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.
POLYOXYETHYLENE (8) AND POLYOXYETHYLENE (40) STEARATES
Explanation
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.
BIOLOGICAL DATA
BIOCHEMICAL ASPECTS
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).
TOXICOLOGICAL STUDIES
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
Mouse
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).
Rat
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,
1956a).
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).
Hamster
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).
Cat
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).
Dog
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).
Monkey
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
Rat
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,
b).
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.,
1955).
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).
OBSERVATIONS IN MAN
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).
Comments:
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
questionable.
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.
EVALUATION
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.*
REFERENCES
Brandner, J. D. (1973) Unpublished report submitted by ICI America
Inc.
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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,
139
Harris, R. S., Sherman, H. & Jetter, W. W. (1951) Arch. Biochem.
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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