Strontium bis(2-ethylhexanoate)

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: 100± <1% dissociation after 1h in simulated gastric fluid (pH 1.5)

No.:

#2

Temp.:

20 °C

Remarks on result:

other: 101± <1% dissociation after 1h in simulated interstitial fluid (pH 7.4)

Simulated gastric fluid 

Solution composition

The measured metal concentration of the reference compound and metal carboxylate in the gastric medium is given in Table 5. The percentage dissolved material of the metal carboxylate at 1 g compound/L is 105 ± 2%, which means that the compound is also highly soluble in the gastric fluid. The reference compound is also completely dissolved (> 100%) in the gastric fluid. 

Table 5 Measured total metal concentration (CM) dissolved during 12h in the simulated gastric fluid and percent solubility (fsol) ± standard deviation. For the metal carboxylate, 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. 

	Measured	Nominal
Compound	CM	CM	fsol
	mM	mM	%
Reference salt
SrCl2.6H2O	1.08 ± 0.01	1.00	108 ± <1
	3.39 ± 0.01	3.00	113 ± <1
MC (metal carboxylate)
Sr(C8H16O2)2	2.64 ± 0.06	2.51	105 ± 2

Free metal ion concentration measurement 

For the reference salts (SrCl2.6H2O) the Sr concentration in solution decreased to <1% of the initial concentration after 1h due to sorption of the metal on the resin (Table 6). The measured Sr concentration in all diluted test solutions is still above the quantification limit (LOQ) of the ICP-MS analysis. The concentration in solution is the free metal in equilibrium with the resin. Binding of Sr to the resin is instantaneous since no differences are observed between measurements at 1h, 6h and 24h. The strong binding of the metal to the resin at the composition and pH of the gastric medium is in agreement with speciation calculations using Visual Minteq. The model predicts an equilibrium Sr concentration in solution that corresponds well with the measured concentration (Table 6, reference salts). 

The initial Sr concentration of the metal carboxylate after 12h dissolution in gastric medium, but before addition of the zero sink resin is within the concentration range of the reference samples. The Sr concentration in solution of the metal carboxylate decreased to < 1% of the initial concentration after 1h due to sorption of the metal on the resin. The metal carboxylate 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 metal carboxylate is thus, in theory, the free metal in equilibrium with the zero-sink and undissociated metal carboxylate. The free metal concentration is calculated from the reference compounds and is after 1h equal to 0.02 ± < 0.01 mM Sr. This is equal to the total measured metal concentration in solution of 0.01 ± < 0.01 mM Sr. After 1h, the calculated dissociated fraction of metal carboxylate is 100 ± < 1%. Therefore, this test indicates that the metal carboxylate dissociates fully in the test media representing gastric fluid. The metal concentration in solution for the reference salt and metal carboxylate remained constant in time after 1h. This indicates that the metal carboxylate dissociates instantaneously (< 1h) in the test media relevant for gastric fluid. 

Table 6 Measured metal concentration in solution at the start (CM,i) and after equilibration (CM,e) and concentration sorbed on the zero sink (CM,s) ± standard deviation at different time points for the reference salts and the metal carboxylate dissolved in the gastric medium. For the metal carboxylate, the equilibrium free metal concentration CM2+ is calculated from the reference compounds and used to calculate the dissociated fraction (fdiss). The CM2+ values of the reference compounds are also calculated with ion exchange principles using Visual Minteq. 

		Measured	Measured	Calculated	Predicted	Calculated
Compound	Time	CM, i	CM,e	CM,s	CM2+	CM2+	fdiss
	h	mM	mM	mmol/g	mM	mM	%
Reference salt	0	1.08 ± 0.01
SrCl2.6H2O	1		0.01 ± < 0.01	0.11 ± < 0.01	0.01
1 mM	6		0.01 ± < 0.01	0.11 ± < 0.01	0.01
	24		0.01 ± < 0.01	0.11 ± < 0.01	0.01
Reference salt	0	3.39 ± 0.01
SrCl2.6H2O	1		0.02 ± < 0.01	0.34 ± < 0.01	0.03
3 mM	6		0.02 ± < 0.01	0.34 ± < 0.01	0.03
	24		0.02 ± < 0.01	0.34 ± < 0.01	0.03
MC (metal carboxylate)	0	2.64 ± 0.06
Sr(C8H16O2)2	1		0.01 ± < 0.01	0.26 ± 0.01		0.02 ± < 0.01	100 ± < 1
	6		0.01 ± < 0.01	0.26 ± 0.01		0.01 ± < 0.01	100 ± <1
	24		0.01 ± < 0.01	0.26 ± 0.01		0.02 ± < 0.01	100 ± < 1

Simulated interstitial fluid 

Solution composition 

The measured metal concentration of the reference compound and metal carboxylate in the gastric medium is given in Table 7. The percentage dissolved material of the metal carboxylate at 1 g compound/L is 102 ± <1, which means that the compound is also highly soluble in the simulated interstitial fluid. The reference compound is also completely dissolved (> 100%) in the simulated interstitial fluid 

Table 7 Measured total metal concentration (CM) dissolved during 12h in the simulated interstitial fluid and percent solubility (fsol) ± standard deviation. For the metal carboxylate, 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. 

	Measured	Nominal
Compound	CM	CM	fsol
	mM	mM	%
Reference salt
SrCl2.6H2O	1.12 ± < 0.01	1.00	112 ± <1
	3.35 ± < 0.01	3.00	113 ± <1
MC (metal carboxylate)
Sr(C8H16O2)2	2.56 ± 0.05	2.51	102 ± <1

Free metal ion concentration measurement 

For the reference salts (SrCl2.6H2O) the Sr concentration in solution decreased to <10% of the initial concentration after 1h due to sorption of the metal on the resin (Table 8). The measured Sr concentration in all diluted test solutions is above the quantification limit (LOQ) of the ICP-MS analysis. The concentration in solution is the free metal in equilibrium with the resin. Binding of Sr to the resin is instantaneous since no differences are observed between measurements at 1h, 6h and 24h. The binding of the metal to the resin in the interstitial fluid is less strong than in the acid gastric medium due to competition between protons and metal cations to bind to the resin, that binding is also well predicted with speciation calculations using Visual Minteq (Table 8). The model predicts an equilibrium Sr concentration in solution that corresponds well with the measured concentration. 

The initial Sr concentration of the metal carboxylate after 12h dissolution in simulated interstitial fluid, but before addition of the zero sink resin is within the concentration range of the reference samples. The Sr concentration in solution of the metal carboxylate decreased to about 10% of the initial concentration after 1h. The metal concentration in solution of the metal carboxylate is thus, in theory, the free metal in equilibrium with the zero-sink and undissociated metal carboxylate. Similarly as in the gastric medium, the metal concentration in solution of the metal carboxylate is explained by the free ion in equilibrium with the zero-sink. The predicted free metal concentration after 1h is 0.25 ± 0.01 mM Sr, this is close to the measured Sr concentration of 0.22 ± < 0.01 mM Sr. After 1h, the calculated dissociated fraction of metal carboxylate is 101 ± < 1%.Therefore, this test indicates that the metal carboxylate dissociates fully in the test media representing interstitial fluid. 

The metal concentration in solution for the reference salt and metal carboxylate remained constant in time after 1h which means that the dissociation is instantaneously (< 1h) in the test media relevant for interstitial fluid. 

Table 8 Measured metal concentration in solution at the start (CM,i) and after equilibration (CM,e) and concentration sorbed on the zero sink (CM,s) ± standard deviation at different time points for the reference salts and the metal carboxylate dissolved in the interstitial medium. For the metal carboxylate, the equilibrium free metal concentration CM2+ is calculated from the reference compounds and used to calculate the dissociated fraction (fdiss). The CM2+ values of the reference compounds are also calculated with ion exchange principles using Visual Minteq. 

		Measured	Measured	Calculated	Predicted	Calculated
Compound	time	CM, i	CM,e	CM,s	CM2+	CM2+	fdiss
	h	mM	mM	mmol/g	mM	mM	%
Reference salt	0	1.12 ± < 0.01
SrCl2.6H2O	1		0.07 ± < 0.01	0.05 ± < 0.01	0.19
1 mM	6		0.07 ± < 0.01	0.05 ± < 0.01	0.19
	24		0.07 ± < 0.01	0.05 ± < 0.01	0.19
Reference salt	0	3.35 ± < 0.01
SrCl2.6H2O	1		0.33 ± < 0.01	0.15 ± < 0.01	0.57
3 mM	6		0.33 ± < 0.01	0.15 ± < 0.01	0.57
	24		0.32 ± < 0.01	0.15 ± < 0.01	0.57
MC	0	2.56 ± 0.05
Sr(C8H16O2)2	1		0.22 ± < 0.01	0.12 ± < 0.01		0.25 ± 0.01	101 ± < 1
	6		0.23 ± < 0.01	0.12 ± < 0.01		0.23 ± 0.01	100 ± <1
	24		0.22 ± < 0.01	0.12 ± < 0.01		0.24 ± 0.01	101 ± < 1

Conclusions:

This test indicates that strontium bis(2-ethylhexanoate) dissociates fully in the test media representing gastric fluid. The metal concentration in solution for the reference salt and metal carboxylate remained constant in time after 1h. This indicates that the metal carboxylate dissociates instantaneously (< 1h) in the test media relevant for gastric fluid.

Strontium bis(2-ethylhexanoate) dissociates fully in the test media representing interstitial fluid. The metal concentration in solution for the reference salt and metal carboxylate remained constant in time after 1h which means that the dissociation is instantaneously (< 1h) in the test media relevant for interstitial fluid.

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: 121±1% dissociation after 1h in water

Solution composition 

The measured concentration of metal and organic carbon in solution of the reference compounds and metal carboxylate is given in Table 2. The percentage dissolved material of the metal carboxylate prepared at 1 g/L after 1h is high (93 ± 6%) and increases to 99 ± 6% after 24h, which is expected based on the high solubility of the compound. Both reference compounds are also completely dissolved (> 100%). The molar metal/organic carbon ratio in solution ranged 0.060-0.064 throughout the experiment. 

Table 2 Measured total concentration metal (CM,T) or organic carbon (COC,T) at 1 g/L and percent solubility (fsol) ± standard deviation at different samplings. For the metal carboxylate, 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. 

		Measured	Measured	Nominal
Compound	Time	CM,T	COC,T	CT*	fsol
	h	mM	mM	mM	%
Reference salt
SrCl2.6H2O	1	4.02 ± 0.21		3.89 ± 0.23	103 ± 1
	6	4.14 ± 0.22			107 ± 1
	24	4.18 ± 0.23			108 ± <1
Reference salt
NaC8H16O2	1		50.2 ± 3.7	49.0 ± 2.7	102 ± 2
	6		49.3 ± 2.2		101 ± 1
	24		49.6 ± 3.0		101 ± <1
MC (metal carboxylate)
Sr(C8H16O2)2	1	2.40 ± 0.12	40.1 ± 2.1	2.57 ± 0.04	93 ± 6
	6	2.51 ± 0.09	39.5 ± 1.5		98 ± 5
	24	2.55 ± 0.11	39.7 ± 1.5		99 ± 6

* For SrCl2.6H2O and the metal carboxylate, the nominal concentration is the metal concentration, for NaC8H16O2 the nominal concentration is the organic carbon concentration. 

Electrical conductivity measurements 

The measured electrical conductivity and concentration of metal and ligand for the metal carboxylate and reference compounds in function of time is given in Table 3. The dissociated fraction is calculated from the measured electrical conductivity. The dissociated fraction of reference compounds is expected to approach 100%, the deviation for both reference compounds (<100% for SrCl2.6H2O and >100% for NaC8H16O2) might be related to inaccuracies of the model, i.e. the theoretical λ0, values. The dissociated fraction of the metal carboxylate is 121 ± 1% after 1h, which indicates that the metal carboxylate dissociates completely. The dissociated fraction remains constant in time after 1h similar as the reference compounds, which means that the dissociation is instantaneously. 

Table 3 Measured electrical conductivity (σ) and concentration of metal (CM,T) and carboxylate ligand (CL,T) of reference salts and metal carboxylate (in duplicate) at different points in time. The dissociated metal concentration (CMn+) and dissociated fraction (fdiss) ± standard deviation are calculated.

Compound	Measured	Measured	Measured	Measured	Measured	Measured	Measured	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	CMn+	fdiss
	h	μS/cm	mM	mM	μS/cm	mM	mM	mM	%
Reference salt
SrCl2.6H2O	1	1055	4.17		950	3.87		3.69 ± 0. 27	92 ± 2
	6	1083	4.30		975	3.99		3.79 ± 0.28	91 ± < 2
	24	1041	4.34		974	4.02		3.71 ± 0.17	89 ± < 1
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	6.46	6.83 ± 0.20	110 ± 2
MC (metal carboxylate)
Sr(C8H16O2)2	1	479	2.32	4.83	505	2.48	5.20	2.99 ± 0.11	121 ± 1
	6	485	2.45	4.80	509	2.57	5.07	2.91 ± 0.10	116 ± < 1
	24	466	2.47	4.82	491	2.62	5.09	2.80 ± 0.10	110 ± 1

Conclusions:

The dissociated fraction of strontium bis(2-ethylhexaniate) is 121 +/- 1% after 1h, which indicates that the metal carboxylate dissociates completely. The dissociated fraction remains constant in time after 1h similar, which means that the dissociation is instantaneously.

Description of key information

The electrical conductivity test in pure water and the zero-sink test in simulated gastric medium (pH 1.5) and simulated interstitial medium (pH 7.4) all conclude that the dissociation of strontium 2-ethylhexanoate in to strontium and 2-ethylhexanoate ions is complete (≥ 100 %) and instantaneous (within 1h).