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Description of key information

No experimental data is 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 susbtance and relevant information on another 'water-soluble' cerium salts (e.g. cerium trichloride, cerium trinitrate).
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 (%):
10
Absorption rate - inhalation (%):
10

Additional information

No toxicokinetic experimental data (animal or huan studies/information) are available on this 'water-soluble' cerium compound. Therefore, a qualitative assessment of the absorption, distribution/accumulation, metabolism and elimination is performed on the basis of the physicochemical properties of cerium ammonium nitrate, toxicological data and available information from public literature on the substance, and relevant information on another 'water-soluble' cerium salts (e.g. cerium trichloride, cerium trinitrate). A summary of the qualitative assessment is included in the discussion. The full assessment (including 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 ammonium nitrate (a water-soluble cerium salt) are not available, information on other water-soluble cerium salts as cerium trinitrate can be used to estimate the absorption and bioavailability of a common metal.

 

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 ammonium nitrate 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 ammonium nitrate is in Ce+4 oxidation state. The molecular weight of Cerium ammonium nitrate is 548.22 g/mol (anhydrous form).

Cerium ammonium nitrate is a very soluble compound in pure water (Walker, 2012). Based on this information, it could be expected that cerium ammonium nitrate will readily dissolve into the gastric fluid. However its high water solubility is influenced by the pH as confirmed by Cornelis et al. (2011) who reported the low water solubility of cerium ammonium nitrate in a more physiologically relevant test medium (presence of NaCl) as well as the pH dependency of the substance’s water solubility (water solubility ~ 150 μg/L at pH 4, not detectable at pH 7-9). This decrease in solubility is also observed in other water-soluble cerium salts as cerium trinitrate and cerium trichloride: when dissolving these rare earth (RE) substances in pure water, the pH of the solution drops due to formation of RE(OH)2+ (limited hydrolysis, stable equilibrium). When neutralizing the solution however, the equilibrium is disrupted and therefore the rare earth content of the solution is reduced through precipitation of RE(OH)3. Therefore, once in the intestines, it is expected that the solubility of the cerium ammonium nitrate 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 ammonium nitrate and its metal ion Ce+4, 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+4) 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 ammonium nitrate (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 trichloride and cerium trinitrate, is used to estimate the absorption and bioavailability of the common metal cerium. 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 ammonium nitrate. This assumption is also supported by the low toxicity of cerium ammonium nitrate after single exposure and toxicological data with cerium trinitrate.

Based on the anticipated low absorption due to the physicochemical properties of cerium ammonium nitrate (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 ammonium nitrate and cerium trinitrate, the oral absorption factor for cerium ammonium nitrate is estimated to be 10% for risk assessment purposes.

Respiratory absorption

Low exposure to cerium ammonium nitrate is expected based on the inherent properties of the substance. So, as the vapour pressure of the cerium ammonium nitrate is too low to enable reliable measurements below its decomposition temperature (214 °C; Walker 2012), it is not likely that cerium ammonium nitrate is available for inhalation as a vapour. Moreover, no particle size distribution test has been performed with cerium ammonium nitrate 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 ammonium nitrate is assessed here below.

Cerium ammonium nitrate 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 ammonium nitrate 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+4) will not exist at a significant concentration in solutiondue to the decreased solubility under the pH conditions in the pulmonary mucosae.

Although toxicokinetic studies evaluating the absorption of cerium ammonium nitrate 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 ammonium nitrate (see attached document).

Based on the anticipated low solubility of cerium ammonium nitrate at physiological pHs and the available animal data on cerium trichloride,the respiratory absorption factor for cerium ammonium nitrate 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 ammonium nitrate physicochemical properties is performed, taking other toxicological data on this substance (obtained after dermal exposure) into consideration.

As cerium ammonium nitrate 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 ammonium nitrate. 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 ammonium nitrate 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 ammonium nitrate crosses the stratum corneum.

No dermal toxicity studies, neither after acute nor repeated exposure to cerium ammonium nitrate, have been performed for this dossier, as this route of exposure is not suitable, for animal welfare reasons, due to the corrosive properties of the substance. Indeed, cerium ammonium nitrate is considered corrosive to skin based on in vivo and in vitro experimental data (‘weight-of-evidence’ approach). Due to this local effects, the very low penetration expected for cerium ammonium nitrate after dermal exposure could be enhanced. Another study is available where animals were dermally exposed to cerium ammonium nitrate: the substance was tested in an in vivo Guinea Pig Maximisation Test (Török-Bathó, 2013). This study showed that cerium ammonium nitrate is sensitizing to the skin, and therefore it is likely that penetration of at least part of the sample applied has occurred. 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 ammonium nitrate, the toxicological data available and the experience from HERAG, very low dermal absorption is expected. However, due to the corrosivity of the substance, dermal penetration can be enhanced if no appropriated protection is used (e.g. gloves). Therefore, a dermal absorption factor of 10% is suggested for risk assessment purposes

Distribution/Accumulation

Studies evaluating the distribution of cerium ammonium nitrate in humans or animals are not available, but there is information on another very soluble cerium salt as cerium trichloride.Summarising, and considering the potential corrosivity of the substance to the mucosae after oral or inhalation exposure, 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, however the amount distributed in each organ compared to the administered 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 ammonium nitrate, 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 ammonium nitrate cannot be totally excluded. However, the assessment of bioaccumulation potential in aquatic and terrestrial organisms included in this dossier indicates that it is expected 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 ammonium nitrate 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 ammonium nitrate 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 ammonium nitrate in humans or animals are not available, but there is some limited information on the water-soluble cerium trichloride. Based on the limited data available on cerium trichloride, it can be concluded that bioavailable cerium after exposure to cerium ammonium nitrate will be first excreted via urine in small portions and later it will be gradually excreted via the bile into the feces.