Acute oral toxicity in rats of 3,7-bis-(4-trifluoromethylphenyl)-1,5,3,7-dioxadiazocane compared with 3,7-bis-(3-trifluoromethylphenyl)-1,5,3,7-dioxadiazocane and N,N'-oxydimethylenebis(2-trifluoromethylaniline).

The acute oral toxicity of 3,7-bis-(4-trifluoromethylphenyl)-1,5,3,7-dioxadiazocane (4-TFMPD) was compared with its 3-substituted isomer, 3,7-bis-(3-trifluoromethylphenyl)-1,5,3,7-dioxadiazocane (3-TFMPD) and with N,N'-oxydimethylenebis(2-trifluoromethylaniline) (N,N'-oxy-DM-bis (2-TFMA)). 4-TFMPD, 3-TFMPD, N,N'-oxy-DM-bis (2-TFMA) and their precursors (4-trifluoromethylaniline (4-TFMA), 3-trifluoromethylaniline (3-TFMA) and 2-trifluoromethylaniline (2-TFMA), respectively) were administered intragastrically to male Wistar rats at a dose of 0.12 mmol/kg body weight/day for three consecutive days and the resulting effects on haematological variables were determined. 4-TFMPD induced the highest methaemoglobinemia as compared with 3-TFMPD and N,N'-oxy-DM-bis (2-TFMA). Haemolytic anaemia with Heinz bodies, neutrophilia, lymphocytosis, enlargement of the spleen and enhanced production of granulocytes/macrophages from multipotential bone marrow cells (as determined by CFU-C test) were observed in animals treated with 4-TFMPD and 4-TFMA, whereas no such effects were observed in the other treatment groups. In conclusion, 4-substituted aniline derivatives exert special haematotoxicity on the red blood cells and induce leucocytosis, which differs from the effects of their 2- and 3-substituted congeners.