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 compounds have been evaluated for acceptable daily intake
    by the Joint FAO/WHO Expert Committee on Food Additives (see Annex 1,
    Refs No. 6 and No. 9) in 1961 and 1964.

         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.



         Sodium nitrite is readily absorbed from the gut and rapidly
    disappears from the bloodstream. 30-40% of absorbed nitrite is
    excreted unchanged in the urine, the fate of 60-70% is not accurately
    known. It can combine with myoglobin to form nitrosomyoglobin and with
    haemoglobin to form methaemoglobin (MAFF, 1962).

         Following absorption of nitrites, the most important biochemical
    reaction that occurs is the conversion of haemoglobin to
    methaemoglobin. There is some controversy concerning the molar ratios
    involved in this reaction. Making an extreme assumption, it may be
    stated that 1 g of sodium nitrite could convert as much as 1855 g of
    haemoglobin to methaemoglobin (Lehman, 1958).

         The sub-acute hazard of nitrites rests on the amount of
    methaemoglobin formed and on the ability of the body to reconvert this
    methaemoglobin back to haemoglobin.

         Inorganic nitrite is oxidized to nitrate by tissue homogenates.
    The reaction depends on catalase content and is mediated by probably a
    D amino acid oxidase or xanthine oxidase system linked with catalase.
    Hydrogen peroxide formed by the oxidation is used by the catalase for
    the coupled oxidation of nitrite (Heppel & Porterfield, 1949). Nitrite
    oxidizes in vivo haemoglobin in preference to glutathione which is
    protected by pentose cycles and prevents Heinz bodies formation in
    human erythrocytes (Harley & Robin, 1962).

         Rats given for two to three weeks a diet deficient in vitamin A
    to deplete liver stores were then given for six days 0.3% sodium
    nitrite in the diet and on the third and fourth day vitamin A or
    carotene orally or s.c.. Assay of liver levels on the sixth day showed
    reduced storage of vitamin A following oral but not s.c. vitamin A
    dosing. Nitrite is known to degrade carotene under acid conditions and
    may have caused this by direct action (Emerick & Olson, 1962).

         Calves receiving 4 ppm (0.0004%) nitrite in drinking-water alone
    or with E. coli or with a thyroid depressant showed interference
    with carotene utilization in all experiments (McIlwain & Schipper,
    1963). Chicks receiving 0.4% potassium nitrite showed growth
    depression, reduced vitamin A storage in liver and enlargement of the
    thyroid gland despite dietary supplementation with vitamin A (Sell &
    Roberts, 1963). When chicks were given doses of 18-60 mg/kg/day of
    sodium nitrite over a few days the liver showed inhibition of vitamin
    A accumulation even if fed vitamin A-rich diets (Brüggemann & Tiews,


    Special studies on nitrosamines

    A.   Carcinogenesis and nitrosamines

         Since the discovery of the carcinogenic property of
    dimethylnitrosamine (Magee & Barnes, 1956), many other nitrosamines
    have been found to induce malignant tumours in various species of
    laboratory animals (Magee & Barnes, 1967). There is growing concern
    with regard to certain nitrosamines as etiological agents for cancer
    in the human environment (Lijinsky & Epstein, 1970). It is generally
    accepted that the use of nitrite as a food preservative may be
    associated with the formation of nitrosamines in foods as well as in
    the animal organism. The nitrosamines vary in their carcinogenic
    potential. They can induce malignant tumours at very low levels, such
    as 2 ppm (0.0002%) in the diet of rats (Terracini et al., 1967),
    equivalent to daily doses of 0.1 mg/kg bw. A single oral dose of
    30 mg/kg bw of nitrosamine proved to be carcinogenic in the rat
    (Druckrey et al., 1969). Tumours of the trachea developed in the
    offspring of hamsters treated either during pregnancy or lactation
    with nitrosamine (Mohr & Althof, 1971).

    1.   In vitro nitrosamine formation

         Nitrosamines are formed when sodium nitrite and various secondary
    amines are incubated with human gastric juice at pH 1.3 (Sander,
    1967). DEN (diethylnitrosamine) was detected when diethylamine and
    sodium nitrite were incubated with gastric juices from man, rat,
    rabbit, cat and dog. Human and rabbit juices (pH 1-2) produced more
    DEN than the less acidic gastric juice (pH 4-5) of the rat (Sen et
    al., 1969). Dimethylamine and sodium nitrite incubated together in the
    molecular proportion 1:4 with the bacterial flora of the rat intestine
    under anaerobic condition at pH7 gave rise to dimethylnitrosamine
    (DMN). DMN formation was enhanced by the addition of glucose and
    riboflavin, but suppressed by neomycin (Klubes et al., 1972). Ender &
    Ceh (1971) reported the formation of various nitrosamines when nitrite

    was incubated with alkylamines, heterocyclic amines, biogenic amines,
    certain amino acids and proteins from meat and fish respectively.
    Nitrosamine formation increased greatly at high incubation
    temperatures and at lower pH-values.

    2.   In vivo nitrosamine formation

         Diphenylnitrosamine, at levels ranging from 0.5 to 11 µg/l, was
    detected in stomach contents of 11 out of 35 patients, following the
    intragastric administration of a test solution containing 300 mg
    sodium nitrate, 10 mg diphenylamine, 100 mg sodium-bicarbonate and
    1000 mg glucose (Sander & Seif, 1969). Synthesis of nitrosopiperidine
    from nitrite or nitrate and piperidine in the gastrointestinal tract
    of the rat was observed (Alam et al., 1971a, 1971b). Intragastric
    injection of sodium nitrite and sarcosine resulted in the detection of
    nitroso-sarcosine in the stomach wall of mice (Friedman, 1972).

    3.   Carcinogenesis with the simultaneous administration of
         nitrite and various amines

         Sander & Bürkle (1969) reported the occurrence of oesophageal and
    hepatic tumours in rats fed N methyl-benzylamine or morpholine mixed
    with sodium nitrite in the diet. Sodium nitrite in the drinking-water
    given together with piperazine, morpholine and N-methylamine
    respectively to mice led to a highly significant increase of lung
    tumours (Greenblatt et al., 1971). Similarly the administration of
    methylurea or ethylurea with sodium nitrite resulted in the induction
    of lung adenomas in mice (Mirvish, 1971).

         Rats fed dimethylurea and 0.3% sodium nitrite for 36 days
    developed tumours of CNS, heart, thymus, kidney or thyroid in all
    animals (Sander, 1970). Mice given either methylurea (5360 ppm
    (0.536%)) or ethylurea (6360 ppm (0.636%)) with 1 g/l sodium nitrite
    for six months showed more lung adenomas in test animals (Mirvish et
    al., 1972). Concurrent administration of 0.1% sodium nitrite and 0.5%
    proline, hydroxyproline or arginine for 26 weeks produced no increase
    in lung adenomas (Greenblatt & Lijinsky, 1972).

    4.   Nitrosamines in foods

         Of the unprocessed foods analysed, only mushrooms were shown to
    contain dimethylnitrosamine at levels ranging from 0.4 to 30 µg/kg
    (Ender & Ceh, 1968). The same authors analysed different smoked fish
    and meat products and found dimethylnitrosamine at levels of 0.5 to
    15 µg/kg. Eighteen samples of smoked, and five of canned fish were
    analysed after cooking with or without sodium nitrite (up to 200 ppm
    (0.02%)). The results indicated that certain kinds of fish, especially
    those rich in amines, formed dimethylnitrosamine at levels ranging
    from 2.5 to 45 µg/kg during cooking with nitrite (Sen et al., 1970).

    Fifty-one samples of a variety of meat products contained 5 µg/kg or
    less dimethylnitrosamine (Fazio et al., 1971). Dimethylnitrosamine was
    found at levels of 10-80 µg/kg in five out of 59 samples of prepared
    meat products (Sen, 1972). Analyses of 40 samples of frankfurters from
    eight large producers in the United States of America revealed the
    presence of dimethylnitrosamine at levels of 2-84 µg/kg only in a
    small proportion of samples (Wasserman et al., 1972). Crosby et al.
    (1972) while analysing various bacons, fish and miscellaneous food
    products, found that frying or baking of fish products almost doubled
    their very low or undetectable dimethylnitrosamine content. Sen et al.
    (1973) reported that various samples of side bacon when fried
    contained 4-25 µg/kg nitrosopyrrolidine; without frying
    nitrosopyrrolidine was undetectable.

    B.   Teratogenesis and nitrosamines

         A single i.v. dose of N-nitrosomethylurea to pregnant rats
    led to increased foetal deaths and reabsorptions and to malformations
    in those surviving (von Kreybig, 1965). It has been shown that
    N-nitrosomethylurea and N-nitrosoethylurea were potent teratogens and
    carcinogens in rats (Druckrey et al., 1966).

    C.   Mutagenesis and nitrosamines

         Chromosomal aberrations and gene mutations were observed
    following the administration of N1-nitro-N-nitrosomethylguanidine and
    N-nitrosomethylurea (Magee & Barnes, 1967). Malling (1971) found that
    both dimethylnitrosamine and diethylnitrosamine were active mutagens
    in the mouse liver-microsome system. Four carcinogenic nitrosamines,
    dimethylnitrosamine, N-nitrosomethylurea, N-nitroso-methylurethane and
    N methyl-N-nitro-N-nitrosoguanidine proved to be effective in
    producing cell killing, chromatid breaks and chromatid rearrangements
    in Chinese hamster ovary cells (Kao & Puck, 1971).

    1.   Comments on studies reported

         From the studies referred to and others in the literature it is
    evident that (a) nitrosamines are potent carcinogens in several
    species of animals, (b) nitrosamines can be formed when nitrites
    and secondary amines are incubated with human gastric juice,
    (c) nitrosamine formation has been detected in in vivo studies and
    (d) nitrosamines have been reported in several foods. While there are
    indications of a dose-response relationship in nitrosamine-induced
    tumour development, a no-effect level for several nitrosamines has not
    as yet been established. It must be remembered that the possibility of
    nitrosamine formation in foods or in the animal organism does not
    depend solely on added nitrite or nitrate. Nitrates occur naturally
    in many foods and nitrite has been detected in saliva at levels of
    5-10 ppm (0.0005-0.001%).

         The role played by nitrites in food preservation is important
    and the ability to inhibit the growth and toxin formation of
    C. botulinum must be weighed against the potential risk associated
    with their role in nitrosamine formation. The whole question of
    nitrosamine formation and effects is under active investigation in
    several countries. One promising area of this investigation involves
    the use of ascorbic acid as a blocking agent in nitrosation of amines.

    Special studies on reproduction and teratogenicity


         The F1b generations of rats raised from parents fed from day 40,
    meat heat-processed with 0, 200, 1000 and 4000 ppm (0.0%, 0.02%, 0.1%,
    and 0.04%) sodium nitrite were sacrificed on day 21 and examined.
    Three control groups were used. Fertility, preimplantation loss and
    resorptions were in no way affected by nitrite. No difference from
    controls was seen regarding litter size, sex ratio and mean pup
    weight. No significant malformations were noted (Carstensen &
    Hasselager, 1972).

         Two groups of 12 pregnant rats received either 2000 or 3000 mg/l
    sodium nitrite in their drinking-water, a group of seven pregnant rats
    was the control. Anaemia was found in pregnant animals and there was
    greater mortality of newborn in the groups with nitrite (30% and 53%
    compared with 6% in controls). Treated pups also gained weight more
    slowly but had no methaemoglobinaemia. Nitrites were shown to pass the
    placental barrier (Gruener & Shuval, 1971).


         Groups of three to four pregnant guinea-pigs were given 50 mg/kg
    or 60 mg/kg sodium nitrite s.c. once. Normal pregnancies ensued at the
    lower level. At the higher dose fetal mortality and abortion occurred
    within one to four days (Sinha & Sleight, 1971).

         Groups were given 300 to 10 000 ppm (0.03-1%) nitrite in their
    diet. Male fertility was unimpaired as all groups conceived. Food,
    water consumption, weight gain were normal except animals on
    10 000 ppm (1%) which showed very reduced weight gain. No live births
    occurred at and above 5000 ppm (0.5%) and maternal deaths, abortions,
    fetal resorptions and mummification were seen. Histology showed
    degenerative placental lesions and inflammation of the uterus and
    cervix. No significant alterations in serum nitrite, blood urea or
    serum potassium were seen but haemoglobin was slightly reduced at
    higher levels. Methaemoglobin did not exceed 20% (Sleight & Atallah,


         Cows, pregnant two months, were given nitrite in their diet to
    produce 40-50% methaemoglobinaemia until they calved or aborted. Only
    one abortion occurred, the rest had normal pregnancies. No gross
    pathology was seen (Winter & Hokanson, 1964).

    Acute toxicity

    Animal             Route      (mg/kg bw)      Reference

    Mouse              oral       220             Greenberg et al., 1945

    Mouse - female     oral       175             Lehman, 1958

    Rat - female       oral       85              Lehman, 1958

         Sodium nitrite has been used for therapeutic purposes as a
    vasodilating agent in dosages of 30-120 mg.

         The acute effects of nitrite include vasodilatation, lowering
    of blood pressure, reduction of vitamin A stores in the liver and
    disturbances of thyroid function. Dogs given a single dose of
    1-2 mg/kg sodium nitrite in sausage showed a rise in respiration and
    heart rate, changes in ECG, methaemoglobinaemia within one to two
    hours, a rise in serum sodium, fall in serum potassium and a rise in
    SGOT (Myasnikov & Pravosudov, 1966).

    Short-term studies


         When mice were given sodium nitrite in their drinking-water at 0,
    100, 1000, 1500 and 2000 mg/l their motor activity decreased
    especially at the highest level (Gruener & Shuval, 1971).


         Rats given 0, 100, 300 and 2000 mg/l sodium nitrite in their
    drinking-water for two months showed in their EEG increased
    frequencies of background waves at the highest level and slightly
    reduced frequencies at lower levels. At all levels there were
    paroxysmal outbursts not seen in pretreatment period. After four
    months observation following treatment only the animals at the
    100 mg/l level returned to normal EEGs, all higher levels continued to
    show EEG abnormalities (Gruener & Shuval, 1971). Rats given in their
    drinking-water for 200 days nitrite at levels of intake of 170 and

    340 mg/kg/day showed methaemoglobinaemia, raised haematocrit, no Heinz
    bodies, raised spleen weights in females, raised heart weights in
    males, some changes in liver weight in females and in kidney weights
    of both sexes (Musil, 1966).

         Rats were fed a sodium nitrite supplement for a period up to
     168 days. One rat received a total of 167 mg of sodium nitrite in
    121 days. This represents 93 ppm (0.0093%) in the daily diet. No
    effects on growth or on the weights of important organs were noted
    (Tarr & Carter, 1942).


         In a similar experiment with cats, one animal received a total of
    about 4100 mg of sodium nitrite during a period of 105 days. This
    represents approximately 390 ppm (0.039%) in the daily diet. No
    effects on the growth rate or on the weight of important organs were
    noted. No histopathological examination has been reported on any
    animal fed with nitrite (Tarr & Carter, 1942).

    Long-term studies


         The continuous administration of sodium nitrite in the drinking-
    water at the rate of 100 mg/kg bw daily over the whole life span and
    in three successive generations (95 rats) resulted in spite of the
    high dosage (67% of the acute LD50) in only a slight inhibition of
    growth (10-20%) and in a shortening of the median life-span from 740
    to 640 days. Reproduction was normal. Neither the blood picture nor
    the organs showed any ill effects. The number of tumours observed in
    the test group (one thymoma and one hepatoma) was not greater than in
    the control group. Cumulative toxic effects were not observed (Lehman,

         Six groups of 30 male and 30 female rats were given standard diet
    (control) or 40% meat (control) or 40% meat heat-processed with 0.5%
    sodium nitrite, 0.5% sodium nitrate and 1% gluconodeltalactone, 0.02%
    sodium nitrite and 1% gluconodeltalactone for 116 weeks. Body weight
    was lower in the group with 0.5% sodium nitrite with or without GDL.
    Food intake was not affected anywhere. Behaviour was normal in all
    groups. Mortality rose equally in all groups after 18 months. No
    adverse effects on haematology were seen except that red cell counts
    were lower in the nitrite groups. BSP, SGPT and drug-metabolizing
    enzymes showed no evidence of liver damage. Spontaneous tumour
    incidence was high but no significant rise in organ tumours likely
    to be caused by nitrosamines appeared. DNA of liver cells nuclei was
    not increased, the ratio diploid/tetraploid cells was normal and
    alpha-fetoproteins in serm showed no evidence of liver tumours. The

    diet with 40% meat treated with 0.5% nitrite is equivalent to 20 ppb
    nitrosamines (= 1 mg/kg per day) (Van Logten et al., 1972). The F1A
    generations of rats raised from parents fed from day 40 with meat
    heat-processed with 0, 200, 1000 and 4000 ppm (0.0, 0.02, 0.1 and
    0.4%) sodium nitrite have been kept on diets containing 46% similarly
    treated meat as the sole protein source. The groups consist of 340,
    120, 120 and 132 males and females and the minimum age so far is
    583 days (Poulsen, 1973).

         Rats were fed 0.2% sodium nitrite for 18 months without adverse
    effects (Lijinsky, 1971). In another study five groups of eight male
    rats were given tap water or 5 mg/kg, 50 mg/kg, 100 mg/kg and
    150 mg/kg sodium nitrite in their drinking-water for 24 months. There
    were no significant differences regarding growth, haemoglobin levels,
    blood glucose, pyruvate and lactate, methaemoglobin was about 5%, 10%
    and 20% in the highest levels and slightly raised for two months only
    at the 5 mg/kg level. Histopathology showed bronchopneumonia in a
    dose-related manner (non-SPF animals) and the highest group showed
    loci of myocardial degeneration. In all test groups but especially at
    the highest level the coronary vessels were thin and dilated (Gruener
    & Shyval, 1971).

         Long-term feeding studies in rats with nitrite-cured meat are in
    progress in the FDA (FDA, 1972).


         Many cases have been reported of accidental poisoning resulting
    from the presence of sodium nitrite in food products. From this
    information it is possible to deduce that the oral lethal dose in man
    varies from 0.18 to 2.5 g, the lower figures being those for children
    and old people (Naidu & Venkratrao, 1945; Greenberg et al., 1945;
    Schmidt et al., 1949; Schrader & Gessner, 1943).


         Though in the long-term studies cited only a slight inhibition of
    growth occurred, the dose causing this effect appears to give the best
    approximation to the threshold dose level. Food for babies less than
    six months should not contain added nitrite.

         From the studies referred to and others in the literature it is
    evident that: (a) nitrosamines are potent carcinogens in several
    species of animals; (b) nitrosamines can be formed when nitrites and
    secondary amines are incubated at pH 1-3 (as exists in human gastric
    juice); (c) nitrosamine formation from nitrites and amines occurs
    in vivo; (d) nitrosamines have been reported as reaction products of
    nitrites and components of foods; while there are indications of a
    dose-response relationship in nitrosamine-induced tumour development,
    a no-effect level for several nitrosamines has not yet been

         It must be remembered that the possibility of nitrosamine
    formation in foods or in the animal organism does not depend solely
    on added nitrite. Some nitrate occurs naturally in many foods and may
    be converted to nitrite by microorganisms. Nitrite has also been
    detected as a normal constituent of saliva at levels of 5-10 ppm

         The role played by nitrites in food preservation is important
    and the ability to inhibit the growth and toxin formation of
    Clostri-dum botulinum must be weighed against the potential risk
    associated with their role in nitrosamine formation. The whole
    question of nitrosamine formation and effects is under active
    investigation in several countries. One promising area of this
    investigation involves the use of ascorbic acid as a blocking agent in
    nitrosation of amines.


    Level causing no toxicological effect

         From consideration of the long-term studies it can be concluded
    that this level will be somewhat below 100 mg/kg bw per day.

    Estimate of acceptable daily intake for man*

         0-0.2 mg/kg bw.**


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    *    Temporary. Pending evaluation of the results of investigations
    now in progress (IARC).

    **   As sodium nitrite.

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    Tarr, H. L. A. & Carter, M. H. (1942) J. Fish. Res. Board. Can., 6, 63

    Terracini, B., Magee, P. N. & Barnes, J. M. (1967) Hepatic Pathology
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    Wasserman, A. E. et al. (1972) Dimethylnitrosamine in Frankfurters,
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    Winter, A. J. & Hokanson, J. F. (1964) Am. J. Vet. Res., 25, 353

    See Also:
       Toxicological Abbreviations