Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2016-09-07 to 2017-01-17
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:
2017
Report Date:
2017

Materials and methods

Objective of study:
bioaccessibility
Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
This report measured bioaccessibility of Zirconium disilicide in body fluid simulants as a surrogate for bioavailability.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Details on test material:
SOURCE OF TEST MATERIAL
- Zirconium disilicide ZrSi2 (HF < 0.2 %)
- Source: HC Starck, Material: 1036384,
- Batch: 87231
- Zr Content: 61.1 % w/w
- Particle size distribution: d50: 76.2 µm
d90: 114.3 µm
Radiolabelling:
no

Test animals

Species:
other: not applicable
Strain:
other: not applicable
Details on species / strain selection:
not applicable
Sex:
not specified
Details on test animals and environmental conditions:
not applicable

Administration / exposure

Route of administration:
other: in vitro study
Vehicle:
other: not applicable
Details on exposure:
not applicable
Duration and frequency of treatment / exposure:
not applicable
Doses / concentrationsopen allclose all
Dose / conc.:
0.2 other: g/L
Remarks:
Loading (Gastric bio-elution test)
Dose / conc.:
2 other: g/L
Remarks:
Loading (Sweat bio-elution test)
Dose / conc.:
2 other: g/L
Remarks:
Loading (Alveolar bio-elution test)
Dose / conc.:
2 other: g/L
Remarks:
Loading (Lyosomal bio-elution test)
No. of animals per sex per dose:
not applicable
Control animals:
other: not applicable
Positive control:
not applicable
Details on study design:
Please see box "Any other information on materials and method incl. tables"
Details on dosing and sampling:
not applicable
Statistics:
not applicable

Results and discussion

Preliminary studies:
not applicable

Toxicokinetic / pharmacokinetic studies

Details on absorption:
not applicable
Details on distribution in tissues:
not applicable
Details on excretion:
not applicable

Metabolite characterisation studies

Metabolites identified:
not measured
Details on metabolites:
not applicable

Bioaccessibility

Bioaccessibility testing results:
The results of the bio-elution tests (see tables 1-5 in box "Any other information on results incl. tables") showed a consistent very low metal release in all the artificial media tested. The highest zirconium release concentration was found in lysosomal fluid with 0.035% after 72 hours of incubation.

Any other information on results incl. tables

Table 1: Summary of Results

Metal release in Gastric test (µg/L)

% Solubility (0.2 g/L loading)

2 h

CV [%]

2 h

CV [%]

0.4

53

0.0003

53

Metal release in Lyosomal fluid (µg/L)

% Solubility (2 g/L loading)

24 h

CV [%]

72 h

CV [%]

72 h

CV [%]

193.1

2

424.0

5

0.035

5

Metal release in Alveolar fluid (µg/L)

% Solubility (2 g/L loading)

24 h

CV [%]

72 h

CV [%]

72 h

CV [%]

40.1

9

75.6

2

0.006

2

Metal release in Perspiration fluid (µg/L)

% Solubility (2 g/L loading)

24 h

CV [%]

168 h

CV [%]

168 h

CV [%]

1.72

14

17.45

5

0.0014

5

Table 2: Results of the Gastric bio-elution test

Gastric test parameters Zirconium, µg/L
  Time [h] T [°C] pH Mean SD CV [%]
Blanks 0 37 1.50 0.10 0.05 72
2 37 1.50 BDL - -
ZrSi2 0 37 1.50 0.1 0.06 85
2 37 1.51 0.4 0.19 53

CV corresponds to the coefficient of variation between vessels. BDL: Below detection limit.

Zr values reported in Blanks for vessels 1 and 2 were below the practical quantitation level for the gastric media (PQL = 0.5 μg/L). The same analysis is valid for Zr samples measurements.

Table 3: Results of the Lyosomal bio-elution test

Lyosomal test parameters Zirconium, µg/L
  Time [h] T [°C] pH Mean SD CV [%]
Blanks 0 37 4.50 - -
2 37 4.48 BDL - -
24 37 4.47 BDL - -
72 37 4.45 BDL - -
ZrSi2 0 37 4.50 BDL - -
2 37 4.45 40.8 0.5 1
24 37 4.43 193.1 3.7

2

72 37 4.45 424.0 20.6

5

CV corresponds to the coefficient of variation between vessels. BDL: Below detection limit.

Table 4: Results of the Alveolar bio-elution test

Alveolar test parameters

Zirconium, µg/L

 

Time [h]

T [°C]

pH

Mean

SD

CV [%]

Blanks

0

37

7.41

BDL

-

-

2

37

7.27

BDL

-

-

24

37

7.29

BDL

-

-

72

37

7.40

BDL

-

-

ZrSi2

0

37

7.41

BDL

-

-

2

37

7.32

8.6

1.1

13

24

37

7.30

40.1

3.6

9

72

37

7.20

75.6

1.6

2

CV corresponds to the coefficient of variation between vessels. BDL: Below detection limit.

Table 5: Results of the Sweat bio-elution test

Alveolar test parameters

Zirconium, µg/L

 

Time [h]

T [°C]

pH

Mean

SD

CV [%]

Blanks

0

30

6.67

BDL

-

-

24

30

6.30

BDL

-

-

168

30

6.07

BDL

-

-

ZrSi2

0

30

6.67

BDL

-

-

24

30

6.36

1.72

0.23

14

168

30

5.63

17.45

0.84

5

CV corresponds to the coefficient of variation between vessels. BDL: Below detection limit.

Applicant's summary and conclusion

Conclusions:
The release of zirconium ions from Zirconium disilicide is very low in artifical body fluids. Based on the results, the bioavailability of Zirconium disilicide can be considered to be very low for all routes of administration.
Executive summary:

A study to estimate the bioaccessibility of Zirconium disilicide in different artificial media: gastric juice, lysosomal, alveolar and perspiration fluids; representing ingestion, inhalation and dermal contact routes of exposure in humans, was performed. The rate and extend of the metal released in these in vitro simulations of biological compartments can be used for human health hazard classification of this substance.

The results showed a consistent very low metal release in all the artificial media tested. The highest zirconium release concentration was found in lysosomal fluid with 0.035% after 72 hours of incubation. Metal release (μg/L) and solubility results (percentage) are summarized in the Table below.

Simulated Body Fluid pH Extraction time (h) µg Zr/L sample % Zr release
Gastric fluid 1.51 2 0.4 0.0003
Lysosomal fluid 4.43 24 193.1  -
4.45 72 424 0.035
Alveolar fluid 7.30 24 40.1 -
7.20 72 75.6 0.006
Perspiration fluid 6.36 24 1.72 -
5.63 168 17.45 0.0014