reaction mass of cerium(IV)oxide, praseodymium(III,IV)oxide and zirconium (IV)oxide

Endpoint summary

Description of key information

Acute toxicity: oral

Based on the results of the available acute oral toxicity studies for praseodymium(III,IV) oxide (Clouzeau, 1994), zirconium dioxide (Phycher, 2008) and the reaction mass of cerium dioxide and zirconium dioxide (De Jouffrey, 1996a), it could be concluded that the reaction mass of cerium dioxide, praseodymium(III,IV) oxide and zirconium dioxide is not expected to be harmful or toxic upon acute oral exposure. The reaction mass does not need to be classified for acute oral toxicity under the CLP Regulation.

Acute toxicity: inhalation

Since a comparison of basic toxicological data (An VII endpoints) available for the individual constituents of the reaction mass demonstrates that the constituents are equally unhazardous, it was considered justified to cover higher endpoints (An VIII) using data for zirconium dioxide alone (i.e. the most dominant constituent of the reaction mass in w/w%). Based on the results of the key acute inhalation toxicity study for zirconium dioxide (Smith, 2010), the reaction mass was concluded to be unharmful upon acute inhalation exposure. Consequently it does not need to be classified for this endpoint under the CLP Regulation either.

Acute toxicity: dermal

As reliable data for endpoint coverage are available already for the oral and inhalation route of exposure, no acute dermal toxicity study is required. Nevertheless, because the criteria for classification for Specific Target Organ Toxicity after Single Exposure (STOT SE) were not met for the individual constituents of the reaction mass and none of the available studies using dermal exposure to the test item have revealed systemic toxicity for its individual constituents, it can be concluded that the reaction mass is not expected to be harmful or toxic after acute dermal exposure either and consequently the reaction mass does not need to be classified for this endpoint under the CLP Regulation.

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:

experimental study

Adequacy of study:

weight of evidence

Study period:

2 March 1994 - 4 May 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
- Age at study initiation: approximately 6 weeks
- Weight at study initiation: 165 ± 7g for the males, 159 ± 6 g for the females
- Fasting period before study: 18 hours before treatment; food was replaced approximately 4 hours after treatment.
- Housing: The animals were housed in groups of 4 to 7 animals of the same sex in polycarbonate cages (48 x 27 x 20 cm) 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; AO4 C pelleted diet (U.A.R., 91360 Villemoisson-sur-Orge, France)
- Water consumption (e.g. ad libitum): ad libitum filtered water contained in bottles
- Acclimation period: 5 days during which they were observed daily
- Source: Iffa Crédo, 69210 L'Arbresle, France

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:

VEHICLE
The vehicle used was an aqueous solution of methylcellulose at 0.5 % (batch No. 73H0365 Prolabo, 75526 Paris, France).
Water for injections (batch No. 7860 Biosédra, 92240 Malakoff, France).

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg

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

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5 animals per sex per dose

Control animals:

no

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 and 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. 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.
- Necropsy of survivors performed: yes (day 15)
- 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

Based on:

test mat.

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 sacrificed at the end of the study revealed no apparent abnormalities.

Interpretation of results:

GHS criteria not met

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 and the test material requires no classification in accordance with EU criteria.

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

from 16-OCT-1995 to 08-MAR-1996

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

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

GLP compliance:

yes (incl. QA statement)

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
- Source: Iffa Credo, 69210 L'Arbresle, France
- Age at study initiation: 6 weeks old
- Weight at study initiation: 173 +/- 4 g for the males, 145 +/- 5 g for the females
- Fasting period before study: 18 hours, they were then given food 4 hours after treatment
- Housing: The animals were housed in groups of 4 to 7 animals of the same sex in polycarbonate cages (48x27x20 cm) during the acclimatisation period and groups of 5 animals of the same sex during the study.
- Diet (e.g. ad libitum): free access to AO4 C pelleted diet (U.A.R., 91360 Villemoisson-sur-Orge, France) except in fasting period
- Water (e.g. ad libitum): drinking water filtered by a Millipore membrane (0.22 micron), ad libitum
- Acclimation period: at least 5 days before the beginning of the study

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 +/- 2°C
- Humidity (%): 30 to 70% relative humidity
- Air changes (per hr): about 12 cycles/hour of filtered, non recycled air
- Photoperiod (hrs dark / hrs light): 12hr/12hr

IN-LIFE DATES: From: 14 nov 1995 To: 28 nov 1995

Route of administration:

oral: gavage

Vehicle:

other: aqueous solution of methylcellulose at 0.5%

Details on oral exposure:

VEHICLE
The vehicle used was an aqueous solution of methylcellulose at 0.5%:
- water for injections, batch N° 5842 (Laboratoire Fresenius, 92316 Sèvres, France)
- methylcellulose, batch N° 15H0241 (Sigma, 38297 Saint-Quentin-Fallavier, France)

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg

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

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

no

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 substance and at least once a day for clinical signs.
- Frequency of weighing: Animals were weighed just before administration of the test substance and then on days 1, 8 and 15.
- Necropsy of survivors performed: yes on day 15
- Other examinations performed: macroscopic examination at necropsy (digestive tract, heart, kidneys, liver, lungs, pancreas, spleen and any other organ with obvious abnormalities)

Statistics:

no data

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Mortality:

No deaths occurred 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 sacrificed at the end of the study revealed no apparent abnormalities.

Interpretation of results:

GHS criteria not met

Conclusions:

Under the experimental conditions of this study, the oral LD50 of the reaction mass of cerium dioxide and zirconium dioxide was higher than 2000 mg/kg in rats. No signs of toxicity were observed at this dose.

Executive summary:

The reaction mass of cerium dioxide and zirconium dioxide has been tested for acute oral toxicity in Sprague Dawley rats, according to OECD guideline No. 401 and in compliance with Good Laboratory Practices. The test article, suspended in 0.5% aqueous methylcellulose, was administered as a single dose of 2000 mg/kg to a group of 5 males and 5 females, at a dosing volume of 10 mL/kg. Following treatment, mortality, clinical signs and body weight were recorded for a two-week observation period. On day 15, the animals were euthanatised and necropsied.

 

No deaths occurred and no clinical signs were observed in this study. Body weight gain was not affected by treatment. At necropsy, a macroscopic examination revealed no abnormality .

 

As the minimal lethal dose was found to be higher than 2000 mg/kg, the reaction mass of cerium dioxide and zirconium dioxide is not classified according to the criteria of EU-CLP Regulation 1272/2008.

This acute oral study is classified as acceptable. It does satisfy the guideline requirements for an acute oral study (OECD 401) in rats.

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

Remarks:

However, 6 animals were dosed at once rather than dosing in steps with 3 animals per step.

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.

Reference 4

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 from studies performed with praseodymium(III,IV) oxide, zirconium dioxide and the reaction mass of cerium dioxide and zirconium dioxide. The read across justification document is attached to IUCLID Section 13.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: The reaction mass of cerium dioxide, praseodymium(III,IV) oxide and zirconium dioxide is expected to have a LD50 value of > 2000 mg/kg bw and therefore does not need to be classified for acute oral toxicity.

Remarks:

This conclusion is based on data obtained with praseodymium(III,IV) oxide (Clouzeau, 1994), zirconium dioxide (Phycher, 2008) and the reaction mass of cerium dioxide and zirconium dioxide (De Jouffrey, 1996a).

Interpretation of results:

GHS criteria not met

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:

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.

Reference 2

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:

Read across based on a study performed with zirconium dioxide. This was considered justified because based on a comparison of basic toxicological data available for the constituents of the reaction mass (An VII endpoints) it could be concluded that the addition of praseodymium(III,IV) oxide and cerium dioxide to zirconium dioxide in the reaction mass does not alter the unhazardous properties of zirconium dioxide. Since zirconium dioxide is the most dominant constituent (in w/w%) in the reaction mass, it was considered justified to cover higher endpoints (An VIII) by data on zirconium dioxide alone. The read across justification document is attached to IUCLID Section 13.

Reason / purpose for cross-reference:

read-across source

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

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

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

other: The reaction mass of cerium dioxide, praseodymium(III,IV) oxide and zirconium dioxide is not expected to be toxic via inhalation and does not need to be classified for this endpoint under the CLP Regulation.

Remarks:

This conclusion is based on the results from a study performed with zirconium dioxide (Smith, 2010), in which no acute adverse effects have been observed at the maximum technically achievable concentration (4.3 mg/L). In a similar study, similar results would be expected with the reaction mass.

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)

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Additional information

1. Information on zirconium dioxide

Acute toxicity: oral

One reliable study was identified (Phycher, 2008; Klimisch 1). In this study, the acute toxicity of zirconium dioxide was determined via the acute toxic class method (OECD Guideline 423 and EU Method B1 tris) in female Sprague-Dawley rats. The LD50 value was > 5000 mg/kg bw and no mortality or gross abnormalities were observed during necropsy. Based on these results, it is concluded that the test material is not classified for acute oral toxicity according to the criteria of the CLP Regulation.

Acute toxicity: inhalation

One reliable study was identified (Smith, 2010; Klimisch 1). In this study, the acute inhalation toxicity of zirconium dioxide was tested according to OPPTS Guideline 870.1300 and OECD Guideline 436. 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, which was the maximum obtainable mean concentration, for 4 hours. The exposure atmosphere was characterised by a mean mass median aerodynamic diameter (± geometric standard deviation) of 2.0 µm ± 1.75 µm. As no mortality occurred during the study, the LC50 of zirconium dioxide was greater than 4.3 mg/L.

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 was considered not feasible as the maximum obtainable mean concentration for exposure was 4.3 mg/L and no mortality occurred at that concentration. Therefore classification for acute inhalation toxicity was deemed unnecessary.

2. Information on praseodymium(III,IV) oxide

Acute toxicity: oral

For praseodymium(III,IV) oxide, the guideline study performed by Clouzeau (1994; Klimisch 1) resulted in an oral LD50 value > 2000 mg/kg bw in rats. No signs of toxicity were observed at this dose and hence, praseodymium(III,IV) oxide requires no classification in accordance with the CLP criteria.

3. Information on the reaction mass of cerium dioxide and zirconium dioxide

Acute toxicity: oral

The reaction mass of cerium dioxide and zirconium dioxide has been tested for acute oral toxicity in Sprague Dawley rats according to OECD guideline No. 401 and in compliance with GLP (De Jouffrey, 1996a). The test material was suspended in 0.5% aqueous methylcellulose and was administered as a single dose of 2000 mg/kg to a group of 5 males and 5 females, at a dosing volume of 10 mL/kg. Following treatment, mortality, clinical signs and body weight were recorded for a two-week observation period. On day 15, the animals were euthanatised and necropsied. During this study, no deaths occurred and no clinical signs were observed in this study. Body weight gain was not affected by treatment. At necropsy, a macroscopic examination revealed no abnormality. As the minimal lethal dose was found to be higher than 2000 mg/kg, the reaction mass of cerium dioxide and zirconium dioxide is not classified according to the criteria of the EU-CLP Regulation 1272/2008.

4. Conclusion on te reaction mass of cerium dioxide, praseodymium(III,IV) oxide and zirconium dioxide

Acute toxicity: oral

Based on the results obtained in studies with its individual constituents (all yielding LD50 values > 2000 mg/kg bw), the reaction mass of cerium dioxide, praseodymium(III,IV) oxide and zirconium dioxide can be concluded not to be harmful or toxic upon acute exposure via the oral pathway either. Consequently, the reaction mass does not need to be classified for this endpoint under the CLP Regulation.

Acute toxicity: inhalation

Based on a comparison of basic toxicological data available for the constituents of the reaction mass (An VII endpoints) it could be concluded that the addition of praseodymium(III,IV) oxide and cerium dioxide to zirconium dioxide in the reaction mass does not alter the unhazardous properties of zirconium dioxide. Since zirconium dioxide is the most dominant constituent (in w/w%) in the reaction mass, it was considered justified to cover higher endpoints (An VIII) by data on zirconium dioxide alone. Based on the results of the key acute inhalation toxicity study for zirconium dioxide performed by Smith (2010), the reaction mass of cerium dioxide, praseodymium(III,IV) oxide and zirconium dioxide can be concluded not to be harmful or toxic upon acute inhalation exposure. Consequently, the reaction mass does not need to be classified for this endpoint under the CLP Regulation.

Acute toxicity: dermal

No reliable data are available for acute toxicity via the dermal route of exposure. However, according to Annex VIII of the REACH Regulation, in addition to the oral route, for substances other than gases, the information mentioned under section 8.5 shall be provided for at least one other route. As information is provided for the inhalation and the oral route, an acute dermal toxicity study should not be performed. Nevertheless, because the criteria for classification for Specific Target Organ Toxicity after Single Exposure (STOT SE) were not met for the individual constituents of the reaction mass and none of the available studies using dermal exposure to the test item have revealed systemic toxicity for its individual constituents, it can be concluded that the reaction mass is not expected to be harmful or toxic after acute dermal exposure either and consequently the reaction mass does not need to be classified for this endpoint under the CLP Regulation.

Justification for classification or non-classification

Based on the read across approach and the available toxicity data on praseodymium(III,IV) oxide, zirconium dioxide and the reaction mass of cerium dioxide and zirconium dioxide, it can be concluded that the reaction mass of cerium dioxide, praseodymium(III,IV) oxide and zirconium dioxide does not need to be classified for acute toxicity after oral, inhalation, or dermal exposure.