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

Endpoint summary

Description of key information

A qualitative judgement on the toxicokinetic behaviour of the reaction mass of cerium(IV) oxide, praseodymium(III,IV) oxide and zirconium(IV) oxide (EC 909-715-0) was performed based on the physicochemical characteristics of the substance. In addition, reliable toxicological data that are available for its constituents cerium dioxide (CeO₂), praseodymium(III,IV) oxide (Pr₆O₁₁) and zirconium dioxide (ZrO₂) are used as supporting information. To cover the toxicological profile of cerium dioxide, data obtained for the reaction mass of cerium dioxide and zirconium dioxide are included in the assessment instead of data for cerium dioxide itself. It should be noted that the read across approach followed for the reaction mass under consideration is based on the comparison of basic toxicological (Annex VII) data for zirconium dioxide, praseodymium(III,IV) oxide and the reaction mass of cerium dioxide and zirconium dioxide, which confirms that the addition of cerium dioxide and praseodymium(III,IV) oxide to zirconium dioxide does not affect the unhazardous character of zirconium dioxide. For this reason, higher (Annex VIII) toxicological endpoints are covered using studies performed on zirconium dioxide alone (or other, related zirconium substances) to predict the toxicological behaviour of the reaction mass.

The reaction mass of cerium(IV) oxide, praseodymium(III,IV) oxide and zirconium(IV) oxide is a brown odourless powder and can be considered as a highly insoluble product as the water solubility was determined to be < 0.02 mg/L at pH 6 and 20°C for both cerium and zirconium (Buchholz, 2018). Initially, the aim was to measure the concentration of zirconium and praseodymium as their individual oxides show the highest water solubility (in pure water). However, as it turned out to be technically unfeasible to measure the concentration of praseodymium, no value was obtained for this element. Nevertheless, it can be expected that the release of praseodymium from the reaction mass will be limited as well based on the following information:

- The water solubility of praseodymium(III,IV) oxide (Pr₆O₁₁) was determined to be 1.27 mg/L (equivalent to 1.035 mg Pr/L) in pure water at 20°C and a pH of 6.59-6.76 (OECD 105, Weissenfeld, 2008).

- In physiologically relevant media, rare earth elements are expected to form insoluble complexes with present ligands. Formation and precipitation of such complexes in physiologically relevant media can be expected to result in lower dissolved rare earth concentrations compared to in pure water at a similar loading rate. For praseodymium from praseodymium oxide, this is supported by the dissolved praseodymium concentrations measured in an acute daphnid toxicity study and an algal growth inhibition study, which were in the µg/L range. The same was true for dissolved cerium and zirconium in all aquatic ecotoxicity studies performed with the reaction mass of cerium dioxide and zirconium dioxide. The complexation behaviour of rare earth elements is further supported by modelling exercises performed with models such as Visual Minteq, which is a chemical equilibrium model for the calculation of metal speciation in aqueous media and is based on the NIST Critically Selected Stability Constants of Metal Complexes Database. More information can be found in the read across assessment document attached to IUCLID Section 13.

Based on abovementioned information, no or only extremely limited amounts of bioavailable cerium, zirconium and praseodymium are to be expected in physiologically relevant media.

The reaction mass of cerium(IV) oxide, praseodymium(III,IV) oxide and zirconium(IV) oxide is further characterised by a molecular weight range between 155.5 and 181.65 g/mol, a median particle size of 2.240 µm (D10 = 0.879 µm and D90 = 6.757 µm) (representative sample of MEL Chemicals, 2016) and a relative density of 5.340 at 20.2°C (Demangel, 2018). The reaction mass does not melt when heated up to 800°C (Dvininov, 2017).

 

Absorption

Oral absorption

The relevant pH range for the uptake in the gut after oral ingestion is 6 (at the entrance of the duodenum) to 7.4 (at the terminal ileum). Because the reaction mass of cerium(IV) oxide, praseodymium(III,IV) oxide and zirconium(IV) oxide is poorly soluble in water at this pH level (see above), absorption after oral exposure is expected to be very limited. During passage through the stomach, the acidic pH of the gastric environment may cause some dissolution of zirconium, praseodymium and cerium from the substance. Any dissolved zirconium, praseodymium or cerium is expected to be rapidly precipitated in the gut due to the presence of ligands (e.g., phosphate, carbonate). For this reason, it is expected that the bioavailability of the elements in the reaction mass will be too low for substantial uptake in the small intestine and thus the oral absorption is expected to be extremely low.

The absence of systemic toxicity in the toxicological experiments carried out with the substance’s constituents praseodymium(III,IV)oxide and zirconium dioxide, with the reaction mass of cerium dioxide and zirconium dioxide, and – for some endpoints – zirconium compounds other than zirconium dioxide, supports the assumption of limited oral absorption:

- Following a single administration by oral route at the limit dose of 2000 mg/kg bw (Phycher Bio Developpement, 2008; Clouzeau, 1994; De Jouffrey, 1996a), no relevant systemic clinical signs or changes in body weight and no gross abnormalities upon necropsy were observed for zirconium dioxide, praseodymium(III,IV) oxide and the reaction mass of cerium dioxide and zirconium dioxide (respectively).

- No adverse effects have been observed in an OECD 422 study performed with the read across substance zirconium acetate in rats (Rossiello, 2013), resulting in NOAEL values ≥ 1000 mg/kg bw/day (i.e. the highest dose tested). Note that the results of this study were considered relevant for zirconium dioxide (and consequently for the reaction mass as well) because the toxicokinetic behaviour and toxicological profile of water soluble zirconium compounds such as zirconium acetate is expected to show a higher-than-expected similarity to that of insoluble zirconium compounds such as zirconium dioxide (and the reaction mass under consideration).

- A 90-day oral toxicity study in rats with the read across substance zirconium basic carbonate (containing 20.9% zirconium dioxide equivalent) did not show any harmful effects. The NOAEL was reported to be ≥ 15100-33900 mg/kg bw/day (zirconium basic carbonate). The equivalent NOAEL for zirconium dioxide was ≥ 3150-7080 mg/kg bw/day (Harrison et al., 1951).

In addition, although not included in the dossier, no adverse effects have been observed in oral repeated dose toxicity studies with cerium dioxide and praseodymium(III,IV) oxide either, which further supports the assumption of limited oral absorption.  

No experimentally obtained data on oral absorption are available for the reaction mass of cerium(IV) oxide, praseodymium(III,IV) oxide and zirconium(IV) oxide. Data on zirconium dichloride oxide in mouse and rat show oral absorption to be at levels of 0.01 to 0.05% of the administered dose (Delongeas et al., 1983). This well water soluble compound could be regarded as a reference for zirconium dioxide as it will instantaneously be converted to zirconium dioxide in aqueous solution (at physiologically relevant pH levels). As already mentioned above, higher-than-expected similarities are expected between water soluble zirconium compounds (such as zirconium dichloride oxide) and insoluble zirconium compounds (such as zirconium dioxide as well as the reaction mass under consideration).

Based on the reasoning above, the oral absorption of cerium, praseodymium and zirconium from the reaction mass of cerium(IV) oxide, praseodymium(III,IV) oxide and zirconium(IV) oxide is expected to be extremely low and – in the absence of direct experimental evidence – a worst case oral absorption factor of 10% is proposed.

Respiratory absorption

Low exposure to the substance is expected based on the inherent properties of the compound. No vapour pressure value has been determined as the product does not melt below 300°C. Therefore, inhalation of the reaction mass of cerium(IV)oxide, praseodymium(III,IV) oxide and zirconium(IV) oxide as a vapour is not likely to occur.

There are no data available on the aerodynamic diameter but based on the small median particle size of a representative sample of the reaction mass, which was determined to be 2.240 µm (MEL Chemicals, 2016), typical grades of the substance can be considered to contain both inhalable and respirable particles. When inhaled, the reaction mass, which has a very low water solubility (Buchholz, 2018), may reach the alveolar region. In the alveolar region, the particles may be engulfed by alveolar macrophages. These macrophages will then either translocate the particles to the ciliated airways or carry particles into the pulmonary interstitium and lymphoid tissues. For this reason, the respiratory absorption is expected to be very low.

Currently there are no inhalation toxicity studies available performed on the reaction mass itself to support the reasoning above. However, the absence of systemic toxicity in the experiments carried out with the substance’s constituent zirconium dioxide supports this assumption both after single and repeated exposure. Following a single inhalation (nose only) exposure assessment during 4 h and at the limit dose of 4.3 mg/L ZrO₂ as aerosol (Smith, 2010), no mortalities and no specific test item related adverse effects in body weight, clinical signs and gross pathology were observed.

A sub-chronic inhalation study (60 days) applying ZrO₂ at a dose of 15.4 mg/m³ air to rats, rabbits, guinea pigs, dogs and cats, and a short-term repeated dose inhalation study (30 days) applying ZrO₂ at a dose of 100.8 mg/m³ air to rats, rabbits and dogs, showed no significant changes in mortality rate, growth, biochemistry, hematology values or histopathology in any of the species tested (Spiegl et al., 1956). Findings on accumulation supporting the macrophage-mediated clean-up mechanism are further discussed in the section on distribution. In addition, although not included in the dossier, no inhalation toxicity studies (single-dose as well as repeated dose) performed with praseodymium(III,IV) oxide or cerium dioxide have resulted in classification so far, which further supports the assumption of limited respiratory absorption.

Based on the reasoning above, and in the absence of direct experimental evidence, a worst case inhalation absorption factor of 10% is proposed.

Dermal absorption

Prior to penetrating the skin by diffusive mechanisms, the reaction mass of cerium(IV) oxide, praseodymium(III,IV) oxide and zirconium(IV) oxide would have to dissolve in the moisture of the skin. However, as the solubility of the reaction mass is very low at physiologically relevant pH levels (relevant to skin), no significant dermal uptake is expected because the substance must be sufficiently soluble in water to partition from the lipid rich stratum corneum into the epidermis.

Furthermore, the reaction mass was concluded to be not irritating to skin nor skin sensitising based on reliable data for its constituents praseodymium(III,IV) oxide and zirconium dioxide (yttrium zirconium oxide for skin sensitisation) as well as the reaction mass of cerium dioxide and zirconium dioxide (skin irritation: Shapiro, 1991a; BIBRA, 1986; Harlan, 2009 and De Jouffrey, 1996b; skin sensitisation: Henzell, 2012; Chemical Inspection and Testing Institute, 1999; De Jouffrey, 1996d) and therefore the expected limited dermal absorption is not expected to be enhanced by any irritating/sensitising effects.

In the absence of measured data on dermal absorption, the ECHA guidance (2017) suggests the assignment of either 10% or 100% default dermal absorption rates. However, the currently available scientific evidence on dermal absorption of some metals (e.g. Zn sulphate, Ni acetate; based on the experience from previous EU risk assessments) indicates that lower figures than the lowest proposed default value of 10% could be expected (HERAG, 2007).

Based on the inherent properties of the reaction mass of cerium(IV) oxide, praseodymium(III,IV) oxide and zirconium(IV) oxide, the toxicological data available, and the experience from HERAG, no significant dermal absorption is expected.

Based on the reasoning above, and in the absence of direct experimental evidence, a worst case dermal absorption factor of 1% is proposed.

Distribution and accumulation

From the above discussion, absorption of the elements zirconium, cerium and praseodymium following exposure to the reaction mass of cerium(IV) oxide, praseodymium(III,IV) oxide and zirconium(IV) oxide via the oral, respiratory or dermal pathway is expected to be (very) limited. Nevertheless, the available information on distribution and accumulation of zirconium is discussed below in order to describe its most likely behaviour once ending up in the circulatory system.

Oral administration

Since there are no oral toxicokinetics studies available informing directly on the distribution and/or accumulation of (zirconium, cerium and praseodymium from) the reaction mass of cerium(IV) oxide, praseodymium(III,IV) oxide and zirconium(IV) oxide or on the distribution and/or accumulation of (zirconium from) zirconium dioxide or other zirconium compounds, the findings from the available oral repeated dose toxicity studies performed with zirconium acetate and zirconium basic carbonate as well as from the acute oral toxicity studies performed with zirconium dioxide, praseodymium(III,IV) oxide and the reaction mass of cerium dioxide and zirconium dioxide are considered more closely.

In the 17-week oral toxicity study performed with the insoluble zirconium basic carbonate (containing 20.9% ZrO₂ equivalent) in rats (Harrison et al., 1951), no abnormalities were observed in heart, lungs, thyroids, thymus, liver, spleen, kidneys, adrenals, stomach, intestines, bladder and genital organs. In the OECD 422 study performed with the water soluble zirconium acetate in rats (Rossiello, 2013), no abnormal findings that could indicate accumulation of the substance in organs were made during histopathological investigation either.

Further, macroscopic investigation of rats that received a single dose of 2000 mg test substance/kg bw did not show any visible accumulation of the test substance in the body (Phycher Bio Developpement, 2008; Clouzeau, 1994; De Jouffrey, 1996a). The findings of the studies mentioned above support the assumption that no substantial distribution to and no accumulation of (zirconium, cerium and praseodymium from) the reaction mass of cerium(IV) oxide, praseodymium(III,IV) oxide and zirconium(IV) oxide in the organs will take place after oral ingestion.

Administration via inhalation

Since there are no respiratory toxicokinetics studies available informing directly on the distribution and/or accumulation of (zirconium, cerium and praseodymium from) the reaction mass of cerium(IV) oxide, praseodymium(III,IV) oxide and zirconium(IV) oxide or (zirconium from) zirconium dioxide or other zirconium compounds, the findings from the available inhalation toxicity studies with zirconium dioxide are considered more closely.

In the short-term (30-day) repeated dose inhalation study in dog, rabbit and rat applying ZrO₂ (Spiegl et al., 1956), an apparently granular material, brownish-black and doubly refracting, was found in the alveolar walls and in phagocytes during the histopathological examination. Occasionally, this dust was also seen in bronchi and lymph nodes. Similar findings were made in the sub-chronic (60-day) study in dogs, rabbits, rats, guinea pigs and cats. This finding suggests that accumulation of poorly soluble ZrO₂ in the lungs may occur under certain conditions, but also that the substance may at least partly be removed by a mechanism involving macrophages and consequent transport to/accumulation in the lymph nodes associated with the lungs. There is no evidence though of true absorption in the circulatory system and consequent distribution to and accumulation in organs.

Dermal administration

There are no dermal toxicity studies available. Based on the predicted very limited dermal absorption of (zirconium, cerium and praseodymium from) the reaction mass of cerium(IV) oxide, praseodymium(III,IV) oxide and zirconium(IV) oxide, no accumulation or distribution is expected either.

Intraperitoneal administration

Olmedo et al. (2002) studied the dissemination of zirconium dioxide after intraperitoneal administration of this substance in rats. The histological analysis revealed the presence of abundant intracellular aggregates of metallic particles of zirconium in peritoneum, liver, lung and spleen.

Other information

Additional data show distribution of several other zirconium compounds through the body with main presence in bone and liver, but also in spleen, kidney and lungs (Spiegl et al., 1956; Hamilton, 1948; Dobson et al., 1948). Data from the latter two studies should be treated with care as substances were administered via injection and thus not only the chemical but also the physical form which becomes systemically available might be different compared to administration via the oral, dermal or inhalation route. In the study from Spiegl et al. (1956) described above for zirconium dioxide, a repeated dose inhalation study was also performed with zirconium dichloride oxide (i.e. a water soluble zirconium compound). In this study, similar observations were made as in the experiments with zirconium dioxide, but very small amounts of zirconium were also found in femur, liver and kidney. These findings can most likely be explained by further distribution throughout the body of accumulated insoluble material in the lymph nodes via fagocytic cells of the reticuloendothelial system, followed by (slow) elimination.

In conclusion, under normal conditions of exposure relevant under REACH, no or only limited systemic distribution of the reaction mass of cerium(IV) oxide, praseodymium(III,IV) oxide and zirconium(IV) oxide is expected, depending on the route of exposure.

 

Metabolism

The elements zirconium, cerium and praseodymium can be neither created nor destroyed within the body. In addition, there are no indications of transformation to more hazardous forms in the liver or kidney, which is also supported by the fact that zirconium dioxide (ZrO₂) and the reaction mass of cerium dioxide (CeO₂) and zirconium dioxide (ZrO₂) were demonstrated not to be mutagenic in vitro, both in the absence and presence of metabolic activation (LAUS, 2008; NOTOX, 2010a,b; Haddouk, 2007b). This was also the case in the Ames test performed with praseodymium(III,IV) oxide (Haddouk, 2007a), which was included in the dossier of the reaction mass under consideration. Note that in an in vitro gene mutation study in mammalian cells – which was not included in the dossier of the reaction mass under consideration according to the read across strategy – performed according to OECD guideline 476 with praseodymium(III,IV) oxide, positive results were obtained with and without metabolic activation. However, the fact that no difference was observed with and without metabolic activation is not in contradiction with the assumption that no transformation to more hazardous forms occurs. Moreover, the positive results of this study were overruled by the negative results of an in vivo test (transgenic rodent assay, OECD 488), which was performed recently.

 

Excretion

Based on the substance’s insoluble nature, low absorption and distribution potential, and absence of obvious metabolism, it is probable that after oral intake, non-absorbed reaction mass will be eliminated via the faeces, either as the reaction mass of cerium(IV) oxide, praseodymium(III,IV) oxide and zirconium(IV) oxide or as other insoluble zirconium, praseodymium and cerium species. After inhalation exposure, as mentioned above, distribution of particulate material may occur to the lung-associated lymph nodes, from which further distribution may occur as well as (consequent) slow excretion/elimination.

No experimental data is available specifically investigating the excretion/elimination pathways and kinetics, apart from a study by Delongeas et al. (1983). In this study, zirconium dichloride oxide, a water soluble zirconium compound which is instantaneously converted to zirconium dioxide or other insoluble zirconium species in aqueous solutions at physiologically relevant pH levels, was administered to rats using a single oral dose of 450 mg/kg bw (i.e., 128 mg Zr/kg bw). In this study, 90-99% of the administered zirconium was eliminated via the faeces within 24 h. The limited absorbed fraction was (at least partly) excreted via the kidneys, with 0.0011 to 0.0015% of the total administered dose being excreted within 72 h.

References

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Buchholz V. Solubility in water of one batch of reaction mass of cerium dioxide, praseodymium oxide and zirconium dioxide. Anadiag, Haguenau, France, 2018.

Chemicals Inspection and Testing Institute. Skin Sensitization Test of TZ-3Y on Guinea Pigs (Maximization Test). Chemicals Inspection and Testing Institute Japan, 1999.

Clouzeau J. Acute Oral Toxicity in Rats. CIT, Evreux, France, 1994.

De Jouffrey S. Acute oral toxicity in rats. CIT, Evreux, France, 1996a.

De Jouffrey S. Acute dermal irritation in rabbits. CIT, Evreux France, 1996b.

De Jouffrey S. Skin sensitization test in guinea pigs (Modified Buehler test: 9 applications). CIT, Evreux, France, 1996d.

Delongeas JL et al. Toxicité et pharmacocinétique de l'oxychlorure de zirconium chez la souris et chez le rat. J. Pharmacol (Paris) 14(4), 437-447, 1983.

Demangel B. Relative density of solids by stereopycnometer method on reaction mass of cerium dioxide, praseodymium oxide and zirconium dioxide. Défitraces, Brindas, France, 2018.

Dobson EL et al. Studies with Colloids Containing Radioisotopes of Yttrium, Zirconium, Columbium and Lanthanum: 2. The Controlled Selective Localization of Radioisotopes of Yttrium, Zirconium, Columbium in the Bone Marrow, Liver and Spleen. University of California, Radiation Laboratory, W-7405-eng-48A, 1948.

Dvininov E. Melting point determination of reaction mass of cerium dioxide, praseodymium oxide and zirconium dioxide. MEL Chemicals, Greater Manchester, UK, 2017.

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Haddouk H. Bacterial reverse mutation test. CIT, Evreux, France, 2007b.

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Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

10

Absorption rate - dermal (%):

1

Absorption rate - inhalation (%):

10