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    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

    Adcock, L. H. & Gray, C. H. (1957) Biochem. J., 65, 554

    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. Sťanc.
         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

    Heinrich, H. C. & Staak, M. (1960) Amer. J. clin. Nutr., 8, 247

    Herndon, J. F., Rice, E. G., Tucker, R. G., Loon, E. J. van &
         Greenberg, S. M. (1958) J. Nutr., 64, 615

    Hers, H. G. (1955) J. biol. Chem., 214, 373

    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).

    Leimdorfor, A. (1954) Arch. int. Pharmacodyn., 100, 161

    McCorkindale, J. & Edson, N. L. (1954) Biochem. J., 57, 518

    Morgan, T. B. & Yudkin, J. (1957) Nature (Lond.), 180, 543

    Morgan, T. B. & Yudkin, J. (1961a) Biochem. J., 79, 5P

    Morgan, T. B. & Yudkin, J. (1961b) Proc. nutr. Soc., 20, ú

    Peters, R. & Lock, R. H. (1958) Brit. med. J., 2, 677

    Seeberg, V. P., McQuarrie, E. B. & Secer, C. C. (1955) Proc. Soc. exp.
         Biol. (N.Y.), 89, 303

    Sherman, W. R. & Stewart, M. A. (1966) Biochemical and biophysical
         research communications, 22, 492

    Smith, W. W., Finkelstein, N. & Smith, H. W. (1940) J. biol. Chem.,
         135, 231

    Staples, R., Misher, A. & Wardell, J. jr (1967) J. Pharm. Sci., 56,
         398

    Stetten, M. R. & Stetten, D., jr (1951) J. biol. Chem., 193, 157

    Tacquet, H. (1957) Unpublished report

    Todd, C. M. (1954) Aust. J. exp. Biol. med. Sci., 32, 827

    Todd, W. R., Myers, J. & West, E. S. (1939) J. biol. Chem., 126, 275

    Treon, J. F. (1963) Unpublished report

    Van Heyningen, R. (1959) Nature, 184, 194

    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)