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Key value for chemical safety assessment

Additional information

There are no experimental nor literature toxicological data available on TATD-CLE. Therefore the read across approach was considered in order to trace a complete toxicological profile of the substance.

 

RA Cefalonium (EC: 226-948-7; CAS: 5575-21-3) [1]

No evidence for mutagenic potential was found in the following mutagenicity tests in prokaryotes (all with and without metabolic activation): the Salmonella microsomal assay (strains TA1535, TA1537 and TA1538), fluctuation tests in Escherichia coli (strains WP2, WP2 uvra, 343/113 lys 60, WP2 pKM101 and PW2 uvra PKM101, at doses up to 10 and 20 µg/ml) and Salmonella (strains TA98, TA100, TA1535 and TA1537, at doses up to 10 and 20 µg/ml) and the gene conversion test in Saccharomyces cerevisiae (strain JD1, up to a dose of 500 µg/ml). Cefalonium was not mutagenic in the mouse lymphoma assay (TK locus) at a dose range of 263 to 1138 µg/ml and 250 to 1081 µg/ml in the absence or presence of metabolic activation, respectively [1].

Cefalonium induced a dose-dependent increase in structural chromosomal aberration (chromatid deletion and gaps) in cultured human peripheral blood lymphocytes at a dose-range of 585 to 900 µg/ml in the absence of metabolic activation. Cefalonium was not mutagenic in two micronucleus tests in two different strains of rats receiving, respectively, a single oral dose of 5000 mg/kg bw and two daily oral doses up to 2000 mg/kg bw. Cefalonium did not induce unscheduled DNA synthesis in cultured liver cells from rats exposed to maximally 2000 mg/kg bw by gavage. There was no evidence for in vivo genotoxicity of cefalonium [1].

 

Positive results were obtained in an in vitro chromosome aberration assay; however, negative results were found in an in vivo micronucleus test at doses up to 1.5 g/kg [2].

 

RA: Ceftaroline fosamil (EC:/; CAS: 400827-46-5)

A series of in vitro and in vivo genotoxicity studies with ceftaroline fosamil and the active metabolite ceftaroline was conducted. Ceftaroline fosamil and ceftaroline caused an increase in chromosomal aberrations in vitro. However, the two compounds were non-mutagenic in the Ames test, did not induce DNA damage in rat hepatocytes and did not cause chromosomal aberrations in vivo. Given that other cephalosporins have a similar profile to that observed with the test articles the CHMP agreed that administration of ceftaroline for up to 14 days is not likely to pose a genotoxic risk to humans [3].

 

Reference

[1] EMEA, Committee for veterinary medicinal products. Cefalonium. Summary report. EMEA/MRL/646/99-Final.August 1999.

[2] NLM/FDA Drug Labelling. CEFTIN (cefuroxime axetil) powder, for suspension. Labeler - GlaxoSmithKline LLC (167380711). Rev. 2011.

[3] EMA, Committee for Medicinal Products for Human Use (CHMP). Assessment report Zinforo. Ceftaroline fosamil. Procedure No.: EMEA/H/C/002252. 21 June 2012.


Short description of key information:
Non mutagen

Endpoint Conclusion: No study available

Justification for classification or non-classification

According to CLP regulation (EC1272/2008), 3.5 germ cell mutagenicity section, to arrive at a classification, test results are considered from experiments determining mutagenic and/or genotoxic effects in germ and/or somatic cells of exposed animals. Mutagenic and/or genotoxic effects determined in in vitro tests shall also be considered. The system is hazard based, classifying substances on the basis of their intrinsic ability to induce mutations in germ cells.

Mutagenicity of TADT-CLE has been evaluated on the basis of the read across with analogues. Considering that the evaluation of the genotoxicity is based on a comprehensive evaluation of all the existing studies, TADT-CLE is expected to be non genotoxic.

In conclusion, according to CLP regulation (EC1272/2008), TADT-CLE is not classified as genotoxic.