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

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

Acute / short-term exposure - systemic and local effects

Inhalation:

As no local or systemic effects have been observed up to the maximal technically achievable concentration in the available acute inhalation toxicity studies with the reaction mass' constituents cerium dioxide and zirconium dioxide, no DNELs need to be derived.

However, it should be noted that for many countries/regions, occupational exposure limits have been derived for zirconium compounds after short-term exposure (e.g. typical STEL (Short Term Exposure Limit, 15 min) of 10 mg Zr/m3). Therefore, although it is considered reasonable not to derive DNELs, the relevant exposure limit should be checked and respected where relevant. Similarly, it should be checked if a STEL value has also been set for cerium (dioxide) and, should this be the case, this value should also be respected where relevant.

Dermal:

As no local or systemic effects have been observed in an acute dermal toxicity study with the reaction mass' constituent cerium dioxide at the limit test dose of 2000 mg/kg bw, no DNELs need to be derived. This is further supported by the fact that based on an acute oral toxicity study with the reaction mass, the substance does not meet the criteria for classification for acute toxicity or Specific Target Organ Toxicity following Single Exposure by the oral route and no systemic effects have been observed in in vivo studies with dermal exposure performed with the reaction mass (e.g., the in vivo skin irritation studies).

Long-term exposure - systemic and local effects

Inhalation:

The available repeated dose inhalation toxicity studies performed with nano or bulk cerium dioxide, with bulk zirconium dioxide, and with Zr-doped nano cerium dioxide did not indicate any signs of systemic toxicity. Therefore, no DNEL for systemic effects after repeated inhalation exposure should be set.

Zirconium dioxide, whether bulk or nano, is consistently found to be toxicologically inert, not resulting in loco-regional adverse effects in the lungs either. For cerium dioxide, whether bulk or nano, loco-regional adverse effects have been consistently observed in rats, but not in mouse. The observed loco-regional effects of cerium dioxide in rats are considered to represent rather a non-specific adaptive response to particle overload of the lung and indicate the sensitivity of rats to this type of condition (Ref. ILSI Risk Science Institute. The relevance of the rat lung response to particle overload for human risk assessment: A workshop consensus report. Inhalation Toxicology, 12: 1-17, 2000). Lung overload-related inflammatory response is commonly observed in rats following inhalation exposure to poorly soluble particles. The concept of overload applies specifically to poorly soluble particles with low cytotoxicity, such as cerium dioxide. The distribution of the retained particles within the lung compartments varies between species. It has been shown that during chronic inhalation exposure, particles are retained to a greater degree in interstitial locations in lungs of non-human primates and dogs than in lungs of rats, and that the interspecies differences in particle location might contribute to corresponding differences in tissue response (Ref. Snipes MB. Current information on lung overload in non-rodent mammals: contrast with rats. Inhalation Toxicology, 8(suppl): 91 -109, 1996). These differences combined with the fact that human macrophages have five times the volume of rat macrophages are considered to account for the tendency of rats to respond to poorly soluble particles with more chronic inflammation and epithelial responses compared to humans (Ref. Oberdörster G. Toxicokinetics and effects of fibrous and non-fibrous particles. Inhalation Toxicology, 14: 29-56, 2002). Therefore the observed loco-regional effects in rats are considered to be less relevant for humans and no DNEL for local effects after repeated inhalation exposure is set.

It should be noted that for many countries/regions, occupational exposure limits have been derived for zirconium compounds after long-term exposure (e.g. typical 8-h TWA (Time Weighted Average) of 5 mg Zr/m3). Therefore, although it is considered reasonable not to derive DNELs, the relevant exposure limit should be checked and respected where relevant. Similarly, it should be checked if an 8-h TWA value has also been set for cerium (dioxide) and, should this be the case, this value should also be respected where relevant. Further, it is recommended to also respect any relevant occupational exposure limit for respirable dust, where relevant.

Dermal:

No data are available that might indicate hazardous systemic or local effects after long-term dermal exposure. Therefore, no long-term DNELs are derived for this route of exposure.

Hazard for the eyes

The reaction mass of cerium dioxide and zirconium dioxide was concluded not to be hazardous for eyes, based on information from an in vivo eye irritation study performed with a representative nanoform of the reaction mass.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

Acute / short-term exposure - systemic and local effects

Oral:

No local or systemic effects have been observed up to and including at the limit test dose of 2000 mg/kg bw in an acute oral toxicity study in rats performed with a representative nanoform of the reaction mass. Therefore, no DNELs need to be derived.

Inhalation:

As no local or systemic effects have been observed up to the maximal technically achievable concentration in the available acute inhalation toxicity studies with the reaction mass' constituents cerium dioxide and zirconium dioxide, no DNELs need to be derived.

Dermal:

As no local or systemic effects have been observed in an acute dermal toxicity study with the reaction mass' constituent cerium dioxide at the limit test dose of 2000 mg/kg bw, no DNELs need to be derived. This is further supported by the fact that based on an acute oral toxicity study with the reaction mass, the substance does not meet the criteria for classification for acute toxicity or Specific Target Organ Toxicity following Single Exposure by the oral route and no systemic effects have been observed in in vivo studies with dermal exposure performed with the reaction mass (e.g., the in vivo skin irritation studies).

Long-term exposure - systemic and local effects

Oral:

The available oral repeated dose toxicity studies with screening for reproductive/developmental toxicity (OECD 422) performed with cerium dioxide and zirconium acetate (i.e. a 'water soluble' zirconium compound which can be considered as representative - as a worst case - for the insoluble reaction mass' constituent zirconium dioxide) have not revealed any adverse systemic or local effects in parent animals, neither did they reveal adverse effects on reproduction/development. No adverse effects have been observed either in a 2-generation reproductive toxicity study performed with an organometallic nanoform of cerium dioxide (cerium and iron oxide isostearate). Therefore, no long-term oral DNELs need to be derived.

Inhalation:

The available repeated dose inhalation toxicity studies performed with nano or bulk cerium dioxide, with bulk zirconium dioxide, and with Zr-doped nano cerium dioxide did not indicate any signs of systemic toxicity. Therefore, no DNEL for systemic effects after repeated inhalation exposure should be set.

Zirconium dioxide, whether bulk or nano, is consistently found to be toxicologically inert, not resulting in loco-regional adverse effects in the lungs either. For cerium dioxide, whether bulk or nano, loco-regional adverse effects have been consistently observed in rats, but not in mouse. The observed loco-regional effects of cerium dioxide in rats are considered to represent rather a non-specific adaptive response to particle overload of the lung and indicate the sensitivity of rats to this type of condition (Ref. ILSI Risk Science Institute. The relevance of the rat lung response to particle overload for human risk assessment: A workshop consensus report. Inhalation Toxicology, 12: 1-17, 2000). Lung overload-related inflammatory response is commonly observed in rats following inhalation exposure to poorly soluble particles. The concept of overload applies specifically to poorly soluble particles with low cytotoxicity, such as cerium dioxide.The distribution of the retained particles within the lung compartments varies between species. It has been shown that during chronic inhalation exposure, particles are retained to a greater degree in interstitial locations in lungs of non-human primates and dogs than in lungs of rats, and that the interspecies differences in particle location might contribute to corresponding differences in tissue response (Ref. Snipes MB. Current information on lung overload in non-rodent mammals: contrast with rats. Inhalation Toxicology, 8(suppl): 91 -109, 1996). These differences combined with the fact that human macrophages have five times the volume of rat macrophages are considered to account for the tendency of rats to respond to poorly soluble particles with more chronic inflammation and epithelial responses compared to humans (Ref. Oberdörster G. Toxicokinetics and effects of fibrous and non-fibrous particles. Inhalation Toxicology, 14: 29-56, 2002). Therefore the observed loco-regional effects in rats are considered to be less relevant for humans and no DNEL for local effects is set.

Dermal:

No data are available that might indicate hazardous systemic or local effects after long-term dermal exposure. Therefore, no long-term DNELs are derived for this route of exposure.

Hazard for the eyes

The reaction mass of cerium dioxide and zirconium dioxide was concluded not to be hazardous for eyes, based on information from an in vivo eye irritation study performed with a representative nanoform of the reaction mass.