Niobium

Endpoint summary

Description of key information

OECD Guideline 422: NOAEL > 1000 mg/kg bw/d

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: oral

Remarks:

combined repeated dose and reproduction / developmental screening

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

14 September 2009 to 12 April 2010

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The data available for the registered substance Niobium are not sufficient to fulfil the toxicological data requirements set out in Annex X of Regulation (EC) No. 1907/2006. In accordance with Annex XI of Regulation (EC) No. 1907/2006 read across from a structural analogue substance, Diniobium Pentoxide, will be performed to reduce animal testing and fulfil the data requirements. The target substance Niobium (Nb) is a metallic element and Diniobium Pentoxide (Nb2O5) is an oxide of this element. During preparation of Nb an oxide layer of Nb2O5 on the surface is formed (Grunder and Halbritter, 2004). Thus, in the majority of uses exposure is not to pure Nb but to the outer oxide layer of Nb, i.e. Nb2O5. Consequently data of Nb2O5 are well suited for read-across to Nb. Beside this similarity the read-across approach is further supported by similar physico-chemical properties resulting in low reactivity and comparable bioavailability of the source and the target substance. Niobium is a soft and ductile transition metal. It is corrosion resistant, insoluble in water and biological media and can be dissolved only under extreme and certainly non-physiological conditions (e.g. hot hydrogen fluoride). Diniobium Pentoxide (Nb2O5) is a solid inorganic compound which can be ground to a powder. Like Nb, it is inert, insoluble in water and biological media and can only be dissolved under strongly oxidizing conditions. Consequently both substances are not bioavailable under physiological conditions and are thus comparable regarding their potential for systemic effects. Therefore, data of the source substance are regarded to be well suited for the read-across to other poorly soluble, unreactive Niobium compounds like compact Niobium.
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
All known components of the target substance are specified in section 1.2 of the technical dossier and 1.1 of the CSR. The target and the source substance have a purity ≥ 98.5% and impurities are not expected to influence properties and the toxicity profiles of analogues.
3. ANALOGUE APPROACH JUSTIFICATION
Structural similarity: Niobium is a metallic element and Diniobium Pentoxide is an oxide of this element. The presence of Diniobium Pentoxide on the surface of Niobium is a main similarity factor of both the target and the source substance. During preparation of Nb an oxide layer of Nb2O5 on the surface is formed. Thus, in the majority of uses exposure is not to pure Nb but to the outer oxide layer of Nb, i.e. Nb2O5. Consequently data of Nb2O5 are well suited for read-across to Nb.
Similar physicochemical properties and common bioavailability: Both, the target and the source chemical, are inert, insoluble in water and can be dissolved only under extreme and certainly non-physiological conditions. Consequently both substances are not bioavailable and possess a low systemic toxicity. Thus data of the poorly soluble, unreactive Niobium compound are well suited for read-across to Nb.
Similar toxicological profile: No systemic toxicity and no mortality were observed after acute dermal application of Nb and Nb2O5 and after acute oral application of Nb2O5. Both, Nb and Nb2O5 are not irritating to skin or eyes and not sensitising based on available data. No data for Nb are available but no treatment related effects were observed within an OECD Guideline study 422 with Nb2O5 up to the limit dose. As discussed within the analogue justification the results obtained with Nb2O5 are a depiction of the health effects of Nb. Thus data of the poorly soluble, unreactive Niobium compound are well suited for read-across to Nb.
4. DATA MATRIX
A detailed analogue justification is attached in Section 13 of this dossier.

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

read-across source

Details on oral exposure:

Dosa

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

no effects observed

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not examined

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Key result

Dose descriptor:

NOAEL

Effect level:

> 1 000 mg/kg bw (total dose)

Based on:

test mat.

Remarks:

nominal

Sex:

male/female

Basis for effect level:

other: no adverse effects up to the highest dose tested

Key result

Critical effects observed:

no

Mortality

	C (0 mg/kg)	LD (250 mg/kg)	MD (500 mg/kg)	HD (1000 mg/kg)
Total number of animals examined: males	10	10	10	10
Total number of animals examined: females	10	10	10	10
No mortality was observed in any male from various treatment and control group during the entire period of the study. One female animal from low dose was found dead on gestation day 15 due to gavaging error (not attributed to test item).

 

 

Clinical Observations – Male

Clinical Finding	C (0 mg/kg)	LD (250 mg/kg)	MD (500 mg/kg)	HD (1000 mg/kg)
Total number of animals examined	10	10	10	10
No clinical signs were observed in any male from various treatment and control group during the entire period of the study.

 

Clinical Observations – Female

Clinical Finding	C (0 mg/kg)	LD (250 mg/kg)	MD (500 mg/kg)	HD (1000 mg/kg)
Total number of animals examined	10	10	10	10
No clinical signs were observed in any female from various treatment and control group during the entire period of the study.

 

Reproductive Indices

Index	Group
		C (0 mg/kg)	LD (250 mg/kg)	MD (500 mg/kg)	HD (1000 mg/kg)
Copulation Index	(%)	100	100	100	100
Fertility Index	(%)	90	100	80	100
Delivery Index	(%)	100	100	100	100
Viability Index	Mean	100.00	100.00	100.00	97.00

Copulation Index (%)= (No. of rats copulated /No.of pairs)X 100

Fertility Index (%)= (No. of Females Pregant/No.of females copulated)x 100

Delivery Index(%)= (No. of dams with live newborns/ No.of pregnant dams)X 100

Viability Index (%)= (No. of live offspring at day 4/ No.of live offspring at birth)x 100

No. of live offspring at day 4/ No.of live offspring at birth)x 100

 

Macroscopic Findings - Male

Findings (External/Internal)	C (0 g/kg)	LD (250 mg/kg)	MD (500 mg/kg)	HD (1000 mg/kg)
Total number of animals examined	10	10	10	10
Left seminal vesicle diminished	1	0	0	0
Epididymidis-yellowish, whitish deposition (bilateral)	1	0	1	0
Right epididymis-yellowish, whitish deposition	0	1	1	0
Lung redish discolouration	0	0	1	0
Left Epididymidis-yellowish, whitish deposition	0	0	1	1
Right seminal vesicle with white spots( 1-2mm)	0	0	0	1

 

Macroscopic Findings- Female

Findings (External/Internal)	C (0 g/kg)	LD (250 mg/kg)	MD (500 mg/kg)	HD (1000 mg/kg)
Total number of animals examined	10	10	10	10
Lymph nodes axillary: left slightly enlarged; right red discolouration at the margin	1	0	0	0
Lung-residuals of the test item	0	2	1	2
Lung-bloody infiltrated,foam	0	1	0	0
Kidney- small cyst on right kidney.	0	0	1	0
Thymus- slightly reduced in size	0	0	2	0
Lung-slight bloody, red spots	0	0	1	0
oesophagos-residuals of the test item	0	0	1	0
Axillary lymphnode-left slightly enlarged	0	0	0	1
Lung- bloody, red discoloured	0	0	0	2

 

Conclusions:

In conclusion, the repeated dose administration of Diniobium Pentoxide (Nb2O5) in deionised water to the male (28-29 days) and female (maximum 54 days) Wistar rats at dosages of 250, 500 and 1000 mg/kg body weight revealed no toxicological findings.
Based on the data generated from this combined repeated dose toxicity and reproduction/ developmental toxicity screening test with Diniobium Pentoxide, the no observed adverse effect level (NOAEL) is believed to be 1000 mg/kg body weight in males and females.

Executive summary:

Both source (Nb2O5) and target substances (Nb) are not bioavailable under physiological conditions. Upon oral exposure the source and the target substance will remain in the gastro-intestinal tract and will be excreted via feces without prior absorption. Consequently both substances will not possess any systemic toxicological hazard due to their very low bioavailability. In general the dose descriptor of the source substance which will be taken into consideration for hazard assessment of the target substance could be modified for differences in molecular weight. Based on the low bioavailability of the source and the target substance and the fact that no NOAEL was established at the limit dose for the source substance this is not appropriate as it is very likely that the NOAEL of Nb will exceed the limit value as well.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The whole database is of good quality.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Repeated dose toxicity of niobium was investigated according to OECD Guideline 422 (combined repeated dose toxicity and reproduction/developmental screening test) with a special preparation of niobium, i.e. ferro niobium (Rudragowda, 2010). Ferro niobium is available in granular form and is, as niobium, chemically inert and practically not water soluble (water solubility < 0.5 µg/L), not flammable and has also no oxidizing properties. Data of the alloy therefore reflect the effects of niobium metal. However, ferro niobium can be powderised more easily compared to niobium metal. This facilitates the study conduct. 10 Wistar rats of each sex were treated with nominal doses of 250, 500 and 1000 mg/kg bw/d via gavage. Application of the nominal dose level turned out to be difficult. This is due to the high density and the fast settling of the particles. The actual doses applied are approximately 40% of the nominal values according to the analytical verification. The test substance was administered daily during 14 days pre-mating and 14 days mating in both males and in females, as well as during gestation period and up to post natal day 3 in females. Males were dosed for 28-29 days. Females were dosed for a maximum of 54 days. No clinical signs of toxicity or any other treatment related effect was observed. Thus, the NOAEL was greater 400 mg/kg bw/d based on the actual dose received and greater 1000 mg/kg bw/d based on the nominal dose applied.

Read across

To further provide evidence that niobium does not result in signs of systemic toxicity at the limit dose upon repeated exposure read-across from diniobium pentoxide was performed in accordance with Annex XI of Regulation (EC) No. 1907/2006. The target substance niobium (Nb) is a soft and ductile transition metal that forms an oxide layer when exposed to air at room temperature. Due to the protection by this oxide layer, niobium is insoluble in water and biological media. It is corrosion resistant, insoluble in water and biological media and can be dissolved only under extreme and certainly non-physiological conditions (e.g. hot HF). Due to its ductility, it cannot easily be ground to a fine powder that is suitable for gavage administration of a suspension. Even if applied as pure powder it can be assumed that niobium metal will not be absorbed in the stomach and intestinal tract due to its insolubility. Diniobium pentoxide (Nb2O5) is a solid inorganic compound which can be ground to a powder. Like Nb it is inert, insoluble in water and biological media and can only be dissolved under strongly oxidizing conditions. Diniobium pentoxide and niobium were found to be hardly soluble in artificial sweat solution (ASW) and in artificial gastric fluid (GST) under pH and temperature mimicking human body conditions (Klawonn, 2014/2014a, IUCLID section 7.1). Consequently both substances are not bioavailable under physiological conditions and data of the source substance are well suited for the read-across to other poorly soluble, unreactive niobium compounds and niobium itself. Beside the comparable bioavailability and low reactivity of the source and the target substance another factor supports the read-across from Nb2O5 to Nb. In fact, contact to Nb is mostly to its oxidized form. The surface of Nb which is exposed to oxygen is covered with a compact and impervious oxide layer composed of NbO and Nb2O as well as Nb2O5 on the outside of the layer (Grunder and Halbritter, 2004). So any exposure to Nb would effectively be to this highly inert and poorly soluble oxide layer. Thus, data of Nb2O5 are well suited for a read-across and will be a depiction of the toxicity of Nb. For a detailed analogue read-across justification please refer to the document attached to IUCLID section 13.

Diniobium pentoxide was tested within a combined repeated dose toxicity and reproduction/developmental screening test conducted according to OECD Guideline 422. Males were dosed for 28-29 days. Females were dosed for a maximum of 54 days. 10 Wistar rats of each sex were treated with nominal doses of 250, 500 and 1000 mg/kg bw/d via gavage. The analytical verification of doses revealed 88 to 98% of the nominal doses. In this study, there were neither adverse systemic effects nor adverse findings in organs and tissues related to oral (gavage) treatment in male and female rats up to the applied limit dose of 1000 mg/kg bw/d (Takawale, 2010). Consequently the NOAEL was > 1000 mg/kg bw/d. Thus this data prove that niobium metal and its insoluble and unreactive compounds do not elicit systemic effects after repeated dose administration at the limit dose.

Waiving of a subchronic toxicity study

According to Regulation (EC) No 1907/2006, Annex IX, 8.6.2, column 2, a subchronic toxicity study (90 days) does not need to be conducted if the substance is unreactive, insoluble and not inhalable and there is no evidence of absorption and no evidence of toxicity in a 28-day ‘limit test’, particularly if such a pattern is coupled with limited human exposure.

As discussed above, niobium is inert and insoluble in water and biological media. Consequently niobium is not bioavailable independently from the route of exposure and no evidence of absorption was observed. No signs of systemic toxicity were observed at the limit dose of 1000 mg/kg bw/d in two OECD Guideline studies and in the acute toxicity studies. The use pattern and the exposure evaluation proved that the use does not pose a risk to human health and therefore exposure can be expected to be negligible/limited.

In the following some considerations regarding the exposure potential of niobium are depicted.

Exposure considerations

The massive form of niobium can be manipulated without formation of any respirable dust. Also inhalation exposure due to use of niobium in hot processes was evaluated and can be excluded. Thus, under normal use and handling conditions, inhalation exposure and availability for respiratory absorption of niobium in the form of dusts/fumes is not relevant. Also dermal exposure during handling of processed niobium in its massive form was considered to be negligible. However, during further use evaluation some uses in granular form were identified for niobium, i.e. niobium is introduced into some processes as ferro niobium which has a particle size < 0.4 mm. The granulometry of ferro niobium however does not favour inhalation exposure (please refer to IUCLID section 4.5 Particle size distribution). The dermal exposure for handling powder of a low dustiness was assessed using the MEASE model. Also dermal exposure to FeNb does not pose a risk to human health and therefore considered to be negligible/limited. For details please refer to the submitted waiving statement in IUCLID section 7.5.1 and the Chemical Safety Assessment.

 

Taken together a subchronic toxicity study (90 days) does not need to be conducted as:

·        no effects at the limit dose of 1000 mg/kg bw/d were observed upon gavage treatment for maximum 54 days,

·        the substance is highly unreactive and insoluble (in water and artificial body fluids),

·        there is no evidence of absorption (the substance is not bioavailable),

·        the exposure assessment showed only very limited exposure of humans not resulting in a potential risk via dermal and inhalation route

·        no further information can be generated by a subchronic toxicity study

 

For reasons of animal welfare and the 3R-concept the study should not be conducted.

 

Justification for classification or non-classification

No classification for repeated dose toxicity is needed.