Reaction mass of Ammonium bisethanedioato bisaquo niobate(V) (anhydrous form) and Ammonium hydrogen ethanedioate ethanedioic acid (anhydrous form)

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

5.085 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):

25

Dose descriptor starting point:

NOAEL

Value:

103 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

127.1 mg/m³

Explanation for the modification of the dose descriptor starting point:

There are no data available assessing repeated dose toxicity via the inhalation route. However, reliable data are available for the oral route.

AF for dose response relationship:

1

Justification:

The dose descriptor starting point is based on a NOAEC.

AF for differences in duration of exposure:

2

Justification:

Subchronic to chronic (ECHA default).

AF for interspecies differences (allometric scaling):

1

Justification:

Not required for inhalation route (ECHA default).

AF for other interspecies differences:

2.5

Justification:

ECHA default.

AF for intraspecies differences:

5

Justification:

ECHA default.

AF for the quality of the whole database:

1

Justification:

Reliable GLP guideline study.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Route of original study:

By inhalation

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

irritation (respiratory tract)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.442 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):

100

Dose descriptor starting point:

NOAEL

Value:

103 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

144.2 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

There are no data available assessing repeated dose toxicity via the dermal route. However, reliable data are available for the oral route.

AF for dose response relationship:

1

Justification:

The dose descriptor starting point is based on a NOAEL.

AF for differences in duration of exposure:

2

Justification:

Subchronic to chronic (ECHA default).

AF for interspecies differences (allometric scaling):

4

Justification:

Rat/human (ECHA default).

AF for other interspecies differences:

2.5

Justification:

ECHA default

AF for intraspecies differences:

5

Justification:

ECHA default

AF for the quality of the whole database:

1

Justification:

Reliable GLP guideline study.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Route of original study:

Dermal

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

A reliable key repeated dose toxicity study with Reaction mass of ammonium diaqua[bis(oxalate)]oxoniobate(1-) hydrate and ammonium hydrogen oxalate oxalic acid (1:1:1) dihydrate is available for the oral route, conducted according to OECD test guideline 408 (subchronic exposure duration), and in compliance with GLP (CBMM Europe BV, Key, 2020, RDT). Renal and urinary bladder changes noted in high dose animals (311 mg/kg bw/day) are considered to be due to the oxalate content of the test item. The same effects were seen in an oral repeated dose toxicity study with Reaction mass of ammonium diaqua[bis(oxalate)]oxoniobate(1-) hydrate and ammonium hydrogen oxalate oxalic acid (1:1:1) dihydrate, conducted according to OECD test guideline 407 (CBMM Europe BV, Key, 2014, RDT). In this study, the effects observed were not reversible after the 14-day recovery period. Therefore, they are considered to be adverse. The toxicological profile of oxalate is identical in rats and humans (Kahn, 1997). Oxalate is not metabolised and the renal pathway is the relevant route of excretion in both rat and man (Hodkinson and Zarembski, 1968), thus, the effects noted in this study are considered relevant for the human risk assessment. Based on the outcome of the 90-day repeated dose toxicity study, the LOAEL was concluded to be 311 mg/kg bw/day for both male and female rats and the NOAEL was set at 103 mg/kg bw/day for males and females.

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References:

Hodgkinson. A.; Zarembski, P. M. (1968) Oxalic Acid Metabolism in Man: A Review. Calcif Tissue Res. 2(2):115-32.

Kahn, S.R. (1997) Animals models of kidney stone formation: an analysis. World J Urol 15:236-243.

 

Repeated-dose toxicity – systemic effects – inhalation route – worker:

The DNEL for systemic effects via inhalation is determined on the basis of route-to-route extrapolation from an oral OECD 408 toxicity study. In this study the NOAEL was set at 103 mg/kg bw/day.

 

The following corrections were made to the NOAEL:

Correction for relative absorption oral vs. inhalation: 2 (ECHA default)

Correction for respiratory volume (rat/worker): 0.38 m³/kg bw (8 h)

Correction for respiratory volume (worker, light physical activity): 6.7 m³/10 m³

Correction for 5 working days / week, instead of a daily, 7 day/week, treatment frequency in the repeated dose toxicity study: 7/5

Therefore the corrected NOAEC for repeated-dose systemic effects via inhalation is:

103 mg/kg bw/2×(1/0.38 m³/kg bw)×(6.7 m³/10 m³) x (7/5) = 127.12 mg/m³

 

The following assessment factors were applied to the corrected NOAEC:

Exposure duration (subchronic to chronic): 2 (ECHA default)

Interspecies differences (toxicodynamics): 2.5 (ECHA default)

Intraspecies differences (worker): 5 (ECHA default)

Total AF: 2×2.5×5 = 25

The overall DNEL (repeated-dose – systemic – inhalation - worker) is therefore:

127.12 mg/m³ / 25 = 5.085 mg/m³.

Repeated-dose toxicity – systemic effects – dermal route – worker:

The DNEL for systemic effects via the dermal route is determined on the basis of route-to-route extrapolation from an oral OECD 408 toxicity study. In this study the NOAEL was set at 103 mg/kg bw.

 

The following corrections were made to the NOAEL:

As no reliable information is available from acute dermal or dermal repeated dose toxicity tests regarding dermal absorption, a conservative approach is applied, and thus the relative dermal absorption was set to 1.

Correction for 5 working days / week, instead of a daily, 7 day/week, treatment frequency in the repeated dose toxicity study: 7/5

The corrected NOAEL is therefore:

103 mg/kg bw×1x(7/5) = 144.2 mg/kg bw

 

The following assessment factors were applied to the corrected NOAEL:

Exposure duration (subchronic to chronic): 2 (ECHA default)

Interspecies differences (toxicodynamics): 2.5 (ECHA default)

Interspecies differences (toxicokinetics, rat/human): 4 (ECHA default)

Intraspecies differences (worker): 5 (ECHA default)

Total AF: 2×2.5×4×5 = 100

The overall DNEL (repeated-dose – systemic – dermal - worker) is therefore:

144.2 mg/kg bw/day/100 = 1.442 mg/kg bw/day.

DNEL for local effects

No dose-response data for local effects is available and a DNEL for local effects cannot be derived. Therefore, for local effects a qualitative assessment was conducted. For details please refer to section 9.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.896 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:

NOAEL

Value:

103 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

44.8 mg/m³

Explanation for the modification of the dose descriptor starting point:

There are no data available assessing repeated dose toxicity via the inhalation route. However, reliable data are available for the oral route.

AF for dose response relationship:

1

Justification:

The dose descriptor starting point is based on a NOAEC.

AF for differences in duration of exposure:

2

Justification:

Subchronic to chronic (ECHA default).

AF for interspecies differences (allometric scaling):

1

Justification:

Not required for inhalation route (ECHA default).

AF for other interspecies differences:

2.5

Justification:

ECHA default.

AF for intraspecies differences:

10

Justification:

ECHA default.

AF for the quality of the whole database:

1

Justification:

Reliable GLP guideline study.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Route of original study:

By inhalation

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

irritation (respiratory tract)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.52 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:

103 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

103 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

There are no data available assessing repeated dose toxicity via the dermal route. However, reliable data are available for the oral route.

AF for dose response relationship:

1

AF for differences in duration of exposure:

6

Justification:

subacute to chronic (ECHA default)

AF for interspecies differences (allometric scaling):

4

Justification:

rat/human (ECHA default)

AF for other interspecies differences:

2.5

Justification:

(ECHA default)

AF for intraspecies differences:

10

Justification:

(ECHA default)

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Route of original study:

Dermal

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.52 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:

103 mg/kg bw/day

AF for dose response relationship:

1

AF for differences in duration of exposure:

6

Justification:

subacute to chronic (ECHA default)

AF for interspecies differences (allometric scaling):

4

Justification:

rat/human (ECHA default)

AF for other interspecies differences:

2.5

Justification:

(ECHA default)

AF for intraspecies differences:

10

Justification:

(ECHA default)

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3 mg/kg bw/day

Most sensitive endpoint:

acute toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

Modified dose descriptor starting point:

NOAEL

Value:

300 mg/kg bw/day

AF for dose response relationship:

1

Justification:

The dose descriptor starting point is based on a NOAEC.

AF for interspecies differences (allometric scaling):

4

Justification:

ECHA default.

AF for other interspecies differences:

2.5

Justification:

Rat/human (ECHA default).

AF for intraspecies differences:

10

Justification:

ECHA default.

AF for the quality of the whole database:

1

Justification:

Reliable GLP guideline study.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties.

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - General Population

A reliable key repeated dose toxicity study with Reaction mass of ammonium diaqua[bis(oxalate)]oxoniobate(1-) hydrate and ammonium hydrogen oxalate oxalic acid (1:1:1) dihydrate is available for the oral route, conducted according to OECD test guideline 408 (subchronic exposure duration), and in compliance with GLP (CBMM Europe BV, Key, 2020, RDT). Renal and urinary bladder changes noted in high dose animals (311 mg/kg bw/day) are considered to be due to the oxalate content of the test item. The same effects were seen in an oral repeated dose toxicity study with Reaction mass of ammonium diaqua[bis(oxalate)]oxoniobate(1-) hydrate and ammonium hydrogen oxalate oxalic acid (1:1:1) dihydrate, conducted according to OECD test guideline 407 (CBMM Europe BV, Key, 2014, RDT). In this study, the effects observed were not reversible after the 14-day recovery period. Therefore, they are considered to be adverse. The toxicological profile of oxalate is identical in rats and humans (Kahn, 1997). Oxalate is not metabolised and the renal pathway is the relevant route of excretion in both rat and man (Hodkinson and Zarembski, 1968), thus, the effects noted in this study are considered relevant for the human risk assessment. Based on the outcome of the 90-day repeated dose toxicity study, the LOAEL was concluded to be 311 mg/kg bw/day for both male and female rats and the NOAEL was set at 103 mg/kg bw/day for males and females.

In addition, reliable key acute toxicity study with Reaction mass of ammonium diaqua[bis(oxalate)]oxoniobate(1-) hydrate and ammonium hydrogen oxalate oxalic acid (1:1:1) dihydrate is available for the oral route, conducted according to OECD test guideline 423, and in compliance with GLP (CBMM Europe BV, Key, 2006, AOT). A first group of 3 female Wistar rats received the test item dissolved in water at a dose of 2000 mg/kg bw via gastric intubation. All animals died on the first day post-dosing. Consequently, a second group consisting of 3 males and 3 females received the test item at a dose of 300 mg/kg bw. There was no mortality observed in any of the males or females treated in this dose group, and no signs of toxicity were noted in any of these animals throughout the study period. Body weight gain in animals dosed with 300 mg/kg bw was as expected. Based on the outcome of this study, the NOAEL was set at 300 mg/kg bw for males and females.

References:

Hodgkinson. A.; Zarembski, P. M. (1968) Oxalic Acid Metabolism in Man: A Review. Calcif Tissue Res. 2(2):115-32.

Kahn, S.R. (1997) Animals models of kidney stone formation: an analysis. World J Urol 15:236-243.

 

Repeated-dose toxicity – systemic effects – inhalation route – general population:

The DNEL for systemic effects via inhalation is determined on the basis of route-to-route extrapolation from an oral OECD 408 toxicity study. In this study the NOAEL was set at 103 mg/kg bw.

 

The following corrections were made to the NOAEL:

Correction for relative absorption oral vs. inhalation: 2 (ECHA default)

Correction for respiratory volume (rat/human): 1.15 m³/kg bw (24 h)

Therefore the corrected NOAEC for repeated-dose systemic effects via inhalation is:

103 mg/kg bw/2×1/1.15 m³/kg bw = 44.78 mg/m³

 

The following assessment factors were applied to the corrected NOAEC:

Exposure duration (subchronic to chronic): 2 (ECHA default)

Interspecies differences (toxicodynamics): 2.5 (ECHA default)

Intraspecies differences (general population): 10 (ECHA default)

Total AF: 2×2.5×10 = 50

 

The overall DNEL (repeated-dose – systemic – inhalation - general population) is therefore:

44.78 mg/m³/50 = 0.896 mg/m³.

 

Repeated-dose toxicity – systemic effects – dermal route – general population:

The DNEL for systemic effects via the dermal route is determined on the basis of route-to-route extrapolation from an oral OECD 408 toxicity study. In this study the NOAEL was set at 103 mg/kg bw.

 

The following corrections were made to the NOAEL:

As no reliable information is available from acute dermal or dermal repeated dose toxicity tests regarding dermal absorption, a conservative approach is applied, and thus the relative dermal absorption was set to 1.

The corrected NOAEL is therefore:

103 mg/kg bw×1 = 103 mg/kg bw

 

The following assessment factors were applied to the corrected NOAEL:

Exposure duration (subchronic to chronic): 2 (ECHA default)

Interspecies differences (toxicodynamics): 2.5 (ECHA default)

Interspecies differences (toxicokinetics, rat/human): 4 (ECHA default)

Intraspecies differences (general population): 10 (ECHA default)

Total AF: 2×2.5×4×10 = 200

 

The overall DNEL (repeated-dose – systemic – dermal - general population) is therefore:

103 mg/kg bw/day/200=0.52 mg/kg bw/day.

 

Repeated-dose toxicity – systemic effects – oral route – general population:

The DNEL for systemic effects via the oral route is determined from an oral OECD 408 toxicity study. In this study the NOAEL was set at 103 mg/kg bw.

 

No corrections were made to the NOAEL.

 

The following assessment factors were applied to the NOAEL:

Exposure duration (subchronic to chronic): 2 (ECHA default)

Interspecies differences (toxicodynamics): 2.5 (ECHA default)

Interspecies differences (toxicokinetics, rat/human): 4 (ECHA default)

Intraspecies differences (general population): 10 (ECHA default)

Total AF: 2×2.5×4×10 = 200

 

The overall DNEL (repeated-dose – systemic – oral – general population) is therefore:

103 mg/kg bw/day/200 = 0.52 mg/kg bw/day.

 

Acute toxicity – systemic effects – oral route – general population:

The DNEL for systemic effects via the oral route after acute exposure is determined from an acute oral toxicity study conducted according to OECD 423. In this study the NOAEL was set at 300 mg/kg bw.

 

No corrections were made to the NOAEL.

 

The following assessment factors were applied to the NOAEL:

Interspecies differences (toxicodynamics): 2.5 (ECHA default)

Interspecies differences (toxicokinetics, rat/human): 4 (ECHA default)

Intraspecies differences (general population): 10 (ECHA default)

Total AF: 2.5×4×10 = 100

 

The overall DNEL (acute – systemic – oral – general population) is therefore:

300 mg/kg bw/day/100 = 3 mg/kg bw/day.

 

DNEL for local effects:

No dose-response data for local effects is available and a DNEL for local effects cannot be derived. As there are no consumer exposure scenarios the local DNELS are not required. For details please refer to section 9.