 

		Measured	Measured	Calculated	Calculated
Compound	time	CZr,i	CZr,e	CZr,s	CZr	fdiss
	h	μM	μM	μmol/g	μM	%
Reference salt	0	9.99±3.45
ZrOCl2.8H2O	1		≤0.17*	≥0.98
	6		≤0.17*	≥0.98
	24		0.33	0.97±0.32
Reference salt	0	605±70
ZrOCl2.8H2O	1		0.22±0.07	60.5±7.0
	6		≤0.17*	≥60.5
	24		1.21±0.61	60.4±7.0
MC	0	1.67 ± 0.10
(C8H15O2)2Zr	1		≤0.17*	≥0.15	≥0.03	≥91
	6		≤0.17*	≥0.15	≥0.01	≥90
	24		≤0.17*	≥0.15	≥0.01	≥90

* For concentrations below the limit of quantification (LOQ), the LOQ is given. 

 

Simulated interstitial fluid 

Solution composition 

The measured metal concentration of the reference compound and MC in the interstitial fluid is given in Table 7. The percentage dissolved material of the MC at 1 g compound/L is very low (< 0.3% based on Zr), which means that the compound is highly insoluble in the interstitial fluid, but the solubility in the interstitial fluid is slightly higher than in pure water or than in the gastric fluid. The reference compound is (almost) completely dissolved in the interstitial fluid. 

Table 7 Measured total Zr concentration (C_Zr) dissolved during 12h in the simulated interstitial fluid and percent solubility (f_sol) ± standard deviation. The nominal concentrations are the expected concentrations in solution based on the metal content of the compound and using the weighted mass of the compounds and volume of stock solution used to prepare the test solutions. 

	Measured	Nominal
Compound	CZr	CZr	fsol
	μM	μM	%
Reference salt
ZrOCl2.8H2O	2.77± 0.10	2.48	112±4
	22.5 ± 1.5	31.0	73±5
MC
(C8H15O2)2Zr	4.87 ± 0.17	2105	<0.3

 

Free metal ion concentration measurement 

For the reference salt (ZrOCl₂.8H₂O) the Zr concentration in solution decreased to < 12% of the initial concentration after 1h due to sorption of Zr(OH)₄° on the adsorbent (Table 8). For the reference salt, the measured Zr concentration in diluted test solutions is above the quantification limit (LOQ) of the ICP-MS analysis, for the MC, some values are below the LOQ. The Zr concentration in solution in the reference salt is the Zr(OH)₄° in equilibrium with the adsorbent. Binding of Zr to the adsorbent is almost instantaneous since relatively small differences are observed between measurements at 1h, 6h and 24h. 

The initial Zr concentration of the MC after 12h dissolution in simulated interstitial fluid, but before addition of the zero sink adsorbent is within the concentration range of the reference samples. The Zr concentration in solution of the MC decreased to < 12% of the initial concentration after 1h due to sorption of Zr(OH)₄° on the adsorbent. The Zr concentration in solution of the MC is thus, in theory, the Zr(OH)₄° in equilibrium with the zero-sink and undissociated MC. The predicted Zr(OH)₄° concentration after 1h is 0.36±0.02 μM Zr, this is close to the measured Zr concentration of 0.60 ± 0.08 μM Zr. After 1h, the calculated dissociated fraction of metal carboxylate is 95±2% and the dissociated fraction remained constant in time. Therefore, this test indicates that the MC dissociates fully and instantaneously (< 1h) in the test media representing interstitial fluid in the presence of a Zr adsorbent acting as zero sink. 

Table 8 Measured Zr concentration in solution at the start (C_Zr,i) and after equilibration (C_Zr,e) and concentration sorbed on the zero sink (C_Zr,s) ± standard deviation at different time points for the reference salt and the MC dissolved in the interstitial medium. For the MC, the equilibrium free ion concentration is calculated from the reference compounds and used to calculate the dissociated fraction (f_diss). 

		Measured	Measured	Calculated	Calculated
Compound	time	CZr,i	CZr,e	CZr,s	CZr	fdiss
	h	μM	μM	μmol/g	μM	%
Reference salt	0	2.77± 0.10
ZrOCl2.8H2O	1		0.32 ± 0.03	0.12 ± <0.01
	6		0.17 ± <0.01	0.12 ± <0.01
	24		0.23 ± 0.03	0.13 ± <0.01
Reference salt	0	22.5 ± 1.5
ZrOCl2.8H2O	1		1.48 ± 0.26	1.05 ± 0.09
	6		0.76 ± 0.05	1.09 ± 0.08
	24		0.48 ± <0.01	1.10 ± 0.08
MC	0	4.87 ± 0.17
(C8H15O2)2Zr	1		0.60 ± 0.08	0.21 ± 0.01	0.36±0.02	95±2
	6		≤0.17*	≥ 0.23	≥0.21±0.01	≥101
	24		0.27 ± 0.07	0.23± 0.01	0.18± <0.01	98 ± 2

* For concentrations below the limit of quantification (LOQ), the LOQ is given. 

Conclusions:

The zero-sink test indicates that the dissociation of zirconium 2-ethylhexanoate is complete (> 91% on average) and instantaneous (within 1h) in the simulated gastric medium (pH 1.5) and the simulated interstitial medium (pH 7.4).

Reference 2

Endpoint:

dissociation constant

Remarks:

dissociation of salts into individual ions

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Qualifier:

according to guideline

Guideline:

OECD Guideline 112 (Dissociation Constants in Water)

GLP compliance:

no

Dissociating properties:

yes

No.:

#1

Temp.:

25 °C

Remarks on result:

other: test inappropriate due to low solubility; the changes I pH and measurement after 24h suggests complete dissociation in water.

Solution composition 

The measured concentration of Zr and organic carbon in solution of the metal carboxylate (MC) is given in Table 2. Both reference compounds (ZrOCl₂.8H₂O and NaC₈H₁₆O₂) are completely dissolved after 1h (f_sol ≥ 100%) and the Zr or OC concentration in the reference samples remained constant in time (no precipitation). 

The OC concentration in solution of the MC increased over time which means that the dissolution is not instantaneously (Table 2). The measured organic carbon (OC) concentration in solution (Table 2) is high compared to the low Zr concentration. The OC concentration after 24h (1097 μM OC) suggest that the dissolved ligand concentration is 137 μM C₈H₁₅O₂, suggesting that the total Zr in solution should be around 69 μM (based on an approximate 1:2 Zr:ligand ratio and molecular formula of Zr(C₈H₁₅O₂)₂ which is by far not observed. The results suggest that the Zr precipitated as ZrO₂. This is different for the ZrOCl₂.8H₂O reference salt, because the pH of that solution was lower than that of the MC (pH 2.50 after 24h instead of 4.28), yielding higher soluble Zr products such as Zr(OH)₄° and ZrOH₃⁺ compared to that with the MC (Table 2). 

The measured OC concentration of 22 mM OC is realistic given that the solubility of 2-ethylhexanoic acid is 1.4 g/L, which corresponds with 78 mM OC. The OC concentration of the reference salt NaC₈H₁₆O₂ (pH 6.85) also indicates the high solubility of the carboxylate. The low Zr concentration in water after 24h is in agreement with the solubility data based on OECD Guideline 105 reported in the ECHA registration dossier. According to that guideline, the water solubility of the compound was < 0.21 μg Zr/L, or 0.002 μM Zr, which is consistent with our low Zr concentratons (Table 2). The Zr solubility in the acid gastric fluid and in the interstitial fluid is higher (1.67-4.87 μM Zr, see Tables 5 and 7) after only 12h compared to that after 24h in water (< 0.02 μM Zr). It is possible that Zr formed complexes with constituents present in the gastric and interstitial media that increased the solubility of the MC in these test media compared to pure water. 

Multi-element analysis with ICP-MS did not show important concentration of other elements in solution, which could interfere with the electrical conductivity measurements. 

Table 2 Measured total concentration Zr (C_Zr,T) or organic carbon (C_OC,T) at 1 g/L and percent solubility (f_sol) ± standard deviation at different samplings. The nominal concentrations are the expected concentrations in solution based on the metal content of the compound and using the exact weighted mass of the compounds. the nominal organic carbon concentration is calculated assuming that the carboxylate content of the compound is 76% (i.e. 100%-reported metal content in the MC). The percent solubility is calculated based on the metal and/or organic carbon concentrations. 

		Measured	Measured	Nominal	Nominal
Compound	time	CZr,T	COC,T	CZr,T	COC,T	fsol,Zr	fsol,OC
	h	μM	μM	μM	μM	%	%
Reference salt
ZrOCl2.8H2O	1	3044 ± 268		3026 ± 26		101± 8
	6	3034 ± 140				100 ± 5
	24	2864 ± 81				95 ± 2
Reference salt
NaC8H16O2	1		50237 ± 3737		48994 ± 2722		102 ± 2
	6		49336 ± 2176				101 ± 1
	24		49562 ± 2979				101 ± <1
MC
(C8H15O2)2Zr	1	< 0.02*	157 ± 17	2647± 23	42517	< 0.001%	0.4%
	6	< 0.02*	355 ± 60			< 0.001%	0.8%
	24	< 0.02*	1097 ± 46			< 0.001%	2.6%

* values lower than the limit of quantification (LOQ) are replaced by the LOQ 

 

Electrical conductivity measurements 

The measured electrical conductivity for the MC and reference compounds in function of time is given in Table 3. The dissociated fraction is calculated from the measured electrical conductivity using the tabulated diffusion coefficients. 

For the reference compound ZrOCl₂.8H₂O, the ions contributing to the conductivity are: Cl^- and H⁺, i.e. the electrical conductivity (σ) of the reference compound is given by: 

σ = (F²/RT)(D_Cl-*z²_Cl-*C_Cl- + D_H⁺*z²_H⁺*C_H⁺)            (Eqn 10)

From the reaction stoichiometry follows that the deprotonated carboxylate concentration (C_RCOO-) equals the proton concentration (C_H⁺), thus the deprotonated carboxylate concentration can be calculated using the diffusion coefficients of the ions in solution and the measured σ based on Eqn.10. 

For the electrical conductivity σ (μS/cm) measured at 24h, at 25°C the constant F²/(RT) = 3.7554 106 sS/mol and with diffusion coefficients D (m²/s) given in Table 1, the expected Cl^- concentration is: 

C_Cl-=σ/(D_Cl- + D_H⁺)*(RT/F²)*10^-7 = 3.86 ± 0.09 mM     (Eqn 11)

This means that the pH of the solution is expected to be 2.41 ± 0.01 (C_H⁺= 3.86 mM), which is in agreement with the measured pH of 2.50±0.01. The expected Zr concentration in solution after 24h is thus equal to 3.86/2 = 1.93 mM, the measured Zr concentration in solution (2.86 mM, Table 3) is higher than expected based on the electrical conductivity data, which suggests that undissociated ZrOCl₂ is present after 24h, i.e. f_diss is equal to 67 ± 4%. The calculations for all time points are given in Table 3. Also for these time points good agreement between calculated and measured pH was found (after 1h, measured pH 2.58±0.01 and calculated pH 2.44±0.01; after 6h, measured pH 2.61±0.02 and calculated pH 2.41±0.01). The dissociated fraction of reference compounds is expected to approach 100%, the deviation for both reference compounds (<100% for ZrOCl₂.8H₂O and >100% for NaC₈H₁₆O₂) might be related to inaccuracies of the model, i.e. the theoretical λ₀ values. 

Because of the low solubility of the MC, also the electrical conductivity was below (after 1 and 6h) or close to the detection limit (LOQ < 15 μS/cm). The dissociated fraction of MC is calculated for all time points, but due to the detection limit issues the test is not appropriate to determine the dissociated fraction for the MC. For the dissociation reaction of the MC, the ions in solution contributing to the conductivity are RCOO^- and H⁺. Based on the conductivity measurement after 24h, this would mean that the deprotonated ligand concentration RCOO^- is equal to 52 ± <1 μM (Table 3) and the pH equal to 4.28. The pH agrees with the measured pH of 4.36. At pH 4.28, the largest fraction of the ligand is protonated, the ratio of protonated/deprotonated ligand is 3 based on the pKa value of 2-ethylhexanoic acid (pKa = 4.76). The total predicted ligand concentration C_L,diss derived from the conductivity measurement (protonated + deprotonated ligand) is thus equal to 209 ± <1 μM (Table 3), from which 52 ± <1 μM is anionic. The expected Zr concentration in solution is thus equal to 209/2 = 105 μM Zr, the measured Zr concentration in solution (< 0.02 μM) is much lower than calculated, which points to precipitation of Zr compounds. The total ligand concentration calculated from the measured conductivity C_L,diss (209 μM) is higher than the total measured ligand concentration in solution (137 μM), which suggests that no additional undissociated metal carboxylate is present after 24h, i.e. f_diss is equal to 152 ± 6%. The calculations for all time points are given in Table 3. Also for these time points good agreement between calculated and measured pH was found (after 1h, measured pH 5.25 and calculated pH 5.09; after 6h, measured pH 4.36 and calculated pH 4.60). 

Table 3 Measured electrical conductivity (σ) and concentration of metal (C_M,T) and carboxylate ligand (C_L,T) of reference salts and MC (in duplicate) at different points in time. For the ZrOCl₂.8H₂O reference salt, C_i is the dissociated metal concentration calculated from the conductivity data and f_diss the dissociated metal fraction (f_diss) ± standard deviation. For the MC and NaC₈H₁₆O₂ reference salt, the C_i is the deprotonated carboxylate ligand concentration calculated from the conductivity data. Because of the relatively low pH, for the MC also the protonated ligand concentration is taken into account to obtain f_diss, C_L,diss is the total ligand concentration (protonated + deprotonated). 

Compound		Measured	Measured	Measured	Measured	Measured	Measured	Calculated	Calculated	Calculated
		Rep. 1	Rep. 1	Rep. 1	Rep. 2	Rep. 2	Rep. 2
	time	σ	CM,T	CL,T	σ	CM,T	CL,T	Ci	CL,diss	fdiss
	h	μS/cm	mM	mM	μS/cm	mM	mM	mM	%
Reference salt
ZrOCl2.8H2O	1	1574	2.85		1528	3.23		1.82 ± 0.04		60 ± 7
	6	1666	3.13		1614	2.93		1.92 ± 0.04		63 ± 2
	24	1674	2.18		1618	2.92		1.93 ± 0.05		67 ± 4
Reference salt
NaC8H16O2	1	517		5.95	551		6.61	7.03 ± 0.32		112 ± 3
	6	519		5.97	553		6.36	7.05 ± 0.32		114 ± < 1
	24	503		5.93	535		6.46	6.83 ± 0.20		110 ± 2
MC			μM	μM		μM	μM	μM	μM
(C8H15O2)2Zr	1	3^$	< 0.02*	18	4$	< 0.02*	21	8 ± 2	12 ± 4	62 ± 12
	6	8^$	< 0.02*	39	12$	< 0.02*	50	26 ± 8	65 ± 30	142 ± 43
	24	20	< 0.02*	141	20	< 0.02*	133	52 ± <1	209 ± <1	152 ± 6

* values lower than the limit of quantification (LOQ) are replaced by the LOQ; $ Electrical conductivity values below the LOQ (LOQ < 15 μS/cm) 

Conclusions:

The solubility of zirconium 2-ethylhexanoate in pure water was too low to measure the dissociation after 1 and 6h; the measurement after 24h suggests complete dissociation in water.

Description of key information

The solubility of zirconium 2-ethylhexanoate in pure water was too low to measure the dissociation after 1 and 6h; the measurement after 24h suggests complete dissociation in water. The zero-sink test indicates that the dissociation of zirconium 2-ethylhexanoate is complete (> 91% on average) and instantaneous (within 1h) in the simulated gastric medium (pH 1.5) and the simulated interstitial medium (pH 7.4).