lambda4-cerium(4+) zirconium(4+) tetraoxidandiide

Endpoint summary

Description of key information

LD50 oral, rat > 2000 mg/kg bw (reaction mass, representative nanoform) - LD50 oral, rat > 5000 mg/kg bw (cerium dioxide and zirconium dioxide/yttrium zirconium oxide)
LC50 inhalation, rat > 4.3 mg/L (ZrO2, maximal technically achievable mean concentration) - LC50 inhalation, rat > 5.05 mg/L (CeO2)
LD50 dermal, rat > 2000 mg/kg bw (CeO2)

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:

key study

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

Key result

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 2

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

November 1982

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

no

Remarks:

study performed before the application of the OECD TG 401 but consistent with technical standards (number of animals used, duration of observation period, observations and measurements, ...)

GLP compliance:

no

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
- Age at study initiation: 6 to 7 weeks old
- Weight at study initiation: 180 - 190 g (males) / 150 - 160 g (females)
- Fasting period before study: approximately 18 hours
- Housing: by groups of 5 in 37.5 x 23.5 x 16 cm cages
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 5°C
- Humidity: 55 ± 15%
- Air changes: 10 per hr
- Photoperiod (hrs dark / hrs light): not specified

IN-LIFE DATES: From 23 November 1982 To 30 November 1982

Route of administration:

oral: gavage

Vehicle:

other: 10% aqueous gum arabic

Details on oral exposure:

No details provided

Doses:

- Preliminary assay: 1000, 2500 and 5000 mg/kg
- Main assay: 0 (vehicle) and 5000 mg/kg

No. of animals per sex per dose:

- Preliminary assay: 2/sex
- Main assay: 5/sex

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Mortality and clinical signs: just after dosing, 1, 2, 6 hours after dosing and daily for 14 days
Body weight: days 0, 1, 2, 4, 7 and 14
- Necropsy of survivors performed: yes

Statistics:

Not included

Preliminary study:

Three groups of 2 rats per sex, fasted for 18 hours, were given a single oral dose of 1000, 2500 or 5000 mg/kg. During a subsequent 14-day observation period, no mortality was observed at any dose level.

Sex:

male/female

Dose descriptor:

LD0

Effect level:

5 000 mg/kg bw

Based on:

act. ingr.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

act. ingr.

Mortality:

No mortality occurred during the dosing and observation periods

Clinical signs:

other: Whitish discoloration of the feces was observed on day 1

Gross pathology:

No relevant findings were seen at necropsy on day 14

Other findings:

No other finding

Interpretation of results:

GHS criteria not met

Conclusions:

Oral LD50 higher than 5000 mg/kg for males and females

Executive summary:

In an acute oral toxicity study (Institut Français de Toxicologie report No. 301229), groups of fasted 6 to 7-week old Sprague-Dawley rats (5/sex) were given a single oral dose of Cerium Oxide, as a suspension in 10% aqueous gum arabic, at doses of 0 (vehicle only) or 5000 mg/kg bw (limit test) and observed for 14 days. Mortality and clinical signs were checked just after administration, at 1, 2, 6 hours after dosing, and daily for 14 days. Body weight was recorded on days 0, 1, 2, 4, 7 and 14.

 

No mortality occurred during the dosing and observation periods. Whitish discoloration of the feces was observed on day 1. No significant changes in body weight were seen when compared to controls. No relevant findings were seen at necropsy on day 14.

 

Therefore, the oral LD50 was higher than 5000 mg/kg for males and females. No classification for acute oral toxicity is warranted based on the absence of mortality up to a limit dose level, according to the criteria of Annex VI Directive 67/548/EEC or UN/EU GHS.

 

This study is classified as acceptable. Its design is compatible with the OECD 401 guideline requirements for acute oral toxicity.

Reference 3

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1990

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: published data with limited level of details

Principles of method if other than guideline:

Standard acute oral dose method

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

yes

Specific details on test material used for the study:

No details provided

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

Animals fasted before dosing. No other details provided.

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

50% w/w solution in distilled water administered. No other details provided.

Doses:

5000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

not specified

Details on study design:

Duration of observation period following administration: 14 days. No other details provided.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

act. ingr.

Interpretation of results:

GHS criteria not met

Conclusions:

The single-dose acute oral LD50 of Cerium Oxide is greater than 5000 mg/kg when administered as a 50% w/w solution in distilled water.

Reference 4

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

2008-01-16 to 2008-04-10

Reliability:

2 (reliable with restrictions)

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 5

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

2001-02-13 to 2001-03-28

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Well documented, scientifically sound study performed according to OECD Guideline 401; however, environmental conditions were not provided.

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

no

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

other: Crj: CD (SD) IGS rat (SPF)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories Japan, Inc.
- Age at study initiation: 5 weeks
- Weight at study initiation: 103.9-113.6 g for males and 89.0-101.2 g for females
- Fasting period before study: overnight before the administration, and for 3-4 hours after the administration
- Housing: no data
- Diet (e.g. ad libitum): no data
- Water (e.g. ad libitum): no data
- Acclimation period: no data


ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data


IN-LIFE DATES: From: 2001-02-20 To: 2001-03-06

Route of administration:

oral: gavage

Vehicle:

other: purified water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: no data
- Amount of vehicle (if gavage): 10 mL/kg
- Justification for choice of vehicle: no data
- Lot/batch no. (if required): A113; Takasugi Pharmaceutical Co., Ltd
- Purity: no data

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg

DOSAGE PREPARATION (if unusual): The animals were put on fasting overnight before the administration, and for 3-4 hours after the administration. The administration was done in the morning by single dose forced oral administration using flexible catheter (Terumo Corporation) and syringes (Terumo Corporation).

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: not applicable

Doses:

2000 mg/kg

No. of animals per sex per dose:

5 male and 5 female

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observed all the samples frequently for up to 6 hours after the administration, then once a day for the next day to 14 days after the administration. All samples were weighed right before the administration, then 1, 3, 7, 14 days after the administration.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight and autopsy

Statistics:

For weight, the average and the standard deviation were calculated for males and females of each group.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Mortality:

There were no deaths in either male or female animals.

Clinical signs:

other: Ash gray stools were observed 1 day after the administration, but they disappeared in 2 days. The ash grey stools seen were considered to be a change resulting from the color of the test agent since it was white, and toxicological significance is conside

Gross pathology:

No abnormality was seen in either males or females.

Other findings:

no data

Conclusions:

The LD50 of the test substance is higher than 2000 mg/kg body weight by the oral route in the rat.

Reference 6

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

2001-02-13 to 2001-03-28

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Well documented, scientifically sound study performed according to OECD Guideline 401; however, no environmental conditions were provided in the report.

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

no

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

other: Crj: CD (SD) IGS rats (SPF)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories Japan, Inc.
- Age at study initiation: 5 weeks
- Weight at study initiation: 98.3 - 114.1 g for males and 88.2 - 97.7 g for females
- Fasting period before study: overnight before the administration, and for 3-4 hours after the administration
- Housing: no data
- Diet (e.g. ad libitum): no data
- Water (e.g. ad libitum): no data
- Acclimation period: no data


ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data


IN-LIFE DATES: From: 2001-02-20 To: 2001-03-06

Route of administration:

oral: gavage

Vehicle:

other: purified water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: no data
- Amount of vehicle (if gavage): 10 mL/kg
- Justification for choice of vehicle: no data
- Lot/batch no. (if required): A113; Takasugi Pharmaceutical Co., Ltd
- Purity: no data

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg

DOSAGE PREPARATION (if unusual): The animals were put on fasting overnight before the administration, and for 3-4 hours after the administration. The administration was done in the morning by single dose forced oral administration using flexible catheter (Terumo Corporation) and syringes (Terumo Corporation).

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: not applicable

Doses:

2000 mg/kg

No. of animals per sex per dose:

5 male and 5 female

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observed all the samples frequently for up to 6 hours after the administration, then once a day for the next day to 14 days after the administration. All samples were weighed right before the administration, then 1, 3, 7, 14 days after the administration.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, and autopsy

Statistics:

For weight, the average and the standard deviation were calculated for males and females of each group.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Mortality:

There were no deaths in either male or female.

Clinical signs:

other: Ash grey stools were observed, but they disappeared in 2 days after the administration. The ash grey stools seen were considered to be a change resulting from the color of the test agent since it was white, and toxicological significance is considered to

Gross pathology:

No abnormality was seen in either males or females.

Other findings:

no data

Conclusions:

The LD50 of the test substance is higher than 2000 mg/kg body weight by the oral route in the rat.

Reference 7

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

2001-07-09 to 2001-08-28

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Well documented, scientifically sound study performed according to OECD Guideline 401; however, environmental conditions were not provided in the report.

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

no

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

other: Crj: CD (SD) IGS rats (SPF)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Japan, Inc.
- Age at study initiation: 5 weeks
- Weight at study initiation: 115.7 - 127.5 g for males and 101.9 - 111.7 g for females
- Fasting period before study: overnight before the administration, and for 3-4 hours after the administration
- Housing: no data
- Diet (e.g. ad libitum): no data
- Water (e.g. ad libitum): no data
- Acclimation period: no data


ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data


IN-LIFE DATES: From: 2001-07-19 To: 2001-08-02

Route of administration:

oral: gavage

Vehicle:

other: purified water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: no data
- Amount of vehicle (if gavage): 10 mL/kg
- Justification for choice of vehicle: no data
- Lot/batch no. (if required): SEJI1860, Wako Pure Chemical Co., Ltd and A116, Takasugi Pharmaceutical Co., Ltd (purified water)
- Purity: no data

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg

DOSAGE PREPARATION (if unusual): The test substance was weighted accurately and ground to a fine powder. The powder was mixed with a suitable amount of arabic gum and purified water. The rest of the arabic gum was added as a solution to obtain a 20.0 w/v % suspension.

The animals were put on fasting overnight before the administration, and for 3-4 hours after the administration. The administration was done in the morning by single dose forced oral administration using Nelaton catheter (Terumo Corporation) and a syringe (Terumo Corporation).

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: not applicable

Doses:

2000 mg/kg

No. of animals per sex per dose:

5 male and 5 female

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observed all the samples frequently for up to 6 hours after the administration, then once a day for the next 14 days. All samples were weighed right before the administration, then 1, 3, 7, 14 days after the administration.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, and macroscopic examination

Statistics:

The mean value and the standard deviation of the body weight were calculated in each group.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Mortality:

No abnormalities were noted in all groups.

Clinical signs:

other: No abnormalities were noted in all groups.

Gross pathology:

No abnormalities were noted in all groups.

Other findings:

no data

Conclusions:

The LD50 of the test substance is higher than 2000 mg/kg body weight by oral route in the rat.

Reference 8

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

Not specified

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

other: published data with limited level of details and a single low dose tested

Qualifier:

no guideline followed

Principles of method if other than guideline:

Single acute dose given orally

GLP compliance:

no

Test type:

other: single acute dose given orally

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Remarks:

2% aqueous solution

Doses:

1000 mg/kg bw (prepared as 50% suspensions in vehicle)

No. of animals per sex per dose:

5 or 10 rats

Control animals:

no

Sex:

female

Dose descriptor:

LD50

Effect level:

> 1 000 mg/kg bw

Based on:

act. ingr.

Animals were observed for 30 days following dosing. Except for an occasional death (test substance not specified), the animals were able to tolerate 1000 mg/kg of the rare earth oxides tested in the study.

Interpretation of results:

GHS criteria not met

Conclusions:

Oral LD50 higher than 1000 mg/kg for females.

Executive summary:

In an acute oral toxicity study (Bruce DW et al., 1963), femal Sprague-Dawley rats were given a single oral dose of Cerium Oxide, as a 50% suspension in 2% aqueous carboxymethylcellulose solution, at the dose of 1000 mg/kg bw and observed for 30 days.

Except for an occasional death (test substance not specified), the animals were able to tolerate 1000 mg/kg of the rare earth oxides tested in the study.

 

Therefore, the oral LD50 was higher than 1000 mg/kg for females.

Reference 9

Endpoint:

acute toxicity: oral

Type of information:

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

Adequacy of study:

supporting study

Justification for type of information:

Read across from supporting studies performed with cerium dioxide and zirconium dioxide/yttrium zirconium oxide.
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

Reason / purpose for cross-reference:

read-across source

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:

> 5 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: The reaction mass of cerium dioxide and zirconium dioxide is expected to have a LD50 value of > 5000 mg/kg bw and therefore does not need to be classified for acute oral toxicity.

Remarks:

This conclusion is based on data obtained with the constituents of the reaction mass, i.e. cerium dioxide and zirconium dioxide, or with zirconium dioxide containing a small w/w % of Y2O3. The key LD50 value for zirconium dioxide and for cerium dioxide was > 5000 mg/kg bw. Therefore it can be concluded that the LD50 for the reaction mass, based on its constituents only, would be at least > 5000 mg/kg bw.

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:

weight of evidence

Study period:

January 1993

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Biological Research Laboratory Ltd., 4414 Fuellinsdorf, Switzerland
- Age at study initiation: 10 (males) / 12 (females) weeks old
- Weight at study initiation: 184.8 - 192.0 g (males) / 183.8 - 195.6 g (females)
- Fasting period before study: no
- Housing: by groups of 5 in makrolon type-4 cages (59 x 38.5 x 20 cm)
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 3°C
- Humidity: 50 ± 20%
- Air changes: 10 to 15 per hr
- Photoperiod: 12 hrs dark / 12 hrs light

IN-LIFE DATES: From 04 January 1993 To 25 January 1993

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

other: unchanged (no vehicle)

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: piston/brush-feed aerosol generator (RBG 1000, Palas GmbH, 7500 Karlsruhe 1, Germany)
- Exposure chamber volume: not specified
- Method of holding animals in test chamber: individual macrolon restraining tubes positioned radially around exposure chamber
- Source and rate of air: compressed air at 1.0 L/min/animal
- Method of conditioning air: filtering + Ni63 charge neutralizer
- System of generating particulates/aerosols: piston/stainless steel brush
- Method of particle size determination: aerosol concentration monitored using a RAM-1 light scattering type monitor / particle size distribution determined once during exposure using a Mercer 7 stage cascade impactor
- Treatment of exhaust air: not specified
- Temperature, humidity, oxygene concentration: 22.1°C, 5.0%, 20.9%, respectively


TEST ATMOSPHERE
- Brief description of analytical method used: aerosol concentration monitored by light scattering / particle size distribution determined by cascade impaction
- Samples taken from breathing zone: yes
- Particle size distribution (cumulative %):
< 0.325 µ = 3%
< 0.715 µ = 5.1%
< 1.06 µ = 16.7%
< 1.6 µ = 43.9%
< 2.13 µ = 64.6%
< 3 µ = 85.4%
< 4.6 µ = 94.1%
> 4.6 µ = 100%


- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): Gravimetric concentration used

- Rationale for the selection of the starting concentration: Maximal concentration for a limit test

Analytical verification of test atmosphere concentrations:

yes

Remarks:

aerosol concentration monitored by light scattering

Duration of exposure:

4 h

Concentrations:

5.047 ± 0.93 mg/L air (mean ± SD)

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 15 days
- Frequency of observations and weighing:
Mortality: once per hour during exposure, once after exposure on day 1, twice daily thereafter
Clinical signs: once per hour during exposure, once after exposure on day 1, once daily thereafter
Body weight: before exposure on day 1 and on days 8 and 15
- Necropsy of survivors performed: yes
- Other examinations performed: lungs, trachea, larynx and nasopharyngeal tissues preserved for histopathology

Statistics:

LOGIT-Model (not applied due to absence of deaths)

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 5.05 mg/L air (analytical)

Based on:

act. ingr.

Exp. duration:

4 h

Sex:

male/female

Dose descriptor:

LC0

Effect level:

5.05 mg/L air (analytical)

Based on:

act. ingr.

Exp. duration:

4 h

Mortality:

No mortality occurred during the exposure and observation periods

Clinical signs:

other: Labored breathing and ruffled fur were noted in 2 males just after exposure. This persisted in one male for up to 24 hours after exposure.

Body weight:

No significant changes in body weight were seen when compared to controls

Gross pathology:

At necropsy, the lungs of all animals were incompletely collapsed with diffuse whitish foci

Interpretation of results:

GHS criteria not met

Conclusions:

Inhalation LC50 was higher than 5.05 mg/L for male and female rats exposed for 4 hours.

Executive summary:

In an acute inhalation toxicity study (RCC Project No. 330974), one group of 10 to 12-week old Wistar rats (5/sex) was exposed by nose-only inhalation route to Cerium Oxide for 4 hours at a mean gravimetric concentration of 5.05 mg/L, and observed for 15 days. Mortality and clinical signs were checked during and just after exposure, and daily for 15 days. Body weight was recorded prior to exposure and on days 8 and 15.

 

No mortality occurred during the exposure and observation periods. Labored breathing and ruffled fur were noted in 2 males just after exposure. This persisted in one male for up to 24 hours after exposure. No significant changes in body weight were seen when compared to controls. At necropsy, the lungs of all animals were incompletely collapsed with diffuse whitish foci.

 

Therefore, the inhalation LC50 was higher than 5.05 mg/L for males and females exposed for 4 hours. No classification for acute inhalation toxicity is warranted based on the absence of mortality at the concentration tested, according to the criteria of Annex VI Directive 67/548/EEC or UN/EU GHS.

 

This study is classified as acceptable. It satisfies the OECD 403 guideline requirements for acute inhalation toxicity.

Reference 2

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

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 3

Endpoint:

acute toxicity: inhalation

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 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

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 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), and a study performed with cerium dioxide (Duchosal, 1993), in which the inhalation LC50 was found to be higher than 5.05 mg/L. The lowest LC50 derived (from zirconium dioxide) is used to conclude on this endpoint. In a similar study, similar results would be expected for the reaction mass.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Acute toxicity: via dermal route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

November - December 1982

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

Remarks:

study performed before the application of the OECD TG 402 but consistent with technical standards (number of animals used, duration of observation period, observations and measurements, ...)

GLP compliance:

no

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
- Age at study initiation: 6 to 7 weeks old
- Weight at study initiation: 180 - 190 g (males) / 150 - 160 g (females)
- Fasting period before study: no
- Housing: individually in 37.5 x 17 x 15 cm cages
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 5°C
- Humidity: 55 ± 15%
- Air changes: 10 per hr
- Photoperiod (hrs dark / hrs light): not specified

IN-LIFE DATES: From 25 November 1982 To 2 December 1982

Type of coverage:

occlusive

Vehicle:

other: 10% aqueous gum arabic

Details on dermal exposure:

TEST SITE
- Area of exposure: dorsal skin
- % coverage: not specified
- Type of wrap if used: aluminium foil and tape

REMOVAL OF TEST SUBSTANCE
- Washing: no
- Time after start of exposure (removal of dressing): 24 hours

TEST MATERIAL
- Suspension in vehicle applied
- No other details provided

VEHICLE
No details provided

Duration of exposure:

24 hours of occlusive dressing

Doses:

- Preliminary assay: 1000 and 2000 mg/kg
- Main assay: 0 (vehicle) and 2000 mg/kg

No. of animals per sex per dose:

- Preliminary assay: 2/sex
- Main assay: 5/sex

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Mortality, clinical signs and local tolerance: just after dosing, 1, 2, 6 hours after dosing and daily for 14 days
Body weight: days 0, 1, 2, 4, 7 and 14
- Necropsy of survivors performed: yes

Statistics:

Not included

Preliminary study:

Two groups of 2 rats per sex, clipped on the back 24 hours before, were applied a single cutaneous dose of 1000 or 2000 mg/kg kept under an occlusive dressing (adhesive tape and aluminium foil) for 24 hours, and observed for 14 days. No mortality was observed at either dose level.

Sex:

male/female

Dose descriptor:

LD0

Effect level:

2 000 mg/kg bw

Based on:

act. ingr.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

act. ingr.

Mortality:

No mortality occurred during the observation period

Clinical signs:

other: Slightly reduced activity was observed on day 1 in rats exposed to the test substance. No signs of cutaneous irritation were seen.

Gross pathology:

No relevant findings were seen at necropsy on day 14

Interpretation of results:

GHS criteria not met

Conclusions:

Dermal LD50 higher than 2000 mg/kg for males and females.

Executive summary:

In an acute dermal toxicity study (Institut Français de Toxicologie report No. 301229), groups of 6 to 7-week old Sprague-Dawley rats (5/sex) were applied a single dermal dose of Cerium Oxide, as a suspension in 10% gum arabic, at doses of 0 (vehicle only) or 2000 mg/kg bw (limit test) under an occlusive dressing applied for 24 hours, and observed for 14 days. Mortality, clinical signs and local tolerance were checked just after application, at 1, 2, 6 hours after dosing, and daily for 14 days. Body weight was recorded on days 0, 1, 2, 4, 7 and 14.

 

No mortality occurred during the observation period. Slightly reduced activity was observed on day1 in rats exposed to the test substance. No signs of cutaneous irritation were seen. No significant changes in body weight were seen when compared to controls. No relevant findings were seen at necropsy on day 14.

 

Therefore, the dermal LD50 was higher than 2000 mg/kg for males and females. No classification for acute dermal toxicity is warranted based on the absence of mortality up to a limit dose level, according to the criteria of Annex VI Directive 67/548/EEC or UN/EU GHS.

 

This study is classified as acceptable. Its design is compatible with the OECD 402 guideline requirements for acute dermal toxicity.

Reference 2

Endpoint:

acute toxicity: dermal

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

Read across from a study performed with cerium dioxide.
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:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

act. ingr.

Remarks on result:

other: The reaction mass of cerium dioxide and zirconium dioxide is not expected to be toxic via dermal exposure 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 cerium dioxide (Monnot, 1983), in which no acute adverse effects have been observed at the maximum technically achievable concentration (2000 mg/kg). In a similar study, similar results would be expected with the reaction mass.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Additional information

Acute toxicity: Oral

One key study was identified on a representative nanoform of the reaction mass of cerium dioxide and zirconium dioxide (De Jouffrey, 1996a; Klimisch 1). The reaction mass of cerium dioxide and zirconium dioxide has been tested for acute oral toxicity in Sprague Dawley rats, according to OECD guideline 401 and in compliance with Good Laboratory Practice. 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, no classification for acute oral toxicity is warranted. As a representative nanoform was tested, the same conclusion is expected to hold for any potential bulk forms, should such forms be placed on the market.

Further information on acute oral toxicity is also available on the constituents of the reaction mass, cerium dioxide as well as zirconium dioxide (or alternatively, zirconium dioxide containing a small w/w % of yttrium oxide). As these constituents showed similar physicochemical, toxicological, ecotoxicological and environmental properties, results of studies performed on both constituents are used as supporting studies.

By oral route, the LD50 of cerium dioxide in rats was higher than 5000 mg/kg bw, as confirmed by two distinct studies (Monnot, 1983; Lambert et al., 1993), therefore warranting no classification. A third study yielded an oral LD50 value of > 1000 mg/kg bw (no higher doses tested, Bruce et al., 1963).

For zirconium dioxide, the oral LD50 value in female Sprague-Dawley rats was > 5000 mg/kg bw (Phycher Bio Developpement, 2008).

The studies performed on zirconium dioxide containing small amounts of yttrium oxide yielded LD50 values > 2000 mg/kg bw (Chemical Evaluation and Research Institute, 2001a,b,c).

Acute toxicity: Inhalation

No study is available for the reaction mass of cerium dioxide and zirconium dioxide. The data on both constituents are considered in a weight of evidence approach to conclude on the acute inhalation toxicity of the reaction mass of cerium dioxide and zirconium dioxide.

Regarding cerium oxide, 2 acute inhalation studies (with Klimisch 1 reliability score) were performed according to OECD guidelines (or equivalent) and in accordance with GLP. In these studies, rats were exposed to cerium dioxide at 5.05 mg/L (Duchosal, 1993; nose only exposure) and 2.01 mg/L, the maximum technically administrable concentration (Traynard, 1983; whole body exposure) for 4 hours. No mortality occurred in both studies, therefore warranting no classification.

Acute inhalation toxicity of zirconium dioxide was tested according to OPPTS Guideline 870.1300 and OECD guideline 436. 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).

An acute inhalation study on the reaction mass of cerium dioxide and zirconium dioxide is therefore not regarderd as scientifically necessary according to section 1 of Reach Annex XI and is not recommended under animal protection considerations.

Acute toxicity: Dermal

No study is available for the reaction mass of cerium dioxide and zirconium dioxide. Based on similar properties of cerium dioxide as compared to the reaction mass of cerium dioxide and zirconium dioxide, a study on acute dermal toxicity performed with cerium dioxide is considered as a key study to conclude on the acute dermal toxicity of the reaction mass of cerium dioxide and zirconium dioxide.

In an acute dermal toxicity study (Institut Français de Toxicologie report No. 301229; Monnot, 1983) quoted as Klimisch 1, Sprague-Dawley male and female rats (5/sex) were treated with a single dermal dose of cerium dioxide, as a suspension in 10% gum arabic, at doses of 0 (vehicle only) or 2000 mg/kg bw (limit test) under an occlusive dressing for 24 hours. The animlas were observed for 14 days.

No mortality occurred during the observation period. Slightly reduced activity was observed on day 1 in rats exposed to the test substance. No signs of cutaneous irritation were seen. No significant changes in body weight were seen when compared to controls and no relevant findings were seen at necropsy on day 14. 

Therefore, the dermal LD50 was higher than 2000 mg/kg for males and females, therefore warranting no classification.

No acute dermal toxicity data are available for zirconium dioxide.

 

An acute dermal study on the reaction mass of cerium dioxide and zirconium dioxide is therefore not regarderd as scientifically necessary according to section 1 of Reach Annex XI and is not recommended under animal protection considerations.

Acute toxicity – LD/LC 50	Reaction mass	Cerium dioxide	Zirconium dioxide
Oral	LD 50 > 2000 mg/kg bw	LD 50 > 5000 mg/kg bw	LD50 > 5000 mg/kg bw
Dermal	-	LD 50 > 2000 mg/kg bw	-
Inhalation	-	LC 50 > 5.05 mg/L	LC50 > 4.3 mg/L (Maximal technically achievable mean concentration)

Justification for classification or non-classification

Based on the available data on the reaction mass and its constituents showing that no mortality occurred after exposure up to the limit dose/concentration regardless the route of exposure (oral, dermal or inhalation), the reaction mass of cerium dioxide and zirconium dioxide is not classified for acute toxicity according to the CLP classification criteria.