Toxicological evaluation of some food
    additives including anticaking agents,
    antimicrobials, antioxidants, emulsifiers
    and thickening agents


    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


    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.



         These substances have been evaluated for acceptable daily intake
    by the Joint FAO/WHO Expert Committee on Food Additives (see Annex 1,
    Ref. No. 7) in 1963.

         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.



         Studies in rats indicated that 60% of the stearate fraction was
    absorbed when polyoxyethylene (8) stearate was fed at a concentration
    of 25% in the diet. In infants, 92.3-100.5% of the polyoxyethylene
    fraction was accounted for after feeding 0.7 g of ester daily.
    Excretion of this fraction was complete in 24 to 32 hours and there
    was no evidence of cumulation in the body. The feeding of
    polyoxyethylene (8) stearate did not increase oxalate excretion
    (National Academy of Science, 1958).

         The average coefficient of digestibility of the fatty acid moiety
    in the rat was 80% (Oser & Oser, 1957a).

         Studies in human subjects showed that polyoxyethylene (40)
    stearate, given by mouth, was poorly absorbed. Only 2.3-3.1% of the
    polyoxyethylene (40) moiety was recovered from the urine and
    90.2-96.6% in the faeces (Culver et al., 1951).

         The digestibility coefficient of the fatty acid moiety was 96%
    (Oser & Oser, 1957a).


         Acute studies in the rat, rabbit and hamster indicate that
    polyoxyethylene (8) stearate has an extremely low toxicity (Eagle &
    Poling, 1956).

         No deaths occurred with 31 600 mg/kg (of "Myrj 45") administered
    orally to the rat and after oral administration of 34 800 mg/kg
    (of "Myrj 52"), two out of 20 rats died (Brandner, 1973).

    Short-term studies


         Groups of eight to 11 mice were fed diets containing 2.5%, 5% and
    10% of polyoxyethylene (40) stearate for three to four months. No
    abnormalities attributable to the feeding of this compound were found
    (Brush et al., 1957).


         In 12 male and 20 female rats, feeding at a level of 20% of
    polyoxyethylene (40) stearate in the diet caused a laxative effect and
    some consequent impairment of weight gain and the general well-being
    of the animals. Levels of 5% and 10% were well tolerated (Oser & Oser,

         Polyoxyethylene (8) stearate at a level of 25% of the diet was
    fed to 13 rats for 59 days and to another group of 30 rats for 70
    days. Neither group showed any gastrointestinal disturbance or
    increase in mortality, but weight gain was reduced in both groups
    (Harris et al., 1951).

         Bread made with chlorine-dioxide-treated flour and containing, in
    addition, polyoxyethylene (8) stearate propyl gallate, butylated
    hydroxyanisole and sodium propionate (all the additives in amounts up
    to 50 times their usual levels) was fed to 182 male rats at a level of
    75% of the diet and had no effect on growth or mortality over a period
    of one year (Graham et al., 1954; Graham & Grice, 1955).

         When polyoxyethylene (8) stearate was added in a concentration of
    5% or 10% to a diet designed to induce hepatic necrosis and this diet
    fed to 10 rats there was a slight retardation of hepatic damage. The
    increase in renal weights observed when polyoxyethylene (8) stearate
    was fed at a level of 25% of the diet was reversed when the ester
    level was reduced to 10% (Frazer, 1959).


         Polyoxyethylene (40) stearate was fed to groups of eight to 12
    hamsters at levels of 1%, 2.5%, 5% and 10% in the diet for 12 months:
    a slight decrease in average body weight and diarrhoea were noted at
    the 5% and 10% levels (Brush et al., 1957).

         Hamsters fed diets containing 5 to 15% polyoxyethylene (8)
    stearate in a number of short-term experiments showed pathological
    changes and in some cases an increased mortality. Other studies over
    10 to 28 weeks have shown that hamsters tolerate 10% and even 20% of
    polyoxyethylene (8) stearate in the diet (Oser & Oser, 1957c; Orten &
    Dajani, 1957).


         Polyoxyethylene (8) stearate at a level of 10% or 20% of the diet
    was fed to six cats for one year. No abnormalities were observed in
    the growth and health of the animals, nor in the main organs on
    histopathological examination (Krehl et al., 1955).


         Diets containing 5% and 10% of polyoxyethylene (40) stearate fed
    for one year to three dogs and two dogs respectively caused no ill
    effects (Brush et al., 1957).


         Two monkeys were fed 1 g of polyoxyethylene (40) stearate for
    eight weeks. No damage, either gross or histological, was observed in
    the important viscera (Krantz, 1947a).

    Long-term studies


         Polyoxyethylene (40) stearate was fed at levels of 5%, 10% and
    20% of the diet over the life-span to three groups of rats, each group
    comprising 12 males and 20 females. No significant effects were
    observed in the group receiving the 5% level and only minor
    modifications in weight gain at the 10% level. When the ester formed
    20% of the diet, litter survival and lactation and survival of females
    were affected; these may have been consequences of the laxative effect
    that occurs at this level of feeding (Oser & Oser, 1956a, b; 1957a,

         In another life-span study, polyoxyethylene (40) stearate was fed
    at levels of 2%, 5%, 10% and 25% of the diet to groups consisting of
    12 males and 12 females. Weight gain was unaffected except in the 25%
    group, and even in this group the survival rate at two years was
    unaffected. As in other studies, a laxative effect was noted,
    especially at the higher dosage levels. Caecal distension was
    observed, especially at the 25% level. Polyoxyethylene (40) stearate
    did not give rise to bladder stones, even at the highest dosage
    levels. There was no increase of tumour incidence, nor were there
    other pathological findings of significance in any of the animals
    ingesting polyoxyethylene over the life-span (Fitzhugh et al., 1959).

         Thirty rats were fed a diet containing 2% of polyoxyethylene (40)
    stearate over the life-span. Growth pattern, survival, blood studies
    and gross examination did not show any differences compared with the
    controls (Krantz, 1947b).

         Polyoxyethylene (8) stearate at levels of 10% and 20% of the diet
    and the polyoxyethylene moiety at a level of 6% were fed to 30 rats
    for one-and-a-half years and gave rise to no significant pathological
    changes observable macroscopically or microscopically (Krehl et al.,

         Two other independent long-term studies have been carried out. In
    one (Oser & Oser, 1956a,b; 1957a,b), polyoxyethylene (8) stearate was
    fed at levels of 5%, 10% or 20% of the diet over the whole life-span.
    In the other (Fitzhugh et al., 1959), polyoxyethylene (8) stearate was
    fed at levels of 2%, 5%, 10% or 25% of the diet, also over the whole
    life-span. Levels of 20% and 25% in the diet gave rise to some effects
    on weight gain, reproductive capacity and survival of litters. Some
    alterations in relative organ weights, affecting the kidneys, liver
    and caecum, were also noted, but the animals remained generally
    healthy. No changes were observed in the blood chemistry, blood
    counts, or total tumour incidence.

         An increase in bladder tumours, some of which were malignant, was
    observed in those animals receiving 20% or 25% of the diet as
    polyoxyethylene (8) stearate. There was not, however, an overall
    increase in tumour incidence in this group. All the animals that had
    tumours also had bladder stones; the total incidence of bladder stones
    at the 25% feeding level was 16%. No bladder stone formation or
    bladder tumours were observed at feeding levels below 20% (Oser &
    Oser, 1956a, b; 1957a, b).


         Polyoxyethylene (8) stearate was administered to 12 human
    subjects as 1% of an X-ray-opaque meal and the effects on gastric
    emptying and intestinal motility were studied. No significant
    differences from control subjects were found (Oler & Craemer, 1955).

         Ten patients convalescing from hepatitis were given 3-6 g of
    polyoxyethylene (8) stearate daily for periods of five to 66 days
    without any demonstrable ill effect (Kruesi & van Itallie, 1956).

         Polyoxyethylene (40) stearate as 1% of an X-ray-opaque meal had
    no untoward effects in 12 human subjects and had no effect on gastric
    or intestinal motility (Oler & Craemer, 1955).


         Deleterious effects observed in the early experiments on hamsters
    have been shown to be related to management rather than toxicity. The
    biological effects of polyoxyethylene (8) stearate have been
    extensively investigated in more recent short-term and long-term
    studies which form an adequate basis for evaluation. It is considered

    that this ester is not carcinogenic and that the bladder tumours at
    20% and 25% levels o£ feeding are attributable to the presence of
    bladder stones which do not occur at lower levels of intake, even
    though these are still greatly in excess of any level likely to be
    used in food. The validity of using levels of feeding above 10% in the
    assessment of the toxicological hazard of a food additive is

         Although the studies with polyoxyethylene (40) stearate are not
    as extensive as those with polyoxyethylene (8) stearate, they are
    sufficiently complete to permit evaluation. The main difference
    between these two esters is the greater absorption of the
    polyoxyethylene (8) moiety and the formation of bladder stones at very
    high dosage levels (20% or more of the diet). The polyoxyethylene (40)
    moiety was not well absorbed and sometimes had a laxative effect at
    dosage levels of 5% or more; such an effect is not relevant to the
    ingestion of lower dosage levels and has no toxicological significance
    in this context.


    Level causing no toxicological effect

         Rat: 50 000 ppm (5%) of the diet equivalent to 2500 mg/kg bw.

    Estimate of acceptable daily intake for man

         0-25 mg/kg bw.*


    Brandner, J. D. (1973) Unpublished report submitted by ICI America

    Brush, M. K. et al. (1957) J. Nutr., 62, 601

    Culver, P. J. et al. (1951) J. Pharmacol., 103, 377

    Eagle, E. & Poling, C. E. (1956) Food Res., 21, 348

    Fitzhugh, O. G. et al. (1959) Toxicol. appl. Pharmacol., 1, 315

    Frazer, A. C. (1955) Voeding, 16, 686

    Frazer, A. C. (1959) Chem. and Ind., p. 317


    *    As total of polyoxyethylene (8) and (40) stearates.

    Graham, W. D., Teed, H. & Grice, H. C. (1954) J. Pharmacol., 6, 534

    Graham, W. D. & Grice, H. C. (1955) J. Pharmacol., 7, 126

    György, P., Forbes, M. & Goldblatt, H. (1958) J. Agric. Food Chem., 6,

    Harris, R. S., Sherman, H. & Jetter, W. W. (1951) Arch. Biochem.
         Biophys., 34, 249

    Krantz, J. C. jr (1947a) Unpublished report No. WER-149-122 to the
         Atlas Chemical Co.

    Krantz, J. C. jr (1947b) Unpublished reports Nos. WER-149-177/207/
         242/A/B to the Atlas Chemical Co.

    Krehl, W. A., Cowgill, G. R. & Whedon, A. D. (1955) J. Nutr., 55, 35

    Kruesi, O. R. & Van Itallie, T. B. (1965) Food Res., 21, 565

    National Academy of Sciences, Food Protection Committee (1958)
         Report (National Research Council Publication No. 646)

    Oler, W. M. & Craemer, V. C. (1955) Gastroenterology, 28, 281

    Orten, J. M. & Dajani, E. M. (1957) Food Res., 22, 529

    Oser, B. L. & Oser, M. (1956a) J. Nutr., 60, 367

    Oser; B. L. & Oser, M. (1956b) J. Nutr., 60, 489

    Oser, B. L. & Oser, M. (1957a) J. Nutr., 61, 149

    Oser, B. L. & Oser, M. (1957b) J. Nutr., 61, 235

    Oser, B. L. & Oser, M. (1957c) Food Res., 22, 273

    See Also:
       Toxicological Abbreviations