CM4 — Toxicology

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In animal studies, CM4, a formulation containing plant glycosides in the absence of polypeptides or glycopeptides, was reported to have an oral LD₅₀ of >3000 mg/kg in mice. CM4 was administered by gastric intubation to groups of 10 Swiss-Webster mice at doses of 0, 250, 500, 1,000, 2,000, and 3,000 mg/kg, and the animals were observed for 24 hours for deaths and/or pharmacological effects. Since no effects were observed, the LD₅₀ in mice for intragastric administration was >3000 mg/kg at 24 hours. This is more than 14,000 times the projected daily oral dose for humans. The oral acute LD₅₀ of powdered CM4 in mice was reported as 31.0 g/kg. Rats administered CM4 daily for 320 days in their drinking water at a dose of 5.0 ml/kg per day showed no toxic manifestations or death after 800 days following birth.

Feeding studies with CM4 mixed with standard ration to minks, rabbits, and piglets revealed no adverse effects on animal growth. Teratogenicity has also been studied in at least three species — rats, rabbits, and minks — with no adverse effects observed.

Intragastric administration of CM4 to groups of 25 animals at concentrations of 0, 80, 160, and 320 mg/kg/day for five days was shown to induce a hypoglycemic response by the third or fourth day without gross pharmacological effects. Average blood glucose was 60 mg% at 80 mg/kg/day dose and 39 mg% at the 320 mg/kg/day dose (all p <0.005). The lowest concentration causing this effect (80 mg/kg) is more than 27,000 times the projected human daily oral dose.

CM4 was administered intragastrically to groups of 10 animals at doses of 16, 20, 32, 40, and 64 ml/kg produced an acute intragastric LD₅₀ of 23 ml/kg. Intravenous administration of CM4 to groups of 8 animals at doses of 2.5, 5.0, 7.5, 10.0, and 12.5 ml/kg produced an acute intravenous LD₅₀ of 8.6 ml/kg. The deaths appeared to be to respiratory depression consistent with acute ethanol toxicity. These effects were induced by amounts of ethanol 1643 times and 614 times the projected human daily oral dose of CM4.

On the basis of animal studies, CM4 has been demonstrated to be non-toxic. The only sure test for human toxicity or safety requires that a substance be administered to humans. Numerous studies in humans involving more than 1,000 subjects have been performed to observe the effects of CM4 on human performance. Serious toxicity or side effects were not reported in any of the studies.