Niobium

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

23.5 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):

75

Modified dose descriptor starting point:

NOAEC

Value:

1 763 mg/m³

Explanation for the modification of the dose descriptor starting point:

NOAECcorr = NOAELoral*(1/0.38 m³/kg bw/day)*(ABSinh-rat/ABSinh-human)*(6.7 m³ (8h)/10 m³ (8h)) = 1000 mg/kg bw/day * 6.7 / (10 x 0.38) = 1763 mg/m3

AF for dose response relationship:

1

Justification:

NOEL was used as starting point

AF for differences in duration of exposure:

6

Justification:

Extrapolation subacute to chronic exposure

AF for interspecies differences (allometric scaling):

1

Justification:

AF not needed for inhalation route.

AF for other interspecies differences:

2.5

Justification:

According to ECHA guidance document R8

AF for intraspecies differences:

5

Justification:

For workers

AF for the quality of the whole database:

1

Justification:

The whole database indicates no systemic toxicity of niobium and thus the data base is conclusive and of good quality.

AF for remaining uncertainties:

1

Justification:

Although the analogue approach may present a remaining uncertainty, this is already covered by using a NOEL instead of a NOAEL as starting point.

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:

3.3 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):

300

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Dermal NOAEL=NOAELoral*(ABSoral-rat/ABSdermal-human) = (1000 mg/kg bw/day)*(1/1) = 1000 mg/kg bw/day.

AF for dose response relationship:

1

Justification:

NOEL was used as starting point

AF for differences in duration of exposure:

6

Justification:

Extrapolation subacute to chronic exposure

AF for interspecies differences (allometric scaling):

4

Justification:

According to ECHA guidance document R8

AF for other interspecies differences:

2.5

Justification:

According to ECHA guidance document R8

AF for intraspecies differences:

5

Justification:

For workers

AF for the quality of the whole database:

1

Justification:

The whole database indicates no systemic toxicity of niobium and thus the data base is conclusive and of good quality.

AF for remaining uncertainties:

1

Justification:

Although the analogue approach may present a remaining uncertainty, this is already covered by using a NOEL instead of a NOAEL as starting point.

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

Niobium metal is not bioavailable via any foreseeable route of exposure. This entails a lack of toxicological hazards. Toxicological threshold values proposed for niobium metal are only achieved to support the conclusion that exposure to niobium is not significant.

Reliable OECD Guideline422 studies with the alloy ferro niobium and with the read-across substance diniobium pentoxide are available. Neither adverse systemic effects nor adverse findings in organs and tissues related to oral (gavage) treatment in male and female rats up to the limit dose of 1000 mg/kg bw/d (Takawale, 2010 and Rudragowda, 2010, respectively) were observed. Consequently the NOAEL was > 1000 mg/kg bw/d. For a detailed rational for read-across please refer to the respective subsection and the analogue justification attached in IUCLID section 13.

Conversion of oral NOAEL to inhalatory NAEC

Since there is no dose descriptor for every exposure route, the dose descriptor was converted into a correct starting point by route-to-route extrapolation based on the ECHA guidance document "Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health", November 2012.

 

The conversion of an oral NOAEL (>1000 mg/kg bw/d) into an inhalatory NAEC is performed using the following equations; for workers the resulting concentration needs to be additionally corrected for the difference between basal caloric demand and caloric demand under light activity:

Corrected inhalatory NAEC = oral NOAEL x1/sRVratx ABSoral-rat/ABSinh-humanxsRVhuman/wRV

                                            = oral NOAEL x 1/0.38m³/kg bw x 1 x 6.7 m³/10 m³ 

sRV: standard respiratory volume, ABS: absorption, wRV: worker respiratory volume

Thus, the corrected starting point for inhalation route was 1000 * 6.7 / (10 x 0.38) = 1763 mg/m³

DNEL derivation using the inhalatory NAEC

In the ECHA Guidance a factor of 2 is suggested for the extrapolation from oral to inhalation absorption. On the contrary, the Technical guidance document on risk assessment in support of Commission directive 93/67/EEC, 2003 appendix IV A and B gives a number of physico-chemical properties that normally determine oral, inhalation and dermal absorption. These parameters include molecular weight, log Kow, pKa values and for inhalation also particle size distribution, vapour pressure etc.

It is assumed that the absorption rate of Niobium metal via either route is negligible (<< 1%, see IUCLID section 7.1) as the substance is insoluble under physiological conditions. Therefore, absorption is limited to dissolution and equal absorption was assumed when extrapolating from oral to inhalation route. Thus, the factor of 2 is considered to be not relevant for niobium when extrapolating from oral to inhalation route. A factor of 6 for the differences in exposure duration was applied. The NOAEL of the sub-acute study is extrapolated to a chronic NOAEL. Factors applied for interspecies differences (2.5) and intraspecies differences (5) were applied according to ECHA guidance document; Chapter R.8. The whole database indicates no systemic toxicity of niobium and the data base is conclusive and of good quality. Additionally a NOEL was used as starting point. Thus no further AF were deemed necessary.

Thus, the inhalatory DNEL is calculated to be 23.5 mg/m³.

 

Conversion of oral NOAEL to dermal NAEL for systemic toxicity

No difference in absorption between routes is expected.

Thus, the corrected starting point for dermal route was 1000 mg/kg bw/d.

DNEL derivation of dermal long-term systemic effects

A factor of 6 for the differences in exposure duration was applied. The NOAEL of the sub-acute study is extrapolated to a chronic NOAEL. Factors applied for allometric scaling (4), interspecies differences (2.5) and intraspecies differences (5) were applied according to ECHA guidance document; Chapter R.8. The whole database indicates no systemic toxicity of niobium and the data base is conclusive and of good quality. Additionally a NOEL was used as starting point. Thus no further AF were deemed necessary.

Thus, the dermal systemic DNEL is calculated to be 3.3 mg/kg bw/d.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

5.8 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):

150

Modified dose descriptor starting point:

NOAEC

Value:

869.6 mg/m³

Explanation for the modification of the dose descriptor starting point:

NOAECcorr = NOAELoral / (ABSinh-rat/ABSinh-human) = 1000 mg/kg bw/day / 1.15 m³/kg bw = 869.6 mg/m³

AF for dose response relationship:

1

Justification:

NOEL was used as starting point

AF for differences in duration of exposure:

6

Justification:

Extrapolation subacute to chronic exposure

AF for interspecies differences (allometric scaling):

1

Justification:

AF not needed for inhalation route

AF for other interspecies differences:

2.5

Justification:

According to ECHA guidance document R8

AF for intraspecies differences:

10

Justification:

For general population

AF for the quality of the whole database:

1

Justification:

The whole database indicates no systemic toxicity of niobium and thus the data base is conclusive and of good quality.

AF for remaining uncertainties:

1

Justification:

Although the analogue approach may present a remaining uncertainty, this is already covered by using a NOEL instead of a NOAEL as starting point.

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:

1.67 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):

600

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Dermal NOAEL=NOAELoral*(ABSoral-rat/ABSdermal-human) = (1000 mg/kg bw/day)*(1/1) = 1000 mg/kg bw/day.

AF for dose response relationship:

1

Justification:

NOEL was used as starting point

AF for differences in duration of exposure:

6

Justification:

Extrapolation subacute to chronic exposure

AF for interspecies differences (allometric scaling):

4

Justification:

According to ECHA guidance document R8

AF for other interspecies differences:

2.5

Justification:

According to ECHA guidance document R8

AF for intraspecies differences:

10

Justification:

For general population

AF for the quality of the whole database:

1

Justification:

The whole database indicates no systemic toxicity of niobium and thus the data base is conclusive and of good quality.

AF for remaining uncertainties:

1

Justification:

Although the analogue approach may present a remaining uncertainty, this is already covered by using a NOEL instead of a NOAEL as starting point.

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:

1.67 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):

600

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Not necessary

AF for dose response relationship:

1

Justification:

NOEL was used as starting point

AF for differences in duration of exposure:

6

Justification:

Extrapolation subacute to chronic exposure

AF for interspecies differences (allometric scaling):

4

Justification:

According to ECHA guidance document R8

AF for other interspecies differences:

2.5

Justification:

According to ECHA guidance document R8

AF for intraspecies differences:

10

Justification:

For general population

AF for the quality of the whole database:

1

Justification:

The whole database indicates no systemic toxicity of niobium and thus the data base is conclusive and of good quality.

AF for remaining uncertainties:

1

Justification:

Although the analogue approach may present a remaining uncertainty, this is already covered by using a NOEL instead of a NOAEL as starting point.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

Niobium is not bioavailable via any foreseeable route of exposure. This entails a lack of toxicological hazards. Toxicological threshold values proposed for niobium are only achieved to support the conclusion that exposure to niobium is not significant.

Reliable OECD Guideline 422 studies with the alloy ferro niobium and with the read-across substance diniobium pentoxide are available. Neither adverse systemic effects nor adverse findings in organs and tissues related to oral (gavage) treatment in male and female rats up to the limit dose of 1000 mg/kg bw/d (Takawale, 2010 and Rudragowda, 2010, respectively) were observed. Consequently the NOAEL was > 1000 mg/kg bw/d. For a detailed rational for read-across please refer to the respective subsection and the analogue justification attached in IUCLID section 13.

Conversion of oral NOAEL to inhalatory NAEC

Since there is no dose descriptor for every exposure route, the dose descriptor was converted into a correct starting point by route-to-route extrapolation based on the ECHA guidance document "Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health", November 2012.

 

The conversion of an oral NOAEL (>1000 mg/kg bw/d) into an inhalatory NAEC is performed using the following equations; for general population the resulting concentration needs to be additionally corrected for the difference between basal caloric demand and caloric demand under light activity:

Corrected inhalatory NAEC = oral NOAEL * ABSinh-rat/ABSinh-human

                                            = oral NOAEL / 1.15 m³/kg bw 

ABS: absorption

Thus, the corrected starting point for inhalation route was 1000 / 1.15 = 869.6 mg/m³

 

DNEL derivation using the inhalatory NAEC

In the ECHA Guidance a factor of 2 is suggested for the extrapolation from oral to inhalation absorption. On the contrary, the Technical guidance document on risk assessment in support of Commission directive 93/67/EEC, 2003 appendix IV A and B gives a number of physico-chemical properties that normally determine oral, inhalation and dermal absorption. These parameters include molecular weight, log Kow, pKa values and for inhalation also particle size distribution, vapour pressure etc.

It is assumed that the absorption rate of niobium via either route is negligible (<< 1%, see IUCLID section 7.1) as the substance is insoluble under physiological conditions. Therefore, absorption is limited to dissolution and equal absorption was assumed when extrapolating from oral to inhalation route. Thus, the factor of 2 is considered to be not relevant for niobium when extrapolating from oral to inhalation route. A factor of 6 for the differences in exposure duration was applied. The NOAEL of the sub-acute study is extrapolated to chronic a NOAEL. Factors applied for interspecies differences (2.5) and intraspecies differences (10) were applied according to ECHA guidance document; Chapter R.8. The whole database indicates no systemic toxicity of niobium and the data base is conclusive and of good quality. Additionally a NOEL was used as starting point. Thus no further AF were deemed necessary.

Thus, the inhalatory DNEL is calculated to be 5.8 mg/m³.

 

Conversion of oral NOAEL to dermal NAEL for systemic toxicity

No difference in absorption between routes is expected.

Thus, no correction of the starting point for dermal route was needed.

DNEL derivation of dermal long-term systemic effects

A factor of 6 for the differences in exposure duration was applied. The NOAEL of the sub-acute study is extrapolated to chronic a NOAEL. Factors applied for allometric scalling (4), i

nterspecies differences (2.5) and intraspecies differences (10) were applied according to ECHA guidance document; Chapter R.8.

The whole database indicates no systemic toxicity of niobium and the data base is conclusive and of good quality. Additionally a NOEL was used as starting point. Thus no further AF were deemed necessary.

Thus, the dermal systemic DNEL is calculated to be 1.67 mg/kg bw/d.

 

DNEL derivation of oral long-term systemic effects

A factor of 6 for the differences in exposure duration was applied. The NOAEL of the sub-acute study is extrapolated to chronic a NOAEL. Factors applied for allometric scalling (4), interspecies differences (2.5) and intraspecies differences (10) were applied according to ECHA guidance document; Chapter R.8. The whole database indicates no systemic toxicity of niobium and the data base is conclusive and of good quality. Additionally a NOEL was used as starting point. Thus no further AF were deemed necessary.

Thus, the oral systemic DNEL is calculated to be 1.67 mg/kg bw/d.