Flufenamic acid

Endpoint summary

Additional information

Flufenamic acid was shown to be not mutagenic with and without metabolic activation in a bacterial reverse mutation assay with the S. typhimurium strains TA 1535, TA 100, TA 1537, TA 98 and TA 102. The study was conducted using the plate incorporation method with substance concentrations up to and including 5000 µg/plate without S9 mix and up and including 1581 µg/plate with S9 mix and the preincubation method with doses of up to and including 1300 µg/plate.

Additionally, results of genotoxicity studies with Flufenamic acid are cited in RTECS and were found in the literature (Nov 2011):

Flufenamic acid was shown to be not mutagenic with and without metabolic activation in a bacterial reverse mutation assay with the S. typhimurium strains TA 1535, TA 1537, TA 1538, TA 100, TA 98 and E. coli B7r WP2 uvr-. The study was conducted with substance concentrations of 5-5000 µg/plate with and without S9 mix. Moreover, no mutagenicity was detected in a repair test with a Bacillus subtilis wild strain and its repair mutant (rec assay) or a E. coli wild strain and its repair mutant (pol assay), respectively.

The effect of Flufenamic acid on DNA synthesis and DNA repair was investigated in mouse splenic cells. The cells were treated with 7 ppm (corresponding to a blood level of 7 µg/ml at a single dose of 600 mg) or 100 ppm (corresponding to a blood level of 100 µg/ml at an excessive overdose of 8500 mg), respectively. At 7 ppm only a very slight inhibition of DNA synthesis and DNA repair could be observed. At 100 ppm DNA synthesis and DNA repair was completely inhibited.

The effect of a daily dose of 400 mg Flufenamic acid for 3 months on DNA synthesis and DNA repair was investigated in lymphocytes of 3 patients with definite or classical chronic rheumatoid arthritis. A slight to moderate inhibition of DNA-synthesis was observed in 3/3 patients and a moderate inhibition of DNA repair in 1/3 patients. More information are not available since only a summary of this study was published.

In summary, Flufenamic acid is not mutagenic in bacterial test systems. The reliability of an in vivo study in humans investigating the effect of Flufenamic acid on DNA synthesis and DNA repair is not assignable since only a summary of this study is available.

Short description of key information:
Gene mutation in vitro (bacterial reverse mutation assay, GLP, OECD TG 471, EU Method B. 13/14, EPA OPPTS 870.5100): negative in all tested Salmonella typhimurium strains with and without metabolic activation
[Bayer AG, Report No. AT01981, 2005-04-22]

Additionally, results of genotoxicity studies with Flufenamic acid are cited in RTECS and were found in the literature (Nov 2011):

Gene mutation in vitro (bacterial reverse mutation assay): negative in all tested Salmonella typhimurium and E. coli strains with and without metabolic activation
Gene mutation in vitro (bacterial repair test - rec and pol assay): negative
(Kadotani, S. et al. (1984); Mutation Research (Elsevier Science Publishers B.V.) - v. 138, p. 133-136)

DNA inhibition (in splenic cells of mice): Slight inhibition of DNA synthesis and DNA repair at 7 ppm (7 µg/ml); complete inhibition of DNA synthesis and DNA repair at 100 ppm (100 µg/ml)
(Klein, G. et al. (1974); Arzneimittelforschung (Drug Research) - v. 24, no. 12, p. 1975-1978)

DNA inhibition (in humans): Slight to moderate inhibition of DNA synthesis in 3/3 patients and moderate inhibition of DNA repair in 1/3 patients
(Studia Biophysica. (Akademie-Verlag GmbH, Postfach 1233, Berlin DDR-1086, Ger. Dem. Rep.) V.1- 1966- v. 50, p. 172, 1975 (STBIBN))

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

Based on the study results a classification according to Directive 67/548/EEC and Regulation (EC) No. 1272/2008 (CLP) is not required.