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Description of key information

No toxicokinetic experimental data (animal or human studies/information) are currently available on this water-soluble lanthanum salt. Therefore a toxicokinetic assessment is done based on the physicochemical characteristics of lanthanum acetate, on toxicological information available on this compound but also on information available on other lanthanum compounds.
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 lanthanum salt. Therefore a toxicokinetic assessment is done based on the physicochemical characteristics of lanthanum acetate, on toxicological information available on this compound but also on information available on other lanthanum compounds. 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 lanthanum 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 lanthanum 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 lanthanum acetate (a water-soluble lanthanum salt) are not available, information on other water soluble lanthanum salts as lanthanum trichloride can be used to estimate the absorption and bioavailability of a common metal ion (La+3).

 

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

Absorption

Oral/Gastro-intestinal (GI) absorption

Lanthanum acetate is a very soluble compound in pure water (> 100g/L; Fox 2012) with a molecular weight of 316.04 (anhydrous basis). Based on this information, it is expected that lanthanum acetate will readily dissolve into the gastrointestinal fluid.

In general, absorption from the gastro-intestinal lumen can occur by passive diffusion but also by specialized transport system. Regarding absorption by passive diffusion, the lipid solubility and the ionization are important. However, inorganic salts of metals are usually not lipid soluble and are thus poorly absorbed by passive diffusion (Beckett, 2007). Regarding the possible absorption through specialized transport systems, it has been shown that several metals can cross cell membranes by specific carriers and ion channels intended for endogenous substrates (Beckett, 2007). 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 (La+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 lanthanum acetate (i.e. decreased solubility at the intestinal tract and the anticipated hampered diffusion as ionized substance), low absorption is expected.

This assumption is also supported by the low toxicity of lanthanum acetate and lanthanum trichloride (another 'water-soluble' lanthanum compound) in animals after both single and repeated oral exposure. Indeed, 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, where water-soluble compounds of the same metal give rise to similar bioavailable/bioaccessible metal at the target site(s). Therefore information on other water-soluble lanthanum salts, as lanthanum trichloride, can be used to estimate the absorption and bioavailability of the common metal ion La+3.

At the beginning of this section it was discussed that, once in the intestines, the solubility of the lanthanum acetate rapidly and significantly decreased due to the pH increase of the intestinal fluid and thus the potential absorption would be significantly hampered as lanthanum acetate would be transformed into insoluble forms of lanthanum. Therefore a ‘higher-than-expected’ similarity can be expected, at this level of the GI tract, between the bioavailability/bioaccessibility of lanthanum acetate and the insoluble lanthanum compounds as lanthanum carbonate. As a consequence, experimental data on lanthanum carbonate can be also used to supplement the assessment of the absorption of lanthanum after oral exposure to lanthanum acetate

Based on the anticipated low absorption due to the physicochemical properties of lanthanum acetate (ie. decrease in solubility with the increase of pH and the hampered diffusion when the substance is ionized), the low toxicity observed on the available toxicological tests with lanthanum acetate despite the local effects in the forestomach, the animal data on lanthanum trichloride (a ‘water-soluble’ lanthanum compound as lanthanum acetate) and the animal and human data on lanthanum carbonate, the oral absorption factor for lanthanum acetate is estimated to be 10% for risk assessment purposes.

Respiratory absorption

Low inhalation exposure to lanthanum acetate is expected based on the inherent properties. So, as lanthanum acetate decomposed starting from approximately 300°C (Fox, 2012), the vapour pressure of the lanthanum acetate is estimated too low to enable reliable measurements below its decomposition temperature. Therefore, it is not likely that lanthanum acetate is available for inhalation as a vapour. Moreover, no particle size distribution test has been performed with lanthanum acetate as the test item forms one clump and can therefore not be characterised with respect to particle size distribution. Thus, the formation of respirable suspended particulate matter is unlikely and, consequently, 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 lanthanum acetate is assessed here below.

Lanthanum acetate 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 lanthanum acetate 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 (Beckett, 2007). 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 (La+3) will not exist at a significant concentration in solutiondue to the decreased solubility under the pH conditions in the pulmonary mucosae.

No studies were identified regarding absorption of lanthanum acetate in humans or animals following inhalation exposure.

Based on the low solubility of lanthanum acetate at physiological pHs and its anticipated hampered diffusion as ionized substance, the respiratory absorption factor is set at 10%, in the absence of specific data.

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 lanthanum acetate physicochemical properties is performed, taking other toxicological data on this substance (obtained after dermal exposure) into consideration. As lanthanum acetate is a solid that appears as a clump, the potential human exposure by the dermal route is expected to be low.

Lanthanum is not expected to cross the intact skin after exposure to water-soluble lanthanum acetate. This assumption is based on the qualitative assessment of the physicochemical properties of the substance: lanthanum acetate would have to dissolve in the moisture on the skin, however, as the solubility of the substance rapidly decrease at physiologically relevant pH, no significant uptake by the skin is expected. 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 lanthanum acetate cross the stratum corneum.

Lanthanum acetate is neither a skin irritant (in vitro skin corrosion and irritation tests; Warren 2013) nor a skin sensitizer (LLNA test according to OECD 429; Henzell 2013) 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 lanthanum acetate after single dermal exposure showed in an acute dermal toxicity study.

No toxicological information is available for animals after repeated exposure via dermal route. Studies evaluating absorption following dermal exposure in humans are not available either.

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 (between 0.1% to 2%) than the lowest proposed default value of 10 % could be expected (HERAG, 2007).

Based on the inherent properties of lanthanum acetate, 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 and accumulation

There is no data specific on how bioavailable lanthanum after exposure to lanthanum acetate is distributed, however there are data available on lanthanum chloride (a ‘water-soluble’ lanthanum compound), including human data. As stated previously, a ‘higher-than-expected’ similarity can be expected between the bioavailability/bioaccessibility of lanthanum acetate and lanthanum carbonate. As a consequence, experimental data on lanthanum carbonate are also used to supplement this assessment.

Summarising, bioavailable lanthanum distributes through the body to lung, kidney, heart, muscle, brain and teeth but there is no evidence of adverse effects in these organs. Regarding the potential accumulation of bioavailable lanthanum after exposure to lanthanum acetate, 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 lanthanum after exposure to lanthanum acetate cannot be totally excluded. However, the assessment of bioaccumulation potential in aquatic organisms of lanthanum acetate included in this dossier indicates that the substance has a low potential for bioaccumulation in aquatic organisms and that the bioaccumulation decreases when ascending the food chain. Thus, for risk assessment purposes it is proposed to consider that lanthanum acetate shows low accumulation potential in humans.

Metabolism

Lanthanum, as an element or ion, is neither created nor destroyed within the human body and is neither a substrate nor an inhibitor of CYP450 (Pennick et al., 2003a).

Furthermore, lanthanum acetate was demonstrated neither mutagenic nor clastogenic in a battery of in vitro genotoxic test, in the presence and in the absence of metabolic activation.

Excretion

Because of the hampered absorption in the GI tract of lanthanum ions when administered as lanthanum acetate, it is expected that a majority of the orally administered compound is eliminated via the faeces without being absorbed. Clinical studies with lanthanum carbonate showed that the bioavailable fraction of lanthanum (around 1%) is excreted predominantly via the liver into bile and directly transported across the gut wall into the lumen (Damment and Pennick, 2007) through the faeces. Only 2% of the bioavailable free lanthanum is eliminated by the kidney when administered intravenous as lanthanum trichloride (Damment and Pennick, 2008).