dilithium trimanganese nickel octoxide

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2022

Report date:

2022

Materials and methods

Objective of study:

bioaccessibility (or bioavailability)

Test guideline

Qualifier:

according to guideline

Guideline:

other: Standard Operating Procedure (SOP) for Bioelution Testing of Metals, Inorganic Metal Compounds, and Metal-Containing Complex Materials: Simulated Gastric Fluid (Eurometaux, November 2 2019)

GLP compliance:

no

Test material

Test material information

impurity 1

Reference substance name:

Dipotassium oxide

EC Number:

235-227-6

EC Name:

Dipotassium oxide

Cas Number:

12136-45-7

Molecular formula:

K2O

IUPAC Name:

Potassium oxide

impurity 2

Reference substance name:

Disodium oxide

EC Number:

215-208-9

EC Name:

Disodium oxide

Cas Number:

1313-59-3

Molecular formula:

Na2O

IUPAC Name:

sodium oxide

impurity 3

Reference substance name:

Lithium sulphate

EC Number:

233-820-4

EC Name:

Lithium sulphate

Cas Number:

10377-48-7

Molecular formula:

H2O4S.2Li

IUPAC Name:

dilithium sulfate

impurity 4

Reference substance name:

Nickel monoxide

EC Number:

215-215-7

EC Name:

Nickel monoxide

Cas Number:

1313-99-1

Molecular formula:

NiO

IUPAC Name:

Nickel (II) oxide

impurity 5

Reference substance name:

dilithium manganese nickel tetraoxide

Cas Number:

128975-24-6

Molecular formula:

Li2MnNiO4

IUPAC Name:

dilithium manganese nickel tetraoxide

Constituent 1

Reference substance name:

dilithium trimanganese nickel octaoxide

EC Number:

663-306-9

Cas Number:

12031-75-3

Molecular formula:

Li2Mn3NiO8

IUPAC Name:

dilithium trimanganese nickel octaoxide

Test material form:

solid: particulate/powder

Specific details on test material used for the study:

Batch no: 2017431383

Results and discussion

Bioaccessibility (or Bioavailability)

Bioaccessibility (or Bioavailability) testing results:

In the test item vessels with a loading of 0.2 g/L LNMO, the following average dissolved element concentrations of:
• 0.510 ± 0.006 mg/L Li (CVbetween-vessel = 1 %; N = 3) or 2.55 ± 0.03 mg/g test item,
• 1.45 ± 0.02 mg/L Mn (CVbetween-vessel = 1 %; N = 3) or 7.22 ± 0.08 mg/g test item,
• 0.366 ± 0.010 mg/L Ni (CVbetween-vessel = 3 %; N = 3) or 1.83 ± 0.05 mg/g test item,
was measured after 2 hours of exposure to the simulated gastric fluid (pH 1.5).
Based on the specific surface area of LNMO (i.e. 0.2 m²/g), this corresponds to an element release per surface of:
• 13 mg/m² lithium,
• 36 mg/m² manganese,
• 9.1 mg/m² nickel.
Based on the element contents (i.e. 3.87 % Li, 44.7 % Mn and 14.9 % Ni) in the test item and the average dissolved element concentrations in the test solutions, a release of:
• lithium of 6.6 % of the content,
• manganese of 1.6 % of the content,
• nickel of 1.2 % of the content,
could be calculated at the 2 hours endpoint.

In the test item vessels with a loading of 2 g/L LNMO, the following average dissolved element concentration of:
• 5.44 ± 0.09 mg/L Li (CVbetween-vessel = 2 %; N = 3) or 2.72 ± 0.05 mg/g test item,
• 14.1 ± 0.5 mg/L Mn (CVbetween-vessel = 3 %; N = 3) or 7.03 ± 0.24 mg/g test item,
• 3.64 ± 0.03 mg/L Ni (CVbetween-vessel = 1 %; N = 3) or 1.82 ± 0.02 mg/g test item,
was measured after 2 hours of exposure to the simulated gastric fluid (pH 1.5).
Based on the specific surface area of LNMO (i.e. 0.2 m²/g), this corresponds to an element release per surface of:
• 14 mg/m² lithium,
• 35 mg/m² manganese,
• 9.1 mg/m² nickel.
Based on the element contents (i.e. 3.87 % Li, 44.7 % Mn and 14.9 % Ni) in the test item and the average dissolved element concentrations in the test solutions, a release of:
• lithium of 7.0 % of the content,
• manganese of 1.6 % of the content,
• nickel of 1.2 % of the content,
could be calculated at the 2 hours endpoint.

Applicant's summary and conclusion

Conclusions:

In the test item vessels with a loading of 0.2 g/L LNMO, the following average dissolved element concentrations of:
• 0.510 ± 0.006 mg/L Li (CVbetween-vessel = 1 %; N = 3) or 2.55 ± 0.03 mg/g test item,
• 1.45 ± 0.02 mg/L Mn (CVbetween-vessel = 1 %; N = 3) or 7.22 ± 0.08 mg/g test item,
• 0.366 ± 0.010 mg/L Ni (CVbetween-vessel = 3 %; N = 3) or 1.83 ± 0.05 mg/g test item,
was measured after 2 hours of exposure to the simulated gastric fluid (pH 1.5).
Based on the specific surface area of LNMO (i.e. 0.2 m²/g), this corresponds to an element release per surface of:
• 13 mg/m² lithium,
• 36 mg/m² manganese,
• 9.1 mg/m² nickel.
Based on the element contents (i.e. 3.87 % Li, 44.7 % Mn and 14.9 % Ni) in the test item and the average dissolved element concentrations in the test solutions, a release of:
• lithium of 6.6 % of the content,
• manganese of 1.6 % of the content,
• nickel of 1.2 % of the content,
could be calculated at the 2 hours endpoint.

In the test item vessels with a loading of 2 g/L LNMO, the following average dissolved element concentration of:
• 5.44 ± 0.09 mg/L Li (CVbetween-vessel = 2 %; N = 3) or 2.72 ± 0.05 mg/g test item,
• 14.1 ± 0.5 mg/L Mn (CVbetween-vessel = 3 %; N = 3) or 7.03 ± 0.24 mg/g test item,
• 3.64 ± 0.03 mg/L Ni (CVbetween-vessel = 1 %; N = 3) or 1.82 ± 0.02 mg/g test item,
was measured after 2 hours of exposure to the simulated gastric fluid (pH 1.5).
Based on the specific surface area of LNMO (i.e. 0.2 m²/g), this corresponds to an element release per surface of:
• 14 mg/m² lithium,
• 35 mg/m² manganese,
• 9.1 mg/m² nickel.
Based on the element contents (i.e. 3.87 % Li, 44.7 % Mn and 14.9 % Ni) in the test item and the average dissolved element concentrations in the test solutions, a release of:
• lithium of 7.0 % of the content,
• manganese of 1.6 % of the content,
• nickel of 1.2 % of the content,
could be calculated at the 2 hours endpoint.

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 lithium, manganese and nickel ions from LNMO 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 LNMO 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 lithium, manganese and nickel concentrations obtained after 2 hours of extraction.

The study was performed at ECTX. Analysis of the concentrations of dissolved lithium, manganese and nickel 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 1.50 for the 0.2 g/L and 1.51 for the 2 g/L loadings, 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 1.50 and 1.50 in the Positive Control. The pH in the test item vessels was between 1.52 and 1.53 for the vessels at the 0.2 g/L loadings and between 1.57 and 1.59 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 36.9 °C and 37.1 °C and corresponded to the required test conditions of 37 °C ± 1 °C.

The Negative Control vessel showed no concentrations of lithium, manganese and nickel above the respectively limit of quantification (i.e. accredited reporting limit) of 0.5 μg/L Li, 2 μg/L Mn and 0.5 μg/L Ni.

In the test item vessels with a loading of 0.2 g/L LNMO, the following average dissolved element concentrations of:

• • 0.510 ± 0.006 mg/L Li (CVbetween-vessel = 1 %; N = 3) or 2.55 ± 0.03 mg/g test item,


• • 1.45 ± 0.02 mg/L Mn (CVbetween-vessel = 1 %; N = 3) or 7.22 ± 0.08 mg/g test item,


• • 0.366 ± 0.010 mg/L Ni (CVbetween-vessel = 3 %; N = 3) or 1.83 ± 0.05 mg/g test item,

 

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

Based on the specific surface area of LNMO (i.e. 0.2 m²/g), this corresponds to an element release per surface of:

• • 13 mg/m² lithium,


• • 36 mg/m² manganese,


• • 9.1 mg/m² nickel.

 

Based on the element contents (i.e. 3.87 % Li, 44.7 % Mn and 14.9 % Ni) in the test item and the average dissolved element concentrations in the test solutions, a release of:

• • lithium of 6.6 % of the content,


• • manganese of 1.6 % of the content,


• • nickel of 1.2 % of the content,

 

could be calculated at the 2 hours endpoint.

 

In the test item vessels with a loading of 2 g/L LNMO, the following average dissolved element concentration of:

• • 5.44 ± 0.09 mg/L Li (CVbetween-vessel = 2 %; N = 3) or 2.72 ± 0.05 mg/g test item,


• • 14.1 ± 0.5 mg/L Mn (CVbetween-vessel = 3 %; N = 3) or 7.03 ± 0.24 mg/g test item,


• • 3.64 ± 0.03 mg/L Ni (CVbetween-vessel = 1 %; N = 3) or 1.82 ± 0.02 mg/g test item,

 

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

Based on the specific surface area of LNMO (i.e. 0.2 m²/g), this corresponds to an element release per surface of:

• • 14 mg/m² lithium,


• • 35 mg/m² manganese,


• • 9.1 mg/m² nickel.

 

Based on the element contents (i.e. 3.87 % Li, 44.7 % Mn and 14.9 % Ni) in the test item and the average dissolved element concentrations in the test solutions, a release of:

• • lithium of 7.0 % of the content,


• • manganese of 1.6 % of the content,


• • nickel of 1.2 % of the content,

 

could be calculated at the 2 hours endpoint.

The results of this study can be used as a tool to correct the hazard classification, establish categories for grouping, or justify test waivers.