Registration Dossier

Diss Factsheets

Administrative data

Link to relevant study record(s)

Referenceopen allclose all

Endpoint:
basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
imilar to OECD Test Guideline 417 Toxicokinetics-distribution with acceptable deviations.
Justification for type of information:
1. HYPOTHESIS FOR THE CATEGORY 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: Sodium tungstate
Target: Ammonium metatungstate
3. CATEGORY APPROACH JUSTIFICATION: See Annex 3 in CSR
4. DATA MATRIX: See Annex 3 in CSR
Reason / purpose for cross-reference:
read-across: supporting information
Objective of study:
distribution
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 417 (Toxicokinetics)
Version / remarks:
: distribution
GLP compliance:
no
Radiolabelling:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals or test system and environmental conditions:
- Body weight: 240 - 265 g
- Supplier: Hilltop Labs
Route of administration:
oral: gavage
Vehicle:
other: purified water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
- Oral dose formulations were prepared on the day of administration by dilution of sodium tungstate dihydrate in purified water; these doses were selected to provide sufficient dose separation for the dose-response analysis of the disposition after oral administration.
- The doses span two log dilutions, and are all well within the tolerable concentration limits for W in rodents.
Duration and frequency of treatment / exposure:
single gavage administration
Remarks:
Doses / Concentrations:
- Oral doses were prepared and administered at 1, 10, or 100 mg/kg.
No. of animals per sex per dose / concentration:
Four female rats were exposed per dose group. One animal per dose group was then sacrificed at each time point. Animals were sacrificed at 1, 2, 4 and 24 hours.
Control animals:
yes
Details on dosing and sampling:
COLLECTION OF SAMPLES:
- Animals were euthanized by an overdose of sodium pentobarbital administered by intraperitoneal injection.
- Plasma and tissues (intestine, liver, kidneys, femur, and uterus) were collected immediately after euthanasia (1, 2, 4 and 24 h after dosing).
- Plasma: blood was collected via cardiac puncture, placed in heparinized containers, and centrifuged at 2000 x g for 20 min.
- Tissues: liver, uterus, intestine (all three sections including contents), femur, and kidneys were harvested, weighed, placed in polypropylene containers, and stored at -70°C.

INSTRUMENTAL ANALYSIS:
- Tungsten concentrations were determined with the use of low-resolution ICP/MS following U.S. Environmental Protection Agency method 200.8
- When tissues and plasma were analyzed, the instrument response was recorded in micrograms of W per sample (ug/ sample).
- The data were then divided by the tissue weight to give micrograms of W per gram of tissue (ug/g), which is how the data in the current study are reported.
- In the case of plasma, direct weights were not recorded.
- Whole blood weights were recorded, and the amount of plasma was conservatively assigned a value of 55% of the whole blood weight.
Details on distribution in tissues:
- As shown by comparisons of 100 mg/kg and 10 mg/kg oral doses and the 10 mg/kg and 1 mg/kg oral doses, W concentrations increased with dose but were not always proportional to dose.
- At 24 h, W was not completely eliminated at the mid and high doses but returned to baseline levels at the low dose.
- A statistically significant difference in the W concentrations in plasma compared with whole blood was not observed, indicating that the plasma profile is a good indicator of blood concentrations and that W partitions equally between red blood cells and plasma.
-the W concentration in each of the rat tissues, with few exceptions, increases at each time point to a maximum at 4 h before becoming greatly reduced at 24 h.
- Intestine and kidneys at the high dose and femur at the mid-dose have a lower W concentration at 2 than at 1 h, but the concentrations still rose at 4 h before decreasing at 24 h.
- The other exceptions are intestine at the low dose, which had the highest W concentration at 2 h, and liver at the low dose, which had a steadily decreasing concentration

No clinical abnormalities or gross tissue pathology were observed during tissue harvest from any of the studies.

Conclusions:
As shown by comparisons of 100 mg/kg and 10 mg/kg oral doses and the 10 mg/kg and 1 mg/kg oral doses, W concentrations increased with dose but were not always proportional to dose. At 24 h, W was not completely eliminated at the mid and high doses but returned to baseline levels at the low dose. A statistically significant difference in the W concentrations in plasma compared with whole blood was not observed, indicating that the plasma profile is a good indicator of blood concentrations and that W partitions equally between red blood cells and plasma. The W concentration in each of the rat tissues, with few exceptions, increases at each time point to a maximum at 4 h before becoming greatly reduced at 24 h. Intestine and kidneys at the high dose and femur at the mid-dose have a lower W concentration at 2 than at 1 h, but the concentrations still rose at 4 h before decreasing at 24 h. The other exceptions are intestine at the low dose, which had the highest W concentration at 2 h, and liver at the low dose, which had a steadily decreasing concentration
Executive summary:

No toxicokinetics data of sufficient quality were available specifically on ammonium metatungstate (target substance). However, toxicokinetics data are available for Sodium tungstate (source substance), which are used for read-across. Due to similar water solubility for the target substance compared to the source substance, the resulting read-across from the source substance to the target substance is appropriate to estimate of potential toxicity for this endpoint. For more details, refer to the read-across category approach description in the Category section of this IUCLID submission or Annex 3 of the CSR.

Endpoint:
basic toxicokinetics
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
Well documented, scientifically sound study that follows OECD Guideline "417- Toxicokinetics", with a few deviations: housing conditions and acclimatization of animals were not discussed, and only distribution parameters were investigated (absorption, excretion, or metabolism were not examined).
Justification for type of information:
1. HYPOTHESIS FOR THE CATEGORY 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: Sodium tungstate
Target: Ammonium metatungstate
3. CATEGORY APPROACH JUSTIFICATION: See Annex 3 in CSR
4. DATA MATRIX: See Annex 3 in CSR
Reason / purpose for cross-reference:
read-across: supporting information
Objective of study:
distribution
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 417 (Toxicokinetics)
Deviations:
yes
GLP compliance:
not specified
Radiolabelling:
no
Species:
mouse
Strain:
other: C57BL/6N
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Hilltop Lab Animals Inc. (Scottdale, PA)
- Age at study initiation: N/A
- Weight at study initiation: 17-20 g
- Fasting period before study: N/A
- Housing: N/A
- Individual metabolism cages: no data
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: N/A


ENVIRONMENTAL CONDITIONS
- Temperature (°C):N/A
- Humidity (%): N/A
- Air changes (per hr): N/A
- Photoperiod (hrs dark / hrs light):N/A

Route of administration:
oral: drinking water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Drinking water doses were prepared every third day at 560 mg/L and administered ad libitum. Water bottles containing 560 mg/L tungstate were weighed prior to placing in cages. After 3 days, the water bottles were weighed again and the difference was considered the volume of the solution consumed in that time period. The weight of administered tungsten was calculated and divided by the animal's body weight to give the administered dose.


Duration and frequency of treatment / exposure:
14 days, ad libitum
Remarks:
Doses / Concentrations:
560 mg/L (actual dose= 3951.8 +/- 216.7 mg/kg)
No. of animals per sex per dose / concentration:
4 animals
Control animals:
other: yes, (n=6) no specific data regarding control treatment
Details on study design:
- Dose selection rationale: Doses were selected to correspond with ongoing NTP studies.
Details on dosing and sampling:
PHARMACOKINETIC STUDY (distribution)
- Tissues and body fluids sampled: plasma, intestines, liver, kidneys, femur, uterus
- Time and frequency of sampling: tissues were harvested immediately after euthanasia, after the 14 days of exposure





Details on distribution in tissues:
There was a significant increase in tungsten tissue concentration for treated mice (vs. endogenous concentrations-control) in plasma and all tissues examined (intestine, liver, kidneys, femur, and uterus).
Conclusions:
After ad libitum drinking water exposure to 560 mg/L (actual dose= 3951.8 +/- 216.7 mg/kg) of the test substance for 14 days, female C57B1/6N mice (vs. endogenous concentrations-control) exhibited significantly elevated tungsten concentrations in plasma and all tissues examined (intestine, liver, kidneys, femur, and uterus).
Executive summary:

No toxicokinetics data of sufficient quality were available specifically on ammonium metatungstate (target substance). However, toxicokinetics data are available for Sodium tungstate (source substance), which are used for read-across. Due to similar water solubility for the target substance compared to the source substance, the resulting read-across from the source substance to the target substance is appropriate to estimate of potential toxicity for this endpoint. For more details, refer to the read-across category approach description in the Category section of this IUCLID submission or Annex 3 of the CSR.

Endpoint:
basic toxicokinetics
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
Well documented, scientifically sound study that follows OECD Guideline "417- Toxicokinetics", with a few deviations: housing conditions and acclimatization of animals were not discussed, and only distribution parameters were investigated (absorption, excretion, or metabolism were not examined).
Justification for type of information:
1. HYPOTHESIS FOR THE CATEGORY 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: Sodium tungstate
Target: Ammonium metatungstate
3. CATEGORY APPROACH JUSTIFICATION: See Annex 3 in CSR
4. DATA MATRIX: See Annex 3 in CSR
Reason / purpose for cross-reference:
reference to same study
Objective of study:
distribution
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 417 (Toxicokinetics)
Deviations:
yes
GLP compliance:
not specified
Radiolabelling:
no
Species:
mouse
Strain:
other: C57BL/6N
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Hilltop Lab Animals Inc. (Scottdale, PA)
- Age at study initiation: N/A
- Weight at study initiation: 17-20 g
- Fasting period before study: N/A
- Housing: N/A
- Individual metabolism cages: no data
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: N/A


ENVIRONMENTAL CONDITIONS
- Temperature (°C):N/A
- Humidity (%): N/A
- Air changes (per hr): N/A
- Photoperiod (hrs dark / hrs light):N/A

Route of administration:
oral: drinking water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Drinking water doses were prepared every third day at 560 mg/L and administered ad libitum. Water bottles containing 560 mg/L tungstate were weighed prior to placing in cages. After 3 days, the water bottles were weighed again and the difference was considered the volume of the solution consumed in that time period. The weight of administered tungsten was calculated and divided by the animal's body weight to give the administered dose.

Gestating females were administered drinking water containing tungsten starting at day 6 of confirmed gestation, through the duration of the study, the days of primary organogenesis.
Duration and frequency of treatment / exposure:
9 days, ad libitum
Remarks:
Doses / Concentrations:
560 mg/L (actual dose = 1238.5 +/- 186.1 mg/kg)
No. of animals per sex per dose / concentration:
4
Control animals:
other: yes, (n=6) no specific data regarding control treatment
Details on study design:
- Dose selection rationale: Doses were selected to correspond with ongoing NTP studies.
Details on dosing and sampling:
PHARMACOKINETIC STUDY (distribution)
- Tissues and body fluids sampled: plasma, intestines, liver, kidneys, femur, uterus, fetus
- Time and frequency of sampling: tissues were harvested immediately after euthanasia, after the 9 days of exposure





Details on distribution in tissues:
There was a significant increase in tungsten tissue concentration for treated mice (vs. endogenous concentrations-control) in plasma and all tissues examined (intestine, liver, kidneys, femur, and uterus). Fetuses also showed a significantly increased tungsten concentration above endogenous levels.
Conclusions:
After ad libitum drinking water exposure to 560 mg/L (actual dose= 1238.5 +/- 186.1 mg/kg) of the test substance for 9 days, female C57B1/6N mice (vs. endogenous concentrations-control) exhibited significantly elevated tungsten concentrations in plasma and all tissues examined (intestine, liver, kidneys, femur, and uterus). In addition, fetuses also showed a significantly increased tungsten concentration above endogenous levels.
Executive summary:

No toxicokinetics data of sufficient quality were available specifically on ammonium metatungstate (target substance). However, toxicokinetics data are available for Sodium tungstate (source substance), which are used for read-across. Due to similar water solubility for the target substance compared to the source substance, the resulting read-across from the source substance to the target substance is appropriate to estimate of potential toxicity for this endpoint. For more details, refer to the read-across category approach description in the Category section of this IUCLID submission or Annex 3 of the CSR.

Endpoint:
basic toxicokinetics
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
Follows OECD Guideline "417- Toxicokinetics", with a few deviations: housing conditions and acclimatization of animals were not discussed, and only distribution parameters were investigated (absorption, excretion, or metabolism were not examined). The study was not GLP certified.
Justification for type of information:
1. HYPOTHESIS FOR THE CATEGORY 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: Sodium tungstate
Target: Ammonium metatungstate
3. CATEGORY APPROACH JUSTIFICATION: See Annex 3 in CSR
4. DATA MATRIX: See Annex 3 in CSR
Reason / purpose for cross-reference:
read-across: supporting information
Objective of study:
distribution
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 417 (Toxicokinetics)
Deviations:
yes
GLP compliance:
not specified
Radiolabelling:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Hilltop Lab Animals Inc. (Scottdale, PA)
- Age at study initiation: N/A
- Weight at study initiation: 223-271 g
- Fasting period before study: N/A
- Housing: N/A
- Individual metabolism cages: no data
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: N/A


ENVIRONMENTAL CONDITIONS
- Temperature (°C):N/A
- Humidity (%): N/A
- Air changes (per hr): N/A
- Photoperiod (hrs dark / hrs light):N/A

Route of administration:
oral: drinking water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Drinking water doses were prepared every third day at 560 mg/L and administered ad libitum. Water bottles containing 560 mg/L tungstate were weighed prior to placing in cages. After 3 days, the water bottles were weighed again and the difference was considered the volume of the solution consumed in that time period. The weight of administered tungsten was calculated and divided by the animal's body weight to give the administered dose.

Duration and frequency of treatment / exposure:
14 days, ad libitum
Remarks:
Doses / Concentrations:
560 mg/L (actual dose= 1224.7 +/- 140.7 mg/kg)
No. of animals per sex per dose / concentration:
4
Control animals:
other: yes, (n=6) no specific data regarding control treatment
Details on study design:
- Dose selection rationale: Doses were selected to correspond with ongoing NTP studies.
Details on dosing and sampling:
PHARMACOKINETIC STUDY (distribution)
- Tissues and body fluids sampled: plasma, intestines, liver, kidneys, femur, uterus
- Time and frequency of sampling: tissues were harvested immediately after euthanasia, after the 14 days of exposure





Details on distribution in tissues:
There was a significant increase in tungsten tissue concentration for treated rats (vs. endogenous concentrations-control) in plasma and all tissues examined (intestine, liver, kidneys, femur, and uterus).
Conclusions:
After ad libitum drinking water exposure to 560 mg/L (actual dose= 1224.7 +/- 140.7 mg/kg) of the test substance for 14 days, female Sprague-Dawley rats (vs. endogenous concentrations-control) exhibited significantly elevated tungsten concentrations in plasma and all tissues examined (intestine, liver, kidneys, femur, and uterus).
Executive summary:

No toxicokinetics data of sufficient quality were available specifically on ammonium metatungstate (target substance). However, toxicokinetics data are available for Sodium tungstate (source substance), which are used for read-across. Due to similar water solubility for the target substance compared to the source substance, the resulting read-across from the source substance to the target substance is appropriate to estimate of potential toxicity for this endpoint. For more details, refer to the read-across category approach description in the Category section of this IUCLID submission or Annex 3 of the CSR.

Endpoint:
basic toxicokinetics
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
Well documented, scientifically sound study that follows OECD Guideline "417- Toxicokinetics", with a few deviations: housing conditions and acclimatization of animals were not discussed, and only distribution parameters were investigated (absorption, excretion, or metabolism were not examined).
Justification for type of information:
1. HYPOTHESIS FOR THE CATEGORY 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: Sodium tungstate
Target: Ammonium metatungstate
3. CATEGORY APPROACH JUSTIFICATION: See Annex 3 in CSR
4. DATA MATRIX: See Annex 3 in CSR
Reason / purpose for cross-reference:
read-across: supporting information
Objective of study:
distribution
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 417 (Toxicokinetics)
Deviations:
yes
GLP compliance:
not specified
Radiolabelling:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Hilltop Lab Animals Inc (Scottdale, PA)
- Age at study initiation: N/A
- Weight at study initiation: 223-271 g
- Fasting period before study: N/A
- Housing: N/A
- Individual metabolism cages: no data
- Diet (e.g. ad libitum): ad libitum
- Water (eg ad libitum): ad libitum
- Acclimation period: N/A


ENVIRONMENTAL CONDITIONS
- Temperature (°C): N/A
- Humidity (%): N/A
- Air changes (per hr): N/A
- Photoperiod (hrs dark / hrs light):N/A

Route of administration:
oral: drinking water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Drinking water doses were prepared every third day at 560 mg/L and administered ad libitum. Water bottles containing 560 mg/L tungstate were weighed prior to placing in cages. After 3 days, the water bottles were weighed again and the difference was considered the volume of the solution consumed in that time period. The weight of administered tungsten was calculated and divided by the animal's body weight to give the administered dose.

Gestating females were administered drinking water containing tungsten starting at day 6 of confirmed gestation, through the duration of the study, the days of primary organogenesis.
Duration and frequency of treatment / exposure:
10 days, ad libitum
Remarks:
Doses / Concentrations:
560 mg/L (actual dose= 1067.9 +/- 299.7 mg/kg)
No. of animals per sex per dose / concentration:
4
Control animals:
other: yes, (n=6) no specific data regarding control treatment
Details on study design:
- Dose selection rationale: Doses were selected to correspond with ongoing NTP studies.
Details on dosing and sampling:
PHARMACOKINETIC STUDY (distribution)
- Tissues and body fluids sampled: plasma, intestines, liver, kidneys, femur, uterus, fetus
- Time and frequency of sampling: tissues were harvested immediately after euthanasia, after the 10 days of exposure





Details on distribution in tissues:
There was a significant increase in tungsten tissue concentration for treated rats (vs. endogenous concentrations-control) in plasma and all tissues examined (intestine, liver, kidneys, femur, and uterus). Fetuses also showed increased tungsten concentration above endogenous levels, though it was not indicated whether or not this increase was significant.
Conclusions:
After ad libitum drinking water exposure to 560 mg/L (actual dose was 1067.9 +/- 299.7 mg/kg) of the test substance for 10 days, female Sprague-dawley rats (vs. endogenous concentrations-control) exhibited significantly elevated tungsten concentrations in plasma and all tissues examined (intestine, liver, kidneys, femur, and uterus). In addition, fetuses also showed increased tungsten concentration above endogenous levels.
Executive summary:

No toxicokinetics data of sufficient quality were available specifically on ammonium metatungstate (target substance). However, toxicokinetics data are available for Sodium tungstate (source substance), which are used for read-across. Due to similar water solubility for the target substance compared to the source substance, the resulting read-across from the source substance to the target substance is appropriate to estimate of potential toxicity for this endpoint. For more details, refer to the read-across category approach description in the Category section of this IUCLID submission or Annex 3 of the CSR.

Endpoint:
basic toxicokinetics
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
Well documented, scientifically sound study that follows OECD Guideline "417- Toxicokinetics", with a few deviations: housing conditions and acclimatization of animals were not discussed, and only distribution parameters were investigated (absorption, excretion, or metabolism were not examined).
Justification for type of information:
1. HYPOTHESIS FOR THE CATEGORY 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: Sodium tungstate
Target: Ammonium metatungstate
3. CATEGORY APPROACH JUSTIFICATION: See Annex 3 in CSR
4. DATA MATRIX: See Annex 3 in CSR
Reason / purpose for cross-reference:
read-across: supporting information
Objective of study:
distribution
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 417 (Toxicokinetics)
Deviations:
yes
GLP compliance:
not specified
Radiolabelling:
no
Species:
mouse
Strain:
other: C57BL/6N
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Hilltop Lab Animals Inc (Scottdale, PA)
- Age at study initiation: N/A
- Weight at study initiation: 17-20 g
- Fasting period before study: N/A
- Housing: N/A
- Individual metabolism cages: no data
- Diet (e.g. ad libitum): ad libitum
- Water (eg ad libitum): ad libitum
- Acclimation period: N/A


ENVIRONMENTAL CONDITIONS
- Temperature (°C): N/A
- Humidity (%): N/A
- Air changes (per hr): N/A
- Photoperiod (hrs dark / hrs light):N/A

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Prepared on the day of administration by the dilution of sodium tungstate dihydrate in purified water.


Duration and frequency of treatment / exposure:
14 days, daily
Remarks:
Doses / Concentrations:
10 mg/kg (actual dose= 10.2 +/- 0.3 mg/kg)
No. of animals per sex per dose / concentration:
4
Control animals:
other: yes, (n=6) no specific data regarding control treatment
Details on study design:
- Dose selection rationale: Doses were selected to correspond with ongoing NTP studies.
Details on dosing and sampling:
PHARMACOKINETIC STUDY (distribution)
- Tissues and body fluids sampled: plasma, intestines, liver, kidneys, femur, uterus
- Time and frequency of sampling: tissues were harvested immediately after euthanasia, after the 14 days of dosing





Details on distribution in tissues:
There was a slight increase in tungsten tissue concentration for treated rodents (vs. endogenous concentrations-control) in the plasma, intestines, liver, and femur after 14 days. No difference in concentration was observed in kidneys. In contrast, the uterus displayed a large increase in tungsten concentration and was significantly above endogenous (control) levels.
Conclusions:
After oral exposure to 10mg/kg/day (actual dose= 10.2 +/- 0.3 mg/kg) of the test substance for 14 days, female C57B1/6N mice (vs. endogenous concentrations-control) exhibited significantly elevated tungsten concentrations in uterus tissue.
Executive summary:

No toxicokinetics data of sufficient quality were available specifically on ammonium metatungstate (target substance). However, toxicokinetics data are available for Sodium tungstate (source substance), which are used for read-across. Due to similar water solubility for the target substance compared to the source substance, the resulting read-across from the source substance to the target substance is appropriate to estimate of potential toxicity for this endpoint. For more details, refer to the read-across category approach description in the Category section of this IUCLID submission or Annex 3 of the CSR.

Description of key information

No toxicokinetics data of sufficient quality were available specifically on ammonium metatungstate (target substance). However, toxicokinetics data are available on ammonium paratungstate and sodium tungstate (source substances), which are used for read-across. Due to similar water solubility of the target substance compared to the source substances, the resulting read-across from the source substance to the target substance is appropriate to estimate of potential toxicity for this endpoint. For more details, refer to the read-across category approach description in the Category section of this IUCLID submission or Annex 3 of the CSR.

One study of low quality was identified for ammonium paratungstate (APT) (source substance) in which APT was administered to rats in the diet (0.69% ammonium paratungstate in purina dog chow). No traces of tungsten were found in the heart, uterus, or brain of females. A trace of tungsten was found in the brain of males. Trace amounts of tungsten were found in the blood and liver of both male and female rats, and kidneys of male rats, and 2 mg tungsten was found in the kidneys of female rats. Nine and 10 mg percent weight tungsten was found in the bone of male and female rats respectively. Two and 9 mg weight tungsten was found in the skin of male and female rats, respectively. Trace amounts of tungsten were found in the male spleen, while 10 mg were found in the female spleen.

At pH of ≥ 6.2 the hexaammonium metatungstate will speciate in water to tungstate ion (WO42-):

(NH4)6(H2W12O40) + 8H2O ↔ 12WO42-+ 6NH4++ 18H+

A characteristic feature of WO42- which only occurs monomerically in alkaline or neutral solutions is its tendency to form condensed, complexed isopolytungstate ions in slightly acidic medium (Figure 1).

At pH >6.2, the monomeric WO42 exists, however at lower pH values the tungstate ions start to condense to polytungstate species. The condensation grade increases with decreasing pH until finally, at pH approximately 1, insoluble, highly polymeric, amorphous tungstic acid is precipitated.

Based on Figure 2, when preparing ammonium metatungstate (AMT) oral doses in aqueous solutions for toxicological studies, AMT will speciate as WO42-, which is the same starting species for sodium tungstate:

Na2WO4+ H2O ↔ WO42-+ 2Na++ H++ OH-

After oral exposure, the WO42 formed during dissolution of AMT will speciate instantaneously at pHs of 6 or 4 or 1 to hexameric paratungstate ion [HW6O20(OH)2]5-and the pseudo-meta-tungstate [HW6O20]3-as well as tungstic acid (WO3•H2O), respectively (Lassner & Schubert, 1999).

 

After passing the stomach, the tungstic acid formed at pH 1encounters a pH of 6.6 in the proximal small intestine, pH of 7.5 in the terminal ileum, and pH of 6.4 in the caecum. The pH then rises progressively from the right to the left colon with a final mean value of 7.0 (Evans et al, 1988). In all of these intestinal (small and large) pHs greater than6.2, the monomericWO42- is the predominant tungsten species(Lassner & Schubert, 1999).

At the gastric pH, ammonium metatungstate (AMT) and sodium tungstate both speciate rapidly to tungstic acid (insoluble). After passing the stomach, tungstic acid speciates to tungstate, which only occurs monomerically in alkaline or neutral solutions (pHs ≥6.2). The read-across to sodium tungstate to support AMT is appropriate and correct based on the common dissolution of tungstate, the most bioavailable form of tungsten.

A number of high quality toxicokinetic studies were available on sodium tungstate on mice, rats, and dogs administered via the oral and inhalation routes. Following oral administration of sodium tungstate in mice, there was a slight increase in tungsten tissue concentration for treated rodents (vs. endogenous concentrations-control) in the plasma, intestines, liver, and femur after 14 days. No difference in concentration was observed in the kidneys. In contrast, the uterus displayed a large increase in tungsten concentration and was significantly above endogenous (control) levels. Following oral administration of sodium tungstate in rats, absorption was rapid (1-3 hours), with the bioavailability ranging from 70 to 92%. There was an observed increase in tungsten tissue concentration for treated rodents (vs endogenous concentrations-control) in plasma, and all tissues examined. The plasma, liver, and uterus showed tungsten levels only slightly above baseline levels; however, the intestine, kidneys, and femur displayed significant increases in the amount of tungsten. The half-life in rats was calculated to range from around 1-3 hours. Following oral administration of sodium tungstate in dogs, the absorption was rapid (Tmax was 1-2 hours), with the bioavailability averaging 66%. Plasma concentration profiles versus time were compatible with a two-compartment model and first-order kinetics. The half life in the dog was calculated to be 4 hours. Following inhalation administration of sodium tungstate to rats, accumulation varied among different tissues with the highest concentration seen in the lung, nasal epithelium, thyroid, femur, and kidney. Tissues with minimal accumulation included lung lymph nodes, heart, thymus, adrenal gland, testes, pancreas, and spleen. Levels of tungsten observed in all brain structures examined paralleled blood concentrations at 2-3% of blood levels and were highest at the end of exposure, returning to background level within 3 days. The highest concentrations of tungsten in the brain were seen in the pituitary gland where levels of tungsten seen in the olfactory bulb, striatum, cerebellum, and cortex were much lower suggesting tungsten is largely excluded by the blood brain barrier. Urine concentrations of radio-labeled tungsten were elevated throughout the first 7 days post exposure. Tungsten elimination from most tissue compartments was rapid. Tissues with slower terminal elimination rates include femur, lung, and spleen. The available toxicokinetic data on sodium tungstate indicate that it is readily bioavailable via the oral route of administration, and that by this route tungsten accumulates primarily in the intestines, kidneys, and femur. When administered via inhalation, tungsten primarily accumulated in the lung, nasal epithelium, thyroid, femur, and kidney. The half-life of tungsten following administration of sodium tungstate ranged from 1-4 hours, which indicates that it is rapidly excreted.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

No toxicokinetics data of sufficient quality are available for ammonium metatungstate (target substance). However, toxicokinetics data are available for sodium tungstate (source substance), which are used for read-across. Due to similar water solubility and lower toxicity for the target substance compared to the source substance, the resulting read-across from the source substance to the target substance is appropriate as a conservative estimate of potential toxicity for this endpoint. In addition, read-across is appropriate because the classification and labelling is more protective 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, conservative for the target substance. For more details, refer to the read-across category approach description in the Category section of this IUCLID submission or Annex 3 of the CSR.