Ammonium wolframate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.4 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

30

Dose descriptor starting point:

BMCL10

Value:

102 mg/kg bw/day

Modified dose descriptor starting point:

BMCL10

Value:

71 mg/m³

Explanation for the modification of the dose descriptor starting point:

No repeat dose toxicity studies were available on ammonium paratungstate. However, a 90-day repeat dose oral toxicity study in rats was available on sodium tungstate, which are used for read-across. Ammonium paratungstate has a solubility of 22.5 g/L at 20 °C and sodium tungstate has a solubility of 732 g/L at 21 °C; hence, sodium tungstate is more soluble, and therefore likely more bioavailable than ammonium paratungstate. In addition, the acute oral LD50 for ammonium paratungstate is >2000 mg/kg,

whereas, the acute oral LD50 for sodium tungstate is 1453 mg/kg. Based on the available information, sodium tungstate is both more soluble, and therefore likely more bioavailable, and more acutely toxic than ammonium paratungstate. Therefore, although data were not specifically available on ammonium paratungstate, the data on sodium tungstate likely represent a worst case. From the 90-day oral toxicity study on sodium tungstate, a BMDL10 of 102 mg sodium tungstate/kg/day was estimated using the kidney effects (mild to severe regeneration of renal cortical tubules) reported in the study. Because no repeat-dose dermal or inhalation studies were available, route-to-route extrapolation from the oral BMDL10 was utilised. No data are available on the bioavailability of the test substance in rats versus humans for the oral route of administration. The default situation, in the absence of information, is to assume the same bioavailability for experimental animals and humans for a particular exposure route.

For route-to-route extrapolation from an oral dose to an inhalation dose, the starting point needs to be modified to correct for the breathing volume of the rat and respiratory volume under standard conditions (6.7 m³/person) versus under conditions of light activity for workers (10 m³/person). Based on ECHA’s recommendations, it is assumed that respiratory absorption is equivalent between the animals and humans.Therefore, the inhalation starting dose = oral BMDL10 x 1/(0.38 m³/kg/day) x 6.7m³/10 m³. In addition, ECHA recommends in the absence of route-specific information on the starting route, to include a default factor of 2 (ie the absorption percentage for the starting route is half that of the end route) in the case of oral-to-inhalation extrapolation.

Inhalation starting dose = 102 mg sodium tungstate/kg/day x 1/(0.38 m³/kg/day) x 6.7m³/10m³x ½ = 90 mg sodium tungstate/m³.

In addition, the starting dose was adjusted for the molecular weight of tungsten since the bioavailable tungsten is considered to be the toxic species and is the basis for the read-across approach. In order to be consistent with this approach, the DNEL value is derived in terms of the tungsten concentration of sodium tungstate (source substance) and then corrected for the molecular weight of ammonium paratungstate (target substance). Using the molecular formula and molecular weight for ammonium paratungstate and sodium tungstate, the correct starting dose for calculation of the inhalation DNEL for ammonium paratungstate is 71 mg ammonium paratungstate/m³.

AF for dose response relationship:

1

Justification:

A 90-day repeat dose oral toxicity study on rats was available on sodium tungstate. From this study, a BMDL10 of 102 mg sodium tungstate/kg/day was estimated using the kidney effects (mild to severe regeneration of renal cortical tubules) reported in the study. Because no repeat dose dermal or inhalation studies were available, route-to-route extrapolation from the oral BMDL10 was utilised.

AF for differences in duration of exposure:

2

Justification:

The AF for extrapolation from a subchronic toxicity study to a chronic is 2

AF for interspecies differences (allometric scaling):

1

Justification:

In the case of the rat, the ECHA-recommended AS factor is 4. However, when the starting point is an inhalation dose, an AS factor is not used

AF for other interspecies differences:

2.5

Justification:

Per ECHA, the interspecies AF should include an allometric scaling (AS) factor plus an additional factor of 2.5. In the case of the rat, the ECHA-recommended AS factor is 4. However, when the starting point is an inhalation dose, an AS factor is not used. Therefore, for the inhalation route, only an interspecies factor of 2.5 is used.

AF for intraspecies differences:

3

Justification:

Eurometaux (2010) recommends an AF of 3 for intraspecies variability in workers, which is based on the ECETOC task force’s analysis of the intraspecies variability of toxicokinetic and toxicodynamic parameters from human data.

AF for the quality of the whole database:

1

Justification:

Quality of the data is properly assessed and found to be adequate.

AF for remaining uncertainties:

2

Justification:

Based on the kidney effects severity of the effect reported in the 90-day oral toxicity study on sodium tungstate, an additional AF of 2 will be used.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.67 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

120

Dose descriptor starting point:

BMDL10

Value:

102 mg/kg bw/day

Modified dose descriptor starting point:

BMDL10

Value:

81 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

For route-to-route extrapolation for the dermal route, the absorption differences between the animal and human need to be considered for both the dermal and oral routes. The default situation, in the absence of information, is to assume the same bioavailability for experimental animals and humans for a particular exposure route. In addition, it will be assumed that dermal absorption will not be higher than oral absorption. Therefore, the starting dose for calculation of the dermal DNEL is 102 mg sodium tungstate/kg/day.The starting dose also was adjusted for the molecular weight of tungsten since the bioavailable tungsten is considered to be the toxic species and is the basis for the read-across approach. In order to be consistent with this approach, the DNEL value is derived in terms of the tungsten concentration of sodium tungstate (the source substance) and then corrected for the molecular weight of ammonium paratungstate (the target substance).Using the molecular formula and molecular weight for ammonium paratungstate and sodium tungstate, the correct starting dose for calculation of the dermal DNEL for ammonium paratungstate is 81 mg ammonium paratungstate/kg/day.

AF for dose response relationship:

1

Justification:

A 90-day repeat dose oral toxicity study on rats was available on sodium tungstate. From this study, a BMDL10 of 102 mg sodium tungstate/kg/day was estimated using the kidney effects (mild to severe regeneration of renal cortical tubules) reported in the study. Because no repeat dose dermal or inhalation studies were available, route-to-route extrapolation from the oral BMDL10 was utilised.

AF for differences in duration of exposure:

2

Justification:

The AF for extrapolation from a subchronic toxicity study to a chronic is 2.

AF for interspecies differences (allometric scaling):

2.5

Justification:

The AF for interspecies variability includes an allometric scaling (AS) factor plus an additional factor of 2.5..

AF for other interspecies differences:

4

Justification:

In the case of the rat, the ECHA recommended AS factor is 4

AF for intraspecies differences:

3

Justification:

Eurometaux (2010) recommends an AF of 3 for intraspecies variability in workers, which is based on the ECETOC task force’s analysis of the intraspecies variability of toxicokinetic and toxicodynamic parameters from human data. Based on the recommendations of Eurometaux (2010), an intraspecies AF of 3 was used for workers

AF for the quality of the whole database:

1

Justification:

Quality of the data is properly assessed and found to be adequate.

AF for remaining uncertainties:

2

Justification:

Based on the severity of the renal adverse effects reported in the 90 -day oral toxicity study on sodium tungstate, an additional AF of 2 will be used.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

The AF for interspecies variability includes an allometric scaling (AS) factor plus an additional factor of 2.5. In the case of the rat, the ECHA recommended AS factor is 4. So, the interspecies AF is equal to 4 x 2.5 = 10. However, for the inhalation route, an AS factor is not used. Therefore, for inhalation, only an interspecies factor of 2.5 is used.

Eurometaux (2010) recommends an AF of 3 for intraspecies variability in workers, which is based on the ECETOC task force’s analysis of the intraspecies variability of toxicokinetic and toxicodynamic parameters from human data. Based on the recommendations of Eurometaux (2010), an intraspecies AF of 3 was used for workers. 

The AF for extrapolation from a subchronic toxicity study to a chronic is 2.

Based on the severity of the effect reported in the 90-day oral toxicity study on sodium tungstate, an additional AF of 2 will be used.

The total AF for the inhalation route is 30 (2.5 x 3 x 2 x 2).

The total AF for the dermal route is 120 (10 x 3 x 2 x 2). 

Worker DNELlong-term for the inhalation route = 71/30 = 2.4 mg APT/m³(1.7 mg W/m³).

Worker DNELlong-term for the dermal route = 81/120 = 0.67 mg APT/kg/day (0.5 mg W/kg/day).

It should be noted that the inhalation DNELlong-term for the worker of 1.7 mg W/m³is consistent with the current threshold limit value (TLV) for soluble tungsten substances of 1 mg W/m³.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.9 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

50

Dose descriptor starting point:

BMCL10

Value:

102 mg/kg bw/day

Modified dose descriptor starting point:

BMCL10

Value:

35 mg/m³

Explanation for the modification of the dose descriptor starting point:

No repeat dose toxicity studies were available on ammonium paratungstate. However, a 90-day repeat-dose oral toxicity study in rats was available on sodium tungstate, which are used for read-across. Ammonium paratungstate has a solubility of 22.5 g/L at 20 °C and sodium tungstate has a solubility of 732 g/L at 21 °C; hence, sodium tungstate is more soluble, and therefore, likely more bioavailable than ammonium paratungstate. In addition, the acute oral LD50 for ammonium paratungstate is >2000 mg/kg, whereas, the acute oral LD50 for sodium tungstate is 1453 mg/kg. Based on the available information, sodium tungstate is both more soluble, and therefore, likely more bioavailable and more acutely toxic than ammonium paratungstate. Therefore, although data were not specifically available on ammonium paratungstate, the data on sodium tungstate likely represent a worst case. From the 90-day oral toxicity study on sodium tungstate, a BMDL10 of 102 mg sodium tungstate/kg/day was estimated using the kidney effects (mild to severe regeneration of renal cortical tubules) reported in the study. Because no repeat-dose dermal or inhalation studies were available, route-to-route extrapolation from the oral BMDL10 was utilised. No data are available on the bioavailability of the test substance in rats versus humans for the oral route of administration. The default situation, in the absence of information, is to assume the same bioavailability for experimental animals and humans for a particular exposure route read-across

For route-to-route extrapolation from an oral dose to an inhalation dose, occupational exposure, the starting point needs to be modified to correct for the breathing volume of the rat. Based on ECHA’s recommendations, it is assumed that respiratory absorption is equivalent between the animals and humans. Therefore, the inhalation starting dose =oral BMDL10 x 1/(1.15 m3/kg/day). In addition, ECHA recommends in the absence of route-specific information on the starting route, to include a default factor of 2 (ie the absorption percentage for the starting route is half that of the end route) in the case of oral-to-inhalation extrapolation.

Therefore, the inhalation starting dose for the general population = 102 mg/kg/day x 1/(1.15 m³/kg/day) x 0.5 = 44 mg sodium tungstate/m³.

In addition, the starting dose was adjusted for the molecular weight of tungsten since the bioavailable tungsten is considered to be the toxic species and is the basis for the read-across approach. In order to be consistent with this approach, the DNEL value is derived in terms of the tungsten concentration of sodium tungstate (source substance) and then corrected for the molecular weight of ammonium paratungstate (target substance). Using the molecular formula and molecular weight for ammonium paratungstate and sodium tungstate, the correct starting dose for calculation of the inhalation DNEL for ammonium paratungstate is 35 mg ammonium paratungstate/m³.

AF for dose response relationship:

1

Justification:

A 90-day repeat dose oral toxicity study on rats was available on sodium tungstate. From this study, a BMDL10 was estimated using the kidney effects (mild to severe regeneration of renal cortical tubules) reported in the study. Because no repeat dose dermal or inhalation studies were available, route-to-route extrapolation from the oral BMDL10 was utilised

AF for differences in duration of exposure:

2

Justification:

The AF for extrapolation from a subchronic toxicity study to a chronic is 2

AF for interspecies differences (allometric scaling):

1

Justification:

In the case of the rat, the ECHA-recommended AS factor is 4. However, for the inhalation route, an AS factor is not used.

AF for other interspecies differences:

2.5

Justification:

The AF for interspecies variability includes an allometric scaling (AS) factor plus an additional factor of 2.5.

AF for intraspecies differences:

5

Justification:

Eurometaux (2010) recommends an AF of 5 for intraspecies variability in the general population, which is based on the ECETOC task force’s analysis of the intraspecies variability of toxicokinetic and toxicodynamic parameters from human data. Based on the recommendations of Eurometaux (2010), an intraspecies AF of 5 was used for the general population.

AF for the quality of the whole database:

1

Justification:

Quality of the data is properly assessed and found to be adequate.

AF for remaining uncertainties:

2

Justification:

Based on the severity of the effect reported in the 90 -day oral toxicity study on sodium tungstate, an additional AF of 2 will be used

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.4 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

200

Dose descriptor starting point:

BMDL10

Value:

102 mg/kg bw/day

Modified dose descriptor starting point:

BMDL10

Value:

81 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

For route-to-route extrapolation for the dermal route, the absorption differences between the animal and human need to be considered. The default situation, in the absence of information, is to assume the same bioavailability for experimental animals and humans for a particular exposure route. In addition, it will be assumed that dermal absorption will not be higher than oral absorption. Therefore, the starting dose for calculation of the dermal DNEL is 102 mg sodium tungstate/kg/day.The starting dose also was adjusted for the molecular weight of tungsten since the bioavailable tungsten is considered to be the toxic species and is the basis for the read-across approach. In order to be consistent with this approach, the DNEL value is derived in terms of the tungsten concentration of sodium tungstate (source substance) and then corrected for the molecular weight of ammonium paratungstate (target substance). Using the molecular formula and molecular weight for ammonium paratungstate and sodium tungstate, the correct starting dose for calculation of the dermal DNEL for ammonium paratungstate is 81 mg ammonium paratungstate/kg/day.

AF for dose response relationship:

1

Justification:

A 90-day repeat dose oral toxicity study on rats was available on sodium tungstate. From this study, a BMDL10 was estimated using the kidney effects (mild to severe regeneration of renal cortical tubules) reported in the study. Because no repeat dose dermal or inhalation studies were available, route-to-route extrapolation from the oral BMDL10 was utilized

AF for differences in duration of exposure:

2

Justification:

The AF for extrapolation from a subchronic toxicity study to a chronic is 2

AF for interspecies differences (allometric scaling):

4

Justification:

In the case of the rat, the ECHA-recommended AS factor is 4

AF for other interspecies differences:

2.5

Justification:

The AF for interspecies variability includes an allometric scaling (AS) of 2.5

AF for intraspecies differences:

5

Justification:

Eurometaux (2010) recommends an AF of 5 for intraspecies variability in the general population, which is based on the ECETOC task force’s analysis of the intraspecies variability of toxicokinetic and toxicodynamic parameters from human data. Based on the recommendations of Eurometaux (2010), an intraspecies AF of 5 was used for the general population

AF for the quality of the whole database:

1

Justification:

Quality of the data is properly assessed and found to be adequate.

AF for remaining uncertainties:

2

Justification:

Based on the severity of the kidney adverse effects reported in the 90 -day oral toxicity study on sodium tungstate, an additional AF of 2 will be used

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.4 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

200

Dose descriptor starting point:

NOAEL

Value:

75 mg/kg bw/day

Modified dose descriptor starting point:

BMDL10

Value:

81 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Therefore, the starting dose for calculation of the dermal DNEL is 102 mg sodium tungstate/kg/day.The starting dose also was adjusted for the molecular weight of tungsten since the bioavailable tungsten is considered to be the toxic species and is the basis for the read-across approach. In order to be consistent with this approach, the DNEL value is derived in terms of the tungsten concentration of sodium tungstate (source substance) and then corrected for the molecular weight of ammonium paratunstate (target substance). Using the molecular formula and molecular weight for ammonium paratungstate and sodium tungstate, the correct starting dose for calculation of the dermal DNEL for ammonium paratungstate is 81 mg ammonium paratungstate/kg/day.

AF for dose response relationship:

1

Justification:

A 90-day repeat dose oral toxicity study on rats was available on sodium tungstate. From this study, a BMDL10 was estimated using the kidney effects (mild to severe regeneration of renal cortical tubules) reported in the study. Because no repeat dose dermal or inhalation studies were available, route-to-route extrapolation from the oral BMDL10 was utilized.

AF for differences in duration of exposure:

2

Justification:

The AF for extrapolation from a subchronic toxicity study to a chronic is 2

AF for interspecies differences (allometric scaling):

4

Justification:

In the case of the rat, the ECHA-recommended AS factor is 4

AF for other interspecies differences:

2.5

Justification:

The AF for interspecies variability includes an allometric scaling (AS) factor plus an additional factor of 2.5

AF for intraspecies differences:

5

Justification:

Eurometaux (2010) recommends an AF of 5 for intraspecies variability in the general population, which is based on the ECETOC task force’s analysis of the intraspecies variability of toxicokinetic and toxicodynamic parameters from human data. Based on the recommendations of Eurometaux (2010), an intraspecies AF of 5 was used for the general population.

AF for the quality of the whole database:

1

Justification:

Quality of the data is properly assessed and found to be adequate.

AF for remaining uncertainties:

2

Justification:

Based on the severity of the kidney adverse effects reported in the 90 -day oral toxicity study on sodium tungstate, an additional AF of 2 will be used.

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

The AF for interspecies variability includes an allometric scaling (AS) factor plus an additional factor of 2.5. In the case of the rat, the ECHA recommended AS factor is 4. So, the interspecies AF is equal to 4 x 2.5 = 10. However, for the inhalation route, an AS factor is not used. Therefore, for inhalation, only an interspecies factor of 2.5 is used.

Eurometaux (2010) recommends an AF of 5 for intraspecies variability in the general population, which is based on the ECETOC task force’s analysis of the intraspecies variability of toxicokinetic and toxicodynamic parameters from human data. Based on the recommendations of Eurometaux (2010), an intraspecies AF of 5 was used for the general population.  

The AF for extrapolation from a subchronic toxicity study to a chronic is 2.

Based on the severity of the effect reported in the 90-day oral toxicity study on sodium tungstate, an additional AF of 2 will be used.

The total AF used to derive the systemicDNELlong-term for the inhalation route for the general populationis 50 (2.5 x 5 x 2 x 2).

The overall AF used to derive the systemic DNELlong-term for the oral and dermal routes for the general population is200 (10 x 5 x 2 x 2).

General population DNELlong-term for the inhalation route = 35/50 = 0.7 mg ammonium paratungstate/m³(0.5 mg W/m³).

General population DNELlong-term for the dermal route = 81/200 = 0.4 mg ammonium paratungstate/kg/day (0.3 mg W/kg/day).

General population DNELlong-term for the oral route = 81/200 = 0.4 mg ammonium paratungstate/kg/day(0.3 mg W/kg/day).