Long-term toxicity and carcinogenicity study of cyclamate in nonhuman primates

Twenty-one monkeys (cynomolgus, rhesus, African green) were fed cyclamate ( 100 mg/kg and 500 mg/kg) in the diet five times per week from a few days af ter birth and continuing for up to 24 years. Malignant tumors were diagnose d in three 24-year-old cyclamate monkeys; these were metastatic colon carci noma (rhesus; 500 mg/kg), metastatic hepatocellular carcinoma (cynomolgus; 500 mg/kg), and a small, well differentiated adenocarcinoma of the prostate (cynomolgus; 100 mg/kg), Benign tumors were found at necropsy in three fem ales; these were adenoma of the thyroid gland (rhesus; 100 mg/kg) and two c ases of leiomyoma of the uterus (rhesus; 100 mg/kg and 500 mg/kg). No tumor s were detected in an age-matched control group of 16 monkeys. Examination of the testes revealed complete testicular atrophy in one of the old cyclam ate monkeys, and focal germ cell aplasia (Sertoli-only tubules) in two othe r cyclamate monkeys. Focal spermatogenic interruption (maturation arrest) a t various germ cell levels mixed with normal spermatogenesis was observed i n both the cyclamate-treated and the control monkeys, all of which were ove r 20 years old. Measurements of terminal cyclohexylamine concentrations sho wed that three of the males dosed with cyclamate at 500 mg/kg were high con verters, with plasma concentrations comparable to the levels that produce t esticular atrophy in rats. However, only one of the three high converters s howed histologic evidence of irregular spermatogenesis. The overall conclus ion is that the testicular abnormalities and the sporadic cases of differen t malignancies found after more than 20 years of dosing do not provide clea r evidence of a toxic or carcinogenic effect of sodium cyclamate in monkeys .