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Joint FAO/WHO Expert Committee
on Food Additives (JECFA)'s Evaluation Report on Stevioside
Extracted from WHO Technical Report Series 891)

Sweetening agent: stevioside 

Stevioside is a sweet glycoside of the diterpene derivative steviol (ent-13-hydroxykaur-16-en-18-oic acid). It is a natural constituent of the plant Stevia rebaudiana Bertoni, belonging to the Compositae family. Stevioside has not been previously evaluated by the Committee.

After oral administration to rats, stevioside is not readily absorbed from the upper small intestine but is hydrolysed to the aglycone, steviol, before absorption from the gut. Steviol is completely absorbed and is excreted in the bile as conjugates; only a very small fraction is detectable in urine. After biliary excretion, the conjugates are hydrolysed, and steviol undergose enterohepatic circulation; its elimination half-life is 24 hours. Steviol is the only feacal metabolite of stevioside that has been identified, and excretion in the faeces is the major route. After intravenous administration, stevioside is rapidly distributed throughout the body, partially secreted by the renal tubular epithelium, and excreted in the urine.

At high concentrations, stevioside affected a variety of biochemical parameters in rat tissues in vitro. It weakly inhibited oxidative phosphorylation; steviol was about 30 times more potent in this respect. The most likely mechanism for this effect is inhibition of the mitochondrial translocation of adenine nucleotides. Steviol also inhibited glucose absorption from rat gut by reducing the ATP content of the intestinal mucosa. Stevioside may also act as a calcium antagonist, showing a hypotensive effect and inducing diuresis, natriuresis and a fall in reabsorption of glucose in the renal tubules. Stevioside may not, however, be able to penetrate cell membranes. Although most of these studies were performed after intravenous injection of stevioside, oral administration of extracts of S. rebaudiana to rats caused similar effects (hypotension and diuresis).

Stevioside has very low acute oral toxicity. Oral administration of stevioside at a concentration of 25g/kg (2.5%) in the diet to rats for 2 years, equal to 970 and 1100mg/kg of body weight per day in males and females, respectively, had no significant effect. Reduced body-weight gain and survival rate were observed at a level of 50g/kg (5%) in the diet. There was no indication of carcinogenic potential in the long-term study and no evidence of potential to promote tumours of the urinary bladder in a separate bioassay.

In reproductive toxicity studies, administration of stevioside at doses of up to 2500mg/kg of body weight per day to hamsters and 3000mg/kg of body weight per day to rats had no effect. Although an aqueous infusion of S. rebaudiana administered orally to female rats was reported to cause a severe, long-lasting reduction in fertility, the contraceptive effects was probably not due to stevioside. Neither teratogenic nor embryotoxic effect were observed in rats given stevioside at doses of up to 1000mg/kg of body weight per day by gavage.

The results of genotoxicity tests with stevioside in various in vitro systems were uniformly negative.

The aglycone, steviol, exhibited greater acute toxicity than stevioside in hamsters but not in rats. Steviol was clearly genotoxic after metabolic activation, inducing forward mutations in bacteria and gene mutations and chromosomal aberrations in lung fibroblasts of Chinese hamsters. Several mechanistic studies indicated that the structural features necessary for the expression of mutagenic activity include a hydroxyl group at position C13 and an unsaturated bond joining the C16 and C17 carbon atoms of steviol. The fact that stevioside is glycosylated at position C13 could explain the absence of mutagenicity. The active metabolite of steviol responsible for its mutagenic activity is not known. While some data suggest that epoxidation may be involved in the metabolic activation of steviol, other data indicate that the active metabolite is not an epoxide. Preliminary data indicate that steviol may be activated to a mutagenic metabloite by human liver microsomes.

The Committee noted a number of shortcomings in the information available on stevioside. In several studies, the material tested (stevioside or steviol) was poorly specified or of variable quality, and no information was available on other constituents or contaminants. Furthermore, no studies of metabolism of stevioside and steviol in humans were available. In addition, data on long-term toxicity and carcinogenicity were available for stevioside in only one species. The mutagenic potential of steviol has been tested sufficiently only in vitro.

In view of the absence of information for the elaboration of specifications for stevioside and since the evaluation of the available toxicological data revealed several limitations, the Committee was unable to relate the results of the toxicological investigations to the commercial product and could not allocate an ADI to stevioside.

Before reviewing stevioside again, the Committee considered that it would be necessary to develop specifications to ensure that the material tested was representative of the commercial product. Further information on the nature of the substance that was tested, data on the metabolism of stevioside in humans and the results of suitable in vivo genotoxicity studies with steviol would also be necessary.

A toxicological monograph was prepared. No specifications were prepared as no information was forthcoming.



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