Lanthanum oxide

Genetic toxicity: in vitro

Administrative data

Endpoint:

in vitro gene mutation study in mammalian cells

Remarks:

Type of genotoxicity: gene mutation

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

Guideline:

OECD Guideline 476 (In Vitro Mammalian Cell Gene Mutation Test)

GLP compliance:

not specified

Type of assay:

mammalian cell gene mutation 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:

CH2O3.2/3La

IUPAC Name:

Dilanthanum tricarbonate

Details on test material:

- Name of test material (as cited in study report): Lanthanum carbonate
- Molecular formula (if other than submission substance): La2(CO3)3
- CAS No: 587-26-8
- Analytical purity: 100.5 %

Method

Target gene:

hprt locus

Species / strain

Species / strain / cell type:

Chinese hamster Ovary (CHO)

Metabolic activation:

with and without

Metabolic activation system:

S9 liver fraction

Test concentrations with justification for top dose:

50, 250, 500, 1000, 1500, and 2000 µg/mL in the absence of S9 mix
25, 250, 500, 2500 and 5000 µg/mL in the presence of S9 mix

Vehicle / solvent:

- sterile distilled water

Controls

Untreated negative controls:

no

Negative solvent / vehicle controls:

yes

True negative controls:

no

Positive controls:

yes

Positive control substance:

other: ethyl methane sulphonate (750 µg/mL) in the absence of S9 mix; benzo[a]pyrene (25 µg/mL) in the presence of S9 mix

Details on test system and experimental conditions:

DURATION
- Exposure duration: 3 h
- Selection time (if incubation with a selection agent): 7 d
SELECTION AGENT (mutation assays): 6-thioguanine
NUMBER OF REPLICATIONS: 2 independant assays with duplicate cultures
DETERMINATION OF CYTOTOXICITY
- Method: relative total growth

Evaluation criteria:

- significant increase of mutation frequency
- dose-response relationship

Statistics:

The significance of any changes in mutation frequency compared with the control was determined using the statistical methods described in Statistical Evaluation of Mutagenicity Test Data (Kirkland, 1989).

Results and discussion

Test results

Test results 1

Species / strain:

Chinese hamster Ovary (CHO)

Metabolic activation:

without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

cytotoxicity

Remarks:

2000 µg/mL: experiment I 80 - 90% reduction; experiment II: approx. 38% reduction); 1500 µg/mL: experiment I approx. 35% reduction; experiment II: approx. 54% reduction)

Vehicle controls validity:

valid

Untreated negative controls validity:

not examined

Positive controls validity:

valid

Test results 2

Species / strain:

Chinese hamster Ovary (CHO)

Metabolic activation:

with

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

no cytotoxicity

Vehicle controls validity:

valid

Untreated negative controls validity:

not examined

Positive controls validity:

valid

Additional information on results:

There were no statistically significant effects on mutation frequency in the presence and absence of S9 mix. In the absence of S9 mix increases in mutation frequency were obtained at isolated concentrations in the first experiment. However, these were not statisitcally significant, there was no obvious dose-response relationship and the effects were not reproducible in a second experiment, indicating that they had arisen by chance and do not indicate a mutagenic effect due to lanthanum carbonate.

Remarks on result:

other: all strains/cell types tested

Remarks:

Migrated from field 'Test system'.

Any other information on results incl. tables

Maximum revertant colonies, control data and data for cytotoxicity (if observed):

(* p< 0.05; n.d. no data given)

Without S9: experiment I

Conc. (µg/mL)	No. of colonies	control (%)	Mutation frequency (x 10E-6)
2000	21.3	16.4	11.4
1500	83.7	64.4	0.9
500	128.3	98.7	16.5
solvent control	130	100	2.5
positive control	n.d.	n.d.	574.4*

Without S9: experiment II

Conc. (µg/mL)	No. of colonies	control (%)	Mutation frequency (x 10E-6)
2000	101.3	62.1	14 .9
1500	95.3	56.6	14.1
50	147.0	90.2	n.d.
solvent control	163	100	15.5
positive control	n.d.	n.d.	540.9*

With S9: experiment I:

Conc. (µg/mL)	No. of colonies	control (%)	Mutation frequency (x 10E-6)
2500	144.8	125.6	6.8
solvent control	115	100	10.6
positive control	n.d.	n.d.	89.6*

With S9: experiment II:

Conc. (µg/mL)	No. of colonies	control (%)	Mutation frequency (x 10E-6)
5000	104.7	96.3	1.5
solvent control	108.7	100	5.0
positive control	n.d.	n.d.	65.6*

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information):
negative

Lanthanum carbonate was not genotoxic in a mammalian cell HPGRT gene mutation assay using CHO cells up to cytotoxic or maximum recommendedconcentrations both in the pesence and absence of at liver S9 mix.

Executive summary:

Damment et al. (2005) investigated the genotoxic activity of lanathanum carbonate in a HPRT mammalian gene mutation assay in Chinese Hamster Ovary (CHO) cells in accordance with recent guideline requirements. The substance was not genotoxic with and without a metabolic activations system (rat liver S9 mix).