Comparison of the acute toxicities of N-nitrosothiazolidine and N-nitrosomorpholine.

The effects of N-nitrosothiazolidine (NNT) and N-nitrosomorpholine (NNM) on different biological parameters were investigated and compared. The oral LD50 value of NNT (1950 +/- 85 mg/kg) showed that it was about 6 times less toxic than NNM (LD50 = 320 mg/kg, po; Druckrey et al., 1967). Lethal and near-lethal doses (greater than or equal to 1500 mg/kg, po) of NNT caused central nervous system depression (reduced spontaneous motor activity, loss of righting and pain reflexes, without loss of consciousness), stereotypical behavior such as, purposeless chewing jaw movements lasting more than one hour, muscular rigidity, and in some rats, rare and brief clonic convulsions, 3 to 24 h after dosing. These neurotoxic signs, as a whole, were reminiscent of opioid intoxication. Rats that died after NNT-treatment had kidney necrosis in the distal tubules, but all survivors had normal kidneys. NNT (500 and 1000 mg/kg, sc) had no effect on the relative liver weights, but it inhibited liver mitosis at 24, 48, and 72 h after treatment. NNM (100 mg/kg, sc) decreased the relative liver weights on 3 posttreatment days; it inhibited liver mitosis after 24 h and enhanced it after 48 h in male rats. Both NNT and NNM increased the relative adrenal weights, but only NNM enhanced adrenocortical mitosis. In general, NNT had no effect on serum enzymes (SGOT, SGPT, LDH, HBDH), but it increased blood urea nitrogen (BUN) and serum creatinine 24 h after administration. Pretreatment of rats with 3 doses of NNT (150 mg/kg X d, po) increased the pentobarbital-induced sleep (PST) by 26% (not significant), while 3 doses of NNM (50 mg/kg X d, po) increased PST by 188%. In addition, NNM caused a severe centrilobular liver necrosis and glycogen depletion, associated with a marked rise in serum enzymes (SGOT, SGPT, LDH, HBDH) and fall in serum glucose. Compared with NNM, NNT, which was found in fried bacon (Kimoto et al., 1982; Gray et al., 1982), seemed to be a relatively nontoxic nitrosamine.