Strontium bis(2-ethylhexanoate)

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vitro / ex vivo

Remarks:

Bioelution in simulated gastric medium

Type of information:

experimental study

Adequacy of study:

key study

Study period:

10 December 2021 to 12 February 2022

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

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

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2022

Report date:

2022

Materials and methods

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

Bioelution in simulated gastric medium according to Eurometaux (2019): The Standard Operating Procedure for Bioelution Testing of Metals, Inorganic Metal Compounds, and Complex Metal-Containing Materials: Simulated Gastric Fluid (Eurometaux Brussels, November 02, 2019).

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

Constituent 1

Reference substance name:

Strontium bis(2-ethylhexanoate)

EC Number:

219-536-3

EC Name:

Strontium bis(2-ethylhexanoate)

Cas Number:

2457-02-5

Molecular formula:

C16H30O4Sr

IUPAC Name:

strontium bis(2-ethylhexanoate)

Test material form:

solid

Remarks:

powder lumps

Details on test material:

Supplier: ORGANOMETAL S.A.
CAS Number: 2457-02-5
Batch/Lot number: 3823121121
Appearance: solid powder lumping
Purity: min 94%
Metal content: 22% Sr
Expiry date: 12 November 2022

Specific details on test material used for the study:

The test item, Strontium bis(2-ethylhexanoate) as received, was tested. Therefore, no further preparation of the test item at ECTX was needed.

Administration / exposure

Vehicle:

other: simulated gastric fluid (0.032 N HCl)

Duration and frequency of treatment / exposure:

1 hour agitation and 1 hour to allow the sample to settle

Positive control reference chemical:

1001 mg/L Strontium standard

Results and discussion

Bioaccessibility (or Bioavailability)

Bioaccessibility (or Bioavailability) testing results:

Bioelution refers to the in vitro extraction methods used to measure the degree to which a substance is dissolved in simulated biological fluids. The resulting value is the “bioaccessibility”, and is defined as the “fraction of a substance that is soluble under physiological conditions and therefore potentially available for absorption into systemic circulation”. Simulated biological fluids (e.g. gastric fluid, interstitial fluid, lysosomal fluid,…), represents relevant exposure routes. In this study, the oral route was investigated. Therefore, simulated gastric fluid, as provided in the SOP, was used to measure the release/dissolution of the elements of interest from Strontium bis(2-ethylhexanoate).

The temperature of the sampled test solutions, including the Negative and Positive Control vessel was between 36.8 °C and 37.0 °C and corresponded to the required test conditions of 37 °C +/- 1 °C.

The measured pH of the test medium at the start of the test was 1.50, i.e. within the specifications of pH 1.5 +/- 0.1. The pH measured in the additional test item vessel at the beginning of the trial was 1.51 for the 0.2 g/L and 1.54 for the 2 g/L loading, respectively, i.e. within the specifications of pH 1.5 +/- 0.1. At the 2 hours endpoint of the test, the pH in the Negative Control vessel was 1.51 and 1.50 in the Positive Control. The pH in the test item vessels was between 1.53 and 1.54 for the vessels at the 0.2 g/L loadings and between 1.63 and 1.65 for the vessels at the 2 g/L loadings.

The Negative Control vessel showed no concentrations of strontium above the limit of quantification (i.e. accredited reporting limit) of 0.5 μg/L Sr.

The following observations could be made in the Positive Control item vessel containing a soluble form of strontium:
  The Positive Control item solution remained clear at the tested concentration level. No precipitation could be observed on the filter and in the Erlenmeyer flask at the end of the experiment.
  The recovery of the dissolved strontium concentration in the Positive Control item was 101 % and met the criterion (recovery: 100 % +/- 10 %) as indicated in the SOP.

The following observations could be made in the test vessels with a loading of 0.2 g/L Strontium bis(2-ethylhexanoate):
- The test solution was clear at the end of the experiment. No undissolved test item could be observed in the Erlenmeyer flasks at the end of the experiment.
- An average dissolved strontium concentration in solution of 38.0 +/- 0.6 mg/L Sr (corresponding to a dissolved strontium concentration per g test item of 189 +/- 3 mg/g Sr) was measured after 2 hours of exposure to the simulated gastric fluid (pH 1.5) with a between-vessel variation of 2 % which met the quality criteria at the 2 hours endpoint.
Based on the strontium content of the test item (i.e. 22 % Sr) and the average dissolved strontium concentration, a strontium release of 86 % could be calculated at the 2 hours endpoint.

The following observations could be made in the test vessels with a loading of 2 g/L Strontium bis(2-ethylhexanoate):
- The test solution was clear at the end of the experiment. No undissolved test item could be observed in the Erlenmeyer flasks at the end of the experiment.
- An average dissolved strontium concentration in solution of 381 +/- 4 mg/L Sr (corresponding to a dissolved strontium concentration per g test item of 191 +/- 2 mg/g Sr) was measured after 2 hours of exposure to the simulated gastric fluid (pH 1.5) with a between-vessel variation of 1 % which met the quality criteria at the 2 hours endpoint.
Based on the strontium content of the test item (i.e. 22 % Sr) and the average dissolved strontium concentration, a strontium release of 87 % could be calculated at the 2 hours endpoint.

Applicant's summary and conclusion

Conclusions:

During this study on Strontium bis(2-ethylhexanoate) at a loading of 0.2 g/L in simulated gastric fluid (pH 1.5), it was shown that for strontium an average dissolved concentration in solution of 38.0 mg/L Sr (CVbetween-vessel = 2 %; N = 3) was found after 2 hours of extraction. This amount corresponds to a dissolved strontium concentration per g test item of 189 mg/g Sr or a strontium release of 86 % of the content.

During this study on Strontium bis(2-ethylhexanoate) at a loading of 2 g/L in simulated gastric fluid (pH 1.5), it was shown that for strontium an average dissolved concentration in solution of 381 mg/L Sr (CVbetween-vessel = 1 %; N = 3) was found after 2 hours of extraction. This amount corresponds to a dissolved strontium concentration per g test item of 191 mg/g Sr or a strontium release of 87 % of the content.

The results are reliable since the test conditions stayed constant during the experiment. The pH in the high loading (2 g/L) test vessels was 1.65 and exceeded the initial range (pH 1.5 +/- 0.1) at the end of the experiment. The recovery of Positive Control met the criteria of acceptance.

Executive summary:

Bioelution refers to the in vitro extraction methods used to measure the degree to which a substance (e.g., metal or mineral ion) is dissolved in artificial biological fluids. Simulated biological fluids represent relevant exposure routes. The release/dissolution of strontium ions from Strontium bis(2-ethylhexanoate) in the simulated gastric fluid was measured. 

The resulting value is the “bioaccessibility”, and is defined as the “fraction of a substance that is soluble under physiological conditions and therefore potentially available for absorption into systemic circulation”. 

This study was conducted according to The Standard Operating Procedure for Bioelution Testing of Metals, Inorganic Metal Compounds, and Complex Metal-Containing Materials: Simulated Gastric Fluid (Eurometaux, November 2, 2019) in which the gastric medium will be prepared starting from a 0.1 M HCl solution. 

The extent of dissolution of Strontium bis(2-ethylhexanoate) in the powder form (as received) was tested in a simulated gastric fluid at 37 °C and pH 1.5 for 2 hours (0.2 g/L and 2 g/L loadings) at an agitation speed of 100 revolutions per minute (rpm) for 1 hour followed by 1 hour of settling (without shaking). The bioelution endpoint is based on the dissolved strontium (Sr) concentrations obtained after 2 hours of extraction. 

The study was performed at ECTX. Analysis of the concentrations of dissolved strontium has been performed at WLN Business B.V. (The Netherlands), an ISO 17025 accredited laboratory, as delegated by ECTX. 

The measured pH of the test medium at the start of the test was 1.50, i.e. within the specifications of pH 1.5 ± 0.1. The pH measured in the additional test item vessel at the beginning of the trial was 1.51 for the 0.2 g/L and 1.54 for the 2 g/L loading, respectively, i.e. within the specifications of pH 1.5 ± 0.1. At the 2 hours endpoint of the test, the pH in the Negative Control vessel was 1.51 and 1.50 in the Positive Control. The pH in the test item vessels was between 1.53 and 1.54 for the vessels at the 0.2 g/L loadings and between 1.63 and 1.65 for the vessels at the 2 g/L loadings. 

The temperature of the sampled test solutions, including the Negative and Positive Control vessel was between 36.8 °C and 37.0 °C and corresponded to the required test conditions of 37 °C ± 1 °C. 

The Negative Control vessel showed no concentrations of strontium above the limit of quantification (i.e. accredited reporting limit) of 0.5 μg/L Sr. 

In the test item vessels with a loading of 0.2 g/L Strontium bis(2-ethylhexanoate), the following average dissolved strontium concentration in solution of: 

• 38.0 ± 0.6 mg/L Sr (CVbetween-vessel = 2 %; N = 3), corresponding to a dissolved strontium concentration per g test item of 189 ± 3 mg/g Sr, 

was measured after 2 hours of exposure to the simulated gastric fluid (pH 1.5). 

Based on the strontium content (i.e. 22 % Sr) in the test item and the average dissolved strontium concentrations in the test solutions, a release of: 

• 86 % of the content could be calculated at the 2 hours endpoint. 

 

In the test item vessels with a loading of 2 g/L Strontium bis(2-ethylhexanoate), the following average dissolved strontium concentration in solution of: 

• 381 ± 4 mg/L Sr (CVbetween-vessel = 1 %; N = 3), corresponding to a dissolved strontium concentration per g test item of 191 ± 2 mg/g Sr, 

was measured after 2 hours of exposure to the simulated gastric fluid (pH 1.5). 

Based on the strontium content (i.e. 22 % Sr) in the test item and the average dissolved strontium concentrations in the test solutions, a release of: 

• 87 % of the content could be calculated at the 2 hours endpoint.