Dilanthanum tricarbonate

Genetic toxicity: in vivo

Administrative data

Endpoint:

in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus

Remarks:

Type of genotoxicity: chromosome aberration

Type of information:

experimental study

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

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

publication

Title:

Evaluation of the potential genotoxicity of the phosphate binder lanthanum carbonate

Author:

Damment, S.J.P. et al.

Year:

2005

Bibliographic source:

Mutagenesis 20 (1): 29-37

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)

Deviations:

yes

Remarks:

three sampling times (24, 48 and 72 h after treatment)

GLP compliance:

not specified

Type of assay:

micronucleus assay

Test material

Test material information

Constituent 1

Reference substance name:

Dilanthanum tricarbonate

EC Number:

209-599-5

EC Name:

Dilanthanum tricarbonate

Cas Number:

587-26-8

Molecular formula:

La2(CO3)3

IUPAC Name:

dilanthanum tricarbonate

Details on test material:

- Name of test material (as cited in study report): Lanthanum carbonate
- Analytical purity: 100.5% w/w

Test animals

Species:

mouse

Strain:

CD-1

Sex:

male/female

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

- carboxymethylcellulose, 0.5% w/v

Duration of treatment / exposure:

24, 48 and 72 h after treatment groups of animals were killed and bone marrow smears were prepared.

Frequency of treatment:

single dose

Doses / concentrations

Remarks:

Doses / Concentrations:
800, 1250 and 2000 mg/kg bw
Basis:
nominal conc.

No. of animals per sex per dose:

5

Control animals:

yes, concurrent vehicle

Positive control(s):

- Mitomycin C
- Route of administration: i.p.
- Doses / concentrations: 4 mg/kg

Examinations

Tissues and cell types examined:

After staining, the incidence of micronuclei was scored in polychromatic erythrocytes (2000/mouse) and the ratio of polychromatic to normochromatic cells was also determined from a sample of 1000 total cells.

Evaluation criteria:

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/female

Genotoxicity:

negative

Toxicity:

no effects

Vehicle controls validity:

valid

Negative controls validity:

not examined

Positive controls validity:

valid

Additional information on results:

In the mouse bone marrow micronucleus assay after oral administration of lanthanum carbonate all treatment and vehicle control groups exhibited normal frequencies of micronucleated polychromatic erythrocytes (MNPCE), with the exception of the vehicle control group (male mice) sampled at 48 h. In this group there was a complete absence of micronuclei for all of the five animals analysed. This resulted in statistically significant differences being recorded for the mean MNPCE in the male groups sampled at 48 h after doses of 1250 and 2000 mg/kg bw. For these two groups the MNPCE frequencies fell well within the historical control range for this strain of mouse. Consequently, this result was not considered to be biologically relevant and was the result of the unusually low micronucleus frequency recorded for the control animals at this sample time.
It can be concluded that lanthanum carbonate does not induce micronuclei in mouse bone marrow after administration of doses up to the maximum practicable oral dose of 2000 mg/kg bw.

Any other information on results incl. tables

MNPCE: micronucleated polychromatic erythrocytes

PCE: polychromatic erythrocytes

NCE: normochromatic erythrocytes

Geometric mean frequency MNPCE and mean PCE/NCE ratio:

Males

concentration (mg/kg)	MNPCE	MNPCE	MNPCE	mean PCE/NCE ratio (%)	mean PCE/NCE ratio (%)	mean PCE/NCE ratio (%)
	24 h	48 h	72 h	24 h	48 h	72 h
vehicle control	1.49	0.00	0.64	115	101	89
800	0.97	0.64	1.61	81	77	125
1250	1.35	1.05*	1.40	92	134	96
2000	0.25	1.17*	1.27	98	134	91
positive control	88.7**			91

*: p < 0.05 (Dunnetts test)

**: p < 0.001 (Student´s test)

Females

concentration (mg/kg)	MNPCE	MNPCE	MNPCE	mean PCE/NCE ratio (%)	mean PCE/NCE ratio (%)	mean PCE/NCE ratio (%)
	24 h	48 h	72 h	24 h	48 h	72 h
vehicle control	3.28	2.10	0.15	91	114	145
800	2.13	1.93	1.17	119	130	208
1250	1.93	1.70	0.52	97	121	229
2000	0.89	1.86	1.17	114	204	181
positive control	75.1*			91

*: p < 0.001 (Student´s test)

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): negative