Dilanthanum tricarbonate

Neurotoxicity

Description of key information

The results from an unpublished developmental neurotoxicity study by Shire (2010), and the absence of adverse findings in  FOB results of a 90-day repeated dose study suggest a NOAEL of 2000 mg/kg bw/day Lanthanum carbonate for neurotoxic effects. 

Key value for chemical safety assessment

Effect on neurotoxicity: via oral route

Endpoint conclusion

Dose descriptor:

NOAEL

2 000 mg/kg bw/day

Additional information

Functional observations (FOB) additionally including approach response, touch response, auditory response, tail pinch response, righting reflex, grip strength and landing foot splay as well as motor activity assessments were performed in the course of a reliable subchronic feeding study conducted according to OECD 408 in rats dosed with Lanthanum carbonate octahydrate after oral intake at doses up to and including 14000 ppm (Reißmüller, 2006; for details refer to section 5.6.1 or IUCLID section 7.5.1). No treatment-related effects were observed in the test battery, except for the observation of a non dose-dependent tilted head in single animals and an occasional slightly increased number of rearing. These effects were not considered treatment related because of the absence of a dose response.

Furthermore, there is an unpublished (The registrant contacted Shire Pharmaceuticals in order to achieve the legitimate posession (LoA) of this study. The company did not agree to share the data.) developmental neurotoxicity study performed according to OECD 426 (Shire, 2010; FDA 2004). In this study, time-mated female Sprague-Dawley rats were orally exposed to Lanthanum carbonate from implantation (GD 6) throughout lactation (PND 20) at doses of 200, 600, 1000 or 2000 mg/kg bw/d. In this study some neurological parameters were also investigated:), static righting reflex (PND5), startle response (PND15), papillary reflex (PND 21). After weaning 20 F1 pups/sex/group were selected randomly for detailed post weaning examinations and rearing and sexual maturity. The remaining pups were necropsied. The selected pups were observed daily for clinical signs. Body weights were recorded weekly. Ophthalmologic examinations auditory function assessment were performed on PND 28 to 35 and E-maze learning assessment on PND 28. There were no effects of maternal treatment on the righting, startle or pupillary light reflexes. Furthermore, there were no treatment-related effects on E-maze learning, auditory function or ophthalmoscopy.

Neurological behaviour was also investigated in an acute inhalation study with Wistar rats exposed to 5928 mg/m³ Lanthanum carbonate octahydrate for 4 hours (Pauluhn, 2005). In comparison to the rats of the control group, none of the rats of the exposure group exhibited a change in reflexes (visual placing response and grip strength on wire mesh, abdominal muscle tone, corneal and pupillary reflexes, pinnal reflex, righting reflex, tail-pinch response, startle reflex with respect to behavioural changes stimulated by sounds (finger snapping) and touch (back)).

 

Justification for classification or non-classification

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