Cerium dioxide

Endpoint summary

Description of key information

LD50 oral, rat > 5000 mg/kg bw
LC50 inhalation, rat > 5.05 mg/L (4 hours)
LD50 dermal, rat > 2000 mg/kg bw

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:

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

Remarks:

The study was performed before the implementation of GLP.

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:

test mat.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

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 UN/EU GHS criteria.

 

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

Reference 2

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

Remarks:

The GLP status was not specified in the published article.

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:

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:

test mat.

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.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

5 000 mg/kg bw

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:

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)

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 5.05 mg/L air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Sex:

male/female

Dose descriptor:

LC0

Effect level:

5.05 mg/L air (analytical)

Based on:

test mat.

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 UN/EU GHS criteria.

 

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:

supporting study

Study period:

November 1982 - December 1982

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

no

GLP compliance:

no

Remarks:

The study was performed before the implementation of GLP.

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: not specified
- Age at study initiation: not specified
- Weight at study initiation: 180 - 186 g
- Fasting period before study: no
- Housing: by groups of 5 in makrolon cages
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3
- Humidity (%): 50 +/- 20
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 12 / 12


IN-LIFE DATES: Exact dates not specified

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

whole body

Vehicle:

other: unchanged (no vehicle)

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: disposable air-tight chamber, particle generator, exposure cages, densitometer, regulator, dust measurer and granulometer
- Exposure chamber volume: 1 m3
- Method of holding animals in test chamber: stainless steel wired cages (35 x 24 x 20 cm) of 5 animals per sex
- Source and rate of air / Method of conditioning air: not specified
- System of generating particulates/aerosols: micronizer with non-powdery, compressed air supplied with test powder through a vibrating tunnel
- Method of particle size determination: granulometer (0.5 µ to 10 µ)
- Treatment of exhaust air: not specified
- Temperature, humidity, pressure in air chamber: 21-22°C, 27-40%, not specified, respectively


TEST ATMOSPHERE
- Brief description of analytical method used: aerosol concentration measured by light relection / mass concentration of dust inside the chamber measured by differential measurement of beta-rays transmission
- Samples taken from breathing zone: yes
- Particle size distribution:
0.5 to 1 µ = 98.3%
1 to 3 µ = 1.7%
- MGMD (Mean Gravimetric Median Diameter): 0.754 µ

- Rationale for the selection of the starting concentration: described as 'maximum technological concentration'

Analytical verification of test atmosphere concentrations:

yes

Remarks:

aerosol concentration measured by light reflection

Duration of exposure:

4 h

Concentrations:

Mean observed concentration = 2.01 mg/L

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Mortality and clinical signs: during exposure, for the following hours, and daily during 14 days
Body weight: just after exposure and on days 1, 2, 4, 7 and 14
- Necropsy of survivors performed: yes
- Other examinations performed: histopathology on macroscopic abnormalities

Statistics:

Not included

Sex:

male/female

Dose descriptor:

LC0

Effect level:

2.01 mg/L air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

other: Maximum technically administrable concentration

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 2.01 mg/L air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

other: Maximum technically administrable concentration

Mortality:

No mortality occurred during the observation period

Clinical signs:

other: No clinical signs were observed

Body weight:

No significant body weight changes occured

Gross pathology:

At necropsy, no macroscopic abnormalities were observed

Interpretation of results:

GHS criteria not met

Conclusions:

Inhalation LC50 higher than 2.01 mg/L (the maximum technically administrable concentration) for male and female rats exposed for 4 hours

Executive summary:

In an acute inhalation toxicity study (Institut Français de Toxicologie report No. 302217 E), one group of Sprague-Dawley rats (5/sex) was exposed by whole-body inhalation route to Cerium Oxide for 4 hours at a mean concentration of 2.01mg/L, the maximum technically administrable concentration, and observed for 14 days. Mortality and clinical signs were checked during and within the few hours after exposure, and daily for 14 days. Body weight was recorded prior to exposure and on days 1, 2, 4, 7 and 14.

 

No mortality occurred during the observation period. No clinical signs were observed. No significant body weight changes occurred. At necropsy, no macroscopic abnormalities were observed.

 

Therefore, the inhalation LC50 was higher than 2.01 mg/L (the maximum technically administrable concentration) 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 UN/EU GHS criteria.

 

This study is classified as acceptable. Its design is compatible with the OECD 403 guideline requirements for acute inhalation toxicity.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

5.05 mg/m³ air

Acute toxicity: via dermal route

Link to relevant study records

Reference

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

Remarks:

The study was performed before the implementation of GLP

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:

test mat.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

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 UN/EU GHS regulations.

 

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

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Additional information

The acute toxicity of cerium dioxide was tested in rats using all three usual routes of administration: oral, inhalatory and dermal. One study of reliability 1 according to Klimisch cotation criteria was available for each route of administration and was selected as a key study.

By oral route, the LD50 of cerium dioxide in rats was higher than 5000 mg/kg bw, as confirmed by two distinct studies (Institut Français de Toxicologie, 1983; Lambert et al., 1993) and supported by the study of Kumari et al., 2014 who tested bulk cerium dioxide up to the dose of 2000 mg/kg. According to these results, no classification according to EU/UN GHS criteria is required.

By inhalation, the LC50 of cerium dioxide in rats exposed for 4 hours was higher than 5.05 mg/L (RCC, 1993), therefore warranting no classification. This was corroborated by another study in rats (Institut Français de Toxicologie, 1983) where no mortality occurred at a test concentration of 2.01 mg/L (maximum technically administrable concentration) over 4 hours.

By dermal route, the LD50 of cerium dioxide in rats exposed for 24 hours was higher than 2000 mg/kg bw (Institut Français de Toxicologie, 1983), therefore warranting no classification.

Further, no systemic effects and no organs lesions were observed in these studies.

Cerium dioxide was not classified for acute toxicity according to the UN/EU GHS.

Justification for classification or non-classification

Cerium dioxide, administrated either by oral, dermal or inhalation route, induced no mortality and no systemic effects in the rat following a single exposure up to a limit dose/concentration and thus does not need to be classified for acute toxicity or STOT SE according to UN/EU GHS classification criteria.