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Description of key information

No experimental data are available on toxicokinetics for this substance. Therefore, a qualitative assessment of the absorption, distribution/accumulation, metabolism and elimination is performed on the basis of the physicochemical properties of the substance, toxicological data and available information from public literature on the substance and relevant information on other 'water-soluble' cerium salts (e.g. cerium trichloride).
A summary of the qualitative assessment is included in the discussion. The full assessment is attached to this section.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - oral (%):
10
Absorption rate - dermal (%):
1
Absorption rate - inhalation (%):
10

Additional information

No toxicokinetic experimental data (animal or human studies/information) are currently available on this water-soluble cerium salt.Therefore, a toxicokinetic assessment is done based on the physicochemical characteristics of cerium trinitrate, on toxicological information available on this compound but also on information available on other water-soluble cerium compounds. A summary of the qualitative assessment is included in this section. The full assessment (including the references) is attached to this section.

 

Indeed, it is generally assumed that for metals and metal compounds, the metal ion (regardless of the counterparts of the metal in the respective metal compounds), is responsible for the observed systemic toxicity. Information on other cerium compounds can thus be used as long as their inherent properties are taken into account. In addition, as indicated in ECHA’s guidance on QSAR and grouping of chemicals (ECHA, 2008), comparison of the water solubility can be used as surrogate to assess the bioavailability of metals, metal compounds and other inorganic compounds. In the case of cerium salts, this simplistic approach assumes that a specific very water-soluble metal-containing compound (target chemical) will show the same hazards as other very water-soluble metal-containing compounds with the same specific metal ion (HERAG, 2007). Therefore, although studies evaluating the toxicokinetic behavior following exposure to cerium trinitrate (a water-soluble cerium salt) are not available, information on other water-soluble cerium salts as cerium chloride can be used to estimate the absorption and bioavailability of a common metal ion (Ce+3).

 

The toxicokinetic behaviour of the counter ion is thus not evaluated.

 

This assessment is therefore mainly based on information from the toxicological review of cerium compounds done by U.S. EPA (2009) and includes the references used in the original document.

 

Absorption

Oral/Gastro-intestinal (GI) absorption

Cerium trinitrate is a solid inorganic salt of cerium, a member of the lanthanide series of metals. When present in compounds, cerium exists in both the trivalent Ce+3 and the tetravalent Ce+4 state. Cerium in cerium trinitrate is in Ce+3 oxidation state. The molecular weight of Cerium trinitrate is 326.13 g/mol (anhydrous form).

Cerium trinitrate is a very soluble compound in pure water (> 600 g/L, pH not reported). Based on this information, it could be expected that cerium trinitrate will readily dissolve into the gastric fluid. However, its high water solubility is influenced by the pH. It is also anticipated that the differences of solubility were (or at least partly) explained by the formation of low soluble forms of cerium (e.g. cerium hydroxides) at high pH. This decrease in solubility is also observed in other water-soluble cerium salts. In physiologically relevant aqueous media moreover precipitation of other insoluble complexes may be expected, such as rare earth phosphates, with formation of the latter also increasing with increasing pH. Therefore, once in the intestines, it is expected that the solubility of the cerium trinitrate rapidly and significantly decreases due to the pH increase of the intestinal fluid and thus the potential absorption will be significantly hampered.

In general, absorption from the gastro-intestinal lumen can occur by two mechanisms: by passive diffusion and/or by specialized transport system. For cerium trinitrate and its metal ion Ce+3, it would not be expected to readily diffuse across biological membranes. For rare earth elements, there is no information available on specialized mechanism of transport. In addition it is believed that the free metal cation (Ce+3) will not exist at a significant concentration in solution due to the decreased solubility under the pH conditions in the gastrointestinal lumen.

Based on the physicochemical properties of the cerium trinitrate (i.e. decreased solubility at the intestinal tract and the anticipated hampered diffusion as ionized substance), low absorption is expected.

As indicated previously, comparison of the water solubility can be used as surrogate to assess the bioavailability of metals, metal compounds and other inorganics compounds. Therefore information on other water-soluble cerium salts as cerium chloride, is used to estimate the absorption and bioavailability of the common metal ion Ce+3. Based on the information available on the absorption after oral exposure to the water-soluble cerium trichloride, similar very low absorption is expected after oral exposure to cerium trinitrate.

This assumption is also supported by the low toxicity of cerium trinitrate after both single and repeated exposure.

Based on the anticipated low absorption due to the physicochemical properties of cerium trinitrate (ie. decrease in solubility with the pH and the hampered diffusion when the substance is ionized), on the animal data with cerium trichloride and the low toxicity observed on the available toxicological tests with cerium trinitrate, the oral absorption factor for cerium trinitrate is estimated to be 10% for risk assessment purposes.

 

Respiratory absorption 

Low exposure to cerium trinitrate is expected based on the inherent properties of the substance. So, as the vapour pressure of the cerium trinitrate is too low to enable reliable measurements below its decomposition temperature, it is not likely that cerium trinitrate is available for inhalation as a vapour. Moreover, no particle size distribution test has been performed with cerium trinitrate due to the special properties of the substance. Thus, as the formation of respirable suspended particulate matter is unlikely, human exposure by inhalation is considered not significant. Despite the fact that the exposure is considered not significant, the absorption of the potentially inhaled particles of cerium trinitrate is assessed here below.

Cerium trinitrate is a very soluble compound in pure water. However its high water solubility is influenced by the pH as discussed previously. Therefore, once deposited on the walls of the airways, it is expected that the solubility of the cerium trinitrate significantly decreases due to the pH of the lung mucosae (the composition of the lung mucosae is mainly water with a pH about 6.6 in healthy individuals) and absorption or translocation from the lung to the circulation is expected to be minimal.

Deposited material in the alveolar region may be engulfed by alveolar macrophages as the substance will not be able to dissolve. The macrophages will then either translocate particles to the ciliated airways or carry particles into the pulmonary interstitium and lymphoid tissues. Deposited substances may be also transported out of the respiratory tract and swallowed through the action of clearance mechanisms, especially those which settle in the tracheo-bronchial region. In that last case the substance needs to be considered as contributing to the oral/GI absorption rather than to the inhalation rate.

As stated before, it has been shown that several metals can cross cell membranes by specific carriers and ion channels intended for endogenous substrates. But, for rare earth elements, there is no information available on such mechanism of transport. In addition, it is believed that the free metal cation (Ce+3) will not exist at a significant concentration in solution due to the decreased solubility under the pH conditions in the pulmonary mucosae.

Although toxicokinetic studies evaluating the absorption of cerium trinitrate following inhalation are not available, information on other water-soluble cerium salts can be used to support the evaluation of the absorption of this substance. Therefore the limited animal data available regarding total deposition and absorption of cerium trichloride within the respiratory tract is used to estimate the absorption following inhalation exposure to cerium trinitrate (See attached document).

Based on the anticipated low solubility of cerium trinitrate at physiological pHs and the available animal data on cerium trichloride, the respiratory absorption factor for cerium trinitrate is set at 10% for risk assessment purposes.

Dermal absorption

Studies evaluating absorption following dermal exposure in humans or animals are not available. Therefore a qualitative assessment of the toxicokinetic behavior based on cerium trinitrate physicochemical properties is performed, taking other toxicological data on this substance (obtained after dermal exposure) into consideration.

As cerium trinitrate is a solid that appears as a clump, the potential human exposure by the dermal route is expected to be low.

Cerium is not expected to cross the intact skin after exposure to water-soluble cerium trinitrate. This assumption is based on the qualitative assessment of the physicochemical properties of the substance: cerium would have to dissolve in the moisture on the skin, however, as the solubility of cerium trinitrate rapidly decrease at physiologically relevant pH, no significant uptake by the skin is expected. Although a part of the substance was dissolved, the amount would significantly decrease with time due to the epidermis buffer potential and the formation of unsoluble forms of cerium (e.g. cerium hydroxides) at high pH. Moreover, and prior diffusion through the skin, dissociation to the metal cation is required but for metals and their inorganic compounds partition coefficients are irrelevant. Therefore it is unlikely that cerium trinitrate crosses the stratum corneum.

Cerium trinitrate is not a skin irritant nor a skin sensitizer and thus it is not expected that low dermal absorption is enhanced by the irritant/sensitizer effect on the skin. This assumption is also supported by the low toxicity of cerium trinitrate after single dermal exposure showed in an acute dermal toxicity study.

No toxicological information is available for animals after repeated exposure via dermal route.

In the absence of measured data on dermal absorption, current ECHA guidance (2012) 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 cerium trinitrate, the toxicological data available and the experience from HERAG, very low dermal absorption is expected. Therefore, a dermal absorption factor of 1% is suggested for risk assessment purposes.

Distribution/accumulation

 

Studies evaluating the distribution of cerium trinitrate in humans or animals are not available, but there is information on other very soluble cerium salts as cerium trichloride. Summarizing, and considering that the irritant potential of the cerium trinitrate to the mucosae after oral or inhalation exposure is estimated less important that the cerium trichloride, the penetration of a small amount of the substance can be facilitated. This phenomenon is covered by the proposed absorption factors. Once cerium is bioavailable, the substance will tend to distribute to the bone, kidney, liver, spleen and lung as confirmed by the abovementioned studies, however the amount distributed in each organ compared to the administer dose is unknown.

Studies with cerium trichloride seem to indicate that the distributed cerium would be localized in the cell, particularly in the lysosomes, where it is concentrated and precipitated in an insoluble form in association with phosphorus.

Regarding the potential accumulation of bioavailable cerium after exposure to cerium trinitrate, the available animal information is insufficient to provide adequate data. Therefore, and based on all the above mentioned data, accumulation of the very small bioavailable fraction of cerium after exposure to cerium trinitrate cannot be totally excluded. However, the assessment of bioaccumulation potential in aquatic and terrestrial organisms of cerium trinitrate included in this dossier indicates that the substance has a low potential for bioaccumulation and that the bioaccumulation decreases when ascending the food chain. Thus, for risk assessment purposes it is proposed to consider that cerium trinitrate shows low accumulation potential in humans.

Metabolism

As an element, cerium is neither created nor destroyed within the body. Experimental data have not demonstrated a change in the oxidation state of the cerium molecule in the body.

Cerium trinitrate was demonstrated not to be mutagenic in vitro, in the absence and presence of metabolic activation.

Studies evaluating the potential impact on general metabolism after exposure to cerium trichloride are available. These data indicate that it can have an effect in the activity of cytochrome isoenzymes .

Excretion

Studies evaluating the excretion of bioavailable cerium trinitrate in humans or animals are not available. Although quantitative estimates of cerium elimination are rare, it appears that the primary route of elimination for cerium, whether inhaled, ingested, or injected, is through the feces, with small (generally < 10%) amounts eliminated in the urine (Lustgarten et al., 1976; Durbin et al., 1956). It has been suggested that the fecel excretion of systematically absorbed cerium is due to elimination in the bile (Lustgarten et al., 1976), since hepatic clearance was due primarily to biliary function.

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