Dilanthanum tricarbonate

Endpoint summary

Description of key information

Oral:
NOAEL (rats) = 10648 ppm Lanthanum carbonat (741 mg/kg bw/d for males, 1126 mg/kg bw/d for females)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEL

741 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Additional information

Oral

Repeated dose toxicity was analysed in a reliable subchronic feeding study with Lanthanum carbonate octahydrate performed under GLP according to OECD guideline 408 (Reißmüller, 2006). Groups of five male and female Wistar rats received nominal doses of 1400, 2400 and 14000 ppm (males: 94.0, 276.1 and 974.2 mg/kg bw/day, females: 135.1, 391.2 and 1480.4 mg/kg bw/day) for 90 days in the diet. In addition to the guideline protocol neurobehavioral tests as well as immunotoxicological examinations were performed in satellite groups. With the exception of single incidental findings no treatment-related adverse effects were detected. Therefore, the NOAEL was found to be 14000 ppm Lanthanum carbonate octahydrate corresponding to 10648 ppm Lanthanum carbonate, anhydrous. Based on the daily food consumption the NOAEL is 741 mg/kg bw/d for males and 1126 mg/kg bw/d females, which is the highest dose tested in the study.

 

In a published study (Behets, 2004), doses of 100, 500 and 1000 mg/kg bw/d Lanthanum carbonate tetrahydrate were given daily by gavage to male Wistar rats for 12 weeks. Two weeks prior to dosing animals of each dose group underwent a nephrectomy to induce a chronic renal failure (CRF). Tetracycline and demeclocycline was given prior to sacrifice. As result, some haematological and urinalysis parameter were statistically changed in the animals with induced chronic renal failure when compared to the groups with normal renal function. Although effects on the mineralization of the bone were found in CRF rats this was regarded as an effect of the nephrectomy and not attributed to Lanthanum carbonate. Thus, the NOAEL was found to be 1000 mg/kg bw/d Lanthanum carbonate tetrahydrate corresponding to 864 mg/kg bw/d Lanthanum carbonate.

 

A similar approach was reported in another published study, where an adenine-induced chronic renal failure was induced in a group of 20 Sprague-Dawley rats and a surgically induced chronic renal failure by nephrectomy in another group of 24 animals (Lacour et al. , 2005). The animals received Lanthanum carbonate dodecahydrate at a dosage of 3% in the diet for 28 days. The administration resulted in haematological changes as well as in organ weight changes. Also, Lanthanum carbonate could be found in several organs with the highest level in the liver. The overall data of this study suggest, that a chronic renal failure imparts a unique predisposition toward higher accumulation and/or retention of Lanthanum in tissues that is different than what occurs in healthy animals. Due to the low dose administered, no effect level could be determined.

 

In a study reported by a secondary source, Lanthanum III carbonate hydrate was administered orally to rats daily in concentrations up to 1500 mg/kg bw/day for 26 weeks (Läkelmedelsverket, 2006). The authors reported a time- and dose-dependent increase in histopathological stomach changes including mineralization, epithelial hyperplasia, mucous cell hyperplasia, consistent with an irritant response.

In addition to the animal studies, a clinical stuy with human volunteers cab be used for assessment (Hutchison et al., 2006). This publication reported a six months and 2 year extension to a 6-month study evaluating the long-term safety, tolerability and efficacy of the phosphate binder Lanthanum carbonate. It was found that Lanthanum carbonate was well tolerated leading to the hypercalcemia incidence of 2.7%, compared with 20.2% during the double-blind phase when the patients switched from calcium carbonate treatment to Lanthanum carbonate. Observed adverse events were mild with mainly gastrointestinal effects with no evidence of an increase in the frequency of adverse events previously associated with traditional phosphate-binder treatment, such as hypercalcemia, microcytic anemia, fractures or bone pain.

Justification for classification or non-classification

The data on repeated dose toxicity is conclusive but not sufficient for classification according to the criteria of Directives 67/548/EEC (DSD) and 1272/2008/EC (CLP).