Hafnium

Endpoint summary

Description of key information

One study is available for acute toxicity via the oral route of exposure (according to OECD 423): the LD50 is > 2000 mg/kg (rat).
No reliable data is available for acute toxicity via the inhalation route of exposure. As Hf powder is pyrophoric, it is not technically possible to generate an inhalable test atmosphere.  Based on the same behaviour and toxicological effects, a read across with ZrO2 is performed. No toxic effect is observed in the available study, the LC50 is therefore > 4.3 mgZrO2/L or >3.18 mg eq Zr/L.

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:

2012

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP study, performed without any deviation

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 ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH, Sandhofer Weg 7, D-97633 Sulzfeld
- Age at study initiation: 8-9 weeks old
- Weight at study initiation: 187 – 204 g
- Fasting period before study: The food but not water was withheld during an overnight period.
- Housing: 3 animals/ cage (Cage type: Type II polypropylene/polycarbonate)
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 °C
- Humidity (%): 30 - 70 %
- Air changes (per hr): 15-20
- Photoperiod: Lighting period: 12 hours daily, from 6.00 a.m. to 6.00 p.m.

Route of administration:

oral: gavage

Vehicle:

water

Remarks:

distilled water

Details on oral exposure:

VEHICLE
- Amount of vehicle (if gavage): 10 mL/kg bw

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: Initially, three female animals were treated with 2000 mg/kg bw of Hafnium because no litterature or other study could indicate a potential hazard of hafnium by ingestion. No mortality was observed, therefore further 3 animals were treated at the dose level of 2000 mg/kg bw.

Doses:

Initially, three female animals were treated with 2000 mg/kg bw of Hafnium. No mortality was observed, therefore further 3 animals were treated at the dose level of 2000 mg/kg bw.

No. of animals per sex per dose:

3 females per group

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Clinical observations were performed at 30 minutes, 1, 2, 3, 4 and 6 hours after dosing and daily for 14 days thereafter. Body weight was measured on Days -1, 0 and 7 and before necropsy.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, macroscopic findings

Sex:

female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: LD50 cut off

Mortality:

Hafnium did not cause mortality at a dose level of 2000 mg/kg bw.

Clinical signs:

other: Treatment with Hafnium did not cause any test item related adverse effect during the 14 days observation period.

Gross pathology:

There was no evidence of the test item-related macroscopic observations at a dose level of 2000 mg/kg bw. Bilateral dilatation of the uterine horns, body and cervix in 1/6 female was considered to be a common background observation, and is usually associated with physiological changes during oestral cycle in females and not related to the administration of test item.

Interpretation of results:

study cannot be used for classification

Remarks:

Migrated information

Conclusions:

Under the conditions of this study, the acute oral LD 50 value of the test item Hafnium was found to be above 2000 mg/kg bw in female CRL:(WI) rats. According the GHS criteria, Hafnium should be ranked as "Category 5" or "Unclassified".

Executive summary:

The single-dose oral toxicity of Hafnium was performed according to the acute toxic class method (OECD 423) in CRL:(WI) rats.

Two groups of three female rats were treated with Hafnium at a dose level of 2000 mg/kg bw by gavage.

Clinical observations were performed at 30 minutes, 1, 2, 3, 4 and 6 hours after dosing and daily for 14 days thereafter. Body weight was measured on Days -1, 0 and 7 and before necropsy. All animals were subjected to a necropsy and a macroscopic examination.

Hafnium did not cause mortality at a dose level of 2000 mg/kg bw, and the treatment did not cause any test item related adverse effect during the 14 days observation period. Body weight gains of Hafnium treated animals during the study showed no indication

of a treatment-related effect. There was no evidence of the test item-related macroscopic observations at a dose level of 2000 mg/kg bw.

In the conditions of this reliable study (Klimlisch 1 reliability, for a GLP study performed without any deviation), the acute oral LD 50 value of the test item Hafnium was found to be above 2000 mg/kg bw in female CRL:(WI) rats.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

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

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: GLP study without restriction, but quoted with 2 because of the read across

Qualifier:

according to guideline

Guideline:

OECD Guideline 436 (Acute Inhalation Toxicity: Acute Toxic Class Method)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1300 (Acute inhalation toxicity)

Deviations:

no

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

no

Species:

rat

Strain:

other: Crl:CD(SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Raleigh, NC; animals were received on 20 April 2010
- Age at study initiation: approximately 11 weeks
- Weight at study initiation: body weight values ranged from 316 g to 357 g for males and from 220 g to 238 g for females. individual body weights at assignment were within ± 20% of the mean for each sex.
- Fasting period before study: during acclimation to restraint and during the exposure period
- Housing: Upon arrival, all animals were housed in individual suspended wire-mesh cages. The animals were maintained by the WIL Animal Husbandry staff in accordance with WIL standard operating procedures (SOPs). On the day of exposure, the animals were placed in nose-only exposure holding tubes in the animal room, transported to the exposure room, exposed for the requisite duration and then returned to their home cages.
- Diet (e.g. ad libitum): The basal diet used in this study, PMI Nutrition International, LLC, Certified Rodent LabDiet 5002, is a certified feed with appropriate analyses performed by the manufacturer and provided to WIL.
- Water (e.g. ad libitum): Municipal water supplying the facility is analyzed for contaminants according to WIL SOP
- No contaminants were present in animal feed or water at concentrations sufficient to interfere with the objectives of this study. The basal diet and municipal water, delivered by an automatic watering system, were provided ad libitum, except during acclimation to restraint and the exposure period.
- Acclimation period: 5 days, the animals were observed twice daily for mortality and moribundity. The animals were subjected to restraint in the nose-only exposure holding tubes for 1 hour on 27 April 2010 prior to the start of exposure. Animals were held in restraint tubes for 35 minutes prior to initiation of exposure.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): The room temperature control was set to maintain environmental conditiosn of 71°F ± 5°F (22°C ± 3°C) and 50% ± 20% relative humidity. Room temperature was monitored using the Metasys DDC Electronic Environmental control system and schedule for data collection was on an hourly basis. Actual mean dialy temperature ranged from 70.3°F to 72.1°F (21.3°C to 22.3°C).
- Humidity (%): The humidity control was set to maintain environmental conditions of 50% ± 20% relative humidity. Relative humidity was monitored using the Metasys DDC Electronic Environmental control system and as scheduled for data collection on an hourly basis. Mean daily relative humidity ranged from 49.2% to 55.9% during the study.
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12 hours light/12 hours dark

IN-LIFE DATES: no data

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

other: air (for compressed air system) and deionized water (for humidified air system)

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: the test substance was delivered using an auger-type feeder (Schenck AccuRate, INc., Whitewater, WI) which fed test substance at a constant rate to a jet mill air micronizer (model 00, Jet-O-Mizer, Fluid Energy Aljet, Hatfield, PA) operating as a particle size reduction and dispersion device.
- Exposure chamber volume: 7.9 L convential nose-only exposure system (designed and fabricated by WIL)
- Method of holding animals in test chamber: Animals were restrained in nose-only exposure holding tubes during exposure
- Source and rate of air: Using 2 regulators, dry compressed air was supplied to the micronizing and inlet ports of the jet mill. The resulting aerosol from the jet mill was delivered to the nose-only exposure system through 22-mm respiratory tubing. A glass cyclone was placed in-line after the jet mill to reduce particle size. A tee fitting was placed at the inlet of the exposure system to provide humidified air. Humidified air was added using a Coilhose Pneumatics regulator and controlled using a rotameter-type flowmeter. Dry compressed air passed through a muffler-type bubbler submerged in a 2-L Erlenmeyer flask filled with deionized water to produce humidified air. The airflows used for the animal exposure is as follows: inlet airflow rate = 28.5-29.2 L/minute, micronizing airflow rate is 18.6L/minute, humidified airflow rate is 7.6 L/minute and total airflow rate is 54.7-55.4 L/minute
- Method of conditioning air: see above (source and rate of air)
- System of generating particulates/aerosols: see above (source and rate of air)
- Method of particle size determination: Three aerosol particle size determinations were conducted for this exposure using a 7-stage stainless steel cascade impactor (model 02-140, In-Tox Products, Moriarty, NM). Pre-weighed, 23-mm stainless steel discs were used as the collection substrates. samples were collected at approximately 1.8 L/minute for 0.25 minutes. The filters were re-weighed and the particle size calculated based on the impactor stage-cut-offs. The aerosol size was expressed as the mass median aerodynamic diameter (MMAD) and the geometric standard deviation (GSD).
- Treatment of exhaust air: Exhaust atmosphere was filtered using a Solberg filter (Solberg Manufacturing, Inc., Itasca, IL) prior to entering the in-house exhaust system with activated charcoal and HEPA-filtration.
- Temperature, humidity, pressure in air chamber: The room temperature and humidity controls were set to maintain environmental conditions of 71°F±5°F (22°C ± 3°C) and 50%±20% relative humidity. Room temperature and relative humidity were monitored using the Metasys DDC Electronic Environmental control system and were scheduled for data collection on an hourly basis. Actual mean daily temperature ranged from 70.3°F to 72.1°F (21.3°C to 22.3°C) and mean daily relative humidity ranged from 49.2% to 55.9% during the study

TEST ATMOSPHERE
- Actual exposure concentrations: Actual exposure concentrations were determined using standard gravimetric methods. Samples were collected on pre-weighed, 25-mm glass-fiber filters (type A/E, PALL Corporation, Ann Arbor, MI) held in an open-faced filter holder positioned in the animal breathing zone within the nose-only exposure system. Following sample collection, the filters were re-weighed and the concentration calculated as the filter weight difference divided by the sample volume. Samples were collected at approximately 2 L/minute for 0.5 mintues.


VEHICLE
- Composition of vehicle (if applicable): not applicable
- Concentration of test material in vehicle (if applicable): not applicable
- Justification of choice of vehicle: not applicable
- Lot/batch no. (if required): not applicable
- Purity: not applicable

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: Effective cut-off diameter: 5.27 µm for stage 1, 4.22 µm for stage 2, 3.20 µm for stage 3, 1.90 µm for stage 4, 1.07 µm for stage 5, 0.41 µm for stage 6 and 0.27 µm for stage 7
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): 2.00 µm (mean MMAD) and 1.75 (Mean GSD)

CLASS METHOD
- Rationale for the selection of the starting concentration: The target exposure concentration was based on toxicity data from similar compounds as outlined in the product MSDS. Under the generation and exposure conditions of this study and requirements for a particle size of 1 to 4 microns and maintenance of a stable concentration for the 4-hour exposure period, it was determined that the maximum obtainable concentration of zirconium dioxide as a dust aerosol was approximately 4.3 mg/L. Since no animals died following exposure to the maximum obtainable concentration of the test substance, additional exposure levels were not required.

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

Actual exposure concentration: 4.3 mg/L (SD 1.39 mg/L), this is the maximum obtainable mean concentration for a 4-hour exposure. The nominal exposure concentration was 41.4 mg/L.

No. of animals per sex per dose:

3

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighting:
Body weights were obtained immediately prior to exposure on study day 0 and on post-exposure days 1, 3, 7, and 14.
Mortality: each animal was observed for mortality at the approximate midpoint of exposure, immediately following exposure on study day 0, and twice daily thereafter for 14 days.
Clinical observations: each animal was observed immediately following exposure on study day 0 and once daily thereafter for 14 days.
- Necropsy of survivors performed: yes; animals at the scheduled necropsy were euthanized by isoflurane anesthesia followed by exsanguination. The major organ systems of the cranial, thoracic, and abdominal cavities were examined for all animals.

Statistics:

no data

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 4.3 mg/L air

Based on:

test mat.

Exp. duration:

4 h

Mortality:

None of the animals died during exposure or during the 14-day post-exposure observation period. Based on the data obtained, the LC50 zirconium dioxide was found to be greater than 4.3 mg/L, the maximum obtainable mean concentration.

Clinical signs:

other: There were no toxicologically significant clinical signs immediately following exposure. Several animals were noted with clear material on the neck, forelimb(s), trunk, and urogenital area, red material around the nose and mouth, and/or yellow material ar

Body weight:

All animals lost weight (10 g to 39 g) from study day 0 to 1. One male lost weight (9 g) from study day 1 to 3. All animals surpassed their initial (study day 0) body weight by study day 14 and were considered normal.

Gross pathology:

There were no macroscopic findings for any animal at the scheduled necropsy.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Based on the results of this study, the LC50 of zirconium dioxide was greater than 4.3 mg/L, the maximum obtainable mean concentration, when male and female albino rats were exposed to a dust aerosol of the test substance as a single, 4-hour, nose-only exposure.

Executive summary:

The acute inhalation toxicity of zirconium dioxide was evaluated in a 4-hour, single‑exposure study in rats. Zirconium dioxide was administered to 1 group of 3 male and 3 female Crl:CD(SD) albino rats via nose-only inhalation exposure as a dust aerosol at a concentration of 4.3 mg/L. The exposure atmosphere was characterized by a mean mass median aerodynamic diameter (± geometric standard deviation) of 2.0 µm ± 1.75 µm. Mortality, clinical observations, body weights, and body weight changes were evaluated over a 14-day post-exposure observation period. Necropsies were conducted on all animals.

Mortality was 0/6 animals for the 4.3 mg/L group. There were no significant clinical observations immediately following exposure. Significant clinical observations for animals during the 14-day post-exposure observation period included decreased defecation and small feces. All animals were considered clinically normal by study day 3. All animals lost weight from study day 0 to 1. One male lost weight (9 grams) from study day 1 to 3. All animals surpassed their initial (study day 0) body weight by study day 14. There were no macroscopic findings for any animal at the scheduled necropsy.

Based on the results of this study, the LC50 of zirconium dioxide was greater than 4.3 mg/L, the maximum obtainable mean concentration, when male and female albino rats were exposed to a dust aerosol of the test substance as a single, 4-hour, nose-only exposure.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Data waiving:

other justification

Justification for data waiving:

other:

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

• Oral toxicity

A single-dose oral toxicity of Hafnium was performed according to the acute toxic class method (OECD 423) in CRL:(WI) rats.

Two groups of three female rats were treated with Hafnium at a dose level of 2000 mg/kg bw by gavage.

Clinical observations were performed at 30 minutes, 1, 2, 3, 4 and 6 hours after dosing and daily for 14 days thereafter. Body weight was measured on Days -1, 0 and 7 and before necropsy. All animals were subjected to a necropsy and a macroscopic examination.

Hafnium did not cause mortality at a dose level of 2000 mg/kg bw, and the treatment did not cause any test item related adverse effect during the 14 days observation period. Body weight gains of Hafnium treated animals during the study showed no indication of a treatment-related effect. There was no evidence of the test item-related macroscopic observations at a dose level of 2000 mg/kg bw.

In the conditions of this reliable study (Klimlisch 1 reliability, for a GLP study performed without any deviation), the acute oral LD 50 value of the test item Hafnium was found to be above 2000 mg/kg bw in female CRL:(WI) rats.

Used for read across approach, HfO2 and ZrO2 were also assessed for oral toxicity in the same way, and these two similar compounds also exhibited no effect in these studies, with LD50 found above 2000 mg/kg bw.

 

• Inhalation toxicity

For inhalation acute toxicity, as this test is technically impossible, due to pyrophoricity of Hf powder, a read across with ZrO2 is realised. Indeed, according to the REACh recommendations, a read across could be used for substances with similar behaviour and toxic effects in the organism. An OECD guideline 436 was available: 3 male and 3 female were exposed nose-only to 4.3 mg/L of ZrO2 for 4 hours. The mean mass median aerodynamic diameter was 2 µm (+/- 1.75 µm). With this particle size, ZrO2 could reach lower parts of respiratory tract, like the bronchioles. No mortality was observed during the test, all animals were considered clinically normal and no macroscopic findings were noted at the scheduled necropsy. The CL50 equivalent for Zr was 3.18 mg/L.

• Dermal toxicity

On the basis of column 2 of annex VIII, in addition to the oral route, for substances other than gases, the information mentioned under acute toxicity sections shall be provided for at least one other route. The choice for the second route will depend on the nature of the substance and the likely route of human exposure. Based on the properties of the substance (inorganic inert chemical), the dermal route of exposure is not considered to be relevant.

Justification for classification or non-classification

Regarding inhalation, taking into account the LC50 strictly higher than 3.18 mg Zr/L (the maximum obtainable mean concentration of Zr used for read across), the inert form of the substance and its capacity to reach lower parts of the respiratory tract (Hf granulometry < 4 µm), Hf was not classified under the CLP regulation 1272/2008 and the directive Classification and Labelling 67/548/EC.

Based on the available oral data, the substance was not classified under the CLP Regulation 1272/2008 and the directive Classification and Labelling 67/548/EC.