Tungsten disulphide

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

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

Objective of study:

bioaccessibility (or bioavailability)

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, July 2016)

Version / remarks:

Based on ASTM D5517-07: Standard Test method for determining the extractability of metals from art materials - ASTM, 2007 (American Society for Testing and Materials)

GLP compliance:

yes (incl. QA statement)

Dose / conc.:

200 ppm (analytical)

Remarks:

Loading 0.2 g/L

Positive control reference chemical:

Not applicable

Details on study design:

Test conditions:
- Temperature controlled at 37 °C ± 1 °C, in the dark,
- pH initially set at pH 1.5 ± 0.1,
- Agitation speed 100 rpm in a temperature controlled orbital laboratory shaker (orbital size: 1 inch, 2.54 cm).

Performance:
One borosilicate Erlenmeyer flask of 250 mL was used for the blank control vessel without test item. In the test vessels, 10 mg test item were weighed in triplicate into three separate 250 mL Erlenmeyer flasks. A fourth replica with test item (named replica X) was prepared only for the measurement of the initial pH (at the start of the test). This additional test vessel was set up to avoid cross contaminations and did not have further utility in the test. 50 mL of extraction fluid (at 37 °C ± 1 °C) was added to the blank control vessel and each test item vessel. After covering the vessels with a screwcap and swirling the flasks to mix the test item and the medium, the flasks were placed into a thermostatic orbital shaker (37 °C ± 1 °C) at an agitation rate of 100 revolutions per minute for one hour. After that, the flasks were settled at 37 °C ± 1 °C for another hour.

Details on dosing and sampling:

At the end of the incubation period (2 hours = 1 hour shaking at 100 rpm and 1 hour settling), each vessel was swirled to homogenise the solution prior to sampling, in order to avoid a concentration gradient after settling.

Sampling was performed for the blank control and each test item vessel as indicated in the sampling scheme below. In each test vessel, a 12-mL sample was taken twice with a 12 mL syringe from the test vessel at a depth of two-thirds of the supernatant. The samples were filtrated through a 0.2 µm syringe filter and transferred to uniquely labelled 15-mL PP sample tubes. The samples were preserved by adding 0.12 mL concentrated HNO3 per 12 mL. The samples were covered (to avoid evaporation and concentration) and stored at room temperature in the dark..

The determination of dissolved tungsten concentrations in the blank control and test item vessels were carried out using an ICP-MS

Statistics:

The data from the analytical laboratory are expressed in µg element per L solution. These data are recalculated (blank corrected and taken into account the actual weighed amount of test item) and expressed in µg element per g test item and as percent metal release of the total available element.

The results are also expressed as released element per surface (mg/m²), based on the results of the N-BET analyses. The dataset of n vessels were analysed. The between-vessel mean, standard deviation, and coefficient of variation of the measured dissolved element concentrations.

A between-vessel coefficient of variation of <20% are quality criteria for the 2 hours endpoint. With very low concentrations close to the detection limit of the analytical method, such as may be with blanks or with a substance that releases element concentrations close to the detection limit, the betweenvessel coefficient of variation can be expected to exceed this target coefficient of variation. Moreover, should the substance be characterised by a wide particle size range, the possibility exists that this coefficient of variation target may not be readily met

Metabolites identified:

no

Bioaccessibility (or Bioavailability) testing results:

he following observations could be made in the test vessels with a loading of 0.2 g/L Tungsten Disulphide:
- A silvery shining layer of particles covered the surface of the test fluid. Remaining test item (grey particles) could be observed at the bottom of the Erlenmeyer flasks at the end of the experiment. The test solutions were colourless. A slight smell of H2S could be observed.

- An average dissolved tungsten concentration of 98.4 ± 1.0 µg/L W (or 491 ± 5 µg/g test item) was measured after 2 hours of exposure to the simulated gastric fluid (pH 1.5) with a between-vessel variation of 1 % which meets the 20 % quality criterion at the 2 hours endpoint.

- Based on the specific surface area of Tungsten Disulphide (2.70 m²/g test item) a tungsten release per surface of 0.18 mg/m² was calculated.
- Based on the tungsten content of the test item (i.e. 74.0 %) and the average dissolved tungsten concentration, a tungsten release of 0.066 % could be calculated at the 2 hours endpoint.

The temperature of the test solutions at the sampling point was between 36.9 °C and 37.1 °C, which was in line with the 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 start of the test was 1.50 i.e. within the specifications of pH 1.5 ± 0.1. At the 2 hours sampling point of the test, the pH in the blank control vessels and the test vessels was between 1.50 and 1.51. The blank control vessel showed no concentrations of tungsten above the reporting limit of 0.5 µg/L W

Conclusions:

During this study on Tungsten Disulphide at a loading of 0.2 g/L in simulated gastric fluid (pH 1.5), it was shown that for tungsten an average value of 98.4 µg/L W (CV = 1 %) was found after 2 hours of extraction, corresponding with a tungsten release of 0.066 % (or 0.18 mg/m²).

Executive summary:

Bio-elution 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 resulting value is the “bio-accessibility”, and is defined as the “fraction of a substance that is soluble under physiological conditions and therefore potentially available for absorption into systemic circulation”. The objective of this study was to obtain knowledge about the bio-elution characteristics of Tungsten Disulphide in simulated gastric fluid. This study has been conducted according to the recommended Standard Operating Procedure (SOP) for Bioelution Testing of Metals, Inorganic Metal Compounds, and Metal-Containing Complex Materials: Simulated Gastric Fluid (Eurometaux, July 2016) which is based on ASTM D5517-07: Standard Test method for determining the extractability of metals from art materials - ASTM, 2007 (American Society for Testing and Materials). The extent of dissolution of Tungsten Disulphide with a particle size <100 µm was tested in a simulated gastric fluid at 37 °C and pH 1.5 during 2 hours (0.2 g/L loading) at an agitation speed of 100 revolutions per minute (rpm). The bio-elution endpoints were based on the dissolved tungsten (W) concentrations obtained after 2 hours of extraction. The study was performed at ECTX. Analysis of the concentrations of dissolved tungsten has been performed at Waterlaboratorium Noord (WLN) (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 start of the test was 1.50 i.e. within the specifications of pH 1.5 ± 0.1. At the 2 hours sampling point of the test, the pH in the blank control vessels and the test vessels was between 1.50 and 1.51. The temperature of the sampled test solutions including the blank test vessel was between 36.9 °C and 37.1 °C and corresponded to the required test conditions of 37 °C ± 1 °C. The blank control vessels showed no concentrations of tungsten above the reporting limit of 0.5 µg/L W. In the blank corrected test item vessels with a loading of 0.2 g/L Tungsten Disulphide, the following average dissolved tungsten concentration of: 98.4 ± 1.1 µg/L W (CV = 1 %), was measured after 2 hours of exposure to the simulated gastric fluid (pH 1.5).

- Based on the specific surface area of Tungsten Disulphide (i.e. 2.70 m²/g), this corresponds with a tungsten release per surface of: 0.18 mg/m².

- Based on the tungsten content (i.e. 74.0 %) in the test item and the average dissolved tungsten concentrations in the test solutions a tungsten release of: 0.066 %, could be calculated at the 2 hours endpoint.

Reference 2

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

Objective of study:

bioaccessibility (or bioavailability)

Qualifier:

according to guideline

Guideline:

other: Standard Operating Procedure (SOP) for the Bio-accessibility Testing Programme of Eurometaux

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: International Tungsten Industry Association/ S606078
- Expiration date of the lot/batch: 06/2017
- Purity test date:

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Room temperature, in the dark

Radiolabelling:

no

Vehicle:

not specified

Dose / conc.:

2 000 ppm

Remarks:

2 g/L loading

Positive control reference chemical:

Not Specified.

Details on study design:

Test conditions
Temperature: controlled at 37 °C ± 1 °C, in the dark,
pH initially set at pH 7.4 ± 0.2,
Agitation speed 171 rpm on a temperature controlled orbital laboratory shaker (orbital size: 1 inch, 2.54 cm), in the dark.

Test Performance:
Three borosilicate Erlenmeyer flasks of 250 mL were used as blank control vessels. In the test vessels 100 mg of test item was weighed into nine separate 250 mL Erlenmeyer flasks, three replicate flasks for each sampling time (i.e. at 24, 72 and 168 hours). A tenth replica with test item (named replica X) was

prepared only for the measurement of the initial pH (at the start of the test). This additional test vessel did not have further utility in the test. 50 mL of extraction fluid (37 °C ± 1 °C) was added to each blank control and test item vessel. After swirling the flasks to mix the test item and the medium, the pH of the solution of replicate X was checked to assure that it was at 7.4 ± 0.2. This procedure was used to avoid cross contaminations. Since the pH did not alter immediately after addition of the test system to the test item, there was no need for pH correction in the test vessels. The flasks were covered with a Duran Schott GL45 membrane screw cap and placed into a thermostatic orbital shaker (37 °C ± 1 °C) at an agitation rate of 171 revolutions per minute. To maintain the pH throughout the extraction at 7.4 ± 0.2, 5% CO2 in air was introduced in the test vessels during the test. A set of one blank control vessel and three test item vessels was removed for sampling after 24 hours of shaking. Another set of one blank control vessel and three test item vessels was sampled after 72 hours of shaking. And the remaining set was sampled at the end of the test (168 hours endpoint).

Details on dosing and sampling:

After the appropriate extraction time, the test vessels have been left to settle for a standardized length of time. After a settling period of 3 to 5 minutes, the test vessels were removed from the thermostatic shaker.
Sampling was performed for each test vessel as indicated in the sampling scheme below. In each test vessel, a 12-mL sample was taken with a 12 mL syringe at a depth of two third of the supernatant. The samples were filtrated through a 0.2 µm syringe filter and transferred to uniquely labelled 15-mL PP sample tubes. The samples were preserved by adding 0.12 mL concentrated HNO3 per 12 mL. The samples were stored at room temperature in the dark

The determination of dissolved tungsten concentrations in the blank control and test item vessels were carried out using an ICP-MS

Statistics:

The data from the analytical laboratory are expressed in µg or mg element per L solution.
These data are recalculated (blank corrected and taken into account the actual weighed amount of test item) and expressed in µg or mg element per g test item and as percent element release of the total available element.
The results are also expressed as released element per surface (mg/m²), based on the results of the NBET analyses.
A between-vessel coefficient of variation of <20 % are quality criteria for the 168 hours endpoint.
With very low concentrations close to the detection limit of the analytical method, such as may be with blanks or with a substance that releases element concentrations close to the detection limit, the between-vessel coefficient of variation can be expected to exceed this target coefficient of variation. Moreover, should the substance be characterised by a wide particle size range, the possibility exists that this coefficient of variation target may not be readily met.

Bioaccessibility (or Bioavailability) testing results:

The following observations could be made in the test vessels with a loading of 2 g/L Tungsten Disulphide:
A silvery shining layer of particles covered the surface of the test fluid. Remaining test item (grey particles) could be observed at the bottom of the Erlenmeyer flasks at all sampling times of the experiment. The test solutions remain colourless during the study. A slight smell of H2S could be observed in the test item vessels.
168 hours endpoint:
An average dissolved tungsten concentration of 60.8 ± 5.9 mg/L W (or 30.4 ± 3.0 mg/g test item) was measured after 168 hours of exposure to the simulated interstitial fluid (pH 7.4) with a between-vessel variation of 10 % which meets the <20 % quality criterion at the 168 hours endpoint.
Based on the specific surface area of Tungsten Disulphide (2.70 m²/g test item) a tungsten release per surface of 11 mg/m² was calculated.
Based on the tungsten content of the test item (i.e. 74.0 %) and the average dissolved tungsten concentration, a tungsten release of 4.1 % could be calculated at the 168 hours endpoint.

The temperature of the sampled test solutions including the blank test vessel was between 36.8 °C and 37.1 °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 7.41, i.e. within the specifications of pH 7.4 ± 0.2. The pH measured in the additional test item vessel at the start of the test was 7.40 i.e. within the specifications of pH 7.4 ± 0.2. Therefore, pH adjustment of the test vessels was not needed. During the test, the pH in the blank control vessel and the test item vessels were between 7.39 and 7.48.

Conclusions:

During this study on Tungsten Disulphide at a loadng of 2g/L in simulated interstitial fluid (pH7.4), it as shown that for Tungsten an average value of 11.6 mg/L W (CV = 9%) was found after 24 hours of extraction, corresponding with a tungsten release of 0.78 (or 2.1 mg/m^2).

Executive summary:

The objective of this study was to obtain knowledge about the bio-elution characteristics ofTungsten Disulphidein simulated interstitial fluid. This study has been conducted according to the recommended Standard Operating Procedure (SOP) for the Bio-accessibility Testing Programme of Eurometaux (November 10, 2010). The extent of dissolution ofTungsten Disulphidewith a particle size <10 µm was tested in a simulated interstitial fluid at 37 °C and pH 7.4 during 168 hours (2 g/L loading) at an agitation speed of 171 revolutions per minute (rpm). The bio-elution endpoints were based on the dissolved tungsten concentrations obtained after 24, 72 and 168 hours of extraction. During this study onTungsten Disulphideat a loading of 2 g/L in simulated interstitial fluid (pH 7.4), it was shown that for tungsten an average value of 11.6 mg/L W (CV = 9 %) was found after 24 hours of extraction, corresponding with a tungsten release of 0.78 % (or 2.1 mg/m²).

At the 72 hours sampling point, an average value of 22.4 mg/L (CV = 6 %) was found, corresponding with a tungsten release of 1.5% (or 4.2 mg/m²). At the 168 hours endpoint, an average value of 60.8 mg/L (CV = 10 %) was found, corresponding with a tungsten release of 4.1% (or 11 mg/m²).

The results can be assumed reliable since the test conditions stayed constant during the experiment.

Reference 3

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

16-01-2017,06-02-2017

Reliability:

1 (reliable without restriction)

Objective of study:

absorption

Qualifier:

according to guideline

Guideline:

other: Standard Operating Procedure (SOP) for the Bio-accessibility Testing Programme of Eurometaux

GLP compliance:

yes (incl. QA statement)

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material:
- Expiration date of the lot/batch: ITIA S606078
- Purity test date:

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material:Room temperature, in the dark

Radiolabelling:

no

Dose / conc.:

200 ppm

Remarks:

2 g/L loading

Positive control reference chemical:

Not Specified

Details on study design:

Test conditions
 Temperature: controlled at 37 °C ± 1 °C, in the dark,
 pH initially set at pH 4.5 to 5.0,
 Agitation speed 171 rpm on a temperature controlled orbital laboratory shaker (orbital size: 1 inch, 2.54 cm), in the dark
Performance
Test set-up
Three borosilicate Erlenmeyer flasks of 250 mL were used as blank control vessels (one for each sampling time). In the test vessels, 100 mg of test item was weighed into nine separate 250 mL Erlenmeyer flasks, three replicate flasks for each sampling time (i.e. at 24, 72 and 168 hours). A tenth replica with test item (named replica X) was prepared only for the measurement and correction of the initial pH (at the start of the test). This additional test vessel had no further utility in the test. 50 mL of extraction fluid
(37 °C ± 1 °C) was added to each blank control and test item vessel. After swirling the flasks to mix the

test item and the medium, the pH of the solution of replicate X was checked to assure that it ranges between 4.5 and 5.0. This procedure was used to avoid cross contaminations. Since the pH did not alter after addition of the test system to the test item, there was no need for pH correction in the test vessels. The flasks were covered with a GL45 screw cap and placed into a thermostatic orbital shaker (37 °C ± 1 °C) at an agitation rate of 171 revolutions per minute. A set of one blank control vessel and three test vessels were removed for sampling after 24 hours of shaking. Another set of one blank control vessel and three test vessels will be sampled after 72 hours of shaking. And the remaining set will be sampled at the end of the test (168 hours endpoint).

Details on dosing and sampling:

Sampling during the test
The following sampling procedure was used at each sampling time to collect and preserve the samples for ICP-MS analyses:
After the appropriate extraction time, the test vessels have been left to settle for a standardized length of time. After a settling period of 3 to 5 minutes, the test vessels were removed from the thermostatic shaker.
Sampling was performed for each test vessel as indicated in the sampling scheme below. In each test vessel, a 12-mL sample was taken with a 12 mL syringe at a depth of two third of the supernatant. The samples were filtrated through a 0.2 µm syringe filter and transferred to uniquely labelled 15-mL PP sample tubes. The samples were preserved by adding 0.12 mL concentrated HNO3 per 12 mL. The samples were stored at room temperature in the dark

Statistics:

The data from the analytical laboratory are expressed in µg or mg element per L solution.
These data are recalculated (blank corrected and taken into account the actual weighed amount of test item) and expressed in µg or mg element per g test item and as percent element release of the total available element.
The results are also expressed as released element per surface (mg/m²), based on the results of the NBET analyses.
The dataset of n vessels is analysed.
A between-vessel coefficient of variation of <20 % are quality criteria for the 168 hours endpoint.
With very low concentrations close to the detection limit of the analytical method, such as may be with blanks or with a substance that releases element concentrations close to the detection limit, the between-vessel coefficient of variation can be expected to exceed this target coefficient of variation. Moreover, should the substance be characterised by a wide particle size range, the possibility exists that this coefficient of variation target may not be readily met.

Bioaccessibility (or Bioavailability) testing results:

A silvery shining layer of particles covered the surface of the test fluid. Remaining test item (grey particles) could be observed at the bottom of the Erlenmeyer flasks at all sampling times of the experiment. The test solutions remain colourless during the study. A slight smell of H2S could be observed in the test item vessels.
168 hours endpoint:
An average dissolved tungsten concentration of 42.5 ± 0.4 mg/L W (or 21.2 ± 0.2 mg/g test item) was measured after 168 hours of exposure to the simulated lysosomal fluid (pH 4.55.0) with a between-vessel variation of 1 % which meets the <20 % quality criterion at the 168 hours endpoint.
Based on the specific surface area of Tungsten Disulphide (2.70 m²/g test item) a tungsten release per surface of 7.9 mg/m² was calculated.
Based on the tungsten content of the test item (i.e. 74.0 %) and the average dissolved tungsten concentration, a tungsten release of 2.9 % could be calculated at the 168 hours endpoint.

The temperature of the sampled test solutions including the blank test vessel was between 36.8 °C and 37.1 °C and corresponded to the required test conditions of 37 °C ± 1 °C.

The blank control vessels showed no concentrations of tungsten above the reporting limit of 5 µg/L W.

The measured pH of the test medium at the start of the test was 4.75, i.e. within the specifications of pH 4.5-5.0.The pH measured in the additional test item vessel at the start of the test was 4.75 i.e. within the specifications of pH 4.5-5.0. Therefore, pH adjustment of the test vessels was not needed. During the test, the pH in the blank control vessel and the test item vessels were between 4.74 and 4.77.

Conclusions:

During this study on Tungsten Disulphide at a loading of 2 g/L in simulated lysosomal fluid (pH 4.5-5.0), it was shown that for tungsten an average value of 15.0 mg/L W (CV = 2 %) was found after 24 hours of extraction, corresponding with a tungsten release of 1.0 % (or 2.8 mg/m²).
At the 72 hours sampling point, an average value of 27.7 mg/L (CV = 0 %) was found, corresponding with a tungsten release of 1.9% (or 5.1 mg/m²).
At the 168 hours endpoint, an average value of 42.5 mg/L (CV = 1 %) was found, corresponding with a tungsten release of 2.9% (or 7.9 mg/m²).
The results can be assumed reliable since the test conditions stayed constant during the experiment.

Executive summary:

The objective of this study was to obtain knowledge about the bio-elution characteristics ofTungsten Disulphidein simulated lysosomal fluid. This study has been conducted according to the recommended Standard Operating Procedure (SOP) for the Bio-accessibility Testing Programme of Eurometaux (November 10, 2010). The extent of dissolution ofTungsten Disulphidewith a particle size <10 µm was tested in a simulated lysosomal fluid at 37 °C and pH 4.5-5.0 during 168 hours (2 g/L loading) at an agitation speed of 171 revolutions per minute (rpm). The bio-elution endpoint was based on the dissolved tungsten (W) concentrations obtained after 24, 72 and 168 hours of extraction.

The study was performed at ECTX. Analysis of the concentrations of dissolved tungsten has been performed at Waterlaboratorium Noord (WLN) (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 4.75, i.e. within the specifications of pH 4.5-5.0.The pH measured in the additional test item vessel at the start of the test was 4.75 i.e. within the specifications of pH 4.5-5.0. Therefore, pH adjustment of the test vessels was not needed. During the test, the pH in the blank control vessel and the test item vessels were between 4.74 and 4.77.

The temperature of the sampled test solutions including the blank test vessel was between 36.8 °C and 37.1 °C and corresponded to the required test conditions of 37 °C ± 1 °C. The blank control vessels showed no concentrations of tungsten above the reporting limit of 5 µg/L W.

At the 168 hours endpoint, an average value of 42.5 mg/L (CV = 1 %) was found, corresponding with a tungsten release of 2.9% (or 7.9 mg/m²).

The results can be assumed reliable since the test conditions stayed constant during the experiment.

Reference 4

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

16-02-2017,09-02-2017

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Objective of study:

bioaccessibility (or bioavailability)

Qualifier:

according to guideline

Guideline:

other: Standard Operating Procedure (SOP) for the Bio-accessibility Testing Programme of Eurometaux

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Dose / conc.:

2 000 ppm

Remarks:

2 g/L loading

Positive control reference chemical:

Not Specified

Details on study design:

Test conditions
 Temperature: controlled at 30 °C ± 1 °C, in the dark,  pH initially set at pH 6.5 ± 0.1.

Performance
Three borosilicate Erlenmeyer flasks of 250 mL were used as blank control vessels (one for each sampling time). In the test vessels, 100 mg of test item was weighed into six separate 250 mL Erlenmeyer flasks, three replicate flasks for each sampling time (i.e. at 24, 72h and 168 hours). A tenth replica with test item (named replica X) was prepared only for the measurement of the initial pH (at the start of the test). This additional test vessel had no further utility in the test. 50 mL of extraction fluid (30 °C ± 1 °C) was added to each blank control and test item vessel. After swirling the flasks to mix the test item and the medium, the pH of the solution of replicate X was checked to assure that it was at pH 6.5 ± 0.1. This procedure was used to avoid cross contaminations. Since the pH did not alter after addition of the test system to the test item, there was no need for pH correction in the test vessels. The flasks were covered

with a GL45 screw cap and placed into a thermostatic orbital shaker (30 °C ± 1 °C) without agitation. The shaker was only be used as a temperature-conditioned space. A set of one blank control vessel and three test vessels were removed for sampling after 24 hours of incubation. Another set of one blank control vessel and three test vessels will be sampled after 72 hours of incubation. The remaining flasks (still one blank control vessel and three test vessels) was sampled at the end of the test (168 hours endpoint).

Details on dosing and sampling:

The following sampling procedure was used at each sampling time to collect and preserve the samples for ICP-MS analyses:
At the end of each incubation period (24, 72 and 168 hours), each vessel is swirled to homogenise the solution prior to a settling period of 3 to 5 minutes and sampling, in order to avoid a concentration gradient after settling.
Sampling was performed for each test vessel as indicated in the sampling scheme below. In each test vessel, a 12-mL sample was taken with a 12 mL syringe at a depth of two third of the supernatant. The samples were filtrated through a 0.2 µm syringe filter and transferred to uniquely labelled 15-mL PP sample tubes. The samples were preserved by adding 0.12 mL concentrated HNO3 per 12 mL. The samples were stored at room temperature in the dark

Statistics:

The data from the analytical laboratory are expressed in µg or mg element per L solution.
These data are recalculated (blank corrected and taken into account the actual weighed amount of test item) and expressed in µg or mg element per g test item and as percent element release of the total available element.
The results are also expressed as released element per surface (mg/m²), based on the results of the NBET analyses.
The dataset of n vessels is analysed.
A between-vessel coefficient of variation of <20% are quality criteria for the 168 hours endpoint.
With very low concentrations close to the detection limit of the analytical method, such as may be with blanks or with a substance that releases element concentrations close to the detection limit, the between-vessel coefficient of variation can be expected to exceed this target coefficient of variation. Moreover, should the substance be characterised by a wide particle size range, the possibility exists that this coefficient of variation target may not be readily met.

Metabolites identified:

no

Bioaccessibility (or Bioavailability) testing results:

A silvery shining layer of particles covered the surface of the test fluid. Remaining test item (grey particles) could be observed at the bottom of the Erlenmeyer flasks at all sampling times of the experiment. The test solutions remain colourless during the study. A slight smell of H2S could be observed in the test item vessels. 3. 168 hours endpoint:
An average dissolved tungsten concentration of 36.9 ± 1.3 mg/L W (or 18.5 ± 0.7 mg/g test item) was measured after 168 hours of exposure to the simulated perspiration fluid (pH 6.5) with a between-vessel variation of 4 % which meets the <20 % quality criterion at the 168 hours endpoint.
Based on the specific surface area of Tungsten Disulphide (2.70 m²/g test item) a tungsten release per surface of 6.8 mg/m² was calculated.
Based on the tungsten content of the test item (i.e. 74.0 %) and the average dissolved tungsten concentration, a tungsten release of 2.5 % could be calculated at the 168 hours endpoint.

The temperature of the sampled test solutions fluctuated between 30.1 °C and 30.3 °C, which was in line with the test conditions of 30 °C ± 1 °C (Annex 1).

The measured pH of the test medium at the start of the test was 6.50, i.e. within the specifications of pH 6.5 ± 0.1.The pH measured in the additional test item vessel at the start of the test was 6.51 i.e. within the specifications of pH 6.5 ± 0.1. Therefore, pH adjustment of the test vessels was not needed. During the test, the pH in the blank control vessel and the test vessels were between 6.49 and 6.52.

The blank control vessels showed no concentrations of tungsten above the reporting limits of 5 µg/L W

Conclusions:

During this study on Tungsten Disulphide at a loading of 2 g/L in simulated perspiration fluid (pH 6.5), it was shown that for tungsten an average value of 1.78 mg/L W (CV = 2 %) was found after 24 hours of extraction, corresponding with a tungsten release of 0.12 % (or 0.33 mg/m²).
At the 72 hours sampling point, an average value of 25.0 mg/L (CV = 3 %) was found, corresponding with a tungsten release of 1.7% (or 4.6 mg/m²).
At the 168 hours endpoint, an average value of 36.9 mg/L (CV = 4 %) was found, corresponding with a tungsten release of 2.5% (or 6.8 mg/m²).
The results can be assumed reliable since the test conditions stayed constant during the experiment.

Executive summary:

The objective of this study was to obtain knowledge about the bio-elution characteristics ofTungsten Disulphidein simulated perspiration fluid. This study has been conducted according to the recommended Standard Operating Procedure (SOP) for the Bio-accessibility Testing Programme of Eurometaux (November 10, 2010). The extent of dissolution ofTungsten Disulphidewith a particle size <100 µm was tested in a simulated perspiration fluid at 30 °C and pH 6.5 during 168 hours (2 g/L loading, without agitation). The bio-elution endpoint was based on the dissolved tungsten (W) concentrations obtained after 24, 72 and 168 hours of extraction.

The study was performed at ECTX. Analysis of the concentrations of dissolved tungsten has been performed at Waterlaboratorium Noord (WLN) (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 6.50, i.e. within the specifications of pH 6.5 ± 0.1. The pH measured in the additional test item vessel at the start of the test was 6.51 i.e. within the specifications of pH 6.5 ± 0.1. Therefore, pH adjustment of the test vessels was not needed. During the test, the pH in the blank control vessel and the test item vessels were between 6.49 and 6.52.

The temperature of the sampled test solutions including the blank test vessel was between 30.1 °C and 30.3 °C and corresponded to the required test conditions of 30 °C ± 1 °C.

The blank control vessels showed no concentrations of tungsten above the reporting limit of 5 µg/L W.

At the 168 hours endpoint, an average value of 36.9 mg/L (CV = 4 %) was found, corresponding with a tungsten release of 2.5% (or 6.8 mg/m²).

The results can be assumed reliable since the test conditions stayed constant during the experiment.

Reference 5

Endpoint:

basic toxicokinetics

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Study period:

2010-08-31 to 2010-01-29

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Remarks:

The reliability of this study for the substance tested is a K1, but in application of read-across to a different substance ECHA’s guidance specifies that the score can be a maximum of K2. Due to similar water solubility, in vitro bioaccessibility in synthetic alveolar, lysosomal, and interstitial fluids simulating inhalation exposure, and available toxicity data for the target (tungsten trioxide) and source (tungsten blue oxide) substances, the resulting toxicity potential would also be expected to be similar so read across is appropriate between these substances. In addition, read across is appropriate for this endpoint because the classification and labeling is the same for the source and target substances, the PBT/vPvB profile is the same, and the dose descriptors are, or are expected to be, sufficiently similar. For more details refer to the attached description of the read across approach.

Justification for type of information:

REPORTING FORMAT FOR THE CATEGORY APPROACH
1. HYPOTHESIS FOR THE ANALOGUE APPROACH: The hypothesis is that properties are likely to be similar or follow a similar pattern because of the presence of a common metal ion, in this case tungstate.
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES):
Source: Tungsten Oxide
Target: Tungsten Disulphide
3. CATEGORY APPROACH JUSTIFICATION: See Annex 1 in CSR
4. DATA MATRIX: See Annex 1 in CSR

Reason / purpose for cross-reference:

read-across: supporting information

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Objective of study:

toxicokinetics

Qualifier:

according to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

Principles of method if other than guideline:

The experimental design included toxicokinetic (TK) animals for analysis of TBO content during the 28 days of exposure (TK Sets 1-4) and to assess the elimination phase of the test substance after one day of exposure (TK Set 5).

GLP compliance:

yes

Radiolabelling:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, (St. Constant, Canada)
- Age at study initiation: approximately 8 weeks
- Weight at study initiation: One day following receipt, body weight ranges of the first shipment of rats 226 to 279 g (males). One day following receipt, body weight range of the second shipment of male rats was 207 to 234 g.
- Fasting period before study: no food or water was provided during exposures.
- Housing: At the start of food consumption measurements, the rats were individually housed in clear polycarbonate rodent cages (Allentown Caging Equipment Co., Allentown, NJ) equipped with an automatic watering system.
-Diet: Certified Rodent Chow 5002 meal (PMI Nutrition International, Inc., Brentwood, MO) was provided ad libitum, except during inhalation exposures and scheduled fasting periods. Diet analysis reports received from the supplier are maintained with facility records. The diet contained no known contaminants at levels that would be expected to interfere with the test substance or the animals or confound interpretation of the study.
- Water (e.g. ad libitum): Each rodent cage was provided with an automatic watering system (Edstrom Industries, Inc., Waterford, WI) supplying fresh city of Chicago water without additional treatment ad libitum, except during inhalation exposures.
- Acclimation period: The animals were quarantined for 2 weeks; To condition the animals for placement and restraint in the nose-only exposure tubes, and reduce stress during the exposure phase, the animals were acclimated to the restraining tubes during a three-day acclimation period. Animals were restrained for 1/4 (1.5 hours), 1/2 (3 hours), and 3/4 (4.5 hours) of the daily exposure duration (6 hours) on three non-holiday weekdays before the animals were exposed.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18.6 to 23.0 degree C
- Humidity (%): 25.1-64.6%
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): automatic 12-hour light/dark cycle was maintained in the exposure and housing chamber laboratories.



IN-LIFE DATES: From: 2010-09-09 To: 2010-10-21

Route of administration:

inhalation: dust

Vehicle:

unchanged (no vehicle)

Details on exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: The nose-only chamber employed for test substance exposure was contained in an acrylic enclosure to isolate the exposure chamber and protect laboratory personnel. The dilution air to the atmosphere generator was of breathable quality and was filtered with a compressed air filter and a carbon absorber. The exhaust from the exposure chamber was moved through a particulate filter by a ring compressor and exhausted outside the building. Inlet and exhaust flows to and from the chamber were continuously monitored by rotameters.
- Method of holding animals in test chamber: During the inhalation exposures, the rats were restrained in nose-only exposure animal holding tubes (CH Technologies, Westwood, NJ). Animal tube loading and unloading, and tube insertion and removal from the exposure chamber were performed according to standard procedures designed to minimize stress to study rats. At all times that rats were restrained in holders, they were observed
frequently and when necessary, action was taken to avoid injury, death, or improper exposure. Prior to the start of the exposure, rats were transferred from their housing cages to the nose-only holding tubes. Following confirmation of correct animal number, the animals in the holders were inserted into the ports of the exposure chambers. Following the exposure, the holders were removed. The rats were removed from the holders and returned to their home cages. Chamber port rotation occurred weekly.
- System of generating particulates/aerosols: Test atmospheres in the exposure chambers were generated by aerosolizing the test substance using a compressed air-operated Wright Dust Aeorsol Generation System positioned over the chamber. Each inhalation exposure system was equipped with a separate aerosol generation system. The test substance was weighed out and packed into a dust reservoir daily. A constant speed rotating scraper separated a thin film of the test substance at the surface of the cake and delivered it into a dispersing unit, drawn in by aspiration and dispersed by a high velocity air jet. The resulting test atmosphere entered a mixing plenum where it was diluted with breathable quality compressed air to the target concentration prior to introduction to the nose-only inhalation exposure chamber.
- Air flow rate: The total airflow was set to produce an airflow range of approximately 0.5 to 1.0 L/min/exposure port.
- Method of particle size determination: The aerosol particle size distribution was monitored twice per week during the exposure phase of the study by an Aerodynamic Particle Sizer (APS) 3321 with Aerosol Diluter 3302A (both manufactured by TSI Inc., Shoreview, MN). The APS sizes particles in the range from 0.5 to 20 um using a time-of-flight technique that measures aerodynamic diameter in real time.


TEST ATMOSPHERE
- Brief description of analytical method used: The test atmosphere mass concentration was monitored gravimetrically by collecting gravimetric samples on pre-weighed glass fiber filters placed in closed-face filter holders. Samples were collected at a constant flow rate equal to the port flow of the delivery tube, and the total volume of air sampled was measured by a dry gas meter. Test atmosphere samples were collected at least three times during the exposure (generally, once during the first two hours, once during the middle two hours and once during the last two hours). The filter-collected samples were weighed and one filter per group per day (including the control to confirm the absence of test substance in the test atmosphere) was analyzed chemically to confirm the mass of TBO collected; percent recovery (chemical analysis concentration vs. gravimetric concentration) was calculated for each filter analyzed. Chemical analysis was conducted by means of ICP-mass spectrometry. In addition, the test atmosphere aerosol concentration in each chamber was monitored with a real-time aerosol sensor (model # pDR-1000AN, MIE, Inc. Bedford, MA). The sensors were employed only as a real-time indicator of short-term changes in aerosol concentration and were used in guiding laboratory personnel if concentration excursions were encountered.
- Samples taken from breathing zone: yes

Duration and frequency of treatment / exposure:

Set 1: 6 hours/day, 7 days/week for 28 days
Set 2: 6 hours/day for 3 days
Set 3: 6 hours/day for 7 days
Set 4: 6 hours/day for 14 days
Set 5: 6 hours with 7 day recovery

Remarks:

Doses / Concentrations:
0.08 and 0.65 mg/L (Target TBO concentration); 15.2 and 123.6 mg/kg/day (Target Inhaled Dose)

No. of animals per sex per dose / concentration:

Animals designated for toxicokinetic analysis were divided into five sets consisting of 4 males/set (time point) in each of the Low and High dose groups.

Control animals:

no

Positive control reference chemical:

no

Details on dosing and sampling:

PHARMACOKINETIC STUDY
- Tissues and body fluids sampled: at necropsy the brain, lungs, bone (femur), liver, kidney, spleen and reproductive organs were collected for analysis of TBO concentration. All toxicokinetic-designated animals were euthanized using sodium pentobarbital and exsanguinated from the abdominal aorta. Toxicokinetic animals were bled and necropsied as follows:

Set 1: Blood collection for the Low and High dose groups was performed on TK Day 0 [study Day 1 (pre-exposure)], and after the daily exposure on TK Days 1, 2, 3, 7, 14 and 28 (study Days 2, 3, 4, 8, 15 and 29); feces and urine were also collected from these animals overnight starting on TK Days 0, 1, 2, 3, 7, 14 and 28 (collection occurred the next day). These animals were necropsied on study Day 29. Blood was also collected on study Day 29, but was not chemically analyzed.

Set 2: Blood collection for the Low and High dose groups was performed on TK Day 3 (study Day 4) after the daily exposure and preserved for future evaluation. These animals were necropsied on TK Day 3.

Set 3: Blood collection for the Low and High dose groups was performed on TK Day 7 (study Day 8) after the daily exposure and preserved for future evaluation. These animals were necropsied on TK Day 7.

Set 4: Blood collection for the Low and High dose groups was performed on TK Day 14 (study Day 15) after the daily exposure and preserved for future evaluation. These animals were necropsied on TK Day 14.

Set 5: Blood collection for the Low and High dose groups was performed on this group on TK Day 0 [study Day 28 (pre-exposure)], after the exposure on TK Day 1 (study Day 29), and recovery Days 2, 3, 4, 5, 6 and 7) (study Days 30, 31, 32, 33, 34 and 35); feces and urine were also collected from these animals overnight starting on TK Days 0, 1, 2, 3, 4, 5, 6 and 7 (collection occurred the next day). These animals were necropsied on TK Day 8 (study Day 36) after the final urine and feces collection. Blood was also collected on TK Day 8, but was not chemically analyzed.

Statistics:

no data

Details on absorption:

In the single dose experiment, tungsten was absorbed systemically and blood tungsten concentration reached maximum (Tmax) at 0 hours post-exposure.

Details on distribution in tissues:

Repeat dose experiment:

From the repeat dose experiments, tungsten concentration in lung tissue was at least one order of magnitude greater than in any other organ collected, the lung being the primary organ for TBO exposure via inhalation. In general, the femur and kidney ranked second and third highest in tungsten concentration on a per organ weight basis, respectively. The results indicated that the lung, femur and liver ranked first, second and third for total tungsten burden, respectively. The study day appeared to have little or no effect on the rank of tungsten distribution in tissue and organs. Tungsten concentration in tissue and organs increased with increasing dose, but not in a dose-proportionate manner.
Tungsten concentration in each organ increased with increasing inhalation exposure time for the lung, liver, kidney, spleen, testes, brain and femur, respectively. The increment was not significantly different between study Days 7 and 14, suggesting that steady-state absorption of inhaled TBO was reached on study Day 14. Compared with the steady-state concentration on study Day 14, tungsten in liver, kidney, testes and brain decreased at least 50% on study Day 29; however, unlike toxicokinetic Set 2 to 4 animals (necropsied immediately following termination of inhalation exposure on study Day 3, 7 or 14, respectively), the Set 1 animals were necropsied 24 hours after termination of exposure on study Day 29 to allow for overnight urine and feces collection. The results suggest that the functional elimination half-life of tungsten in those organs was less than 24 hours. On the contrary, tungsten in femur on study Day 29 was no different as compared to study Day 14, indicating that elimination of tungsten from femur was relatively slow as compared to other organs. The results were consistent with the Set 5 results (animals necropsied on Recovery Day 8 following a single inhalation exposure). Tungsten in femur on Recovery Day 8 (Set 5) was approximately one third as compared to that on study Day 3 (Set 2 animals) following multiple inhalation exposure, while tungsten concentration in the rest of organs was at least one order of magnitude lower.

Single administration experiment:

Following inhalation exposure of TBO, tungsten was absorbed systemically, as indicated by maximum blood concentration at 0 hour post-exposure. At 48 hours post-exposure, there was a slow elimination phase following an initial fast elimination phase for the 0.65 mg/L dose group (High). However, the second slow elimination phase was not evident for the 0.08 mg/L dose group (Low), which may be due to background noise of tungsten concentration. Based on the concentrations in the blood, the terminal phase half-life values were determined to be 23 ± 4.3 and 154 ± 92.8 hours for the 0.08 and 0.65 mg/L dose groups, respectively. Maximum blood tungsten concentration was 0.819 ± 0.215 and 10.9 ± 4.7 1.1g/g and area under the blood concentration-time curve extrapolated to infinity was 11.8 ± 3.29 and 148 ± 33.7 hr*i.tg/g for the 0.08 and 0.65 mg/L dose groups, respectively. These two exposure parameters increased proportionally with increasing TBO dose level. The systemic clearance based on the concentrations in the blood was 1.24 ± 0.39 and 0.78 ± 0.18 L/hr/kg for the 0.08 and 0.65 mg/L dose groups, respectively.

Details on excretion:

Repeat dose experiment:

The results from the repeat dose experiments indicate that the amount of tungsten excreted from feces was approximately three orders of magnitude greater than from urine. Since the nasal cavities are the major deposition site for inhaled particles in the rate, the study results suggest that most of the inhaled TBO was deposited in the nasal passages and subsequently ingested into the gastrointestinal tract and excreted with the feces. The study results also indicate that the excretion rate of tungsten from feces and urine and tungsten concentration in blood increased with increasing TBO dose level; however, the effect of study day was sporadic and a discernible trend was not observed.

Single administration experiment:

From the single dose experiment, the results indicate that excretion of tungsten from the gastrointestinal tract was negligible after post-exposure Day 2 and 3 for Groups 2 (Low) and 4 (High), respectively. The results are consistent with the general consensus that insoluble particles deposited in the nasal and tracheobronchial airways would be cleared within 24 hours through mucus escalator followed by ingestion into gastrointestinal tract and excretion with the feces. In contrast, there was still detectable tungsten in urine on post-exposure Day 7.

Key result

Toxicokinetic parameters:

AUC: 11.8 ± 3.29 hr ug/g for the 0.08 mg/L dose group

Key result

Toxicokinetic parameters:

Cmax: 0.819 ± 0.215 ug/g for the 0.08 mg/L dose group

Key result

Toxicokinetic parameters:

half-life 1st: 23 ± 4.3 hours for the 0.08 mg/L dose group

Key result

Toxicokinetic parameters:

AUC: 148 ± 33.7 hr ug/g for the 0.65 mg/L dose group

Key result

Toxicokinetic parameters:

Cmax: 10.9 ± 4.7 ug/g for the 0.65 mg/L dose group

Key result

Toxicokinetic parameters:

half-life 1st: 154 ± 92.8 hours for the 0.65 mg/L dose group

Metabolites identified:

not measured

The mean MMADs of the test atmosphere were 2.63 and 2.74 um with GSDs of 1.89 and 1.92 for the low and high dose groups, respectively.

Overall means for TBO concentrations were determined gravimetrically to be 0.081and 0.652 mg/L for the low and high dose groups, respectively. The TBO % recovery ranged from 100.83-102.38%. Small amounts of TBO in the chemically-analyzed filters for the Filtered Air Control group were attributed to contamination during the filter analysis processing and/or the calibration curve. The Filtered Air Control group filter-collected mean gravimetric value was 0.000 mg/L. The particle size distribution of the test atmosphere was within the respirable range. The overall mean TBO inhaled dose levels were 14.8 and 118.8 mg/kg/day for the lowand high dose groups, respectively. The overall mean male TBO inhaled dose levels were 13.7 and 110.2 mg/kg/day for the low and high dose groups, respectively. The overall mean female TBO inhaled dose levels were 15.8 and 127.3 mg/kg/day for the low and high dose groups, respectively. The male inhaled dose levels were 10-11% below the target levels for all groups, while the female inhaled dose levels were 3-5% above the target levels for all groups. Prior to exposure initiation, the homogeneity of the test atmosphere in each TBO exposure chamber was confirmed.

Conclusions:

Following inhalation exposure to TBO, tungsten was absorbed systemically with blood tungsten concentrations reaching maximum at 0 hours post-exposure. The exposure parameters of Cmax and AUC increased proportionally with increasing TBO dose level: Cmax was 0.819 ± 0.215 and 10.9 ± 4.7 fig/g and AUC was 11.8 ± 3.29 and 148 ± 33.7 hr*Rg/g for the 0.08 and 0.65 mg/L dose groups, respectively. The systemic elimination half-life was 23 ± 4.3 and 154 ± 92.8 hours for the 0.08 and 0.65 mg/L dose groups, respectively, and the clearance rate was 1.24 ± 0.39 and 0.78 ± 0.18 L/hr/kg for the 0.08 and 0.65 mg/L dose groups, respectively. The majority of the inhaled TBO was excreted through the gastrointestinal tract.
Tungsten concentration in lung tissue was at least one order of magnitude greater than in any other organ collected. In general, the femur and kidney ranked second and third highest, respectively, in tungsten concentration on a per organ weight basis. In terms of total tungsten burden in the organs, the lung, femur and liver ranked first, second and third, respectively. Tungsten distribution in tissue and organs reached steady-state on study Day 14. With the exception of the femur, the functional elimination half-life of tungsten in most organs was less than 24 hours.

Executive summary:

No toxicokinetics data of sufficient quality are available for tungsten disulphide (target substance). However, toxicokinetics data are available for tungsten metal (source substance), which will be used for reading across. Due to similar water solubility and toxicity for the target substance compared to the source substance, the resulting read across from the source substance to the target substance is appropriate. In addition, read across is appropriate because the classification and labelling is similar for the source substance than the target substance, the PBT/vPvB profile is the same, and the dose descriptors are, or are expected to be, lower for the source substance. For more details, refer to the read-across category approach included in the Category section of this IUCLID submission and/or as an Annex in the CSR.

Description of key information

In a GLP in vitro study conducted according to SOP for Bioelution Testing of Metals, Inorganic Metal Compounds, and Metal-Containing Complex Materials: Simulated Gastric Fluid (Eurometaux, July 2016) which is based on ASTM D5517 -07: Standard Test Method for determining the extractability of metals from art materials - ASTM, 2007 (American Society for Testing and Materials), the bioavailability of tungsten disulphide was determined in human gastric, perspiration, lysosomal, and interstitial fluids. The mean percent of available tungsten in simulated gastric fluid sampled at 2 hours was 0.066% (1% coefficient variability, CV). The mean percent of available tungsten in simulated perspiration fluid sampled at 24, 72, and 168 hours was 0.12 (2% CV), 1.7 (3% CV), and 2.5% (4% CV), respectively. The mean percent of available tungsten in simulated lysosomal fluid sampled at 24, 72, and 168 hours was 1 (2% CV), 1.9 (0% CV), and 2.9% (1% CV), respectively. The mean percent of available tungsten in simulated interstitial fluid sampled at 24, 72 and 168 hours was 0.78 (9% CV), 1.5 (6% CV), and 4.1% (10% CV), respectively. The bioavailability of tungsten from tungsten disulphide in the fluids ranged from 0.06% (gastric fluid) to 4.1% (interstitial fluid). The maximum bioavailability of tungsten from tungsten disulphide was determined at 168 hours for the simulated lysosomal fluids (4.1%). Based on the results, the bioavailability of tungsten from tungsten disulphide would be expected to insignificant for the oral route of administration, and low for the inhalation route (represented by the lysosomal fluid).

In addition, a toxicokinetic study conducted according to OECD 417 on tungsten oxide (source substance) was used for reading across. When tungsten oxide was administered via the inhalation route, tungsten was absorbed systemically with blood tungsten concentrations reaching maximum at 0 hours post-exposure. Cmax and AUC increased proportionally with increasing TBO dose level: Cmax was 0.819 ± 0.215 and 10.9 ± 4.7 ug/g, and AUC was 11.8 ± 3.29 and 148 ± 33.7 hr*ug/g for the 0.08 and 0.65 mg/L dose groups, respectively. The systemic elimination half-life was 23 ± 4.3 and 154 ± 92.8 hours for the 0.08 and 0.65 mg/L dose groups, respectively, and the clearance rate was 1.24 ± 0.39 and 0.78 ± 0.18 L/hr/kg for the 0.08 and 0.65 mg/L dose groups, respectively. Most of the inhaled tungsten oxide was excreted through the gastrointestinal tract. Tungsten concentration in lung tissue was at least one order of magnitude greater than in any other organ collected. In general, the femur and kidney ranked second and third highest, respectively, in tungsten concentration on a per organ weight basis. In terms of total tungsten burden in the organs, the lung, femur and liver ranked first, second and third, respectively. Tungsten distribution in tissue and organs reached steady-state on study Day 14. Except for the femur, the functional elimination half-life of tungsten in most organs was less than 24 hours

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential