Registration Dossier

Toxicological information

Neurotoxicity

Currently viewing:

Administrative data

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The results from an unpublished developmental neurotoxicity study by Shire (2010), and the absence of adverse findings in  FOB results of a 90-day repeated dose study suggest a NOAEL of 2000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

Key value for chemical safety assessment

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 which is converted to Lanthanum chloride in the acidic environment of the stomach after oral intake at doses up to and including 14000 ppm (Reißmüller, 2006; for details refer to section 5.6.1.1 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Furthermore, there is an unpublished (The registrant contacted Shire Pharmaceuticals in order to achieve the legitimate posession (LoA) of this study.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 nor 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.

Two non-standard studies, that suffered from a number of experimental, evaluation and reporting deficiencies have claimed effects on behavioral developments of rats exposed to Lanthanum chloride during gestation and different length of postnatal periods.

In a non-standard study by He et al. (2008), maternal rats were orally exposed to Lanthanum chloride at concentrations of 0, 0.1, 2, 40 mg/kg/day from gestation day 0 through postnatal day 20. From postnatal day 21, pups (males only) were directly exposed to Lanthanum chloride until 6 months of age. Tests were performed at 6 months of age to assess the effects of Lanthanum exposure on behavioural performance (Morris water maze test). In addition, various biochemical parameters were examined.

The performance in the Morris water maze test was reported to have been significantly influenced by exposure: High-dose rats showed statistically significant prolongations in the mean escape latency. The mean general pathway was also reported to be statistically significantly prolonged in rats from the middle- and high-dose groups. These results were interpreted as an impaired aquisition of spatial learning and memory after exposure. The biological significane, however, is not clear. The spatial reference memory was tested in a probe trial on the fifth day. Middle- and high-dose animals were reported to show a significantly decreased preference for the target quadrant compared to control rats (16.6 and 19.4%, respectively). All groups were tested for their ability to escape to a visible platform. No significant differences in the performance between groups were observed.The study suffers from a numbe rof deficiencies: It is unclear why only male offspring was chosen for the specific tests and the rationale for the testing timepoint is not given as well. In particular the effect of litter on the results were not considered as the animals were randomly selected from the dose groups irrespective of the litter. The litter bias introduced by that is known to be prone to lead to false positive results (Holson et al, 2008). Furthermore the variation in historical control data is unknown. Therfore the study is not considered of sufficient reliability to be considered in the risk assessment.

The effects of Lanthanum chloride on physical and neurobehavioural development in rats upon subchronic oral exposure was published by Feng et al. (2006). In this non-standard study rats were exposed to Lanthanum chloride at doses of 0, 0.1, 2 and 40 mg/kg from gestation day 0 through 5 months of age. Physical parameters and neurobehaviour (body weight gain, pinna detachment, eye opening, surface righting reflex and swimming endurance) were examined prior to weaning. DNA concentration and protein to DNA ratio was determined in whole brain homogenates of 30 day old pups.The Morris water maze test was conducted at postnatal day 150. Statistically significant differences were reported for body weight gain, surface righting reflex and swimming endurance in rats exposed to 2 and 40 mg LACl3/kg. At these dose levels, brain DNA concentration was reported to be significantly decreased. Protein to DNA ratio was reported to be significantly increased in rats exposed to 0.1 mg LaCl3/kg, but no significant increase or dose-response was observed at the higher dose levels. The Morris water maze test was claimed to give an indication of impaired memory and learning abilities in animals exposed to 40 mg Lanthanum chloride/kg.The pre-weaning tests were statistically evaluated on a litter basis, while all post-weaning tests were conducted from randomly selected pups per group and a litter bias cannot be excluded. As stated by Holson et al. (2008) not using the litter as a statistical basis can lead to false positive correlations, also in the post-weaning assays and therefore no firm conclusions on possible substance related effects can be drawn from statistical differences not derived on a litter base.

Body weights were not significantly reduced in any dose group up to PND90. Treated animals in the mid and high dose groups were reported to perform better than controls in the surface-righting reflex. No difference in swimming ability was observed on PND10, while on PND 20 males and females of the high dose group were reported to have reduced swimming times. Again the variation was very high and in the absence of historical control data it remains questionable if the observation is test substance related. In the Morris water maze test performed on PND150 the authors reported significantly slower escape latency in the high dose group animals on day 3 to day 5 (the test was performed during 8 consecutive days). However, as the animals were randomly selected and not evaluated on a litter base, no firm conclusions on a test substance related effect can be drawn from this study. In conclusion, although some effects were reported in this study, no conclusions on possible substance-related adverse effects can be drawn.

 

As guideline studies performed at dose levels up to 2000 mg/kg bw/day did not show an indication of a test substance related effect on the nervous system in rats it is concluded that there is no convinving evidence for a possible neurotoxic or devlopmental neurotoxic effect of Lanthanum chloride in experimental animals.

 

References

FDA (2004). Drug approval package, Fosrenol®(Lanthanum carbonate) tablets.http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-468_Fosrenol.cfm.

Holson, R. R. et al. (2008). Statistical issues and techniques appropriate for developmental neurotoxicity testing. A report from the ILSI Research Foundation/Risk Science Instituteexpert working group on neurodevelopmental endpoints. Neurotoxicology and Teratology 30, 326-348.

Justification for classification or non-classification

The available data is conclusive but not sufficient for classification.