Tungsten oxide

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

Study period:

2009-01-28 to 2009-05-01

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

The bioaccessability study described in this report was performed according to the "Draft Guidance for RIP 3.6: Bioavailability and Read-Across for Metals and Minerals". GLP study.

Reason / purpose for cross-reference:

reference to other study

Objective of study:

absorption

Qualifier:

according to guideline

Guideline:

other: Draft Guidance for RIP 3.6: Bioavailability and Read-Across for Metals and Minerals

Deviations:

no

GLP compliance:

yes

Radiolabelling:

no

Species:

other: Human simulated fluids

Strain:

not specified

Sex:

not specified

Route of administration:

other: In vitro study

Vehicle:

other: Not applicable

Details on exposure:

Preparation of Testing Fluids: The simulated fluids used in this study were gastric, lung alveolar, lung interstitial, lysosomal and artificial sweat. All salts and reagents used for the simulated fluid preparation were obtained from Sigma-Aldrich (St. Louis, MO).

Extraction Experiments: Extractions of the test substances in the simulated fluids were performed at pre-set time periods (up to 72 hours) while protected from light, using 0.1 g of sample in 50 ml of simulated fluid, at 37 °C and with continuous shaking (for all fluids except sweat, for which only initial shaking was performed). The experiments were carried out as follows:
- Simulated Gastric Fluid: The reactions were sampled for the determination of tungsten at 5 hours.
- Simulated Interstitial, Alveolar and Lysosomal Fluids: 5% CO2 in nitrogen was bubbled into solution at a rate of 50 ml/min. The reactions were sampled for the determination of tungsten at 2, 5, 24 and 72 hours.
- Simulated Sweat: The reactions were sampled for the determination of tungsten after 12 hours. No shaking was performed after the initial set up.

Sample Preparation: The simulated fluid extract samples were filtered immediately after sampling using 50 ml centrifuge tubes equipped with 0.45 microns PVDF filters (Grace Alltech, Deerfield, IL). The filtrates were stored in plastic bottles at 35 °C until analysis.

The extracts were then analyzed for tungsten by inductively coupled plasma-mass spectrometry (ICP-MS).

Duration and frequency of treatment / exposure:

Single application of tungsten with fluids. Simulated Gastric Fluid was sampled for the determination of tungsten at 5 hours. Simulated Interstitial, Alveolar and Lysosomal Fluids were sampled for the determination of tungsten at 2, 5, 24 and 72 hours. Simulated Sweat was sampled for the determination of tungsten after 12 hours.

Remarks:

Doses / Concentrations:
0.1 g of test substance in 50 mL of simulated fluid

Control animals:

no

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: Simulated gastric fluid, Simulated interstititial fluid, Simulated alveolar fluid, Simulated lysosomal fluid and Simulated sweat
- Time and frequency of sampling: Simulated gastric fluid sampled at 5 hours, Simulated interstititial fluid sampled at 2, 5, 24 and 72 hours, Simulated alveolar fluid sampled at 2, 5, 24 and 72 hours, Simulated lysosomal fluid sampled at 2, 5, 24 and 72 hours and Simulated sweat sampled after 12 hours.

Sample analysis: Samples were diluted (if necessary), spiked with an internal standard [bismuth (Bi) at 1,000 pg/mL, prepared from dilution of a 1,000 ug/mL Certified Standard; Ultra Scientific, North Kingston, RI and analyzed directly on a Perkin Elmer Elan DRC II ICP-MS equipped with a dynamic reaction cell (DRC) and PerkinElmer AS-93 Plus autosampler instrument, according to methods established at IITRI for this study. A standard curve (prepared from dilutions of a 10,000 5%HNO3/6% HF; inorganic Ventures, Lakewood, NJ was analyzed along with samples on each day of analysis. Instrument calibrators were prepared by diluting Certified Standard with 0.5% nitric acid to concentrations of approximately 200; 400; 800; 1,600; 3,200; 6,400; 13,000 and 25,000 pg/mL.

Statistics:

Calibration curves, regression coefficients and r-squared values were calculated using PerkinElmer ICP-MS software and Microsoft Excel software. Concentration values of tungsten in the study samples were calculated from linear regression coefficients derived from calibration standards that bracketed the expected concentration levels of tungsten in the study samples.

Transfer type:

other: Not applicable since this was an in vitro study

Toxicokinetic parameters:

other: not applicable since this was an in vitro study

Metabolites identified:

not measured

Bioaccessibility (or Bioavailability) testing results:

The fluid extracts were diluted 1:500 to 1:125000 for analysis. The average amount of tungsten found in the extracts was in the 0.0767 to 60% range. The maximum solubility was determined at 72 hours for the simulated alveolar, lysosomal and interstitial fluids (41, 60 and 40%, respectively). % RSDs ranged from 0.81 to 71%.
Gastric Fluid: The percent of available tungsten in simulated gastric fluid sampled at 5 hours was 0.0767 +/- 0.0014 % (1.8 % relative standard deviation).
Sweat Fluid: The percent of available tungsten in simulated sweat fluid sampled at 12 hours was 7.7 +/- 0.31 % (4.1 % relative standard deviation).
Alveolar Fluid: The percent of available tungsten in simulated alveolar fluid sampled at 2, 5, 24 and 72 hours was 1.02 +/- 0.0116%, 4.6 +/- 3.3%, 39 +/- 5.2% and 41 +/- 5.4 %, respectively, with percent relative standard deviations of 1.1, 71, 13 and 13 % RSD, respectively.
Lysosomal Fluid: The percent of available tungsten in simulated lysosomal fluid sampled at 2, 5, 24 and 72 hours was 0.90 +/- 0.049, 2.4 +/- 0.019, 35 +/- 1.7 and 60 +/- 5.8 %, respectively, with percent relative standard deviations of 5.4, 0.81, 4.7 and 9.6 % RSD, respectively.
Interstitial Fluid: The percent of available tungsten in simulated interstitial fluid sampled at 2, 5, 24 and 72 hours was 2.1 +/- 0.12%, 3.6 +/- 0.26%, 23 +/- 8.9% and 40 +/- 0.59 %, respectively; with percent relative standard deviations of 5.5, 7.3, 39 and 1.5 % RSD, respectively.

Conclusions:

Interpretation of results (migrated information): bioaccumulation potential cannot be judged based on study results
The average amount of tungsten found in the extracts was in the 0.0767 to 60% range. The maximum solubility was determined at 72 hours for the simulated alveolar, lysosomal and interstitial fluids (41, 60 and 40%, respectively). % RSDs ranged from 0.81 to 71%.
In the simulated gastric fluid the percent of available tungsten sampled at 5 hours was 0.0767 +/- 0.0014 % (1.8 % relative standard deviation). In the simulated sweat fluid the percent of available tungsten sampled at 12 hours was 7.7 +/- 0.31 % (4.1 % relative standard deviation). In the simulated alveolar fluid the percent of available tungsten sampled at 2, 5, 24, and 72 hours was 1.02 +/- 0.0116%, 4.6 +/- 3.3%, 39 +/- 5.2% and 41 +/- 5.4 %, respectively, with percent relative standard deviations of 1.1, 71, 13 and 13 % RSD, respectively. In the simulated lysosomal fluid the percent of available tungsten sampled at 2, 5, 24 and 72 hours was 0.90 +/- 0.049, 2.4 +/- 0.019, 35 +/- 1.7 and 60 +/- 5.8 %, respectively, with percent relative standard deviations of 5.4, 0.81, 4.7 and 9.6 % RSD, respectively. In the simulated interstitial fluid the percent of available tungsten sampled at 2, 5, 24 and 72 hours was 2.1 +/- 0.12%, 3.6 +/- 0.26%, 23 +/- 8.9% and 40 +/- 0.59 %, respectively; with percent relative standard deviations of 5.5, 7.3, 39 and 1.5 %RSD, respectively.

Reference 2

Endpoint:

basic toxicokinetics

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2010-08-31 to 2010-01-29

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

Well documented, scientifically sound GLP 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 tungsten oxide 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 (eg 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 °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 tungsten oxide 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 tungsten oxide 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:

yes

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 tungsten oxide 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 tungsten oxide 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 tungsten oxide 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 exposures, while tungsten concentration in the rest of organs was at least one order of magnitude lower.

Single administration experiment:

Following inhalation exposure of tungsten oxide, 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 tungsten oxide 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 tungsten oxide 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 tungsten oxide 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 tungsten oxide concentrations were determined gravimetrically to be 0.081and 0.652 mg/L for the low and high dose groups, respectively. The tungsten oxide percent recovery ranged from 100.83-102.38%. Small amounts of tungsten oxide 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 tungsten oxide inhaled dose levels were 14.8 and 118.8 mg/kg/day for the lowand high dose groups, respectively. The overall mean male tungsten oxide inhaled dose levels were 13.7 and 110.2 mg/kg/day for the low and high dose groups, respectively. The overall mean female tungsten oxide 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 tungsten oxide exposure chamber was confirmed.

Conclusions:

Following inhalation exposure to tungsten oxide, 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 tungsten oxide 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 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. With the exception of the femur, the functional elimination half-life of tungsten in most organs was less than 24 hours.

Description of key information

In a GLP in vitro study conducted according to Draft Guidance for RIP 3.6: Bioavailability and Read-Across for Metals and Minerals (Eurometaux, 2008), the bioavailability of tungsten oxide was determined in human gastric, sweat, alveolar, lysosomal, and interstitial fluids. The average amount of tungsten found in the extracts was in the 0.0767 to 60% range. The maximum solubility was determined at 72 hours for the simulated alveolar, lysosomal and interstitial fluids (41, 60 and 40%, respectively). The percentage of relative standard deviations (RSDs) ranged from 0.81 to 71%. In the simulated gastric fluid the percent of available tungsten sampled at 5 hours was 0.0767 +/- 0.0014 % (1.8 % relative standard deviation). In the simulated sweat fluid the percent of available tungsten sampled at 12 hours was 7.7 +/- 0.31 % (4.1 % relative standard deviation). In the simulated alveolar fluid the percent of available tungsten sampled at 2, 5, 24 and 72 hours was 1.02 +/- 0.0116%, 4.6 +/- 3.3%, 39 +/- 5.2% and 41 +/- 5.4 %, respectively, with percent relative standard deviations of 1.1, 71, 13 and 13 % RSD, respectively. In the simulated lysosomal fluid, the percent of available tungsten sampled at 2, 5, 24 and 72 hours was 0.90 +/- 0.049, 2.4 +/- 0.019, 35 +/- 1.7 and 60 +/- 5.8 %, respectively, with percent relative standard deviations of 5.4, 0.81, 4.7 and 9.6 %RSD, respectively. In the simulated interstitial fluid the percent of available tungsten sampled at 2, 5, 24 and 72 hours was 2.1 +/- 0.12%, 3.6 +/- 0.26%, 23 +/- 8.9% and 40 +/- 0.59 %, respectively; with percent relative standard deviations of 5.5, 7.3, 39 and 1.5 % RSD, respectively. Bioavailability data in gastric and sweat fluids indicated that tungsten oxide will not be significantly absorbed when orally ingested or dermally exposed. However, when administered via the inhalation route, some bioavailability is expected.

In a toxicokinetic study conducted according to OECD 417, 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 tungsten oxide 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*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 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. With the exception of 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:

low bioaccumulation potential