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Key value for chemical safety assessment

Additional information

In-Vitro Gene Mutation Assays :

The mutagenic activity of the test item CIMENT FONDU® was assessed by means of the Ames’s test in the five Salmonella typhimurium strains TA1535,TA1537, TA98, TA100 and TA102 tested either in presence or in absence of metabolic activation, in two to four independent assays. Indeed, 3 complementary assays were carried out in strain TA102 only in presence of S9-mix. Under these experimental conditions an equivocal to weak mutagenic activity was revealed exclusively in strain TA102 only in the presence of metabolic activation. In return, no mutagenic activity was found either with and without metabolic activation in strains TA1535, TA1537, TA98 and TA100. In the complementary assays, no mutagenic activity was found when the test item was in contact with water up to 5 hours. Only a weak mutagenic activity was noted when suspensions were used 24 hours after the preparation. Previous equivocal to weak effect was not reproduced. In the fifth assay, the increase in doses did not allow to confirm the mutagenic activity of the test item and to definitely conclude. The overall conclusion is that CIMENT FONDU® can not be considered as mutagenic under these experimental conditions as the non reproducible equivocal to weak effects observed in few assays were considered as non specific.

In-Vitro Mammalian Cell Assays:

A recent gene-mutation study conducted by Covance, Inc. (Covance, 2010b) using aluminium hydroxide (tested up to 10 mM in suspension and subsequently “cleaned” by Percoll density gradient centrifugation), did not find significant mutations at the thymidine kinase (tk) locus of mouse lymphoma L5187Y cells at any of the doses tested. This study type detects both gene mutations and chromosomal damage.

There is some evidence that soluble aluminium salts may induce DNA damage, probably by an oxidative mechanism, but these findings were not confirmed in the recent GLP studies using the sensitive mouse lymphoma (tk) assay. 

Animal Studies – In-vivo Somatic Cell Tests :

The potential clastogenic activity of CIMENT FONDU® was tested using thein vivo micronucleus test in the rat, by oral route, at doses of 2000 - 1000 and 500 mg/kg, respectively administered at 10mL/kg.

Regarding the frequency of micronuclei, no statistically significant increase in the frequencies ofmicronucleated polychromatic erythrocytes was found in the animalsat any dose, both sexes combined or males and females separately, when compared with the control group.

CIMENT FONDU® induced no genotoxic activity under these experimental conditions.

An other relevant and methodologically strong study has been performed by Covance (2010a)

Covance (2010a) investigated the induction of micronuclei in the bone marrow of rats treated with aluminium hydroxide by oral gavage. This study was conducted in accordance with GLP and recognized testing guidelines (Klimisch Score=1). No induction of micronuclei was observed even at the highest dose administered – 2000 mg Al(OH)3/kg bw/day, two administrations 24 hours apart, equivalent to ca. 690 mg Al/kg bw/day.

Other Relevant Information :

In a weight of evidence assessment for a mutagenic effect in humans, the levels at which effects are seen in animal studies and the systemic bioavailability of the target substances need to be considered. The study conducted by Covance (2010b) in non-fasted rats observed no induction of micronuclei in bone marrow at the acute maximum tolerated dose (MTD) for aluminium hydroxide when administered by oral gavage, namely 2000 mg Al(OH)3/kg bw/day. The MTD had been determined previously in a range-finding experiment. Although current toxicokinetic information does not allow the prediction of time profiles of levels of aluminium in target tissues as a function of realistic external exposures, when administered orally or by inhalation the target substances exhibit low bioavailability.


Short description of key information:
Ciment fondu® is has not been considered as mutagenic in the Ames test. The in vivo micronucleus test is negative. Other relevant studies in vivo and in vitro with aluminium hydroxide are negative.
Overall, Ciment fondu® is not considered as genotoxic.

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

Based on the results from GLP tests conducted in accordance with accepted OECD guidelines, classification with respect to this endpoint is not required.