Toxicological evaluation of some food
additives including anticaking agents,
antimicrobials, antioxidants, emulsifiers
and thickening agents
WHO FOOD ADDITIVES SERIES NO. 5
The evaluations contained in this publication
were prepared by the Joint FAO/WHO Expert
Committee on Food Additives which met in Geneva,
25 June - 4 July 19731
World Health Organization
Geneva
1974
1 Seventeenth Report of the Joint FAO/WHO Expert Committee on
Food Additives, Wld Hlth Org. techn. Rep. Ser., 1974, No. 539;
FAO Nutrition Meetings Report Series, 1974, No. 53.
SORBITOL
Explanation
This substance has been evaluated for acceptable daily intake by
the Joint FAO/WHO Expert Committee on Food Additives (see Annex 1,
Refs Nos. 7 and 13) in 1963 and 1965.
Since the previous evaluation, additional data have become
available and are summarized and discussed in the following monograph.
The previously published monograph has been expanded and is reproduced
in its entirety below.
BIOLOGICAL DATA
BIOCHEMICAL ASPECTS
The absorption of sorbitol is much slower than that of glucose or
fructose. Both normal and diabetic human subjects excreted in the
urine less than 3% of an oral dose of 35 g. No sorbitol was detected
in the faeces. In experiments with uniformly labelled 14C-sorbitol
(sorbitol-U-14C), at least 75% of the dose given orally was
metabolized to CO2. In normal subjects, there was no significant
increase in the blood sugar levels; in diabetic subjects the blood
sugar increased slightly. The concentration of sorbitol in the blood
was immeasurably small (Adcock & Gray, 1957).
In experiments on rats given sorbitol-U-14C by intraperitoneal
injection, 57.4% of the activity was excreted as CO2, 17.3% in the
urine, 4.2% was found as liver glycogen and 0.6% as liver fatty acids.
In diabetic rats, a smaller proportion was oxidized and the major
portion was excreted in the urine (Stetten & Stetten, 1951). Sorbitol
has a strong glycogenic effect in the fasted diabetic rat (Stetten &
Stetten, 1951; Todd et al., 1939). The polyol has a more efficient
antiketogenic effect in liver slices of fasted rats than glucose or
fructose (Blakley, 1951, 1952), and behaved similarly in the intact
rat (Todd, 1954). Sorbitol is oxidized to fructose by a DPN-linked
polyol dehydrogenase (Embden & Griesbach, 1914; McCorkindale & Edson,
1954).
The intravenous infusion of sorbitol in rabbits caused a prompt
fructosaemia and a variable secondary glucosaemia occurred later
(Seeberg et al., 1955). Experiments in rats (Wick et al., 1955) given
sorbitol-U-14C support the view that at least two pathways exist for
the oxidation of sorbitol in the body: (a) oxidation after conversion
to glucose, and (b) the direct oxidation of the primarily formed
fructose (Hers, 1955). Sorbitol was not metabolized by hepatectomized
animals (Wick & Drury, 1951).
Sorbitol has a sparing effect for some B-vitamins (thiamine,
pyridoxine, biotin) (Morgan & Yudkin, 1957, 1961a).
It has been shown that the slowly absorbed polyol promotes the
proliferation of intestinal bacteria which synthesize B-vitamins
(Griem & Lang, 1960; Griffith et al., 1957). When administered in
amounts of 20 to 40 g daily, sorbitol increased the excretion of
thiamine, riboflavin and N1-methylnicotinamide in man (Treon, 1963).
According to Heinrich & Staak (1960), sorbitol is an inhibitor of
the intestinal absorption of vitamin B12 in man, and in the rat,
guinea-pig and pig, as shown by administering physiological doses of
the 60Co-labelled vitamin. On the other hand, Wolff & Herbeuval
(1962), after Chow et al. (1956) and Greenberg et al. (1957), have
shown that sorbitol exerts an important stimulating action on
digestive absorption of vitamin B12 in man. The increase of
vitaminaemia, that of the faecal contents, that of urinary
elimination, and of its storage in the kidney in rats have been
studied in succession in order to show up this action, the mechanism
which is unknown.
In rats, sorbitol enhances the absorption of iron (Herndon et
al., 1958) and also that of strontium.
Rats fed sorbitol, at a level of 16% in their diet for three
months showed persistently high calcium absorption and retention with
heavy citric acid excretion. Thickening of the skeleton was produced
(Founier et al., 1967). These effects are similar to those produced by
lactose in the same conditions. In feeding experiments on rats,
sorbitol showed the same caloric value as glucose (Morgan & Yudkin,
1961b).
It has been shown that fructose present in the seminal vesicles
is formed from glucose via sorbitol (Hers, 1960). The same pathway is
present in the lens (Van Heyningen, 1959; Kuck, 1961; Kinoshita et
al., 1963). The finding of relatively high levels of free fructose in
mammalian nerve led to the identification of sorbitol in nervous
tissue (Sherman & Stewart, 1966).
TOXICOLOGICAL STUDIES
Acute toxicity
LD50 Reference
Animal Route (mg/kg bw)
Mouse - male oral 23 200 )
)
Mouse - female oral 25 700 )
)
Rat - male oral 17 500 ) Treon, 1963
)
Rat - female oral 15 900 )
)
Rat - male i.v. 7 100 )
)
Rat - female i.v. 7 300 )
Short-term studies
Rat
Five groups of 10 female Charles River rats, weighing 150 to
210 g, were administered, by stomach tube, three times daily for three
days sorbitol at respective doses of 0.675. 1.35. 2.70, 3 (conc. 45%)
3 (conc. 25%) g/kg bw in aqueous solution at the concentration w/vol
of 90% (undiluted sorbitol solution USP) for the three lower doses and
of 45 and 25% for the highest one. Parallel experiments were made
with glycerol. The animals were sacrificed about one hour after the
second dose on the third day. The stomach and attached portion of the
duodenum of each animal were removed and the mucosal surface was
examined grossly and microscopically to estimate the degree of
irritation. The observations made clearly indicate that, at equivalent
undiluted oral doses, glycerol produced gastrointestinal irritation to
a much greater degree than did sorbitol. The degree of severity of the
irritant effect of each compound was dose dependent and was reduced by
dilution of the dose (Staples et al., 1967).
Rabbit
The intravenous infusion of sorbitol together with amino acids
for 10 days to three rabbits between 2.9 and 3 kg of weight was
associated with a positive nitrogen balance. The histopathological
examination of the organs showed no abnormalities Griem & Lang, 1960).
Dog
Sorbitol was excreted by glomerular filtration; the renal
clearance in the dog was found to be 74-77 ml/min (Smith et al.,
1940).
Injection of 2.5 ml/kg bw of a 50% solution in different
conditions (six dogs weighing from 6.4 to 18.9 kg) had a marked
diuretic effect for about one hour (Leimdorfor, 1954).
Two adult mongrel dogs of either sex, weighing 8.9 to 16 kg,
were given by stomach tube, three times daily for three days, sorbitol
in 90% w/vol aqueous solution, at respective doses of 0.675 and
1.35 g/kg bw. Only at the highest dose, stomach appears hyperaemic.
As in rats, glycerol, administered in the same conditions, produced a
much more severe irritation (Staples et al., 1967).
Long-term studies
Rat
Fifteen weanling male rats Wistar given sorbitol at levels of 10%
or 15% in the diet for 17 months showed no evidence of deleterious
effect on weight gain, reproduction, lactation or histopathological
appearances of the main organs. The only difference with the controls
was slight diarrhoea and, consequently, a retardation in growth, with
rapid return to the normal. In supplement, a reproduction study made
on 30 rats (equally divided by sex) and extended over four generations
did not reveal any abnormalities (Le Breton, 1956).
OBSERVATIONS IN MAN
In amounts of 40 g daily, spread throughout the day's intake of
food, sorbitol was well tolerated for a long period by human subjects
(Treon, 1963). A total of 25 g daily in two doses caused no laxative
effect in 86 subjects. In about 5% of these subjects a somewhat
increased amount of gas appeared in the bowel (Peters & Lock, 1958).
Quantities greater than 50 g daily were laxative. This effect was
presumably due to the relatively slow rate at which sorbitol was
absorbed from the small bowel (Tacquet, 1957).
Sorbitol has been used for many years in the diet, especially of
diabetics. There have been no indications of significant harmful
effects.
Comments:
Considering the biochemical and toxicological data obtained on
animals and man and the known facts about the nutritional properties
of sorbitol, there appears to be no need for the limitation of
sorbitol as a food additive on toxicological grounds.
EVALUATION
Estimate of acceptable daily intake for man
Not limited*
REFERENCES
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Blakley, R. L. (1951) Biochem. J., 49, 257
Blakley, R. L. (1952) Biochem. J., 52, 269
Chow, B. F., Horonick, A. & Okida, K. (1956) Amer. J. Clin. Sc., 4,
434-439
Embden, G. & Griesbach, W. E. (1914) Z. physiol. Chem., 91, 281
Founier, P. L., Gambier, J. & Fontaine, N. (1967) C.r.hebd. Séanc.
Acad. Sci., Paris, 264, 1301
Greenberg, S. M., Herndon, J. F., Rice, E. G., Parmelee, E. T.,
Gulesich, J. J. & Van Loon, E. J. (1957) Nature, 180,
1401-1402
Griem, W. & Lang, K. (1960) Klin. Wschr., 38, 336
Griffith, V. M., Morgan, T. B. & Yudkin, J. (1957) Abstracts of the
papers presented at the fourth International Nutrition Congress
Paris, 1957, p. 81
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Kinoshita, J. H., Futterman, S., Satoh, K. & Merola, L. O. (1963)
Biochim. Biophys. Acta, 74, 340
Kuck, J. (1961) Arch. Ophthal., 65, 100
Le Breton, E. (1956) Unpublished report
* See relevant paragraph in the seventeenth report (pages 10-11).
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McCorkindale, J. & Edson, N. L. (1954) Biochem. J., 57, 518
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135, 231
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Todd, W. R., Myers, J. & West, E. S. (1939) J. biol. Chem., 126, 275
Treon, J. F. (1963) Unpublished report
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Wick, A. N., Morita, T. N. & Barnet, H. N. (1955) Food Res., 20, 66
Wick, A. N. & Drury, D. R. (1951) Amer. J. Physiol., 166, 421
Wolff, R. & Herbeuval, R. (1962) Pathologie and Biologie, 10, 979-984
See Also:
Toxicological Abbreviations
Sorbitol (FAO Nutrition Meetings Report Series 40abc)
Sorbitol (WHO Food Additives Series 13)
SORBITOL (JECFA Evaluation)