Tantalum

Endpoint summary

Description of key information

The acute toxicity of tantalum was investigated in guideline studies conducted according to OECD 423 respectively 403 addressing the oral and inhalation toxicity of the test material. Tantalum was tested orally at 2000 mg/kg bw and via the inhalation route at 5.18 mg/L without showing any adverse effects.

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:

26 September 2000 to 12 October 2000

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

Qualifier:

according to guideline

Guideline:

EU Method B.1 (Acute Toxicity (Oral))

Deviations:

no

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 5 - 7 weeks
- Weight at study initiation: 92 - 115 g
- Fasting period before study: overnight prior to and approximately 4 hours following dosing
- Housing: in groups of three by sex in metal cages with mesh floors
- Diet: Standard laboratory rodent diet ad libitum (Special Diet Services RM1(E) SQC expanded pellet)
- Water: ad libitum
- Acclimation period: 5 days (min.)
- Source: Harlan UK Ltd., Bicester, Oxon, England


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 ºC
- Humidity (%): 30 - 70 %
- Photoperiod (hrs dark / hrs light): 12 hours dark / 12 hours artificial light (0600 - 1800 hours)

IN-LIFE DATES: From 26 September 2000 to 12 October 2000

Route of administration:

oral: gavage

Vehicle:

other: 1 % w/v aqueous methylcellulose

Details on oral exposure:

VEHICLE - 1 % w/v aqueous methylcellulose

DOSE VOLUME APPLIED: 10 mL/kg bw

TEST MATERIAL PREPARATION: the test material was formulated at a concentration of 20 % w/v in 1 % w/v aqueous methylcellulose and administered at a volume of 10 mL/kg bw. The test material was prepared on the day of dosing.

The appropriate dose volume of the test material was administered to each rat by oral gavage using a plastic syringe and catheter (8 ch). The day of dosing was designated day 1.

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

3 females; 3 males

Control animals:

no

Details on study design:

- Treatment procedure: a group of three fasted female rats received the limit dose. As results at this dosage indicated the acute lethal oral dose to be greater than 2000 mg/kg bodyweight, in compliance with the study guidelines, a group of three fasted males was dosed at 2000 mg/kg to confirm the results and complete the study.
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Mortality was checked at least twice daily while animals were observed for clinical signs soon after dosing and at frequent intervals for the remainder of day 1. On subsequent days, animals were observed once in the morning and again at the end of the experimental day. The nature and severity of the clinical signs and time were recorded at each observation. The bodyweight of each rat was recorded on days 1 (prior to dosing), 8 and 15. Individual weekly bodyweight changes and group mean bodyweights were calculated.
- Necropsy of survivors performed: yes - all animals were killed on day 15 by carbon dioxide asphyxiation and subjected to a macroscopic examination which consisted of opening the cranial, thoracic and abdominal cavities. The macroscopic appearance of all examined organs was recorded.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

There were no deaths during the study.

Clinical signs:

other: Clinical signs of reaction to treatment were confined to piloerection and hunched posture, seen in all rats, with abnormal gait observed in all females. Recovery of rats, as judged by external appearance and behaviour, was complete by either day 2 (female

Gross pathology:

No abnormalities were revealed at the macroscopic examination at study termination on day 15.

Table 2: Signs of Reaction to Treatment

Clinical signs	No of rats in groups of 3 showing signs
	Male	Female
Piloerection	3	3
Hunched posture	3	3
Abnormal gait	0	3

Table 3: Individual Bodyweights and Bodyweight Gains

Dose (mg/kg)	Sex	Animal No.	Bodyweight (g) on day			Bodyweight gains (g) on day
			1*	8	15	8	15
2000	Male	4	109	185	237	76	52
		5	100	164	213	64	49
		6	115	184	237	69	53
		Mean	108	178	229
	Female	1	98	142	166	44	24
		2	92	134	157	42	23
		3	98	137	160	39	23
		Mean	96	138	161

*Prior to dosing

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Under the conditions of the test accoridng to OECD 423, the acute median lethal oral dose to rats of the test material was demonstrated to be greater than 2000 mg/kg bw. The study is considered to be reliable, relevant and adequate for risk assessment and classification and labelling purposes.

Executive summary:

The acute oral toxicity of the test material was determined in accordance with the standardised guidelines OECD 423 and EU Method B.1. During the test, 3 male and 3 female rats received a single oral gavage dose of 2000 mg/kg bw test material, formulated at a concentration of 20 % w/v in 1 % w/v aqueous methylcellulose and administered at a volume of 10 mL/kg bw. During the study, animals were dosed and assessed for signs of toxicity for 14 days following dosing. Bodyweights were recorded at weekly intervals during the study. All animals were killed on day 15 for macroscopic examination post-mortem.

None of the animals died during the study and no significant clinical signs were observed. Furthermore, all animals gained weight during the study and no abnormalities were revealed at the macroscopic examination at study termination on day 15. The acute median lethal oral dose to rats of the test material was therefore demonstrated to be greater than 2000 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

GLP guideline study

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 to 31 October 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:

yes

Remarks:

see "Principles of method if other than guideline"

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1300 (Acute inhalation toxicity)

Deviations:

yes

Remarks:

see "Principles of method if other than guideline"

Qualifier:

according to guideline

Guideline:

other: J-MAFF test guidelines for acute inhalation studies

Deviations:

not specified

Principles of method if other than guideline:

The mass median aerodynamic diameter (MMAD) of the test aerosol was 4.6 µm. This volume is slightly in excess of the guideline maximum of 4.0 µm. However it is considered that the value obtained was the minimum practical at the concentration achieved given the nature of the test material.

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 7 and 8 weeks (males and females respectively)
- Housing: by sex, in groups of 5 in holding cages made of stainless steel sheet and wire mesh suspended on a movable rack
- Diet: SDS rat and mouse diet (RM1 (E) SQC expanded pellet) ad libitum.
- Water: Anglian tap water ad libitum.
- Acclimation period: 6 days
- Source: Charles River UK Limited, Manston Road, Margate, Kent, England.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.5 - 20.5 ºC
- Humidity (%): 39 - 65 %
- Air changes (per hr): 15 air changes/ hour
- Photoperiod (hrs dark / hrs light): 12 hours dark / 12 hours light (06:00 - 18:00 GMT)

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: a Wright Dust Feed mechanism was used to produce and maintain atmospheres containing a particulate aerosol by suspending material scraped from the surface of a compressed powder in a stream of dry air. The concentration of particulate aerosol was altered by changing the rate at which the scraper blade is advanced into the compressed powder held in the test material canister. The Wright Dust Feed was mounted on a glass cylinder attached to the top of the exposure chamber. The conditioned test atmosphere entered through a port at the top centre of the chamber and passed out through a port at the base section below the level of the rats.
- Exposure chamber volume: 30 L
- Method of holding animals in test chamber: snout-only exposure chambers (animals held in moulded polycarbonate restraining tubes and held in a forward position by an adjustable foamed plastic stopper, which also provided a seal for the tube)
- Source and rate of air: clean, dry air was passed through an electronic neutraliser, connected to a generator and the supply pressure adjusted to give a flow rate of 16 litre/minute. An in-line flow meter was used to monitor the generator air supply throughout the exposure. The exhaust airflow was calibrated and adjusted to produce a slightly negative pressure.
- Method of particle size determination: particle size measured with a Marple cascade impactor. The volume of air sampled was measured using a wet-type gas meter. The amount of material collected on the stages of the sampler was determined gravimetrically. The particle size distribution of the test atmosphere was then assessed using linear regression analysis.
- Treatment of exhausted air: the exposure system was positioned inside a large cabinet equipped with an extract fan exhausting to atmosphere through an absolute filter.
- Temperature and humidity in air chamber: 20.0 - 20.1 °C, 42 - 58 % (mean values)

TEST ATMOSPHERE
- Brief description of analytical method used: five samples of air were removed from the test chamber following equilibration and hourly thereafter. Each air sample was withdrawn at a rate of 2 L/min through a pre-weighed glass fibre filter. The volume of air sampled was measured using a wet-type gas meter. The filters were reweighed following sampling for gravimetric analysis of the test aerosol.

TEST ATMOSPHERE
- MMAD (Mass median aerodynamic diameter): 4.6 µm (approximately 67 % of the aerosol generated consisted of particulate of size < 7 µm)

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

The nominal concentration was 92.2 mg/L. The mean chamber concentration was 5.6 % of the nominal concentration that reflects losses of the test material due to impaction, deposition and cohesion due to static within the exposure system. The mean chamber concentration of total particulate was 5.18 mg/L and was in good agreement with target (5 mg/L).

No. of animals per sex per dose:

5 animals per sex per dose.

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days.
- Environmental conditions in the exposure chamber: air temperature was measured using an alcohol-in-glass thermometer and relative humidity was measured using a Casella type T6900 relative humidity meter. The temperature and relative humidity were recorded at the start of exposure and then at 30 minute intervals during the 4 hour exposure.
- Frequency of observations and weighing: throughout the study, all cages were checked at least twice daily for dead or moribund animals. Rats were observed intermittently for signs of reaction to the test material during exposure and at least twice daily throughout the observation period. Clinical signs were recorded at the end of the chamber equilibration period, at 0.25, 0.5 and 1.0 hours then hourly during the exposure. Clinical signs were recorded immediately following exposure and then at 1.0 and 2.0 hours post-exposure. During the observation period, clinical signs were recorded twice daily. Bodyweights were recorded twice during the week prior to exposure (day 0) and then weekly during the observation period and on the day of death.
- Necropsy of survivors performed: yes.
- Other examinations performed: at the end of the 14-day observation period, the rats were killed by intraperitoneal injection of pentobarbitone sodium followed by exsanguinations from the brachial blood vessels and 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.

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 5.18 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 a proportion of test rats from 15 minutes and in all test rats from 30 minutes into exposure. Grey staining of the fur was noted for all test rats from 3 hours into exposure. Soiling of the fur wit

Body weight:

There were no treatment-related effects.

Gross pathology:

There were no treatment-related effects at necropsy.
Incidental effects noted included: small dark foci noted on the lungs of two male test rats and a male control rat. Hair loss from head was noted for a male test rat.

Other findings:

Lung weight: there were no treatment-related effects.

Table 1: Chamber Concentration of Test Material

Sample	Time taken (h:min)	Gravimetric conc. (mg/L)	Nominal conc. (mg/L)
1	0:10	4.95
2	1:00	5.00
3	2:00	5.48
4	2:58	5.04
5	3:54	5.41
	Mean	5.18	92.2
	SD	0.249

Table 2: Particle Size Distribution of Test Material

Sample	Time taken (h:min)	Stage	Cut-off size (µm)	Amount collected (mg)
PSD 1	1:31	1	21.30	0.06
		2	14.80	0.07
		3	9.80	0.35
		4	6.00	0.63
		5	3.50	0.34
		6	1.55	0.26
		7	0.93	0.01
		8	0.52	0.00
		Filter	0.00	0.08
			Total	1.80
PSD 2	3:31	1	21.30	0.00
		2	14.80	0.09
		3	9.80	0.39
		4	6.00	0.77
		5	3.50	0.40
		6	1.55	0.29
		7	0.93	0.06
		8	0.52	0.03
		Filter	0.00	0.08
			Total	2.11

Table 3: Individual and Group Mean Bodyweights

Group	Rat	Day of observation
		-7	-4	-2	-1	0	7	14
1 M (Control)	101	215	246		268	278	331	377
	102	221	253		277	284	331	368
	103	223	245		274	280	332	349
	104	235	265		288	298	350	386
	105	228	265		292	295	359	404
	Mean	224	255		280	287	341	377
2 M (Test)	81		219	239		258	306	352
	82		220	239		257	297	332
	83		228	243		261	299	335
	84		228	249		263	300	343
	85		218	235		253	300	343
	Mean		223	241		258	300	341
1 F (Control)	106	204	223		234	237	256	265
	107	189	199		199	204	209	205
	108	208	220		228	229	243	252
	109	204	222		225	233	255	255
	110	209	222		231	236	245	247
	Mean	203	217		223	228	242	245
2 F (Test)	86		199	215		222	238	242
	87		205	211		212	227	235
	88		203	207		216	233	237
	89		208	212		219	222	211
	90		196	205		209	218	229
	Mean		202	210		216	228	231

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Under the conditions of the test, the median lethal concentration of the test material was estimated to be in excess of 5.18 mg/L to male and female rats. The study is considered to be reliable, relevant and adequate for risk assessment and classification and labelling purposes.

Executive summary:

The acute inhalation toxicity of the test material was determined in accordance with the standardised guidelines OECD 403 and EPA OPPTS 870.1300. Five male and five female rats were exposed for a period of 4 hours to a particulate aerosol generated from the test material at a target concentration of 5 mg/L (5.18 mg/L measured). A further group, acting as a concurrent common control was exposed to clean air only.

During the 4 hour exposure period, and the 14 day post-exposure observation period, no unscheduled deaths occurred. Clinical signs during the exposure period were limited to exaggerated breathing in test rats 15 to 30 minutes into exposure and grey staining on the fur 3 hours into exposure. During the observation period, clinical signs were limited to exaggerated breathing in all test rats immediately post exposure, persisting to day 4 of the observation period. A black/grey substance on the fur of the snout and jaws was evident on all test animals, persisting to day 2 of the observation period and hair loss from head of a single male test rat on day 14 of the observation period. All animals gained weight during the study. There were no macroscopic abnormalities at examination post mortem.

The median lethal concentration of the test material was estimated to be in excess of 5.18 mg/L to male and female rats.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

5 180 mg/m³ air

Quality of whole database:

Three studies have been provided. Wilcox (2001) was selected as the key study as it was performed in compliance with GLP and standardised guidelines (Klimisch score 1).
Two further studies were provided as supporting information.
Firstly, a short abstract by Kammler (1972) reporting on the deposition of tantalum in the lungs. However, there is not sufficient information available to assess the reliability of the findings presented and hence a reliability score of 4 was assigned.
The study by Bianco (1974), in which dogs were administered with radiolabelled tantalum dust is also provided. The study was assigned a reliability score of 3 since data relate to a non-standard test method, reported in literature.

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Oral:

The acute oral toxicity of the test material was determined in accordance with the standardised guidelines OECD 423 and EU Method B.1. During the test, 3 male and 3 female rats received a single oral gavage dose of 2000 mg/kg bw test material, formulated at a concentration of 20 % w/v in 1 % w/v aqueous methylcellulose and administered at a volume of 10 mL/kg bw. During the study animals were dosed and assessed for signs of toxicity for 14 days. Bodyweights were recorded at weekly intervals during the study. All animals were killed on day 15 for macroscopic examination post-mortem.

None of the animals died during the study and no significant clinical signs were observed. Furthermore, all animals gained weight during the study and no abnormalities were revealed at the macroscopic examination at study termination on day 15. The acute median lethal oral dose of the test material to rats was therefore estimated to be greater than 2000 mg/kg bw.

 

Inhalation:

During the key study, the acute inhalation toxicity of the test material was determined in accordance with the standardised guidelines OECD 403 and EPA OPPTS 870.1300. Five male and five female rats were exposed for a period of 4 hours, to a particulate aerosol generated from the test material at a target concentration of 5 mg/L (5.18 mg/L measured). A further group, acting as a concurrent common control was exposed to clean air only.

During the 4 hour exposure period, and the 14 day post-exposure observation period, no unscheduled deaths occurred. Clinical signs during the exposure period were limited to exaggerated breathing is test rats 15 to 30 minutes into exposure and grey staining on the fur 3 hours into exposure. During the observation period, clinical signs were limited to exaggerated breathing in all test rats immediately post exposure, persisting to day 4 of the observation period. A black/grey substance on the fur of the snout and jaws was evident on all test animals, persisting to day 2 of the observation period and hair loss from head of a single male test rat on day 14 of the observation period. All animals gained weight during the study. There were no macroscopic abnormalities at examination post mortem. The median lethal concentration of the test material was estimated to be in excess of 5.18 mg/L to male and female rats.

Supporting information is available in the form of a short abstract by Kammler who reported that tantalum dust was observed to deposit in the lungs of dogs exposed to powdered tantalum (particle size 2 - 5 µm). However, retained tantalum was not found to cause unfavourable tissue reaction.

A further study by Bianco (1974) in which dogs were administered with radiolabelled tantalum dust, either by nose-only exposure or by intubation for a period of less than one hour, is included as supporting information. Findings indicate that tantalum had a prolonged retention time in the lungs with a mean biological removal half-time of greater than 2 years. Mucociliary transport, the dominant clearance mechanism was longer following tantalum exposure than exposure to other insoluble dusts. The study indicated a rapid early tracheobronchial phase and a later prolonged alveolar clearance phase. The study was assigned a reliability score of 3 since data relate to a non-standard test method, reported in the literature.

Justification for classification or non-classification

In accordance with the criteria for classification as defined in Annex I, Regulation 1272/2008, the test material does not require classification for acute toxicity, as dosing at the limit dose for each of the two examined routes of exposure, oral and inhalation, failed to induce any toxic effects.