Flufenamic acid

Endpoint summary

Description of key information

One internal repeated dose toxicity study was conducted with Flufenamic acid:
Oral subchronic (rat, 8 weeks, non GLP): no NOAEL, LOAEL = 70 mg/kg
[Troponwerke, Report No. 10048, 1971-04-04] 
This study was also published and is cited in RTECS
(Arzneimittel-Forschung. Drug Research. (Editio Cantor Verlag, Postfach 1255, W-7960 Aulendorf, Fed. Rep. Ger.) V.1- 1951- v.27, p. 1333, 1977 (ARZNAD))
Results of further repeated dose toxicity studies are cited in RTECS database and published in literature (Nov 2011):
Oral, 25 days (male rat): LOAEL = 100 mg/kg/day
(Journal of the Medicinal Society of Toho University, v.17(2), p. 153, 1970) 
Oral, 14 days or 31 days and 31 days recovery (rat): LOAEL (14 d) = 50 mg/kg/day; LOAEL (31 d) = 100 mg/kg
(Oyo Yakuri. Pharmacometrics (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-81, Japan) V.1- 1967- v. 18, p. 597, 1979 (OYYAA2))
Oral, 30 days (rat): TDLo = 1500 mg/kg/30D
(Oyo Yakuri. Pharmacometrics (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-81, Japan) V.1- 1967- v. 6, p. 1495, 1972 (OYYAA2))
Oral, 90 days (rat): LOAEL = 1350 mg/kg/90D
(Oyo Yakuri. Pharmacometrics (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-81, Japan) V.1- 1967- v. 8, p. 1549, 1974 (OYYAA2))

Additional information

One internal repeated dose toxicity study was conducted with Flufenamic acid:

Male and female rats were orally treated with 70 mg/kg Flufenamic acid for 8 weeks. Within this study 40% of the animals died. The died animals showed signs of subsided peritonitis and adhesions in the region of the stomach and the intestine. Additionally, reduced body weight, reduced RBC count and increased leucocytes were observed as well as increased relative organ weights of the liver, the kidney, the adrenals, the spleen and the ovaries. Histopathology of the surviving animals showed damage of the kidneys (necrosis of the renal papilla and associated tubulat changes). The oral LOAEL of this study was 70 mg/kg/day.

Results of further repeated dose toxicity studies are cited in RTECS database and published in the literature (Nov 2011):

The daily oral application of 50 and 100 mg/kg Flufenamic acid to male rats for 25 days resulted in extremely inhibited growth and mortality of 40% of the animals in the high dose group. At 50 mg/kg no growth inhibition was observed.

Daily oral application of Flufenamic acid to rats at doses of 50, 70 and 100 mg/kg for 14 days led ulcerations of the small intestine in all dose groups and to a decreased body weight and food intake and mortality (1/6) in the highest dose group. The oral LOAEL of this study was 50 mg/kg/day.

Daily oral application of Flufenamic acid to rats at a dose of 100 mg/kg for 31 days led to mortality in some animals of both sexes (5/15). The died animals showed ulcerations in the small intestine and hyperplasia of the mesenterial lymph nodes and the spleen. Additionally, reduced RBC count, Hb and Hc, reduced serum iron levels and elevated leucocytes were observed. Histopathology of the surviving animals showed hemosiderosis in the spleen, ulcerations of the small intestine and an enlargement of the mesenterial lymph nodes. These effects were almost reversible within the 31 days recovery period. The oral LOAEL of this study was 100 mg/kg/day.

Repeated oral application of Flufenamic acid to rats for 30 days resulted in behavioral changes such as somnolence (general depressed activity) and death. The lowest published toxic dose in this study was 1500 mg/kg/30D.

Subchronic oral application of Flufenamic acid to rats for 90 days resulted in organ weight changes of the liver, the spleen and the ovaries. The lowest published toxic dose in this study was 1350 mg/kg/90D.

In summary, the daily oral administration of 100 mg/kg Flufenamic acid to rats for 31 days resulted in mortalities, ulcerations of the small intestine and hemosiderosis in the spleen together with changed hematological parameters. The effects are mostly reversible within 1 month after cessation of treatment. The chronic application of toxic dosages to rats led to gastrointestinal ulcer or erosions as well as to damage of the kidneys.

These effects are regarded partly due to the pharmacological mode of action of the NSAID Flufenamic acid (e.g. ulcerations in the intestine, damage to the kidneys) and partly point out to possible methemoglobin-forming properties (e.g. decreased Hb and Hc and hemosiderosis in the spleen).

Justification for classification or non-classification

Since the observed effects in the repeated dose toxicity studies occurred at relatively high doses, were partly expected pharmacological effects (observed in pharmacological effective dosages) and the possible methemoglobin-forming property is mainly an acute effect and therefore, is regarded to be already covered by the acute toxicity classification, no further classification of Flufenamic acid according to Directive 67/548/EEC and Regulation (EC) No. 1272/2008 (CLP) is required.