2-ethylhexanoic acid, cerium salt

Endpoint summary

Description of key information

Some experimental data (open public data and grey literature) are available on the toxicokinetic behavior of a ‘water-soluble’ cerium salt. These data together with information on the physicochemical characteristics of cerium trichloride as well as the toxicological information available on this compound are used to perform a qualitative assessment of the absorption, distribution/accumulation, metabolism and elimination of this substance.

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

Some experimental data (open public data and grey literature) are available on the toxicokinetic behavior of a ‘water-soluble’ cerium salt. These data together with information on the physicochemical characteristics of cerium trichloride as well as the toxicological information available on this compound are used to perform a qualitative assessment of the absorption, distribution/accumulation, metabolism and elimination of this substance. A summary of the assessment is included here below. The full assessment (including the references) is attached to this section.

The toxicokinetic behaviour of the counter ion is not evaluated.

Absorption

Oral/Gastro-intestinal (GI) absorption

Some experimental data are available on cerium trichloride behaviour after oral exposure. In adult animals, observed absorption of radioactive cerium trichloride from the GI tract ranged from 0.05% to less than 0.1% of the administered dose (Kostial, 1989b; Shiraishi and Ichikawa, 1972). Gut retention was also reported byStineman (1978).

Cerium trichloride was orally administered to adult male and female mice (Kawagoe, 2005) at two dose levels (20 ppm and 200 ppm) for 6 and 12 weeks to investigate the possible association between cerium exposure and oxidative stress. Although cerium was detected in some organs, giving some indication on the absorption and distribution of cerium trichloride after oral exposure, the study design of this mechanistic study was considered not suitable to evaluate the total amount of cerium absorbed.

Summarising, it can be concluded that cerium trichloride is poorly absorbed after oral exposure based on the abovementioned experimental data. This is also confirmed by the low toxicity of cerium trichloride after acute exposure (LD50 = 2800 mg/kg bw) and the physicochemical properties of the substance.

From a physicochemical point of view, cerium trichloride is a very soluble compound in ‘pure’ water (miscible up to a 1:1 ratio at 20°C and pH 1.3-1.4) and its solubility is anticipated to decrease significantly with increasing pH, as it occurs with other ‘water-soluble’ cerium salts as cerium trinitrate. Thus, it could be expected that cerium trichloride will readily dissolve into the gastric fluid. However as its high water solubility is influenced by the pH, once in the intestines, it is expected that the solubility of the cerium trichloride rapidly and significantly decreases due to the pH increase of the intestinal fluid and thus the potential absorption will be significantly hampered.

Often, the more toxic metal cation is released in the medium under consideration (e.g., bodily fluids or environmental media), the more bioavailable/bioaccessible the metal will be. Therefore, similar behaviour is expected between cerium trichloride and cerium trinitrate. Thus, experimental data on cerium trinitrate (a 'water-soluble' cerium salt) can be used to substantiate the assessment of the absorption after oral exposure to cerium trichloride (another 'water-soluble' cerium salt): the absence of systemic adverse effects in a repeated oral toxicity study with cerium trinitrate (performed according to OECD 422 guideline) supports the assumption of the 'low absorption' after oral exposure.

Based on all the above mentioned information (the experimental data on the adsorption after oral exposure to cerium trichloride, its physicochemical characteristics, and the toxicological data available after oral exposure to cerium trichloride and cerium trinitrate), the oral absorption factor for cerium trichloride is estimated to be 10% for risk assessment purposes.

Respiratory absorption

Low exposure to cerium trichloride is expected based on the inherent properties of the substance. So, as the vapour pressure of the cerium trichloride is too low to enable reliable measurements below its decomposition temperature, it is not likely that cerium trichloride is available for inhalation as a vapour. Moreover, no particle size distribution test has been performed with cerium trichloride due to the special properties of the substance (i.e. the test item forms one clump and can therefore not be characterised with respect to particle size distribution). 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 trichloride is assessed.

Cerium trichloride 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 trichloride 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.

Summarising, it can be assumed that cerium trichloride is poorly absorbed following inhalation exposure. This assumption is also supported by the relevant but limited experimental data available in animals.

Based on the available animal data on cerium trichloride and its low solubility at physiological pHs, 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 trichloride physicochemical properties is performed, taking other toxicological data on this substance (obtained after dermal exposure) into consideration.

As cerium trichloride 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 trichloride. This assumption is based mainly on the qualitative assessment of the physicochemical properties of the substance: cerium would have to dissolve in the moisture on the skin prior to penetrating skin by diffusive mechanisms. However, as the solubility of cerium trichloride rapidly decrease at physiologically relevant pH, no significant uptake by the skin is expected.

No dermal toxicity studies, neither after acute nor repeated exposure to cerium trichloride have been identified to support this assessment. However, cerium trichloride was not considered as skin sensitiser in an in vivo GMPT study, showing that the penetration of at least a part of the sample is unlikely.

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 trichloride, the toxicological data available and the experience from HERAG, very low dermal absorption is expected. However, due to the corrosivity properties 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

Some experimental data are available to assess the distribution of cerium trichloride. Summarising, and considering the irritant potential 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 as confirmed by the abovementioned studies, however the amount distributed in each organ compared to the administered dose is unknown.

Other few studies also 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 trichloride, the available animal information is insufficient to provide adequate data. Therefore, and based on all the mentioned data, accumulation of the very small bioavailable fraction of cerium after exposure to cerium trichloride cannot be totally excluded. However, the assessment of bioaccumulation potential in aquatic and terrestrial organisms of cerium trichloride 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 trichloride shows low accumulation potential in humans.

Metabolism

As an element, cerium is neither created nor destroyed within the body. Cerium trichloride was demonstrated not to be mutagenic in an in vitro Ames test, in the absence and presence of metabolic activation. In conclusion it is not expected that cerium, as element or ion, is metabolized. However some data available indicate that it can have an effect in the activity of cytochrome isoenzymes.

Excretion

Studies evaluating the excretion of bioavailable cerium trichloride 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 fecal 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.