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Toxicological information

Genetic toxicity: in vivo

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Administrative data

Endpoint:
in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus
Remarks:
Type of genotoxicity: chromosome aberration
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well documented publication which meets basic scientific principles.

Data source

Reference
Reference Type:
publication
Title:
Evaluation of the potential genotoxicity of the phosphate binder lanthanum carbonate
Author:
Damment S.J.P., Beevers C., Gatehouse D.G.
Year:
2005
Bibliographic source:
Mutagenesis 20 (1): 29-37

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
Deviations:
yes
Remarks:
only males tested
GLP compliance:
not specified
Type of assay:
micronucleus assay

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Lanthanum chloride
- Analytical purity: 98.7%

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male

Administration / exposure

Route of administration:
intravenous
Vehicle:
- sodium chloride (physiological saline)
Details on exposure:
- Lanthan chloride was formulated as 10% w/v aqueous stock solution in 0.9% w/v sodium chloride (physiological saline)
- dose volume: 5 mL/kg
Duration of treatment / exposure:
Groups of animals were killed 24 and 48 h after treatment and bone marrow smears were prepared.
Frequency of treatment:
single
Doses / concentrations
Remarks:
Doses / Concentrations:
0.025, 0.05 and 0.1 mg/kg
Basis:
nominal conc.
No. of animals per sex per dose:
6 (only males)
Control animals:
yes, concurrent vehicle
Positive control(s):
- cyclophosphamide
- Route of administration: oral
- Doses / concentrations: 20 mg/kg

Examinations

Tissues and cell types examined:
- bone marrow: erythrocytes (MNPCE: micronucleated polychromatic erythrocytes, PCE: polychromatic erythrocytes, NCE: normochromatic erythrocytes)
- blood: plasma lanthanum concentration
Details of tissue and slide preparation:
The incidence of micronuclei was scored in polychromatic erythrocytes (2000/rat) and the ratio of polychromatic to normochromatic cells was also determined from a sample of 1000 total cells.
In addition, blood was taken 2, 15 and 60 min after administration (from a satellite group) and the plasma lanthanum concentration was analysed using inductively coupled plasma mass spectrometry (ICP-MS).
Evaluation criteria:
Dose-related increase in the number of micronucleated cells or a clear increase in the number of micronucleated cells in a single dose group at a single sampling time.
Statistics:
Statistical analysis was performed using the statistical methods described in Statistical Evaluation of Mutagenicity Test Data (Kirkland, 1989).

Results and discussion

Test results
Sex:
male
Genotoxicity:
negative
Toxicity:
no effects
Vehicle controls validity:
valid
Negative controls validity:
not examined
Positive controls validity:
valid
Additional information on results:
In the rat bone marrow micronucleus assay after i.v. administration of lanthanum chloride all treatment and vehicle control groups exhibited normal frequencies of MNPCE.
It is noteworthy that the mean peak plasma lanthanum concentration (Cmax) at this dose was 2093 +/- 106 ng/mL (Figure 2), which is > 2000-fold higher than the steady state human plasma Cmax in dialysis patients receiving an oral dose of 3 g elemental lanthanum (as lanthanum carbonate).

Any other information on results incl. tables

MNPCE: Mean frequency of MNPCE +/- SD (per 2000 cells)

PCE/NCE: mean PCE/NCE ratio

 Conc (mg/kg) MNPCE  MNPCE  PCE/NCE  PCE/NCE 
  24 h  48 h  24 h  48 h 
vehicle control  0.42 ± 0.38  0.83 ± 0.52  1.48  1.70 
0.025  0.17 ± 0.26  nt  2.18  nt 
0.05  0.33 ± 0.61  nt  1.57  nt 
0.01  0.75 ± 0.61  0.25 +/-0.42  1.38  1.42 
positive control  7.5 ± 2.67*  nt  0.46  nt 

nt : not tested

* p < 0.001 (chi2 -test)

MNPCE: micronucleated polychromatic erythrocytes

PCE: polychromatic erythrocytes

NCE: normochromatic erythrocytes

Applicant's summary and conclusion