Barium sulfate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vitro / ex vivo

Remarks:

Bioaccessibility

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2020-02-17 to 2020-05-02

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2021

Materials and methods

Objective of study:

bioaccessibility (or bioavailability)

Test guideline

Qualifier:

according to guideline

Guideline:

other:

Version / remarks:

OECD Series on Testing and Assessment No. 29 (23-Jul-2001): Guidance document on transformation/dissolution of metals and metal compounds in aqueous media

Principles of method if other than guideline:

An internationally agreed guideline does not exist for this test (e.g. OECD). However, similar tests have been conducted with several metal compounds in previous risk assessments (completed under Regulation (EEC) No 793/93) and in recent preparation for REACH regulation (EC) No 1907/2006. The test was conducted on the basis of the guidance for OECD-Series on testing and assessment Number 29 and according to the bioaccessibility test protocol provided by the study monitor. The test media were artificial physiological media: gastric fluid (GST), phosphate-buffered saline (PBS) and Gamble's solution (GMB)

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

Constituent 1

Reference substance name:

Barium sulfate

EC Number:

231-784-4

EC Name:

Barium sulfate

Cas Number:

7727-43-7

Molecular formula:

BaO4S

IUPAC Name:

barium sulfate

Test material form:

solid: nanoform

Details on test material:

Trade name: Sachtoperse HU-N
Appearance: solid, white powder
Chemical formula: BaSO4
Molecular weight: 233.39 g/mole
EC-No.: 231-784-4
CAS-No.: 7727-43-7
Appearance: Solid, white odourless powder
Relative density: 4.24
Substance humidity: 0.05 % (by DMT)
Substance stability: Stable under normal conditions

Radiolabelling:

no

Test animals

Species:

other: in vitro (simulated human body fluids)

Details on test animals or test system and environmental conditions:

Test principle in brief:
- three different artificial physiological media,
- single loading of test substance of 2 g/L,
- GST and PBS media: samples taken after 2 and 24 hours agitation (100 rpm) at 37 ± 2 °C
- GMB media: samples taken after 2, 24 and 168 hours agitation (100 rpm) at 37 ± 2 °C
- the study was performed in triplicate
- three vessels with test solution and two blanks per medium (measurement in duplicate)
- analysis of two fractions (0.2 µm filtered and 0.2 µm + 3 kDa filtration)

The aim of this test was to assess the dissolution of Barium sulfate (Sachtoperse HU-N) in three artificial physiological media: Phosphate buffered saline (PBS, pH 7.2-7.4), Artificial gastric fluid (GST, 1.5-1.6) and Gamble’s solution (GMB). The test media were selected to simulate relevant human-chemical interactions (as far as practical), e.g. a substance entering the human body by ingestion into the gastro-intestinal tract (GST).

Administration / exposure

Duration and frequency of treatment / exposure:

Barium concentrations were determined after 2 and 24 hours of incubation in GST, PBS and GMB. In GMB media, barium concentrations were additionally determined after 168 h.

Doses / concentrations

Dose / conc.:

2 other: g of test item/L artificial media

Details on study design:

Test setup
Three replicate flasks (500 mL glass flasks) per test medium (PBS, GST, GMB) were prepared with a loading of 2g/L. The test item was weighed into flasks, adjusted to volume with the respective artificial physiological medium and agitated at 100 rpm in the dark at 37 °C ± 1 °C. Furthermore, the test with GMB was performed in a 5% CO2 atmosphere. Samples of GST and PBS medium were taken after 2 h and 24 h and GMB samples after 2 h, 24 h and 168 h (7 d). Barium concentrations were determined after filtration (Syringe Filter w / 0.2 μm, polyethersulfon membrane, DIA Nielsen, Dueren, Germany) and centrifugal filtration (i.e., 0.2 μm filtration and Vivaspin 20 3kDa centrifugal filtration, Sartorius, Göttingen, Germany) via ICP-MS.

Sample fortification:
In addition, samples of the artificial physiological media were fortified with a known amount of barium (by standard addition of commercial standards) to determine the standard recovery. For detailed information please refer to "Any other information on materials and methods incl. tables".

Barium analysis:
- Standards for metal analysis: A commercially available single element standard was used as barium standard (Merck Certipur Barium ICP standard 1000 mg/L lot no. HC85523104; Darmstadt, Germany) to prepare appropriate stock solutions and subsequently calibration solutions for ICP-MS measurements
- Certified reference materials: As quality control standards, certified aqueous reference material TMDA-64.3 (lot no. 1219) obtained from Environment Canada and a multi-element standard (Carl Roth ICP standard 100 mg/L, lot no. 648617 and lot no. 675451; Karlsruhe, Germany) were analysed for total dissolved barium by ICP-MS.

Results and discussion

Main ADME results

Main ADME results 1

Type:

other: Bioaccessibility GST, 2h @ 37°C (2 g/L loading, 0.2 µm + 3 kDa filtration for phase separation)

Results:

7.99 ± 1.00 mg Ba/L (dissolved)

Main ADME results 2

Type:

other: Bioaccessibility GST, 24h @ 37°C (2 g/L loading, 0.2 µm + 3 kDa filtration for phase separation)

Results:

6.57 ± 0.31 mg Ba/L (dissolved)

Main ADME results 3

Type:

other: Bioaccessibility PBS, 2h @ 37°C (2 g/L loading, 0.2 µm + 3 kDa filtration for phase separation)

Results:

0.58 ± 0.03 mg Ba/L (dissolved)

Main ADME results 4

Type:

other: Bioaccessibility PBS, 24h @ 37°C (2 g/L loading, 0.2 µm + 3 kDa filtration for phase separation)

Results:

1.89 ± 0.14 mg Ba/L (dissolved)

Main ADME results 5

Type:

other: Bioaccessibility GMB, 2 h @ 37°C (2 g/L loading, 0.2 µm + 3 kDa filtration for phase separation)

Results:

0.23 ± 0.01 mg Ba/L (dissolved)

Main ADME results 6

Type:

other: Bioaccessibility GMB, 24h @ 37°C (2 g/L loading, 0.2 µm + 3 kDa filtration for phase separation)

Results:

0.65 ± 0.04 mg Ba/L (dissolved)

Main ADME results 7

Type:

other: Bioaccessibility GMB, 168h @ 37°C (2 g/L loading, 0.2 µm + 3 kDa filtration for phase separation)

Results:

0.80 ± 0.02 mg Ba/L (dissolved)

Bioaccessibility (or Bioavailability)

Bioaccessibility (or Bioavailability) testing results:

Please refer to "any other information on results incl. tables" below.

Any other information on results incl. tables

Barium concentrations in simulated artificial body fluids

The bioaccessibility of barium sulfate (Sachtoperse HU-N) was determined in vitro by simulating dissolution under physiological conditions considered to mimic artificial body fluids with a loading of 2 g test item/L. Dissolved barium concentrations were operationally defined as the dissolved Ba fraction after 0.2 µm filtration and centrifugal filtration (~2.1 nm, see table 2). With a maximum mean released fraction of 0.68% after 2 h, dissolution of Sachtoperse HU-N was highest in artificial gastric fluid (GST).

In addition, dissolved/dispersed mean barium concentrations (operationally defined as the dissolved Ba fraction after 0.2 µm filtration) are summarized in table 3.

 

Table 2 is provided as an Attachment to this entry.

Table 3 is provided as an Attachment to this entry.

 

Solution pH

During the study, the pH of all media incl. blanks remained stable.

Table 5: pH – GST. Target pH = 1.5, N.d. = not determined

Sample name	pH prior to the test	pH after 2 h	pH after 24 h
GST 1	1.505	n.d.	1.514
GST 2	1.499	n.d.	1.495
GST 3	1.496	n.d.	1.495
GST 4	1.514	1.506	1.495
GST blank vessel 1	1.511	1.518	1.546
GST blank vessel 2	1.510	1.528	1.542

 

 

Table 6: pH – PBS. Target pH = 7.2 - 7.4, N.d. = not determined

Sample name	pH prior to the test	pH after 2 h	pH after 24 h
PBS 1	7.291	n.d.	7.246
PBS 2	7.29	n.d.	7.254
PBS 3	7.32	n.d.	7.283
PBS 4	7.303	7.292	7.251
PBS blank vessel 1	7.317	7.31	7.325
PBS blank vessel 2	7.306	7.315	7.326

Table 7: pH – GMB. Target pH = 7.4, N.d. = not determined

Sample name	pH prior to the test	pH after 2 h	pH after 24 h	pH after 168 h
GMB 1	7.4	n.d.	n.d.	7.495
GMB 2	7.4	n.d.	n.d.	7.482
GMB 3	7.408	n.d.	n.d.	7.482
GMB 4	7.405	7.551	7.534	7.483
GMB blank vessel 1	7.401	7.651	7.588	7.581
GMB blank vessel 2	7.409	7.631	7.585	7.576

 

Temperature

The temperature in the thermostatically controlled incubation cabinet was within the limit of 37 °C ± 1 °C to simulate the human body temperature.

 

Method validation summary (ICP-MS)

Limits of detection (LODs), limits of quantification (LOQs) and correlation coefficients (r)

Limits of detection (LOD) within all measurement series: < 0.23 µg Ba/ L.

Limits of quantification (LOQ) within all measurement series: < 0.69 µg Ba/ L.

Correlation coefficients (r) within all measurement series: >0.9974

Barium filter adsorption/leaching tests:

No significant adsorption of barium to the filters used in this test (0.2 µm, 3 kDa) was observed in the three media GMB, PBS and GST (confirmed by spiking experiments). In addition, no significant barium contamination was detected in the filter systems.

 

GST

Recovery of fortified samples (n = 5): 91.4 - 106 %

Mean recoveries for certified reference material TMDA-64.3 (concentration range 5.74 – 71.8 µg Ba / L, n = 10): 96.8 - 97.8%

Mean recoveries for quality control standard (concentration range 2 -100 µg Ba / L, n = 20): 95.6 – 101 %

Mean recoveries for internal standard (concentration range 2.5 -125 µg Ba / L, n = 17): 97.8 - 108 %

 

PBS

Recovery of fortified samples (n = 5): 91.2 - 97.5 %

Mean recoveries for certified reference material TMDA-64.3 (concentration range 5.74 – 71.8 µg Ba / L, n = 7): 91.2 – 99.0 %

Mean recoveries for quality control standard (concentration range 2 -100 µg Ba/ L, n = 18): 94.2 – 99.7 %

Mean recoveries for internal standard (concentration range 2.5 -125 µg Ba / L, n = 16): 94.2 – 102 %

 

GMB

Mean recovery of fortified samples (n = 7): 97.2 - 104 %, one sample 137 %

Mean recoveries for certified reference material TMDA-64.3 (concentration range 5.74 – 71.8 µg Ba / L, n = 10): 105-107 %

Mean recoveries for quality control standard (concentration range 2 -100 µg Ba/ L, n = 22): 99.6 – 107 %

Mean recoveries for internal standard (concentration range 2.5 -125 µg Ba / L, n = 21): 98.1 – 104 %

Applicant's summary and conclusion

Conclusions:

The bioaccessibility of barium sulfate (Sachtoperse HU-N) was determined in vitro by examining dissolution in artificial body fluids at 37°C. At a loading of 2 g test item/L, dissolved barium concentrations (operationally defined as the dissolved Ba fraction after 0.2 µm filtration and centrifugal filtration (~2.1 nm, < 3 kDa)) were determined with 7.99 and 6.57 mg Ba/L after 2 and 24 h in artificial gastric fluid (GST, pH = 1.5, respectively, corresponding to a maximum mean released barium fraction of 0.68 % after 2h. With mean concentrations of 0.58 and 1.89 mg Ba/L after 2 and 24 h incubation, dissolved barium concentrations in phosphate buffered saline (PBS, pH = 7.4) were also very low. Mean barium concentrations in Gamble´s solution (GMB, pH = 7.4) were determined with 0.23, 0.65 and 0.80 mg Ba/L after 2, 24 and 168 hours of incubation, respectively. In sum, maximum mean dissolved barium fractions in GST, PBS and GMB were below 0.7, 0.2 and 0.07 %, respectively. Therefore, barium sulfate (Sachtoperse HU-N) can be considered poorly soluble in artificial body fluids.