Zirconium oxide (ZrO2), erbium-doped

Endpoint summary

Description of key information

1. Information on zirconium dioxide (CAS# 1314-23-4)
Acute toxicity: oral

The LD50-value for acute oral toxicity determined via the acute class method in female Sprague-Dawley rats was > 5000 mg/kg.

Acute toxicity: inhalation

The LC50 was higher than 4.3 mg/L (maximal technically achievable mean concentration) in male and female Crl:CD(SD) albino rats via nose-only inhalation exposure (dust aerosol of zirconium dioxide).

2. Information on erbium oxide (CAS# 12061-16-4)
The oral LD50 of the test material was > 2000 mg/kg in rats. No signs of toxicity were observed at this dose.

3. Conclusion on erbium zirconium oxide
It is expected that the substance will have a similar toxicity profile as the read across substances zirconium dioxide and erbium oxide, more specifically that it is not expected to cause any adverse acute toxic effects after oral, inhalation or dermal exposure.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

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

Adequacy of study:

weight of evidence

Justification for type of information:

Read across based on a study from Phycher (2008) with zirconium dioxide and a study from Clouzeau (1994) with dierbium trioxide. The read across justification document is attached in IUCLID Section 13.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Key result

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: Based on the results of the study from Phycher (2008) with zirconium dioxide and the study from Clouzeau (1994) with dierbium trioxide it could be concluded that the LD50 for erbium zirconium oxide would be > 2000 mg/kg bw.

Clinical signs:

other:

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

2 March 1994 - 16 March 1994

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

no

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
- Strain: Sprague-Dawley ICO:OFA-SD (IOPS Caw)
- Age at study initiation: approximately 6 weeks
- Weight at study initiation (means): 164 ± 4g for the males, 161 ± 5 g for the females
- Fasting period before study: 18 hours before treatment; food was replaced approximately 4 hours after treatment
- Housing: animals were housed in groups of 4 to 7 animals of the same sex in polycarbonate cages (48 x 27 x 20 cm) covered with a stainless steel lid during the acclimatisation period and groups of 5 animals of the same sex during the study. Each cage contained graded, dust-free sawdust.
- Food consumption (e.g. ad libitum): ad libitum
- Water consumption (e.g. ad libitum): ad libitum filtered water contained in bottles
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 °C
- Humidity (%): 50 ± 20 % relative humidity
- Air changes (per hr): 13 cycles/hour of non-recycled and filtered air
- Photoperiod (hrs dark / hrs light): 12hr/12hr

In-life dates: From 02 to 16 March 1994

Route of administration:

oral: gavage

Vehicle:

other: aqueous solution of methylcellulose at 0.5 %

Details on oral exposure:

DOSAGE PREPARATION:
On the day of the treatment, the test material was ground using a mortar and pestle, then was suspended in the vehicle.

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5 animals per sex per dose

Control animals:

other: The body weight of the animals treated with the test material was compared to laboratory historical control data for animals dosed by the oral route.

Details on study design:

DETAILS ON STUDY DESIGN
- Duration of observation period following administration: 14 days
- Frequency of observations: the animals were observed frequently after administration of the test material, for detection of possible treatment-related clinical signs and for mortality or signs of morbidity. Observations of the animals were made at least once a day for clinical signs and at least twice a day for mortality.
- Frequency of weighing: Animals were weighed just before administration of the test material and then on days 5, 8 and 15.
- Necropsy of survivors performed: yes (day 15). Animals were sacrificed by excess CO2 inhalation.
- Other examinations performed: macroscopic examination at necropsy (digestive tract, heart, kidneys, liver, lungs, pancreas, spleen and any other organ with obvious abnormalities).

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Mortality:

No deaths occured during the observation period.

Clinical signs:

other: No clinical signs were observed during the study.

Gross pathology:

The macroscopic examination of the main organs of the animals sacrified at the end of the study revealed no apparent abnormalities.

Interpretation of results:

other: Not classified according to EU criteria.

Conclusions:

Under the experimental conditions of this study, the oral LD50 of the test material was > 2000 mg/kg in rats. No signs of toxicity were observed at this dose; the test material therefore requires no classification in accordance with EU criteria.

Executive summary:

The acute oral toxicity of the test material was evaluated in a limit test which was conducted in accordance with the standardised guideline OECD 401.

Groups of fasted, 6 week old Sprague-Dawley rats (5 per sex) were given a single oral dose of the test material in an aqueous solution of methylcellulose at 0.5 % at a dose of 2000 mg/kg bw (dose volume 10 mL/kg) and observed for 14 days.

No mortality and no clinical signs were observed during the study. The body weight gains of the treated rats were normal. No gross abnormalities were observed at necropsy.

The oral LD50 (males and females) was >2000 mg/kg bw and therefore the test material is not classified for acute oral toxicity in accordance with EU criteria.

Reference 3

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

2008-01-16 to 2008-04-10

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 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

Certificate provided by Groupe Interministeriel Des Produits Chimiques

Test type:

acute toxic class method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Elevage JANVIER (53940 Le Genest St Isle, France)
- Age at study initiation: 8 weeks old
- Weight at study initiation: between 188 g and 207 g
- Fasting period before study: 1 day
- Housing: Three healthy female rats were kept in solid-bottomed clear polycarbonate cages with a stainless steel mesh lid.
- Diet: foodstuff provided ad libitum; food was removed at D-1 and then redistributed 4 hours after the test item administration.
- Water: tap-water from public distribution system provided ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 22 degree C
- Humidity (%): 39 and 55%
- Air changes (per hr): not applicable
- Photoperiod (hrs dark / hrs light): 12 hours daily

IN-LIFE DATES: From: 2008-02-05 To: 2008-02-20

Route of administration:

oral: gavage

Vehicle:

other: distilled water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: no data
- Amount of vehicle (if gavage): no data
- Justification for choice of vehicle: no data

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg body weight

DOSAGE PREPARATION (if unusual): The animals of the treated group received an effective dose of 2000 mg/kg body weight of the test item, diluted in distilled water and administered by gavage under a volume of 10 mL/kg body weight using a suitable syringe graduated fitted with an oesophageal metal canula.

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

6 female rats

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The animals were weighed on D0 (just before administering the test item), then on D2, D7, and D14.
Weight changes were calculated and recorded.
- Necropsy of survivors performed: yes; Only those organs likely to be modified in cases of acute toxicity were examined. Those presenting macroscopic anomalies can be removed and preserved in view of microscopic examinations.
- Other examinations performed: Systematic examinations were carried out to identify any behavioural or toxic effects on the major physiological functions 14 days after administration of the test item.
Observations and a mortality report were then carried out every day for 14 days.

Statistics:

no data

Sex:

female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Mortality:

No mortality occurred during the study.

Clinical signs:

other: No clinical signs related to the administration of the test substance were observed.

Gross pathology:

The macroscopic examination of the animals at the end of the study did not reveal treatment-related changes.

Other findings:

no data

Interpretation of results:

GHS criteria not met

Conclusions:

The LD50 of CC10 Zirconium Oxide is higher than 5000 mg/kg body weight by oral route in the rat.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: inhalation

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

The endpoint was covered using an acute inhalation study performed with zirconium dioxide. The read across justification is attached to IUCLID section 13.

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

other: read across conclusion

Remarks on result:

other: Based on the results of the study from Smith (2010) with zirconium dioxide, it was concluded that erbium zirconium oxide is not expected to present a hazard for acute inhalation toxicity either.

Reference 2

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

27 April 2010 - 31 May 2010

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1300 (Acute inhalation toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

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

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 conditions 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 daily 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 (if applicable)
- 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 weighing:
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

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 4.3 other: mg/L (actual exposure concentration: maximum technically achievable concentration)

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 of 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:

GHS criteria not met

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.

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:

study scientifically not necessary / other information available

Justification for data waiving:

the study does not need to be conducted because the substance does not meet the criteria for classification as acute toxicity or STOT SE by the oral route and no systemic effects have been observed in in vivo studies with dermal exposure (e.g. skin irritation, skin sensitisation)

other:

Clinical signs:

other:

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

1. Information on zirconium dioxide (CAS# 1314-23-4)

- Based on the available data and according to the CLP criteria zirconium dioxide should not be classified for acute toxicity via the oral route of exposure.

- No reliable data are available on the acute toxicity via the dermal route of exposure. However, since the oral LD50 was > 2000 mg/kg bw, and no systemic effects have been observed in the available in vivo studies with dermal exposure, zirconium dioxide can be concluded not to be classified for acute toxicity after dermal exposure.

- Based on available data and according to the CLP criteria, zirconium dioxide should not be classified for acute toxicity via the inhalation route of exposure. Although the LC50 of zirconium dioxide dust aerosol is higher than 4.3 mg/L, which is lower than the classification cut-off value of 5 mg/L for category 4 classification (CLP), further testing would not be considered feasible as the maximum technically obtainable mean concentration for exposure is 4.3 mg/L and no mortality and no overt toxicity occurred at this concentration. Classification for acute inhalation toxicity is therefore deemed unnecessary.

2. Information on erbium oxide (CAS# 12061-16-4)

- Based on the available data and according to the CLP criteria erbium oxide should not be classified for acute toxicity via the oral route of exposure.

- No data are available on the acute toxicity via the dermal route of exposure. However, since the oral LD50 was > 2000 mg/kg bw, and no systemic effects have been observed in the available in vivo studies with dermal exposure, erbium oxide can be concluded not to be classified for acute toxicity after dermal exposure.

- Based on available data (not included in this dossier) erbium oxide should not be classified for acute toxicity via the inhalation route of exposure.

3. Conclusion on erbium zirconium oxide

As erbium zirconium oxide is expected to have similar properties as the read across substances zirconium dioxide and erbium oxide, it does not need to be classified as acutely toxic.