Benzoic acid, 2-[[3-(trifluoromethyl)phenyl]amino]-, butyl ester

Endpoint summary

Description of key information

No internal repeated dose toxicity studies of Flufenaminsäurebutylester are available. 
Results of repeated dose toxicity studies are cited in RTECS database (May 2011):
Oral, 31 days and 31 days recovery (rat): NOAEL = 60 mg/kg/day
(Oyo Yakuri. Pharmacometrics (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-81, Japan) V.1- 1967- v. 18, p. 597, 1979 (OYYAA2))
Dermal, 3 months and 6 weeks recovery (rat): NOAEL = 100 mg/kg/day
(Oyo Yakuri. Pharmacometrics (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-81, Japan) V.1- 1967- v. 18, p. 943, 1979 (OYYAA2))
Additionally, results of a further repeated dose toxicity study are published in the literature (May 2011)
Oral, 6 months and 1 month recovery (rat): NOAEL = 30 mg/kg/day
(Oyo Yakuri. Pharmacometrics (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-81, Japan) V.1- 1967- v. 19, p. 455, 1980 (OYYAA2))

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEL

60 mg/kg bw/day

Study duration:

subacute

Species:

rat

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEL

100 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Additional information

No internal repeated dose toxicity studies of Flufenaminsäurebutylester are available.

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

The daily oral application of HF-264 (equivalent to Flufenaminsäurebutylester) to rats at dosages of 30, 60, 120 and 180 mg/kg/day over 31 days resulted in mortality from doses of 120 mg/kg/day onwards. The died animals showed ulcerations in the small intestine and hyperplasia of the mesenterial lymph nodes and the spleen. Additionally, reduced body weight gain, reduced RBC count, Hb and Hc, reduced serum iron levels and elevated leucocytes were observed in animals of the two highest dose groups. 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 NOAEL of this study was 60 mg/kg/day.

Daily dermal application of HF-264 (equivalent to Flufenaminsäurebutylester) to rats at dosages of 25, 100 and 200 mg/kg/day (administered 500 mg/kg/day of 5%, 20% and 40% ointments) over 3 months led to no local irritations. In the high dose group a slight growth inhibition, a slight increase of the kidney weight, mild decreases of RBC count, Hb, Hc, total protein and the serum iron as well as a slight increase of reticulocytes were observed. Additionally, one male and one female of the high dose group showed ulcer in the small intestine and mild dilatations of the renal tubules. In the six weeks recovery groups no substance-related alterations were found except for healed ulcer in one male of the high dose group. The dermal NOAEL of this study was 100 mg/kg/day.

The daily oral application of HF-264 (equivalent to Flufenaminsäurebutylester) to rats at dosages of 15, 30, 60, and 90 mg/kg/day over 6 months resulted in mortality from doses of 60 mg/kg/day onwards. The died animals showed ulcerations in the small intestine. Additionally, slightly reduced Hb and Hc were observed in animals of the two highest dose groups. Histopathology of the surviving animals showed hemosiderosis in the spleen and ulcerations of the small intestine. Animals of the 90 mg/kg/day dose group showed slightly reduced body weight gain and a decrease in serum iron. These effects were almost reversible within the 1 month recovery period. The oral NOAEL of this study was 30 mg/kg/day.

In summary, after repeated administration (oral or dermal) of Flufenaminsäurebutylester ulcerations of the small intestine and hemosiderosis in the spleen together with changed hematological parameters can be observed. The effects are mostly reversible within 1 month after cessation of treatment.

These effects are regarded partly due to the pharmacological mode of action of the NSAID Flufenaminsäurebutylester (ulcerations in the intestine) and partly point out to possible methemoglobin-forming properties (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 Flufenaminsäurebutylester according to Directive 67/548/EEC and Regulation (EC) No. 1272/2008 (CLP) is required.