Niobium

Endpoint summary

Description of key information

LD50 dermal > 2000 mg/kg bw
LC50 inhalation > 5 mg/L
LD50 oral > 2000 mg/kg bw

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

20 July 2009 - 16 September 2009

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

Test System
Species/strain: Healthy rats, WISTAR rats Crl: WI(Han) (Full-Barrier)
Source: Charles River, Sulzfeld, Germany
Sex: female, non-pregnant, nulliparous
Number of animals: 3 per step
Age at the beginning of the study: 8 - 10 weeks old
Body weight at the beginning of the study:
Animals no. 1 – 3, step 1: 162 – 181 g;
Animals no. 4 – 6, step 2: 165 – 170 g;
The animals were derived from a controlled full barrier maintained breeding system (SPF). According to Art. 9.2, No.7 of the German Act on Animal Welfare the animals were bred for experimental purposes.

Housing and Feeding Conditions
- Full barrier in an air-conditioned room
- Temperature: 22 +- 3 °C
- Relative humidity: 55 +- 10%
- Artificial light, sequence being 12 hours light, 12 hours dark
- Air change: 10 x / hour
- Free access to Altromin 1324 maintenance diet for rats and mice (lot no. 1131)
- Free access to tap water, sulphur acidified to a pH value of approx. 2.8 (drinking water, municipal residue control, microbiologically controlled at
frequent intervals)
- The animals were kept in groups in IVC cages, type III H, polysulphone cages on Altromin saw fibre bedding (lot no. 050109)
- Certificates of food, water and bedding are filed at BSL BIOSERVICE
- Adequate acclimatisation period

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

The test item was suspended in deionised water at a concentration of 0.2 g/mL and administered at a dose volume of 10 mL/kg.

Doses:

The starting dose was selected to be 2000 mg/kg body weight. No compound related mortality was recorded for any animal of step 1 or 2. Based on these results and according to the acute toxic class method regime no further testing was required.

No. of animals per sex per dose:

6 female WISTAR Crl: WI (Han) rats (3 per step)

Control animals:

no

Details on study design:

Preparation of the Animals
The animals were marked for individual identification by tail painting.
Prior to the administration a detailed clinical observation was made of all animals. Prior to the administration food was withheld from the test animals for 16 to 19 hours (access to water was permitted). Following the period of fasting the animals were weighed and the test item was administered. Food was provided again approximately 4 hours post dosing.

Administration
The test item was administered at a single dose by gavage using a feeding tube. For all animals, the test item was administered at a dose volume of 10 mL/kg body weight.

Dose Level
The starting dose was selected to be 2000 mg/kg body weight. No compound related mortality was recorded for any animal of step 1 or 2. Based on these results and according to the acute toxic class method regime no further testing was required.

Observation Period
All animals were observed for 14 days after dosing for general clinical signs, morbidity and mortality.

Weight Assessment
The animals were weighed on day 1 (prior to the administration) and on day 8 and on day 15.

Clinical Examination
A careful clinical examination was made several times on the day of dosing (at least once during the first 30 minutes and with special attention given during the first 4 hours post-dose). As soon as symptoms were noticed they were recorded. Thereafter, the animals were observed for clinical signs once daily until the end of the observation period. All abnormalities were recorded. Cageside observations included changes in the skin and fur, eyes and mucous membranes. Also respiratory, circulatory, autonomic and central nervous systems and somatomotor activity and behaviour pattern were examined. Particular attention was directed to observations of tremor, convulsions, salivation, diarrhoea, lethargy, sleep and coma.

Pathology
At the end of the observation period, the animals were sacrificed by an overdosage of pentobarbital injected intraperitoneally (Narcoren®, Merial; lot no.: 189039; expiry date: March 2012) at a dosage of approx. 8 mL/kg bw. All animals were subjected to gross necropsy. All gross pathological changes were recorded.

Evaluation of Results
Results were interpreted according to OECD Guideline 423, Annex 2 (see also flow charts in the appendix of the study plan). Individual reactions of each animal were recorded at each time of observation. Toxic response data were recorded by dose level. Nature, severity and duration of clinical observations were described. Body weight changes were summarised in tabular form. Necropsy findings were described.

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: No LD50 Cut Off value needs to be established (i.e. unclassified)

Mortality:

Under the conditions of the present study, single oral application of the test item Diniobium Pentaoxide (Nb2O5) to rats at a dose of 2000 mg/kg body weight was neither associated with signs of toxicity nor mortality.

Clinical signs:

other: No signs of toxicity during the whole observation period.

Gross pathology:

With the exception of acute injection of blood vessels in the abdominal region, which is due to the euthanasia injection, no special gross pathological changes were recorded for any animal of the two steps.

Interpretation of results:

other: CLP/EU GHS criteria not met, no classification according to Regulation (EC) No 1272/2008

Conclusions:

CLP: not classified

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

> 2 000 mg/kg bw

Quality of whole database:

The whole database is of good quality.

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

11 October 2000 - 03 November 2000

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

Ten male and 10 female albino rats were selected from a consignment of animals obtained from Charles River UK Limited, Manston Road, Margate, Kent, England on October 2000. The animals were ordered so that males and females would be approximately 7 and 8 weeks old respectively on the day of arrival.
On arrival the animals were allocated to 1 of 2 groups, each of 5 males and 5 females and were identified individually by a number tattooed on the ear pinnae and on the right hind foot to indicate 100’s. The animals were housed by sex, in groups of 5 and acclimatized to laboratory conditions for 9 days before the day of exposure. Data from Group 1 (control) animals were also reported as concurrent controls in study numbers SKC/015 and SKC/024.
The holding cages were made of stainless steel sheet and wire mesh and were suspended on a movable rack. While in their cages all animals had free access to an excess amount of food, DSD rat and mouse diet (RM1 (E) SQC expanded pellet), and tap water supplied by Anglian Water. Tap water was available from individual polypropylene water bottles that were emptied and re-filled daily. There was no information available to indicate to the Study Director the presence, in the food or water, of any non-nutrient substance likely to influence the outcome of this study. The results of chemical analyses on batches of diet and water supplied to the animals during this study are lodged in the Huntingdon Life Sciences Archives.
The animals remained in a holding room except for the 4 h exposure and an overnight post exposure period when the animals in the test group were kept in a ventilated cabinet to allow dispersal of any residual test substance.
The temperature and relative humidity of the animal room were recorded continuously using a Kent Clearspan recorder. The room conditions were maintained within the environmental control settings of 22°C +/- 3 for temperature and 50% +/- 20% for relative humidity.
Temperature maximum: 20.5°C
minimum: 19.5°C
Relative humidity maximum 68%
minimum 39%
Air extraction was via a balanced system providing at least 15 air changes per hour. Room lighting was controlled to give 12 hours light (06:00 – 18:00 GMT) and 12 hours dark per 24 hours.

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

clean air

Details on inhalation exposure:

A single group of animals was exposed continuously for 4 hours to a test atmosphere containing a particulate aerosol generates from hand ground Nb2O5 NIOBIUM PENTOXIDE GRADE LN.
A further group acting as a control received clean air only for 4 hours.
The group identification and date of exposure for the groups were:
Group 1 (control): 20 october 2000
Group 2 (Test): 20 october 2000

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

Chamber concentration of Nb2O5 NIOBIUM PENTOXIDE GRADE LN
The mean chamber concentration was 5.45 mg/L and was in good agreement with target (5 mg/L).

Nominal concentration
The nominal concentration was 26.1 mg/L. The mean chamber concentration was 20.9% of the nominal concentration and reflects losses of the test material due to impaction and deposition with the exposure system. When generating Niobium pentoxide static agglomeration was considered to be a significant factor in the particulate losses within the aerosol generation system. The use of a neutralized air supply, both to the WDF and diluents supply, was necessary to achieve the concentration attained. In addition, neutralized air was passed over the external surface of the elutriator to reduce electrostatic losses. The relatively low efficiency observed in this study is not unusual for the exposure system and test compound employed.

Particle size distribution
The mass median aerodynamic diameter (MMAD) of the test aerosol was 3.3 µm and was within the acceptable range (10 µm to 4 µm) for an acute inhalation study. Approximately 88% of the particulate were considered of a respirable size (<70 µm in aerodynamic diameter).

No. of animals per sex per dose:

5

Control animals:

yes

Details on study design:

Procedure
The substance was hand ground with a pestle and mortar prior to use.
A sample of the processed test substance was packed inteo the container of the Wright Dust Feed mechanism (WDF) using a hydraulic bench press to assist packing. An even density of the test substance was achieved by packing the container on stafes and applying a force of 2.5 ton to compress the powder. The applied force was sufficiente to prevent disintegration of the packed powder during the generation procedure. The packed container was weighed.
A supply of cleam dry air was connected to the generator and the supply pressure was adjusted to give a flow rate of 25 litres/minute, measured at the generator oulet. A neutralised diluent air supply, adjusted to give 10 litres/minute, was connected to the elutriator to provide a total air supply of 25 litres/minute.
The neutralised air supply was also passed externally over the elutriator to aid the removal of any electrostatic charge.
In-line flow meters were used to monitor the generator and diluent air supplies and exhaust airflow throughout the exposure. The exhaust airflow was calibrated and adjusted to produce a slightly negative pressure.
The WDF was positioned horizontally on a stand at the side of the exposure chamber and the output was connected to the top inlet port of the chamber via the elutriation column. A speed controller setting of ‘70% of the maximum speed’ of the WDF was selected, as a result of preliminary generation trials, to generate a concentration of total particulate at the target concentration of 5 mg/L.
Each animal was placed into a separate restraining tube and the tubes were then attached to the exposure chamber.
The powder container of the WDF was advanced manually until a trace o suspended dust was seen to emerge from de WDF outlet. The gearing on the generator was then engaged and the generator motor switched to start the exposure.
After an equilibration period of 3 minutes, the exposure was timed for 4 hours. The WDF canister was replaced with further packed canisters as required during the exposure. The generator was then switched off and the chamber was allowed to clear before the animals were removed for examination.
Following exposure, the animals were returned to the holding cages where food and water were available. The test animals were kept in a ventilated cabinet overnight and then returned to the holding room for the remainder of the observation period.
The control group was treated similarly but received clean air only for 4 h. The control animals were returned to the holding room at the end of the exposure period.

TERMINAL STUDIES

At the end of the 14-day observation period, the animals were killed by intraperitoneal injection of pentobarbitone sodium followed by exanguination from the brachial blood vessels. All animals were subjected to a detailed macroscopic examination. The lungs (including the larynx and trachea) were removed, dissected clear of surrounding tissue, weighed and the weights recorded. Lungs were discarded following necropsy.

Preliminary study:

not applicable

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 5.45 mg/L air

Based on:

test mat.

Exp. duration:

4 h

Mortality:

There were no unscheduled deaths.

Clinical signs:

other: During exposure: Exaggerated breathing was observed in most test rats from 1 h, and all test rats from 2 h into exposure. Observation period: Exaggerated breathing was observed in all test rats immediately post exposure, persisting to Day 4 of the observa

Body weight:

A slightly reduced mean bodyweight gain was evident for male test rats during the first week following exposure. Thereafter, the mean bodyweight gain was similar to that of the control values. Bodyweight gain values of the female test rats were similar to that of the control values.

Interpretation of results:

other: CLP/EU GHS criteria not met, no classification according to Regulation (EC) No 1272/2008

Conclusions:

The LC50 (4 h) for Nb2O5 NIOBIUM PENTOXIDE GRADE LN is in excess of 5.45 mg/L in air.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

> 5 mg/L air

Quality of whole database:

The whole database is of good quality.

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

07.08.2009-27.11.2009

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

yes

Remarks:

Deviation from the study plan due to physical state , the applied doses deviate from the intended level of 2000 mg/kg bw (deviations for males: +5 to +9%; females:-0.2 to -2%). The deviation did not influence the quality or integrity of the present study.

GLP compliance:

yes (incl. QA statement)

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River, Sulzfeld, Germany
- Age at study initiation: females: 9-10 weeks; males: 6-7 weeks
- Weight at study initiation: females: 201-212 g; males: 222-230 g
- Fasting period before study: none
- Housing: individdually in IVC cages, type III H, polysulphone cages on Altromin saw fibre bedding
- Diet (ad libitum): ad libitum
- Water (ad libitum):ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22+-3
- Humidity (%): 55+-10%
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light):12/12


IN-LIFE DATES: From: 2009-09-01 To: 2009-09-29

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: dorsal area of the trunk
- % coverage: 10
- Type of wrap if used: gauze-dressing and non-irritant tape


TEST MATERIAL
- For solids, paste formed: no

Duration of exposure:

24 h

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: day 0, 7 and 14
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, organ weights, histopathology, other: clinical examinations were made several times on the day of dosing, thereafter once daily

Statistics:

not applicable

Preliminary study:

Not applicable.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

None

Clinical signs:

other: None

Gross pathology:

None

Other findings:

Slight marks of pressure caused by the test item were noted in all males and females on the day of dosing. No signs of skin irritation were noted in any animal

Sex	Dose (mg/kg bw)	Number of animals tested / number of dead animals	LD50 (mg/kg bw)
Males	2000	5/0	> 2000
Females	2000	5/0	> 2000

Interpretation of results:

other: CLP/EU GHS criteria not met, no classification according to Regulation (EC) No 1272/2008

Conclusions:

Under the conditions of the present study, single dermal application of niobium to rats at a dose of 2000mg/kg bw was associated with no signs of toxicity or mortality.
CLP: not classified

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

> 2 000 mg/kg bw

Quality of whole database:

The whole database is of good quality.

Additional information

Acute dermal toxicity of niobium was tested according to OECD Guideline 402 in Wistar rats. At the limit dose of 2000 mg/kg bw no mortality and no clinical signs of toxicity were observed. Thus the dermal LD50 is greater than 2000 mg/kg bw. Additionally data of the alloy ferro niobium are available for the inhalation route. Ferro niobium is a special preparation according to REACh. Data of the alloy reflect the effects of niobium. However, ferro niobium can be powderised more easily compared to niobium metal what facilitates the study conduct. Acute inhalation toxicity of the alloy ferro niobium was tested according to OECD Guideline 403. Sprague-Dawley rats were exposed nose only to ferro niobium aerosol at the limit dose of 2 mg/L (actual 2.07 mg/L) for 4 h. The mass median aerodynamic diameter (MMAD) of the test aerosol was 3.9 µm and particle size distribution was 0-9 µm. Thus, 100% of the particles were of a respirable size. No mortality, no clinical signs of toxicity and no effects on body weight or upon gross pathology were observed. The inhalation LC50 is greater than 2 mg/L.

No reliable data on acute oral toxicity of niobium metal are available. Only one Russian publication is available, where niobium metal was tested for its acute oral toxicity (Mezhdunarodnaya Kniga, 1990). In this study the acute oral LD50 was found to be greater than 10,000 mg/kg bw in mice and rats. To support further the data base of inhalation toxicity, read-across from diniobium pentoxide was performed. The possibility of a read-across from diniobium pentoxide to niobium in accordance with Annex XI of Regulation (EC) No. 1907/2006 was assessed. 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. It is corrosion resistant, insoluble in 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 niobium metal would be 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 easily 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) or in artificial gastric fluid (GST) under pH and temperature mimicking human body conditions (Klawonn, 2014, 2014a). 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 like niobium metal. Beside the comparable bioavailability and low reactivity of the source and the target substance the above mentioned oxide layer of niobium 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. So any exposure to Nb would effectively also be to this highly inert and poorly soluble oxide layer. Thus, data of Nb2O5 are well suited to close potential data gaps or support already achieved conclusions of Nb. For a detailed analogue read-across justification please refer to the document attached to IUCLID section 13.

Acute oral toxicity of diniobium pentoxide was tested according to OECD Guideline 423. Wistar rats were treated via gavage at the limit dose of 2000 mg/kg bw. No mortality and no clinical signs of toxicity were observed. Thus the LD50 is greater than 2000 mg/kg bw.

Acute inhalation toxicity of diniobium pentoxide was tested according to OECD Guideline 403. Sprague-Dawley rats were exposed nose only to an aerosol of diniobium pentoxide at the limit dose of 5 mg/L (actual 5.45 mg/L) for 4 h. The mass median aerodynamic diameter (MMAD) of the test aerosol was 3.3 µm and approximately 88% of the particulate were considered of a respirable size (<70 µm in aerodynamic diameter). No mortalities occurred. Exaggerated breathing was observed latest from 2 h exposure which persisted to day 4. A slightly reduced mean bodyweight gain was evident for male test rats during the first week following exposure. Thereafter, the mean bodyweight gain was similar to that of the control values. Bodyweight gain values of the female test rats were similar to that of the control values. Body weight gain of males was only slightly reduced and this finding was not observed in females. Thus this effect is deemed to be not treatment related. Exaggerated breathing seems to be related to an overload of the respiratory pathways. That high limit concentrations of powders can result in impaired respiration due to dust loading is already recognized in the Guidance Document on Acute Inhalation Toxicity Testing (Document 39): “At very high concentrations, dry powder aerosols and chemically reactive liquid aerosols (e.g., polymers) tend to form conglomerates in the proximal nose causing physical obstruction of the animals’ airways (e.g., dust loading) and impaired respiration which may be misdiagnosed as a toxic effect.” The inhalation LC50 is greater than 5 mg/L.

 

 

Reference:

Gigiena Truda i Professional'nye Zabolevaniya  Labor Hygiene and Occupational Diseases.(V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-36, 1990.

Justification for classification or non-classification

Dermal and oral LD50 values are greater than 2000 mg/kg bw. Inhalation LC50 is greater 5 mg/L. No classification for acute lethal effects is necessary.