Ammonium wolframate

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

documentation insufficient for assessment

Remarks:

Insufficient information provided on methods and results to accurately evaluate the study; no guideline available.

Reason / purpose for cross-reference:

reference to other study

Objective of study:

distribution

Qualifier:

no guideline followed

Principles of method if other than guideline:

Distribution of tungsten in various organs of the rat following oral ingestion of tungsten compounds.

GLP compliance:

no

Radiolabelling:

no

Species:

rat

Strain:

not specified

Sex:

male/female

Details on test animals or test system and environmental conditions:

Thirty-seven day old rats were placed on a basal diet of ground purina dog chow in which the finely ground tungsten compounds had been incorporated. For each experimental diet, 2 female and 2 male rats were used with the sexes separately caged. Diet and water were given ad libitum.

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on exposure:

For each experimental diet, 2 female and 2 male rats were used.

Duration and frequency of treatment / exposure:

Approximately 100 days.

Remarks:

Doses / Concentrations:
Diet D: 0.6912 percent Ammonium paratungstate (0.5 per cent W) in Purina dog chow.

No. of animals per sex per dose / concentration:

2 females and 2 males

Control animals:

yes, concurrent no treatment

Positive control reference chemical:

no

Details on study design:

The tissues of both rats of each sex on the same diet were combined, weighed, rinsed free of blood, and prepared for analysis. The method of Aull and Kinard was used for the determination of the tungsten.

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: brain, heart, uterus, lung, muscle, testis, blood, kidney and liver

Statistics:

no data

Details on distribution in tissues:

No traces of tungsten were found in the heart, uterus, or brain of females. A trace amount of tungsten was found in the brain of males. No relation was observed between diet or sex and the presence or absence of tungsten in the lungs, muscle, or testis. Trace amounts of tungsten were found in the blood and liver of both male and female rats, and kidneys of male rats and 2 mgm of tungsten was found in the kidneys of female rats. Nine and 10 mgm percent tungsten was found in the bone of male and female rats respectively. Two and 9 mgm 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 mgm where found in the female spleen.

Metabolites identified:

not measured

In no instance was there any trace of tungsten found in the animals kept on the control diet.

Reference 2

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:

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 paratungstate
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 paratungstate (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.

Reference 3

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 paratungstate
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 (eg 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.

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 paratungstate (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.

Reference 4

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 paratungstate
3. CATEGORY APPROACH JUSTIFICATION: See Annex 3 in CSR
4. DATA MATRIX: See Annex 3 in CSR

Reason / purpose for cross-reference:

read-across source

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 (eg 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:

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 paratungstate (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.

Reference 5

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 paratungstate
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 (eg 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.

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 pratungstate (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.

Reference 6

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 paratungstate
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 (eg 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 paratungstate (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.

Reference 7

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 paratungstate
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 (eg 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 paratungstate(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

Only one study of low quality was identified for ammonium paratungstate in which tungsten was administered to rats in the diet. 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 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.

The theoretical hydration of the paratungstate A ion has been published and it is written as [HW₆O₂₀(OH)₂)]^5-or as HW₆O₂₁^5-•H₂O. At pH of ≥ 6.2 the paratungstate A ion will speciate in water to tungstate ion (WO₄^2-): (NH₄)₁₀(H₂W₁₂O₄₂) + 6H₂O ↔ 12WO₄^2-+ 10NH₄⁺+ 14H⁺. A characteristic feature of WO₄^2-which only occurs monomerically in alkaline or neutral solutions is its tendency to form condensed, complexed isopolytungstate ions in slightly acidic medium. At pH >6.2, the monomeric WO₄^2- 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 paratungstate (ammonium wolframate) oral doses in aqueous solutions for toxicological studies, ammonium paratungstate will speciate as WO₄^2-, which is the same starting species for sodium tungstate: Na₂WO₄+ H₂O ↔ WO₄^2-+ 2Na⁺+ H⁺+ OH^-. After oral exposure,the WO₄^2- formed during dissolution of ammonium paratungstate) 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 than 6.2, the monomericWO₄^2-is the predominant tungsten species (Lassner & Schubert 1999).

At the gastric pH, ammonium paratungstate 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). Then read- across to sodium tungstate to support ammonium paratungstate 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 paratungstate (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 in the Category section of this IUCLID submission or Annex 3 in the CSR.