Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

Key value for chemical safety assessment

Additional information

Summary toxicokinetics

Toxicokinetic data via the intravenous route are available for the water-soluble compound lanthanum trichloride. Additionally, there are oral pharmacokinetic studies published for lanthanum carbonate and for the drug Fosrenol®(Shire Pharmaceuticals), which contains lanthanum carbonate hydrate. Like lanthanum oxide, lanthanum carbonate is practically insoluble in water. It was however reported to dissociate in the acid environment of the upper gastrointestinal tract and liberate free lanthanum ions (Curran and Robinson, 2009) which may not be readily the case with lanthanum oxide. Thus, read across was conducted based on the structurally related compound lanthanum carbonate that has very similar water solubility and it can reasonably be assumed that the bioavailability of lanthanum ions from both substances is comparable. For dermal absorption data from Cerium chloride will be used as a surrogate. Cerium3+ can in this case be used as a surrogate for lanthanum oxide as well, because the atomic radius is very of the two metals is very similar (0.1879 for La and 0.1824 for Ce (Leveque et al. 2001) and the oxidation state is the same (3+). Due to the higher solubility of the chlorides compared to the oxides the dermal absorption of the chloride is likely higher than that of the oxide.

 

Absorption

Oral

Soluble lanthanum ions bind dietary phosphate in the lumen of the gut and form highly insoluble lanthanum phosphate complexes. These complexes can not easily pass through the wall of the gastrointestinal tract and are excreted in the faeces. Therefore, the absorption of lanthanum from the gastrointestinal tract is expected to be very low (< 0.002%). After oral administration of lanthanum carbonate, poor absorption of lanthanum was experimentally confirmed in animals (rats and dogs) (Damment and Pennick, 2007, FDA (2002, 2004)) and in humans (Pennick et al., 2006).

In healthy humans intravenously administered lanthanum trichloride (120 µg elemental lanthanum over a 4-hour period) was well tolerated (Pennick et al., 2006). The mean plasma concentration of lanthanum increased to a maximum of 5.1 ± 0.9 ng/mL at 3.3 ± 0.8 hours after start of the infusion. Plasma lanthanum concentrations subsequently declined triphasically, with a mean terminal elimination half-life of 37 ± 22 hours. Lanthanum plasma exposure (mean AUC) after intravenous dosing was 38.9 ± 10.5 ng*h/mL. Following intravenous injection of 0.3 mg/kg lanthanum trichloride in rats, plasma lanthanum levels decreased rapidly from a peak of 3231 ± 233 ng/mL measured at 5 min, to approx. 14% of Cmaxby 2 h post dose. Thereafter, plasma concentrations declined at a slower rate and returned to 3.08 ± 2.91 ng/mL by 48 hours (Damment and Pennick, 2007).

Dermal

Inaba et al (1979) studied the uptake of radiolabled Cerium chloride (144Ce) through stripped and intact guinea pig skin during a 3 hour exposure period. The uptake through intact skin was negligible (<= 0.001%) while from stripped skin ca. 4% of the radioactivity were absorbed. The study demonstrated that absorption of a soluble cerium salt, cerium trichloride through intact guinea pig skin is very low (<= 0.001%). It can be assumed that the uptake of less soluble compounds is even lower. Cerium3+ can in this case be used as a surrogate for lanthanum oxide as well, because the atomic radius is very of the two metals is very similar and the oxidation state is the same (3+). It can therefore be concluded that dermal absorption of lanthanum oxide through intact skin can be considered negligible.

Inhalation

An in vitro dissolution bioavailability test was performed with Lanthanum trioxide ((purity >99.9%, particle size (by electron microscopy) D50 1.89 micro-m). in water, physiological saline and Gambles fluid simulating alveolar fluid after an incubation of 1 and 7 days. Lanthanum was below the detection limit in water and saline and in Gambles fluid the concentration was 3.5 micro-g/L after 1 day and 17.3 micro-g/L after 7 days. The maximum solubility was 0.00016% after 7 days in alveolar simulation fluid. From this experiment it can be concluded that the systemic availability of Lanthanum from Lanthanum oxide after inhalation exposure will be low. (Takaya et al. 2006).

Metabolism

Lanthanum is not metabolized and is neither a substrate nor an inhibitor of CYP450 (Pennick et al., 2003a).

 

Distribution/Excretion

In animal studies, lanthanum was also poorly absorbed. After oral administration of soluble lanthanum salts it was reported that in lysosomes of the intestinal epithelial cells insoluble lanthanum phosphate is formed which is not systemically available. Normal cell exfoliation results in excretion in the faeces again (Florent et al., 2001; Fehri et al., 2005). The small fraction of absorbed lanthanum is extensively (> 99.7%) bound to plasma proteins (Damment and Pennick, 2007). After oral administration (drinking water) of radiolabled lanthanum chloride to rats some distribution apart from teeth and the GI tract was also observed mainly into lungs, kidney, liver, spleen and bones (Rabinowitz et al, 1988).

Following oral administration of lanthanum carbonate, the great majority of the dose is excreted unabsorbed in the faeces: 99% and 93% of the dose was recovered in the faeces of rats (Damment and Pennick, 2007) and dogs (FDA (2002, 2004), respectively. The small absorbed fraction is excreted predominantly via the liver into 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 after i.v. administration of lanthanum chloride to rats.

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 mL/min). Lanthanum was widely distributed with an apparent volume of distribution of 164 ± 84 L. Intravenous administration confirmed low renal clearance (0.95 ± 0.60 mL/min), just 1.7% of total plasma clearance. The systemic clearance of lanthanum in rats after a single intravenous 0.3 mg/kg dose of lanthanum trichloride 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.

In human studies, fecal lanthanum excretion was not quantifiable after intravenous administration owing to the natural high background levels of lanthanum in faeces (Pennick et al., 2006). After a single intravenous 0.3 mg/kg dose of lanthanum trichloride in rats, recovery of lanthanum over 42 days was 76.4 ± 5.7% of the administered dose, predominantly in the faeces (Damment and Pennick, 2007). In contrast, only 1.94 ± 0.24% of the dose was excreted in urine over the 42-day collection period. The data imply that the kidneys are not significantly involved in the clearance of absorbed lanthanum.

The relatively low total recovery is attributed in part by the authors to the underestimation of fecal excretion due to the high background levels in faeces. Another reason may be a tissue distribution e.g. into bone tissue at the high i.v. dose that were associated with non-linar pharmacokinetics and are suggestive of a saturation of plasma binding and/or clearance mechanisms. An internal dose of 40 micro-g of La for a 250 g rat may have exceeded a calculated plasma binding capacity of 15 micro-g of La per 50 g rat as stated by the authors.

In conclusion:

Lanthanum oxide is poorly absorbed via the oral, dermal and inhalation routes of exposure. The available kinetic data suggest that the absorption is comparable between the three exposure routes and that no significant differences exist between rats and humans after oral absorption. As a metal cation lanthanum ions do not undergo biotransformation and seem not to interact with liver enzymes. After oral administration the low absorbed amount is predominantly distributed to liver, kidney, lungs and bones. After long term administration in humans bone levels of lanthanum increased slowly with time without reaching levels that impaired bone function. Excretion after oral and i.v. administration is predominantly via the faeces. Only very low amounts are excreted via the kidneys in urine.

References:

Curran, M.P. and Robinson, D.M (2009). Lanthanum carbonate: a review of its use in lowering serum phosphate in patients with end-stage renal disease. Drugs 69(16): 2329-2349.

Leveque A., Sabot J.L., Maestro P (2001), Lanthnides, in Kirk-Othmer Encyclopedia of Chemical Technology, Vol 14, 1-28, John Wiley and Sons

Inaba, J. and Yasumoto, M.S. (1979). A kinetic study of radionuclide absorption through damaged and undamaged skin of the guinea pig. Health Phy 37:592-595.

Florent, C. et al. (2001). Analytical microscopy observations of rat enterocytes after oral administration of soluble salts of lanthanides, actinides and elements of group III-A of the periodic chart. Cell Mol Biol (Noisy-le-grand) 47: 419-425.

Fehri, E. et al. (2005). Lanthanides and microanalysis: effects of oral administration of two lanthanides: ultrastructural and microanalytical study. Arch Inst Pasteur 82: 59-67.

FDA (2004) Center of Drug Evaluation and Research Package for Application No. 21-468 Fosrenol® ( Shire Pharmaceuticals, (2002, 2004).

Takaya et.al. (2006), Dissolution of functional materials and rare earth oxides into pseudo alveolar fluid, Industrial Health, 44 (4) 639-644.