Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2014-09-19 to 2015-02-17
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Meets generally accepted scientific standards, well documented and acceptable for assessment.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2015
Report date:
2015

Materials and methods

Objective of study:
bioaccessibility (or bioavailability)
Test guideline
Qualifier:
no guideline available
Deviations:
not applicable
Principles of method if other than guideline:
This report measured bioaccessibility of titanium nitride in body fluid simulants as a surrogate for bioavailability.
GLP compliance:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Titanium nitride
EC Number:
247-117-5
EC Name:
Titanium nitride
Cas Number:
25583-20-4
Molecular formula:
NTi
IUPAC Name:
titanium nitride
Test material form:
not specified
Details on test material:
- Name of test material (as cited in study report): Titanium nitride
- Substance type: inorganic
- Analytical purity: 76.8 % titanium
Radiolabelling:
no

Test animals

Species:
other: not applicable
Strain:
other: not applicable
Sex:
not specified
Details on test animals or test system 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 / concentrations
Remarks:
Doses / Concentrations:
0.1 g of test substance in 50 mL of simulated fluid
No. of animals per sex per dose / concentration:
Not applicable
Control animals:
other: not applicable
Positive control reference chemical:
Not applicable
Details on study design:
Titanium nitride was extracted in simulated leaching fluids for two time points: 2 hrs and 24 hrs. The extractions were performed using 0.1 gram of sample in 50 mL of simulated fluid. A shaker water bath at a temperature of 37± 2 °C was used. All extractions were performed in duplicate. The extracts were analyzed for soluble titanium using EPA Method #200.8 (ICP/MS). Results were reported as µg Ti/g sample and as % Ti release/Ti content.
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 (or Bioavailability)

Bioaccessibility (or Bioavailability) testing results:
see below (Table 1-5)

Any other information on results incl. tables

Table 1: Soluble Titanium in Simulated Gastric Fluid

Extraction

Weight used (g)

µg Titanium/

g Sample

% Titanium release/ Titanium content

2 hours

0.1014

2,643

0.34

(dup)

0.1012

2,619

0.34

24 hours

0.1021

17,777

2.31

(dup)

0.1024

18,138

2.36

 

Table 2: Soluble Titanium in Simulated Interstitial Fluid

Extraction

Weight used (g)

µg Titanium/

g Sample

% Titanium release/ Titanium content

2 hours

0.1003

<50

-

(dup)

0.1017

<50

-

24 hours

0.1011

<50

-

(dup)

0.1023

<50

-

 

Table 3: Soluble Titanium in Simulated Lysosomal Fluid

Extraction

Weight used (g)

µg Titanium/

g Sample

% Titanium release/ Titanium content

2 hours

0.1028

269

0.04

(dup)

0.1006

270

0.04

24 hours

0.1015

842

0.11

(dup)

0.1010

827

0.11

 

Table 4: Soluble Titanium in Artificial Perspiration

Extraction

Weight used (g)

µg Titanium/

g Sample

% Titanium release/ Titanium content

2 hours

0.1003

<50

-

(dup)

0.1019

<50

-

24 hours

0.1006

82

0.01

(dup)

0.1010

97

0.01

Table 5: Soluble Titanium in PBS

Extraction

Weight used (g)

µg Titanium/

g Sample

% Titanium release/ Titanium content

2 hours

0.1033

<50

-

(dup)

0.1007

<50

-

24 hours

0.1003

53

0.01

(dup)

0.1006

61

0.01

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): low bioaccumulation potential based on study results
The release of titanium ions from titanium nitride is low in artifical body fluids. The more acidic the simulated fluid, the more titanium ions are released, i.e. 2.34 % titanium in simulated gastric fluid (pH 1.5) and 0.11 % in simulated lysosomal fluid (pH 4.5) after 24 hours.
Executive summary:

This report measured bioaccessibility of titanium nitride as a surrogate for bioavailability. Soluble titanium was measured using the EPA method #200.8 (ICP/MS) after incubation of titanium nitride in simulated body fluids (simulated gastric fluid, simulated interstitial fluid, simulated lysosomal fluid, and artificial perspiration). Results were reported as µg Ti/g sample and % Ti release/Ti content.

Overall, 24 hours of extraction time resulted in higher values of solved titanium as after 2 hours of extraction time. The amount of solved titanium, given as µg Ti/g sample and % Ti release/Ti content are summarized in the table below (mean values of the duplicates):

Simulated Body Fluid pH Extraction Time  µg Ti/
g sample
% Ti release/
Ti content
Gastric fluid pH 1.5 2 h 2,631 0.34
24 h 17,96 2.34
Intersitital fluid pH 7.4± 0.2 2 h

<50

 BDL

24 h

<50

 BDL

Lysosomal fluid pH 4.5-5.0 2 h 270 0.04
24 h 835 0.11
Artificial Perspiration pH 6.5 ± 0.1 2 h

<50

 BDL

24 h

89.5

0.01

BDL: Below detection limit. In summary, release of titanium ions from titanium nitride is highest at acidic pH 1.5. The bioavailability in the fluids ranged from BDL (simulated interstitial fluid and artifical perspiration) to 2.34 % (simulated gastric fluid, 24 h extraction). Based on the results, the bioavailability of titanium nitride would be expected to be low and depends on the route of administration.