Reaction mass of cerium dioxide and lanthanum oxide and lanthanum fluoride

Endpoint summary

Additional information

There are three forms of lanthanides: insoluble (oxides, carbonates), solubles (chlorides, nitrates, acetates) and chelated compounds. Most of the available information on lanthanide absorption, comes from the soluble lanthanide salts. Different forms of lanthanides have different organ distribution and excretion rates. The lanthanide oxides have been shown in in vitro bioaccessibility studies to have a very low gastrointestinal bioaccessibility of ~6% (Lambert CE, 2005).

The following basic toxicokinetic information can be extrapolated from the experimental toxicology data available on the reaction mass of Cerium dioxide and Lanthanum oxide and Lanthanum fluoride as well as on its constituents cerium dioxide, lanthanum oxide and lanthanum fluoride, all four chemicals are insoluble inorganic substances and showed similar physico-chemical, toxicological, ecotoxicological and environmental properties:

- Regarding absorption:

Following a single administration either by oral route (at the limit dose of 2000 mg/kg of reaction mass and up to 5000 mg/kg of cerium dioxide or lanthanum oxide), inhalation (at the concentration of5.05mg/L of cerium dioxide for 4 hours), or dermal route (at the limit dose of 2000 mg/kg of cerium dioxide), no relevant systemic clinical sign or changes in body weight was observed. Labored breathing and/or ruffled fur (noted after inhalation exposure) or slightly reduced activity on the day of dermal dosing are poorly specific signs which may be attributed to the technical procedures rather than to the test substance.

No specific study on dermal absorption is available. However, as the reaction mass of Cerium dioxide and Lanthanum oxide and Lanthanum fluoride, and its main constituents cerium dioxide and lanthanum oxide are insoluble inorganic test substances (no logP can be calculated), no significant dermal absorption is expected. As an illustration, following acute exposure of rats to a dermal dose of 2000 mg/kg cerium dioxide and observation up to 14 days following application, no noteworthy systemic clinical sign (other than slightly reduced activity on day 1) was observed.

Following repeated dose administration by the oral route at doses up to the limit dose of 1000 mg/kg cerium dioxide for up to approximately 42 days in male rats and 54 days in female rats, there was no relevant sign of toxicity in any of the parameters studied, including clinical signs, functional observational battery, body weight, food consumption, hematology or blood biochemistry. The absence of toxic effects indicate that the test substance and/or its degradation products or metabolites are not absorbed or devoid of toxicity following oral dosing with cerium dioxide.

Following inhalation exposure to cerium dioxide for up to 90 days in rats, the effects observed were consistent with "portal-of-entry" effects and a lung-overload inflammatory response syndrome. No systemic effect resulting from significant absorption was evidenced.

The toxicokinetics of lanthanum salts was evaluated during the development of lanthanum carbonate as a drug in dogs (Fosrenol^TM). It was demonstrated that lanthanum carbonate is absorbed following oral administration to healthy dogs, although bioavailability was extremely low. Average bioavailability for both sexes was estimated to be 0.00005% of the administered dose (see US Food and Drug Administration, New Drug Application (NDA)21468). The main toxicokinetic parameters in dogs were as follows:

 

Sex	AUC0-24 h(ng.h/mL)		Bioavailability (%)
	Oral (2000 mg/kg/day)	Intravenous (0.003 mg/kg/day)
Male	14.61	36.72	0.00006
Female	9.01	33.85	0.00004
AUCs shown are Day 1 values (from a 4-week administration study)

 

The absorption of reaction mass of Cerium dioxide and Lanthanum oxide and Lanthanum fluoride is therefore expected to be extremely low.

- Regarding distribution:

Following repeated dose administration of cerium dioxide by inhalation (nose only) at concentrations up to 0.5075 mg/L (507.5 mg/m3) for 13 weeks in rats, only loco-regional "portal-of-entry" effects were observed, as changes in segmented neutrophil counts, lung and spleen weights, lung and lymph node gross appearance at necropsy and respiratory tract and lymphoreticular system histopathology. These effects were illustrative of an inflammatory response subsequent to lung overloading with poorly soluble particles, without functional impairment of the immune system. No relevant systemic effects specific to cerium dioxide as such were evidenced.

The toxicokinetics of lanthanum salts was evaluated during the development of lanthanum carbonate as a drug in dogs (Fosrenol^TM). During a 52-week oral toxicity study in dogs receiving the very high dose level of 2000 mg La carbonate/kg bw/day, dose-related plama and tissue lanthanum exposures were observed (see US Food and Drug Administration, New Drug Application (NDA)21468). Lanthanum accumulated in most tissues with tissue levels after 52 weeks of oral dosing that were several orders of magnitude higher than plasma lanthanum levels (2,24 or 1,77 ng/g in males or females, respectively). Particularly high tissue lanthanum levels were observed in the gastrointestinal system (median concentrations between 11,4 and 348,9 µg/g), liver (median concentrations of 7,3 or 11,1 µg/g), lungs (median concentrations of 2,5 or 4 µg/g), and bone (median concentrations between 1,1 and 2,9 µg/g). Heart lanthanum levels were higher than plasma levels but much lower than those determined in the other tissues. However, following tissue loading with 4 weeks of oral administration of 2000 mg La carbonate/kg bw/day, lanthanum carbonate was shown to clear slowly from several tissues, including several portions of the gastrointestinal tract, liver, lungs, bone and teeth.

Therefore, under normal conditions of exposure, only limited systemic distribution of reaction mass of Cerium dioxide and Lanthanum oxide and Lanthanum fluoride is expected.

- Regarding metabolism:

The presence or absence of exogenous metabolic activation system made no difference in the results of in vitro mutagenicity testing with the reaction mass of Cerium dioxide and Lanthanum oxide and Lanthanum fluoride or its main constituents cerium dioxide and lanthanum oxide. No conclusion can therefore be made regarding the transformation of the test substances and/or their degradation products or metabolites by hepatic microsomal fractions.

No microscopic finding in the major metabolizing tissues (liver, kidneys) illustrative of metabolic activity were seen following repeated dose administration of cerium dioxide by the oral route at doses up to the limit dose of 1000 mg/kg for up to approximately 42 days in male rats and 54 days in female rats or by inhalation (nose only) at concentrations up to 0.5075 mg/L for 13 weeks in rats.

- Regarding elimination:

Following a single administration by oral route (at the limit dose of 5000 mg/kg of cerium dioxide), whitish discoloration of the feces was observed, likely indicative of fecal elimination of the test substance as unchanged material (Institu Français de Toxicologie, 1983).

Following dietary administration of lanthanum oxide in mice up to 400 ppm over three successive generations, the concentrations of lanthanum oxide were shown to increase about fivefold in the feces during the digestive process (Hutcheson et al., 1975).

The toxicokinetics of lanthanum salts was evaluated during the development of lanthanum carbonate as a drug in dogs (Fosrenol^TM). It was demonstrated that following a single oral dose of 1000 mg lanthanum carbonate/kg, lanthanum was eliminated primarily via the fecal route, consistent with low oral bioavailability (see US Food and Drug Administration, New Drug Application (NDA)21468). A small percentage of the administered lanthanum carbonate was recovered in urine (0.2% and 2.0% for the two male dogs evaluated). Most of the lanthanum carbonate administered in this single dose study was recovered in the feces within 24 hours of dosing.

Based on their insoluble nature, low absorption and distribution potentials, and absence of obvious metabolism, it is probable that the reaction mass of Cerium dioxide and Lanthanum oxide and Lanthanum fluoride and its constituents will be eliminated under an unmodified form.