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Toxicological information

Genetic toxicity: in vitro

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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:
OECD Guideline 476 (In Vitro Mammalian Cell Gene Mutation Test)
GLP compliance:
not specified
Type of assay:
mammalian cell gene mutation assay

Test material

Reference
Name:
Unnamed
Type:
Constituent
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 resultsopen allclose all
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
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).