Niobium

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

OECD 422 NOAEL reproduction toxicity >1000 mg/kg bw/day

OECD 422 NOAEL maternal toxicity >1000 mg/kg bw/day

No further data available.

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

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

Clinical signs:

no effects observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Other effects:

no effects observed

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

no effects observed

Reproductive performance:

no effects observed

Clinical Observation and Mortality
No test item related clinical observations and mortalities were observed in male and
female animals during the entire period of the study. One female animal from low dose (18) was found dead on gestation day 15 due to gavaging error which was confirmed by microscopic evaluations and therefore not attributed to the treatment.

Detailed Clinical Observations/Functional Observation Battery
No relevant differences were observed concerning functional and behavioural examinations in male and females.
No abnormalities were recorded concerning posture, gait, palpebral closure, lacrimation, piloerection, arousal and vocalization.
No convulsions, tremors, stereotypy or bizarre behaviour were observed in animals of any groups.
For supported and unassisted rears, no abnormalities were detected. Responses to reflex testing were normal in all groups.
On measures such as counts of urination and defecation differences could not be detected.

Body Weight and Body Weight Change
In males, no effect on body weight and body weight change was observed through out the study period in treated groups when compared with controls.However, statistically significant decrease in overall body weight change during premating day 1 to terminal sacrifice was observed in mid dose group when compared with controls. Due to lack of dose dependency, this effect could be considered incidental and indicates no toxicological significance.
In females, statistical analysis of body weight and body weight change data revealed no difference during premating, gestation and lactation period except increase in body weight change during gestation period 0-7/8 in mid dose group as compared to controls. As increase was marginal and due to lack of dose dependency no toxicological relevance can be attributed to this finding.

Food consumption
In males, statistically significant decrease in food consumption during post mating period 1-7 was observed in low and mid dose group as compared to controls. However, lack of consistent and dose dependent pattern of effect on food consumption in treated groups indicates no toxicological relevance.
In females, No effect on food consumption was observed in treated groups during premating, gestation and lactation period as compared to controls.

Litter Weight Data
Statistical analysis of litter weight data revealed decrese in male litter weight on PND 0 in low and mid dose group and on PND 4 in low dose group. However, neither dose dependency nor an effect on group mean litter weight, total litter weight and female litter weight on PND 0 and PND 4 was observed when compared with controls. Therefore, this effect cannot be considered as test item related.

Precoital Interval, Duration of gestation and fertility Index
No treatment related effect was observed on precoital interval, duration of gestation when compared with controls and values were comparable between the groups. All pregnancies resulted in normal births.
Successful mating resulted in 9, 10, 8 and 10 pregnancies in control, low mid and high dose respectively.
Reduced fertility index (No. of pregnant females/No. of copulated females X 100) was observed in control (90%) and mid dose group (80 %) as compared to low (100 %) and high dose group (100 %).

Key result

Dose descriptor:

NOAEL

Remarks:

systemic

Effect level:

> 1 000 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no adverse effects up to the highest dose tested

Clinical signs:

no effects observed

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Sexual maturation:

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings:

no effects observed

Group mean number of corpora lutea, No. of implantation sites, number of live pups born on PND 0, percent preimplantation loss and post implantation loss remained unaffected due to treatment when compared with controls.
No treatment related effect was observed on litter data such as total number of pups born, live pups, No. of female pups, still birth and runt on PND 0 and total No. of live pups and No. of female pups on PND 4.
No statistically significant effect on survival of the pups from PND 0 to PND 4 was observed in any treatment group when compared with controls.
One pup (Pup No. 1 male) from female No. 35 and two pups (pup no 4 male and 10 female) from female No 36 of high dose group were found dead on PND 1. Gross necropsy findings of found dead pup revealed no specific findings.

Key result

Dose descriptor:

NOAEL

Remarks:

fertility/reproduction

Generation:

F1

Effect level:

> 1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no adverse effects up to the highest dose tested

Reproductive effects observed:

not specified

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     Tabular Study Summary OBSERVATIONS Group Dosage (units). C (0 mg/kg) LD (250 mg/kg) MD (500 mg/kg) HD (1000 mg/kg) Pairs started (N) 10 10 10 10 Females showing evidence of copulation (N) 10 10 10 10 Females achieving pregnancy (N) 9 10 8 10 Conceiving days 1 - 5 (N) 9 10 10 10 Conceiving days 6 - . . .(1) (N) 1 0 0 0 Pregnancy = 21 days or below (N) 0 0 0 0 Pregnancy = 22 days (N) 6 5 7 7 Pregnancy ³ 23 days (N) 3 4 1 3 Dams with live young born (N) 9 9 8 10 Dams with live young at day 4 pp (N) 9 9 8 10 Corpora lutea/dam (mean) 12.56 12.67 12.88 12.30 Implants/dam (mean) 11.33 10.67 11.00 10.70 Live pups/dam at birth (mean) 10.89 10.11 10.63 10.20 Live pups/dam at day 4 (mean) 10.89 10.11 10.63 9.90 Sex ratio (m/f) at birth (mean) 1.78 0.85 0.98 1.16 Sex ratio (m/f) at day 4 (mean) 1.78 0.85 0.98 1.12 Litter weight at birth (mean) 65.10 62.70 62.64 59.61 Litter weight at day 4 (mean) 111.18 107.44 108.90 101.48 Pup weight at birth (mean) 6.02 6.26 5.91 5.87 Pup weight at day 4 (mean) 10.19 10.74 10.42 10.30 ABNORMAL PUPS Dams with 0 8 8 6 8 Dams with 1 1 0 2 1 Dams with 2 0 1 0 1 Dosage (units). C (0 mg/kg) LD (250 mg/kg) MD (500 mg/kg) HD (1000 mg/kg) LOSS OF OFFSPRING Pre-implantation (corpora lutea minus implantations) Females with 0 4 1 3 3 Females with 1 2 2 2 1 Females with 2 1 3 2 4 Females with 3 and more 2 3 1 2 Pre-natal (implantations minus live births) Females with 0 6 5 5 6 Females with 1 2 3 3 3 Females with 2 1 1 0 1 Females with 3 0 0 0 0 Post-natal (live births minus alive at post natal day 4) Females with 0 9 9 8 8 Females with 1 0 0 0 1 Females with 2 0 0 0 1 Females with 3 0 0 0 0

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 major 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.

Effect on fertility: via oral route

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

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Reproduction 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 (MMAD: 991 µM) 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 was related to the high density and the fast settling of the ferroniobium in granular form. 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 postnatal 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. None of the reproductive indices or fertility parameters was affected by the treatment. No treatment related effect on pubs was observed. Thus, the NOAEL for reproduction and systemic toxicity was greater 400 mg/kg bw/d based on the actual dose received and greater 1000 mg/kg bw/d based on the nominal dosed applied.

Read across

To further provide evidence that niobium does not result in reproductive/developmental or systemic toxicity at the limit dose, 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. 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. 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. Male rats were dosed for 28-29 days. Female rats were dosed for a maximum of 54 days. In this study, there were neither adverse systemic effects nor adverse findings in organs and tissues related to oral (gavage) treatment in males and females up to the applied limit dose of 1000 mg/kg bw/d (Takawale, 2010). None of the reproductive indices or fertility parameters was affected by the treatment. No treatment related effect on pubs was observed. Thus, the NOAEL for reproduction and systemic toxicity was greater 1000 mg/kg bw/d.

In conclusion, this data prove that niobium and its insoluble and unreactive compounds do not elicit systemic effects after repeated dose administration at the limit dose. No indication for adverse reproductive or developmental properties of niobium and its insoluble, unreactive compounds was observed.

Waiving of an extended one-generation reproductive toxicity study

According to Regulation (EC) No 1907/2006, Annex IX, 8.7.3, column 1, an extended one-generation reproductive toxicity study has to be performed in one species, male and female, using the most appropriate route of exposure, if the available repeated dose toxicity studies indicate adverse effects on reproductive organs or tissues. According Annex X, 8.7, column 2 of the same regulation, an extended one-generation reproductive toxicity study has not to be conducted if the substance is of low toxicological activity, it can be proven from toxicokinetic data that no systemic absorption occurs via relevant routes of exposure and there is no or no significant 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. This is supported by the OECD Guideline 422 with diniobium pentoxide and ferro niobium where no evidence of absorption was observed. Dermally, an OECD Guideline 402 study is available, which showed that except for slight marks of pressure caused by the test item at the application site on the day of dosing, neither systemic nor irritation-related findings were noticed (Leoni, 2009). Due to the physical state of the substance, no dermal absorption is to be expected; this is supported by the fact that the substance is neither irritating (Leoni, 2009) nor sensitising (Stelter, 2009) to skin (ECHA, 2017). Also in two acute inhalation toxicity studies according to OECD Guideline 403 with diniobium pentoxide and the special preparation ferro niobium (Wilcox 2001 and Oley, 2009, respectively) no systemic toxicity was observed. In both studies the mass median aerodynamic diameter (MMAD) of the test aerosol was below 4 µm and at least 88% of the articles had a respirable size. Therefore, a very low bioavailability in humans is anticipated for the substance after any route of exposure. Also the lack of systemic toxicity in any of the available studies is very likely related to this fact. Anyway, the missing systemic toxicity in any of the available studies proved that niobium has a low toxicological activity. Finally there is no significant human exposure to niobium.

Exposure considerations

It should be mentioned that metallic niobium can be manipulated without formation of any respirable dust. Dermal exposure to massive niobium will be not significant, as human exposure is limited to the massive niobium metal e.g. present as ingot or metal sheets. Here abrasion and transfer of a significant amount to the skin is unlikely due to the high ductility of the metal itself. In the final products niobium is usually embedded in a matrix (e.g. superconducting alloys). Also inhalation exposure due to use of niobium in hot processes was evaluated and can be excluded. Thus, under normal use and handling conditions of massive niobium, inhalation and dermal exposure is not relevant.

However, during further use evaluation some uses of fine particles 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 in granular form can be considered negligible based on the exposure assessment. For details please refer to the submitted waiving statement in IUCLID section 7.8.1 and the Chemical Safety Assessment.

 Inhalation and dermal exposure is in any case very limited. Even when assuming worst case assumptions for relevant parameters and no personal protective equipment the exposure estimate is around the general occupational dust threshold values and well below the DNEL. The general population will not come into contact with niobium in granular form.

Therefore, the use of niobium does not result in significant exposure and an extended one-generation reproductive toxicity study with niobium is scientifically not justified.

 

Effects on developmental toxicity

Description of key information

According to Regulation (EC) No 1907/2006, Annex IX, 8.7 the study does not need to be conducted as niobium is of low toxicological activity, is not bioavailable and no significant exposure to niobium occurs.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

No developmental toxicity study according to OECD Guideline 414 is available for niobium metal. According to Regulation (EC) No 1907/2006, Annex X, 8.7.2, column 1, a pre-natal developmental toxicity study has to be performed in one species, male and female, using the most appropriate route of exposure. According to Regulation (EC) No 1907/2006, Annex X, 8.7 Column 2 the study does not need to be conducted if the substance is of low toxicological activity, it can be proven from toxicokinetic data that no systemic absorption occurs via relevant routes of exposure and there is no or no significant human exposure.

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). Niobium was found to be hardly soluble in artificial sweat solution (ASW) or in artificial gastric fluid (GST) under pH and temperature mimicking human body conditions (Klawonn, 2014). Consequently niobium is not bioavailable under physiological conditions. Due to its ductility, Nb cannot easily be ground to a fine powder that is suitable for gavage administration of a suspension. Even if application as pure powder would be possible it can be assumed that niobium metal will not be absorbed in the stomach and intestinal tract due to its insolubility. Consequently niobium is not bioavailable independently from the route of exposure. This is supported by two OECD Guideline 422 studies performed either with the analogue substance diniobium pentoxide or the special preparation of niobium, ferro niobium, where no evidence of absorption was observed (for details refer to section reproduction toxicity; for a read across justification please refer to the discussion of effects on fertility). The missing systemic toxicity in any of the available studies proved that niobium has a low toxicological activity.

 

Finally there is no significant human exposure to niobium via the dermal and the inhalation route. This was assessed for massive niobium metal and ferro niobium of a low dustiness (e.g. ferro niobium granular form <0.4 mm). For a detailed discussion on exposure considerations please refer to the discussion of effects on fertility or to the respective section of the CSR.

 

In conclusion, the data requirements for waiving a developmental toxicity study are fulfilled and the conduct of a pre-natal developmental toxicity study is not needed.

 

Justification for classification or non-classification

No classification for reproduction toxicity is needed.