Lanthanum trinitrate

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

10

Absorption rate - dermal (%):

1

Absorption rate - inhalation (%):

10

Additional information

Lanthanum trinitrate (also named lanthanum nitrate) is a solid inorganic salt of lanthanum, a member of the lanthanide series of metals. When present in compounds, lanthanum mainly exists in the trivalent state La+3 as it is the most stable oxidation state (the other oxidation state being La+2).

There are three main forms of lanthanides: insoluble (oxides, carbonates), soluble (chlorides, nitrates, acetates) and chelated compounds. The toxicokinetic behavior of these and other lanthanum salts is described to support this assessment.

Lanthanum trinitrate is a very soluble compound in water (> 100g/L at pH 1.79; the solubility seems to decrease with increasing pH; Demangel, 2012), with a molecular weight of 324.9 (anhydrous basis).  

Results on a skin sensitisation study in mice (Henzell 2013; LLNA test- OECD 429) with lanthanum trinitrate were equivocal and no conclusion on the skin sensitising potential of the substance could be stated on the basis of the LLNA test. Therefore, a Guinea Pig Maximisation Test (OECD 406) was performed. Based on the results of this test, it could be concluded that lanthanum trinitrate is not a skin sensitiser (Török-Bathó, 2013).

Lanthanum trinitrate is not classified as a skin irritant when tested in vitro on epidermis model (Warren, 2013b). An acute skin irritation (in vivo) study is performed in which a single 4 -hour, semi-occluded application of the test item to the intact skin of two rabbits produced well-defined erythema (grade 2) and very slight edema (grade 1) (Bradshaw J, 2013b). No corrosive effects were noted. The individual mean scores for erythema were 1.7 or 1.0 and the individual mean scores for edema were 0.3 for both animals. Slight desquamation, which is considered to be completely reversible, was noted at one treated skin site at the 7 days observation and the observations were terminated on this animal. Moderate desquamation was noted at the other treated skin site at the 7 days observation with no evidence of skin irritation at the 14 day observation. Observations were therefore terminated on this animal at the 14 days observation. Based on these results the substance did not meet the criteria for classification as a skin irritant according to Regulation (EC) No 1272/2008.

The toxicokinetic behaviour of the counter ion is not evaluated.

 

Absorption

Oral/Gastro-intestinal (GI) absorption

Lanthanum trinitrate is a very soluble compound in water (>100 g/L) with a molecular weight of 324.92 (anhydrous basis).Based on this information, it is expected that lanthanum trinitrate will readily dissolve into the gastrointestinal fluid.

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 expected to be poorly absorbed by passive diffusion (Beckett, 2007).

It has been reported that lanthanum carbonate (an insoluble lanthanum salt)dissociates in the acidic environment of the upper gastrointestinal tract to release lanthanum ions (La+3) (Curran and Robinson, 2009). Lanthanum trinitrate being more soluble than lanthanum carbonate, the same process is expected to occur. The released substance (i.e. La+3) is an ionic substance and thus it is not expected to readily diffuse across biological membranes.

Regarding the possible absorption through specialized transport systems, it has been reported that absorption mechanisms for some essential metal ions sometimes serve to transfer nonessential metals into body as well (Beckett, 2007). There is no specific information on the lanthanum ion available but it is not expected that ionized lanthanum is transported through the membrane. The results of the toxicological studies with lanthanum acetate, used as read-across substance (described here below) do not provide reasons to deviate from this assumption on lanthanum trinitrate.

Based on the high water solubility of lanthanum trinitrate, the decrease of solubility with the increase of pH and its anticipated hampered diffusion as ionized substance, low absorption of the lanthanum ion is expected.

Studies evaluating the absorption of lanthanum trinitrate following oral exposure in animals and humans are not available.

After single oral administration of lanthanum carbonate, poor absorption of lanthanum was experimentally confirmed in animals (Damment and Pennick, 2007; 99% of La carbonate excreted via faeces following ingestion in rats) and in humans (Pennick, 2006). Although lanthanum trinitrate is more soluble compared to lanthanum carbonate, similar behavior of the La+3 ion in solution is expected and therefore limited absorption anticipated.

Although absorption might occur to some extent, this absorption would not be significant. The absence of systemic toxicity after acute oral (gavage) exposure to lanthanum trinitrate when administered up to 4500 mg/kg bw (LD50) in rats is in agreement with this assumption (Cochran, 1950).

In a publication (Chen, 2003) a 6-month repeated oral toxicity study with lanthanum nitrate is reported. In this study lanthanum trinitrate was administered to rats at 20.0, 10.0, 2.0, 0.2, and 0.1 mg/kg bw/ day. The study design did not follow any guideline. The main goal was to assess potential liver effects from a pharmacological point of view only rather than to evaluate the toxicity. Other endpoints were not assessed. Authors concluded that, based on the study results, lanthanum trinitrate had different effects on rats, depending on dose and sex. Low-dose lanthanum trinitrate promoted growth of the animal, had antioxidation properties and protected hepatocytes. Higher dose of lanthanum trinitrate (20 mg/kg bw/day) damaged the liver to different degrees. No information on the levels of lanthanum trinitrate in the liver where reported.

In the absence of relevant repeated toxicity data on lanthanum trinitrate after oral exposure, the read-across to lanthanum acetate (another very soluble salt) is proposed. Details on the justification supporting this read-across can be found in the correspondent document added in Section 13 of the IUCLID file.

In a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test in Wistar rats, lanthanum acetate was tested at 110, 330 and 1000 mg/kg bw/day. The NOAEL (No Observed Effect Level) for systemic toxicity of the parent animals was considered to be 1000 mg/kg/day. There were no effects upon mortality of parent animals, no clinical findings (daily or weekly), no differences in the functional observational battery (including grip strength and locomotor activity), no differences in mean absolute or relative organ weights, and no overt macroscopical findings of toxicological relevance. Histopathological evaluation showed a treatment-related gastritis due to a repeated administration of the test material by gavage. These changes were considered to be a local effect of the test item rather than one of systemic toxicological relevance. No differences on the completeness of stages or cell populations of the testes were recorded between controls and high dose animals (Braun, 2013). The results of this study does not provide reasons to deviate from the assumption that absorption of lanthanum nitrate through the GI tract is low.

Based on the high water solubility of lanthanum trinitrate and its anticipated hampered diffusion as ionized substance, the oral absorption factor is set to 10%. The results of the toxicity studies do not provide reasons to propose a higher value.

 

Respiratory absorption

No vapour pressure value has been reported as the substance does not melt below 600°C. Therefore it is not likely that lanthanum trinitrate is available for inhalation as a vapor.

Lanthanum trinitrate is hygroscopic and forms aggregates, consisting mainly of 3 to 4 particles. The size distribution of the aggregates was found to range from approximately 325 µm to 2000 µm. Therefore, the human exposure potential by the inhalation route is not significant as the particle size is outside of the respirable/inhalable region.

Once in the respiratory tract, lanthanum trinitrate would deposit on the walls of the airways. Deposited substances may be absorbed directly from the respiratory tract or, through the action of clearance

mechanisms, may be transported out of the respiratory tract and swallowed. In that last case the substance needs to be considered as contributing to the oral/GI absorption rather than to the inhalation rate. In the case of the lanthanum trinitrate, due to its water solubility, it could be expected that mucus clearance would predominate.

For metals in general and for the direct absorption of potentially deposited material through the lung membrane, a small amount may be taken up by phagocytosis (alveolar macrophages) and transported to the blood via the lymphatic system. Recently new information has become available on other mechanisms of active transport and distribution of metals in the body. In particular, it has been shown that several metals can cross cell membranes by specific carriers and ion channels intended for endogenous substrates (Beckett, 2007). There is no specific information available on rare earth elements.

 

Direct absorption of the dissolved lanthanum trinitrate by passive diffusion through the membranes is not expected as the released substance (i.e. La+3) is an ionic substance.

No studies were located regarding absorption of lanthanum trinitrate in humans or animals following inhalation exposure.

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

 

Dermal absorption

Lanthanum trinitrate appears as granules. Therefore, the human exposure potential by the dermal route is expected not be significant.

Lanthanum ion is not expected to cross the intact skin because of the high polarity of the forms in which it is most commonly encountered. This conclusion is also supported when toxicokinetic behavior based on physico-chemical properties is assessed. Lanthanum trinitrate is a solid substance and dry particulates will have to dissolve into the surface moisture of the skin before uptake can begin. Furthermore, as lanthanum trinitrate is a well water soluble compound, it is expected that it will not be able to cross the stratum corneum. Partition from the stratum corneum into deeper strata of the epidermis after penetration would be enhanced due to high water solubility of the substance.

Studies evaluating absorption following dermal exposure in humans or animals are not available.

Limited toxicological information is available from animals after acute exposure via dermal route to lanthanum trinitrate. Results on a skin sensitisation study in mice (Henzell 2013; LLNA test- OECD 429) with lanthanum trinitrate were equivocal and no conclusion on the skin sensitising potential of the substance could be stated on the basis of the LLNA test. Therefore, a Guinea Pig Maximisation Test (OECD 406) was performed. Based on the results of this test, it could be concluded that lanthanum trinitrate is not a skin sensitiser (Török-Bathó, 2013).

Lanthanum trinitrate is not a skin irritant and was not corrosive when tested in vitro on epidermis model (Warren, 2013a and b).

An acute skin irritation (in vivo) study is performed in which a single 4 -hour, semi-occluded application of the test item to the intact skin of two rabbits produced well-defined erythema (grade 2) and very slight edema (grade 1) (Bradshaw J, 2013b). No corrosive effects were noted. The individual mean scores for erythema were 1.7 or 1.0 and the individual mean scores for edema were 0.3 for both animals. Slight desquamation, which is considered to be completely reversible, was noted at one treated skin site at the 7 days observation and the observations were terminated on this animal. Moderate desquamation was noted at the other treated skin site at the 7 days observation with no evidence of skin irritation at the 14 day observation. Observations were therefore terminated on this animal at the 14 days observation. Based on these results the substance did not meet the criteria for classification as a skin irritant according to Regulation (EC) No 1272/2008.

In the absence of acute toxicity data on lanthanum trinitrate after dermal exposure, the read-across to lanthanum acetate (another very soluble salt) is proposed. Details on the justification supporting this read-across can be found in the correspondent document, added in Section 13 of the IUCLID file.

 

In an acute dermal toxicity study (Bradshaw, 2013a), rats were exposed for 24 hours to 2000 mg/kg (limit concentration) of lanthanum acetate, using a semi-occluded system on intact skin. There were no death, no sign of toxicity (clinical observations) nor abnormality at necropsy. The absence of systemic signs of toxicity after acute dermal exposure to lanthanum acetate suggests that the substance is poorly absorbed and / or essentially non-toxic. This is supported by the results from a LLNA test (OECD 429)(Henzell 2013) and an in vitro skin irritation/corrosion test (Warren 2013a,b), where lanthanum acetate was evaluated as non-sensitising and non-irritating. Similar behaviour is expected for lanthanum nitrate.

 

In the absence of measured data on dermal absorption, current guidance suggests the assignment of either 10% or 100% default dermal absorption rates. Furthermore, the currently available scientific evidence on dermal absorption of metals (predominantly based on the experience from previous EU risk assessments) yields substantially lower figures than the lowest proposed default value of 10% (HERAG, 2007).

Based on the above considerations, no significant dermal absorption is expected. A dermal absorption factor of 1% is suggested for risk assessment purposes as worst-case scenario.

 

Distribution and accumulation

There is no specific data on lanthanum trinitrate. Data on other lanthanum salts (as lanthanum chloride which is also a soluble lanthanum salt and therefore comparable to lanthanum trinitrate) or data on the systemic free lanthanum ion after repeated oral administration of lanthanum carbonate are available.

 

After oral administration of lanthanum carbonate, intestinal epithelial cells appear to concentrate lanthanum and through normal exfoliation eject it back into the intestinal lumen for excretion (Floren et al., 2001; Fehri et al., 2005).

The small fraction of absorbed lanthanum after oral administration of lanthanum carbonate is extensively bound to plasma proteins (> 99.7%; Damment and Pennick, 2007).

Irrespective of the duration of treatment, no animal experiments have shown liver concentrations exceeding 3 µg/g wet weight after oral administration of lanthanum carbonate (Bervoets et al., 2007). Bone is the only other tissue that consistently shows concentrations of lanthanum above 1 µg/g in animal distribution studies (Slatopolsky et al., 2005; Behets et al., 2004; Damment and Shen, 2005).

After a single intravenous 0.3mg/kg dose of lanthanum chloride in rats, the systemic clearance of lanthanum was relatively low (0.66 mL/min*kg). It can be suggested that lanthanum was distributed into tissues, from where it was eliminated at a slower rate (Damment and Pennick, 2007).

Following intravenous infusion of lanthanum trichloride in humans (Pennick et al. 2006), the total clearance of lanthanum (55± 15 mL/min) was low relative to average hepatic blood flow (1470 L/min). Lanthanum was widely distributed with an apparent volume of distribution of 164±84 L.

In clinical studies, lanthanum has been shown to accumulate in bone in patients. Tissue accumulation and the possible toxicity that was considered to be associated with this phenomenon were the critical issue in determining the clinical safety of lanthanum carbonate as Medicinal Product. It was concluded that, at the tissue levels seen in non-clinical studies, oral lanthanum carbonate does not cause any unacceptable toxicity (Swedish Medical Products Agency, 2006).

 

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, 2003).

 

Excretion

Several studies are available evaluating the excretion of bioavailable lanthanum in living organisms. Floren et al. (2001) and Fehri et al. (2005) reported that intestinal epithelial cells concentrate lanthanum after oral exposure of rats to lanthanum carbonate and then, through normal exfoliation, eject it back into the intestinal lumen for elimination. Damment and Pennick (2007) observed that after oral exposure of rats to lanthanum carbonate, the majority of the dose was excreted via the faeces (99%). The small absorbed fraction is excreted predominantly via the liver into the bile (Pennick et al., 2006; Damment and Pennick, 2007). Biliary elimination (80%) and direct transport across the gut wall into the lumen (13%) represent the main routes of elimination. The study of Pennick et al. (2006) administering lanthanum trichloride intravenously to humans, showed that kidneys are not significantly involved in the clearance of absorbed lanthanum. Indeed, Damment and Pennick (2008) demonstrated that only 2% of the bioavailable free lanthanum was eliminated by the kidney after intravenous administration of lanthanum trichloride in humans.