The evaluations contained in this document were prepared by the
    Joint FAO/WHO Expert Committee on Food Additives*
    Rome, 21-29 April 1976

    Food and Agriculture Organization of the United Nations

    World Health Organization

    *Twentieth Report of the Joint FAO/WHO Expert Committee on Food
    Additives, Geneva, 1976, WHO Technical Report Series No. 599, FAO Food
    and Nutrition Series No. 1.



         These compounds have been evaluated for acceptable daily intake
    by the Joint FAO/WHO Expert Committee on Food Additives in 1961, 1964
    and 1973 (see Annex I, Ref. No. 6, p. 72; No. 9, p. 37; and No. 33,
    p. 97).

         Since the previous evaluation, additional data have become
    available and are summarized and discussed in the following monograph.
    The previously published monographs have been expanded and are
    reproduced in their entirety below.



    Absorption, distribution and excretion

         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).

    Effects on enzymes and other biochemical parameters

         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).

         The formation of methaemoglobin by sodium nitrite in mice can be
    antagonized by the administration of methylene blue at levels of up to
    20 mg/kg and this effect is enhanced by the administration of oxygen
    (Sheehy & Way, 1974).

         The in vitro conversion of nitrate to nitrite by preparations
    from parts of the gastrointestinal tract was studied. Relatively large
    conversions took place in monogenates of mucosa which had been treated
    with 0.9% hypochlorite and with caecal contents. However, more than 24
    hours were needed for substantial conversions to take place; after
    five hours only traces of nitrite were produced in any of the
    preparations (Fritsch et al., 1975).

         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 pH 7 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).

         Wistar rats fed diets containing 0-4000 ppm dimethylamine or
    0-8000 ppm pyrrolidine were given drinking-water containing sodium
    nitrite at levels of 0, 100, 1000 or 3000 ppm. Analysis of the stomach
    contents revealed that nitrosamines were formed only at levels greater
    than background if concentrations of the added amines exceeded
    1000 ppm. The concentration of amine appeared to have a bigger
    influence on N-nitrosamine formation in the stomach of rats than the
    concentration (at levels of up to 1000 ppm) of nitrite in the
    drinking-water (Telling et al., 1976).

    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).

         The effects of long-term feeding of diets containing 0-1000 ppm
    of nitrite and 0-1000 ppm morpholine or 0-50 ppm N-nitrosomorpholine
    to rats and hamsters were studied. Several combinations of nitrite and
    morpholine, as well as nitrosomorpholine itself, induced a high
    incidence of hepatocellular carcinoma in rats. The nitrite
    concentration in the diet appeared to have the greater influence on
    the incidence of angiosarcomas and hepatocellular carcinomas in the
    rat than the morpholine concentration. There was no significant
    increase in tumour incidence in hamsters receiving any of the
    treatments (Shank & Newborne, 1976).

         Diethylamine hydrochloride (2 or 4 g/l) and sodium nitrite (0.4
    or 0.8 g/l) were administered simultaneously in the drinking-water of
    groups of 20 guinea-pigs for up to 30 months. There was no increase in
    the tumour incidence of these animals as a result of this treatment.
    However, 18 out of 20 guinea-pigs given 15 mg diethylnitrosamine/l in
    the drinking-water developed liver tumours within 12 months. It was
    suggested that the synthesis of diethylnitrosamine from the ingested
    amine and nitrite was low because of the strongly basic nature of
    diethylamine (Sen et al., 1975).

    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-nitroso-
    methylurea 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-nitroso-methylurea (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-nitrosomethylurethane 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).

    Special studies on reproduction and teratogenicity


         The F1b generation 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 was
    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-
    feto-proteins in serum 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
    foci of myocardial degeneration. In all test groups but especially at
    the highest level the coronary vessels were thin and dilated (Gruener
    & Shuval, 1971).

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

         Groups of between 96-159 rats and 16-40 hamsters received 0 or
    1000 ppm sodium nitrite in the diet for up to 129 weeks (rats) or 110
    weeks (hamsters). Several groups received various concentrations of
    morpholine in addition to nitrite. A significant increase in the
    incidence of lymphoreticular tumours was found in the group of rats
    receiving nitrite alone but this was probably coincidental since no
    similar increase occurred in groups receiving morpholine in addition.
    The presence of nitrite in the diet of hamsters was not associated
    with an increased tumour incidence (Shank & Newborne, 1976).


         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).

         The presence of nitrite in human saliva has been known for many
    years. The concentrations found are fairly consistent (usually between
    6 and 10 ppm) and do not appear to be influenced by the composition of
    the meals consumed by the individuals studied. This nitrite is thought
    to originate from microbial reduction of nitrate, naturally present in
    saliva (Tannenbaum et al., 1974).

         Other observations have shown that consumption of vegetables rich
    in nitrate sometimes raised salivary nitrite concentrations to levels
    of several hundred ppm (Ashiwata et al., 1975).


         The dose causing inhibition in the long-term studies cited,
    appears to give the best approximation to the threshold dose level.

         From the studies referred to and from others in the literature it
    is evident that (a) many N-nitroso compounds are carcinogenic in
    several species of animal, (b) N-nitroso compounds can be formed when
    nitrites and secondary amines are incubated at pH 1-3 (as exists in
    the human stomach), (c) N-nitroso compounds formation from nitrites
    and amines occurs in vivo, and (d) N-nitroso compounds have been
    reported as reaction products of nitrites and food components. While
    there are indications of a dose-response relationship in N-nitroso
    compounds induced tumour formation, a no-effect level for N-nitroso
    compounds has not yet been established.

         The possibility of N-nitroso compound formation in food or in
    animals does not depend solely on added nitrite. Some nitrate occurs
    naturally in many foods and may be converted to nitrite by micro-
    organisms. Nitrite also occurs in human saliva at 10 ppm or much
    higher concentrations.

         Nitrites are important as food additives mainly because of their
    ability to inhibit growth and toxin formation of Clostridium
    botulinum. This must be weighed against the potential risk
    associated with their role in N-nitroso compound formation.

         Examination of reports of a WHO task group and the IARC on
    N-nitroso compounds did not lead the Committee to change its


    Level causing no toxicological effect

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

    Estimate of acceptable daily intake for man1

         0-0.2 mg/kg bw.2

    Further work required

         These compounds should be kept under regular review of future
    meetings as new information becomes available.


    1    Temporary. The Committee agreed that experimental data
    available on nitrite were sufficient to recommend an ADI for nitrite
    per se. Nevertheless, because of potential nitrosamine formation
    when nitrite is consumed or incorporated into food, it was recommended
    that the ADI should be temporary. The "temporary" status also
    reflected the Committee's view that the subject should be reviewed
    continually. However, evidence from some studies in which nitrite
    treated food containing nitrosamines at realistic levels failed to
    induce an increase in cancer incidence when fed to animals, gave
    reassurance that recommendation of an ADI was justified. More studies
    of this type are desirable.

    2    Food for babies less than six months old should not contain
    added nitrite.


    Alam, B. S., Saporoschetz, I. B. & Epstein, S.S. (1971a) Nature, 232,

    Alam, B. S., Saporoschetz, I. B. & Epstein, S.S. (1971b) Nature, 232,

    Ashiwata, H., Boritoon, P., Nakamura, Y., Harada, M., Tanimura, A. &
         Ashidata, M. (1975) J. Fod. Hyg. Soc. Japan, 16, 19

    Brüggemann, J. & Tiews, J. (1964) Int. Z. Vitaminforsch., 2, 233

    Carstensen, J. & Hasselager, L. B. (1972) Int. Meetg on Terat. Act.,

    Crosby, N. T. et al. (1972) Estimation of steam-volatile N-nitro-
         samines in foods at the 1 µg/kg level, Nature, 238, 342-343

    Druckrey, H., Ivankovic, S. & Preussmann, R. (1966) Teratogenic and
         carcinogenic effects in the offspring after single injection of
         ethylnitroso-urea to pregnant rats, Nature, 210, 1378-1397

    Druckrey, H., Preussmann, R. & Ivankovic, S. (1969) N-nitroso
         compounds in organotropic and transplacental carcinogenesis,
         Ann. N.Y. Acad. Sci., 163, 676-696

    Emerick, R. J. & Olson, O. E. (1962) J. Nutr., 78, 73

    Ender, F. & Ceh, L. (1968) Occurrence of nitrosamines in foodstuffs
         for human and animal consumption, Fd Cosmet. Toxicol., 6,

    Ender, F. & Ceh, L. (1971) Conditions and chemical reaction mechanisms
         by which nitrosamines may be formed in biological products with
         reference to their possible occurrence in food products, Zschr.
         Lebensmittel-Untersuchung u. Forsch., 145, 133-142

    Fazio, T., White, R. H. & Howard, J. W. (1971) Analysis of nitrite
         and/or nitrate-processed meats for N-nitrosodimethylamine,
         J. Ass. Off. Analyt. Chem., 54, 1157

    FDA (1972) Reply to Fountain Committee

    Friedman, M. A. (1972) Nitrosation of sarcosine: Chemical kinetics and
         gastric assay, Bull. Environm. Contamination & Toxicol., 8,

    Fritsch, P., Saint-Blanquat, G. de & Derache, R. (1975) Transformation
         des nitrates dans le tube digestif, European Journal of
         Toxicology, 8

    Greenberg, M., Birnkrant, W. B. & Schiftner, J. J. (1945) Amer. J.
         publ. Hlth, 35, 1217

    Greenblatt, M. & Lijinsky, W. (1972) J. Nat. Cancer Inst., 48(5), 1389

    Greenblatt, M., Mirvish, S. & So, B. T. (1971) Nitrosamine studies:
         Induction of lung adenomas by concurrent administration of sodium
         nitrite and secondary amines in Swiss mice, J. Nat. Cancer
         Inst.,  46, 1029-1034

    Gruener, N. & Shuval, H. I. (1971) Environmental Quality & Safety,
         vol. II

    Harley, J. D. & Robin, H. (1962) Blood, 20, 710

    Heppel, L. A. & Porterfield, V. T. (1949) J. Biol. Chem., 178, 549

    International Agency for Research on Cancer (1972) N-Nitroso compounds
         analysis and formation

    Kao F. T. & Puck, T. T. (1971) Mutagenesis by carcinogenic nitroso
         compounds, J. Cell. Physiol., 78, 139-144

    Klubes, P. et al. (1972) Factors affecting dimethylnitrosamine
         formation from simple precursors by rat intestinal bacteria,
         Fd Cosmet. Toxicol., 10, 757-767

    von Kreybig, T. (1965) Die Wirkung einer carcinogenen Methylnitroso
         harnstoffdosis auf die Embryonalentwicklung der Ratte,
         Z. Krebsforsch., 67, 46-50

    Lehman, A. J. (1958) Quart. Bull. Ass. Food Drug. Off., 22, 136

    Lijinsky, W. (1971) Statement to Fountain Committee

    Lijinsky, W. & Epstein, S.S. (1970) Nitrosamines as environmental
         carcinogens, Nature, 225, 21-23

    van Logten, M. J. et al. (1972) Fd Cosmet. Toxicol., 10, 475

    MAFF (1962) Food Standards Committee Report on Preservatives, HMSO,

    Magee, P. N. & Barnes, J. M. (1956) Brit. J. Cancer, 10, 144

    Magee, P. N. & Barnes, J. M. (1967) Carcinogenic nitroso compounds,
         Adv. Cancer Res., 10, 163-246

    Malling, H. V. (1971) Dimethylnitrosamine: Formation of mutagenic
         compounds by interaction with mouse liver microsomes,
         Mutat. Res., 13, 425-429

    McIlwain, P. K. & Schipper, I. A. (1963) J. Amer. Vet. Med. Ass., 142,

    Mirvish, S. (1971) Kinetics of nitrosation of secondary amines, In:
         International Agency for Research on Cancer (1971) Annual Report,
         Lyon, p. 81

    Mirvish, S.S., Greenblatt, M. & Choudari Kommineni, V. R. (1972)
         J. Nat. Canc. Inst., 48(5), 1311

    Mohr, U. & Althoff, J. (1971) Carcinogenic activity of aliphatic
         nitrosamines via mother's milk in the offspring of Syrian golden
         hamsters, Proc. Soc. Exper. Biol. & Med., 136, 1007-1009

    Musil, J. (1966) Acta biol. med. Germ., 16, 388

    Myasnikov, S. P. & Pravosudov, V. P. (1966) Gig. Sanit., 31, 38

    Naidu, S. R. & Venkratrao, P. (1945) Calcutta med. J., 42, 79

    Poulsen, E. (1973) Personal communication

    Sander, J. (1967) Kann Nitrit in der menschlichen Nahrung Ursache
         einer Krebsentstehung durch Nitrosaminbildung sein? Arch. Hyg.
         Bakt., 151, 22

    Sander, J. (1970) Arzneim. Forsch., 20(3)

    Sander, J. & Bürkle, G. (1969) Induktion maligner Tumoren bei Ratten
         durch gleichzeitige Verfütterung von Nitrit und Secundären
         Aminen, Z. Krebsforsch., 73, 54-66

    Sander, J. & Seif, F. (1969) Bakterielle Reduktion von Nitrat im Magen
         des Menschen als Ursache einer Nitrosamin-Bildung,
         Arzneimittel- Forschung, 19, 1091-1093

    Schmidt, H., Stick, W. & Kluge, F. (1949) Dtsch. med. Wschr., 74, 961

    Schrader, G. & Gessner, O. (1943) Samml. Vergiftungsf., 13, 101

    Sell, J. L. & Roberts, W. K. (1963) J. Nutr., 79, 171

    Sen, N. P. (1972) The evidence for the presence of dimethylnitrosamine
         in meat products, Fd Cosmet. Toxicol., 10, 219

    Sen, N. P., Smith, Dorothy C., Moodie, C. A. & Grice, H. C. (1975)
         Failure to induce tumours in guinea pigs after concurrent
         administration of nitrite and diethylamine, Fd Cosmet.
         Toxicol., 13, 423

    Sen, N. P. et al. (1973) Nitrosopyrrolidine and dimethylnitrosamine in
         bacon, Nature, 241, 473-474

    Sen, N. P. et al. (1970) Formation of nitrosamines in nitrite-treated
         fish, Can. Inst. Food Technol. J., 3, 66-69

    Sen, N. P., Smith, D.C. & Schwinghamer, L. (1969) Formation of
         N-nitrosamines from secondary amines and nitrite in human and
         animal gastric juice, Fd Cosmet. Toxicol., 7, 301-307

    Shank, R. C. & Newborne, P.M. (1976) Dose-response study of the
         carcinogenicity of dietary sodium nitrite and morpholine in rats
         and hamsters, Fd Cosmet. Toxicol., 14, 1

    Sheehy, Maureen W. & Way, J. L. (1974) Nitrite intoxication:
         Protection with methylene blue and oxygen, Toxicol. appl.
         Pharmacol., 30, 221

    Sinha, D. P. & Sleight, S. D. (1971) Toxic. appl. Pharm., 18, 340

    Sleight, S. D. & Atallah, O. A. (1968) Toxic. appl. Pharm., 12, 179

    Tannenbaum, S. R., Sinskey, A. J., Weismann, M. & Bishop, W. (1974)
         Nitrite in human saliva, its possible relationship to nitrosamine
         formation, J. Nat. Cancer Inst., 53, 79

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

    Telling, G. M., Hoar, D., Caswell, D. & Collings, A. J. (1976) Studies
         on the effect of feeding nitrite and secondary amines to Wistar
         rats. Unpublished report, submitted to WHO by Unilever Research
         Laboratory, Colworth House, Sharnbrook, Beds., United Kingdom

    Terracini, B., Magee, P. N. & Barnes, J. M. (1967) Hepatic pathology
         in rats on low dietary levels of dimethylnitrosamine, Brit. J.
         Cancer, 21, 559-565

    Wasserman, A. E. et al. (1972) Dimethylnitrosamine in frankfurters,
         Fd Cosmet. Toxicol., 10, 681-684

    Winter, A. J. & Hokanson, J. F. (1964) Am. J. Vet. Res., 25, 353

    See Also:
       Toxicological Abbreviations