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    ZINC

    Explanation

         Zinc was previously evaluated by the Joint FAO/WHO Expert
    Committee on Food Additives for a provisional maximum acceptable daily
    level in 1966 (see Annex I, Ref. 12). No toxicological monograph was
    prepared.

    Introduction

         Zinc is an essential element in the nutrition of man, animals and
    plants. It functions as an integral part of numerous enzymes. Two
    classes of zinc enzymes have been identified: (1) the zinc-enzyme
    complexes in which the binding between the enzyme and the ion is weak,
    and there may be a low specificity for zinc in activating the enzyme;
    and (2) zinc metalloenzymes in which the zinc is bonded firmly with a
    definite stoichiometry. Because of its essentiality, zinc is present
    in all plant and animal tissues. The total body zinc for a 70 kg
    individual has been estimated to be 2.3 g. Protein foods are important
    dietary sources of zinc. Oysters are the richest source of zinc (up to
    1000 ppm (0.1%) zinc), with lesser amounts in other seafoods, muscle
    meats and nuts (30-50 ppm (0.003-0.005%) range). Whole cereals may
    contain 20-25 ppm (0.002-0.0025%) zinc, but most of this is lost
    during milling procedures (e.g., flour may contain 3-9 ppm
    (0.0003-0.0009%) zinc). Sugar, citrus fruits and non-leafy vegetables
    are poor sources of zinc (about 1 ppm (0.0001%)). The average zinc
    intake via the diet depends on protein sources. For an adult the
    intake ranges from 14 to 20 mg/day. The recommended dietary allowance
    (RDA) for adult men and women is 15 mg/day; however, the requirement
    for zinc changes throughout life. In countries where whole cereals
    form an important part of the diet, a higher requirement may be
    needed, because phytate, a constitutent of the cereal, reduces the
    bioavailability of the zinc (WHO, 1973).

    BIOLOGICAL DATA

    BIOCHEMICAL ASPECTS

    Absorption, metabolism and excretion

         Zinc, as contained in food and drink, is absorbed through the gut
    mucosa which is the normal route of entry into the body. It is
    absorbed at several sites in the gastrointestinal tract. The initial
    site of absorption is the stomach and occurs within 15 minutes after
    ingestion; however, the major site is the second portion of duodenum.
    Absorption also occurs in other segments of both the small and large
    intestine (Henkin & Aamodt, 1975; Methfessel & Spencer, 1973a,b).

         The exact mechanism by which zinc is transported across the
    gastrointestinal mucosa and serosa is not known. The formation of a
    low molecular weight organic zinc chelate is thought to be the initial
    event, possibly a tetrahedral quadradentate ligand formed from a small
    organic molecule and the zinc, and it is this complex which is
    absorbed from the gastrointestinal tract (Suso & Edwards, 1971a,b).
    Studies on rats suggest that metallothionein, a low molecular weight
    cytoplasmic metalloprotein, plays a key role in zinc haemostasis
    (Richards & Cousins, 1976; Hall et al., 1979). It has been shown in
    rats that there is a direct correlation between the dietary zinc
    intake and the binding of zinc of intestinal mucosal metallothionein
    (Hall et al., 1979). The absorption of zinc can be affected by many
    substances. Both phytate and soy protein inhibit the formation of the
    zinc-protein complex and as a result diminish the absorption of zinc
    (Davis, 1972; O'Dell & Savage, 1960; Reinhold et al., 1973). Other
    substances which adversely affect zinc absorption include cotton-seed,
    peanut, safflower, calcium, phosphate, food and zinc itself (Davis,
    1972; Heth et al., 1966; Nielsen et al., 1966a,b; Pecoud et al., 1975;
    Schelling et al., 1973; Smith et al., 1962). The body burden of zinc
    can be diminished either by reductions in the amount of zinc absorbed
    as seen in several types of malabsorptive processes or by increases in
    the removal of zinc from the body. The latter is evidenced by
    increases in excretion seen in intrinsic kidney disease, reduced
    plasma metal binding which is congenital in origin and inborn errors
    of metabolism (Slavik et al., 1973a,b). The absorption of zinc has
    been shown to be enhanced by the presence of histidine, cysteine,
    methionine and ethylenediamine tetracetic acid. These are thought to
    act by promoting the formation of the low molecular weight organic
    zinc complex (Giroux, 1972; Nielsen, 1966a,b). The diminution of zinc
    absorption can be species dependent, since in the rat a low protein
    diet is associated with a reduction in zinc absorption, while the
    reverse is the case with humans. Feeding studies with rats showed
    that for absorbed zinc the faeces constitutes the major route of
    elimination. Only minor amounts are eliminated in the urine.
    Administration of large amounts of zinc did not result in elevated
    tissue levels of zinc (Heller & Burke, 1927; Drinker et al., 1927a,b),
    since increasing the level of zinc in the diet results in decreased
    absorption.

         In rats the absorption of zinc was measured following
    administration of a single tracer dose of 0.5 Ci 65Zn by gavage. The
    net absorption of zinc varied from 0.7 to 1.8% in total groups of
    animals receiving either 1.8 or 2.9 mg/zinc, respectively. In other
    radiotracer studies with rats the addition of the zinc to the diet did
    not affect stable zinc levels in the blood, heart, liver, kidney,
    semitendinosus muscle, left tibia and small intestine, whereas the
    faecal excretion of 65Zn increased with the length of feeding time on
    the zinc diet (Ansari et al., 1975).

         Oral tracer studies with 65Zn in mice have shown that although
    liver, pancreas and kidney retain high levels of the radioisotope 96
    hours after dosing the highest concentrations over longer periods of
    time were found in bone tissues followed by liver and kidney (Ansari
    et al., 1975).

         Oral radiolabelled tracer studies in humans have shown the
    presence of the isotope in the blood within 20 minutes of
    administration, peak plasma levels within 2-4 hours and the recovery
    of 50% of the total dose in the faeces within 15 days. The net
    absorption in these various studies varied between 30% and 70%
    (Richmond et al., 1962; Rosoff & Spencer, 1965; Spencer et al., 1965).

         In humans the daily elimination of absorbed radiolabelled zinc as
    in the order of 1% per day (Lombeck et al., 1975). The major route of
    elimination was via the faeces which accounted for three-quarters of
    the zinc eliminated with the remainder being removed by means of
    the urine. In older adult males who were given a single dose of
    radiolabelled zinc the majority of gastrointestinal absorption
    occurred within 4 hours. By day 3, 66% of the isotope was found in the
    faeces. After 21 days the following dietary retention of the
    radiolabel was observed: 28% remained in the body, 2% was present in
    the urine and 70% in the faeces (Richmond et al., 1962; Rosoff &
    Spencer, 1965; Spencer et al., 1965). Studies on retention patterns of
    intravenously administered 65Zn, by normal human subjects, indicate
    that there is a 2-component exponential pattern of retention. One a
    rapid component which comprises 20% of the radiolabelled zinc with a
    biological half-life of 8 days, and the other a slow component with a
    biological half-life of 300-500 days (Aamodt et al., 1975; Richmond et
    al., 1962; Henkin & Aamodt, 1975; Honstead & Brady, 1967).

    TOXICOLOGICAL STUDIES

    Special studies on carcinogenicity

    Mouse

         Mice exposed to drinking-water or mineral water containing levels
    of zinc ranging from 10 to 20 ppm (0.001-0.002%) in 1 study and 0 to
    200 ppm (0-0.02%) in another, developed tumours following 5 or more
    months exposed to the zinc-containing water (DeSzilvay, 1964; Halme,
    1961). However, the information provided in the publications relating
    to these studies is inadequate for evaluation.

         In another study mice were fed diets containing 50 000 ppm (5%)
    zinc oleate, but after 3 months the level was reduced to 25 000 ppm
    (2.5%) and after a further 3 months to 12 500 ppm (1.25%), because of
    deaths due to anaemia. All surviving mice were killed at week 45. Mice

    that died during the study or were killed at week 45 were autopsied
    and lesions examined histologically. The incidence of tumours at all
    sites showed no significant difference between test and control
    animals (Walters & Roe, 1965).

    Hamster

         Random-bred Syrian hamsters, 2 months of age (N=49), were
    injected directly into the testicles with 0.05 ml of a 4% solution of
    zinc chloride. Treatment was daily for a period of 6 weeks. At either
    week 17 or 18 the animals were sacrificed and the testes and pituitary
    were removed for histological examination. Most of the testes
    exhibited areas of coagulative necrosis surrounded by a zone of
    pigmented and foamy macrophages and a variable amount of surviving
    testes. In 2 animals sacrificed at 10 weeks, a small focus of
    embryonal carcinoma adjacent to the area of necrosis was found in 1
    testis. No metastases were noted in these animals, nor were any other
    testicular neoplasms indicated in any of the other animals (Guthrie &
    Guthrie, 1974).

    Special studies on interactions with other metals

         Dietary zinc has been shown to affect the metabolism of a number
    of essential dietary elements, e.g., Cu and Fe, and also toxic
    elements such as lead and cadmium (NRC, 1979). Excess dietary zinc in
    the diet of pregnant rats adversely affects the zinc, copper, iron and
    calcium status of the developing foetus (Cox et al., 1969).

         Copper.  Male Wistar rats were fed either a basal diet
    containing 5 ppm (0.0005%) of copper and 80 ppm (0.008%) of zinc or
    the basal diet plus 1.0% zinc carbonate for no longer than 15 days. To
    ascertain whether zinc affected intestinal absorption of copper, all
    of the animals were given orally or intraperitoneally copper alone or
    copper and zinc in combination. The 1% zinc diet produced a reduction
    in growth, haemoglobin concentration, ceruloplasmin activity and
    copper concentration in liver, kidney and spleen with a concomitant
    marked increase in the concentration of zinc in these tissues. The
    administration of 64CuCl2 (35 Ci) by stomach tube in the zinc-fed
    rats, followed by measurements of 64Cu levels in blood showed that
    zinc interfered with the absorption and utilization of copper (Ogiso
    et al., 1974). In a study on the metabolism of zinc and copper in the
    gastrointestinal tract of rats, it was shown that as the zinc content
    of the stomach or duodenum increased, the copper content decreased.
    Most of the zinc was present in the mucosal layer and was associated
    with a low molecular weight protein (Ogiso et al., 1979). In another
    study in which rats received diets containing adequate amounts of zinc
    and copper, followed by a marked increase in dietary zinc, it was
    shown that, while dietary zinc levels up to 450 ppm (0.045%) had a no
    effect on intestinal absorption of copper, a level of 900 ppm (0.09%)

    resulted in a 40% reduction in copper uptake. Increasing the level of
    copper in the diet resulted in a marked decrease in zinc retention
    (Hall et al., 1979).

         Iron.  In studies in which young rats were fed basal diets
    containing 0.75% zinc carbonate, there was a reduction of iron storage
    in the liver and spleen, while at the same time there was no reduction
    in haemoglobin level. If a diet was used that was low in copper, the
    zinc supplementation resulted in anaemia and lower levels of hepatic
    copper in the test animals. The mechanism of depletion of iron stores
    is not known, but it does not appear to be due to interference by zinc
    with iron absorption from the diet, with cellular uptake of iron from
    circulating transferrin, nor with capacity to store iron (O'Neil-
    Cutting et al., 1981).

         Selenium.  Studies with pigs failed to show any interaction
    between zinc and selenium (Van Vleet et al., 1981).

         Cadmium.  The effect of zinc on cadmium toxicity has been
    discussed by Friberg et al. (1974). Many of the toxic effects
    associated with administration of dietary cadmium, e.g., anaemia,
    weight loss and also the acute toxic effects on the testes, could be
    prevented by the simultaneous administration of zinc. However, dietary
    zinc failed to prevent a decrease in the activity of liver enzymes
    caused by cadmium (Friberg et al., 1974).

         Lead.  The influence of zinc on the biological effects of
    orally ingested lead has been reviewed by Petering (1980). Lead
    absorption in rats is markedly reduced when the level of zinc in the
    diet is increased. In 1 study in rats, the Zn level was raised from 8
    to 200 ppm (0.0008-0.02%). The absorption of lead as well as the blood
    lead levels were reduced by about 60% (Cerklenski & Forbes, 1976). A
    study of workers exposed to lead and zinc rather than lead alone
    resulted in a reduced excretion of urinary 8-aminolevulinic acid and a
    tendency to lower blood lead levels (Ditkiewicz et al., 1979; Meredith
    & Moore, 1980).

         Calcium.  Interactions have been reported between dietary zinc
    and calcium. In 1 study in which young rats were fed 0.75% zinc in the
    diet (as zinc carbonate), there was a marked decrease in bone calcium
    and phosphorus (Stewart & Magee, 1964). However, in another study with
    rats, administration of high levels of calcium or calcium and
    phosphorus in the diet increased the zinc requirement (Cabell & Earle,
    1965). In a study with dogs, administration of zinc in the drinking-
    water for 9 months increased the level of zinc in bone, but no changes
    were noted in Haversian bone remodelling, blood chemistry and
    circulating immunoactive parathyroid hormone levels (Anderson &
    Danylchuk, 1979). Zinc deficiency also affects calcium metabolism
    resulting in bone abnormalities in chicks and rat embryos (NRC, 1979).
    However, it does not appear to affect collagen and mucopolysaccharide
    formation (Philip & Kurup, 1978).

    Effects on other biochemical parameters

         Studies have been carried out with experimental animals to
    determine the relationship between zinc levels in the diet and
    zinc/copper antagonism and levels of serum cholesterol. In studies in
    which animals were maintained on diets in which the zinc/copper ratio
    was increased, either by decreasing copper levels at constant zinc
    intakes or by increasing zinc at constant copper intake, it was first
    suggested that this resulted in increased serum cholesterol levels
    (Klevay, 1973). However, subsequent studies by Murthy et al. (1974)
    showed that the effect was due to copper rather than zinc content of
    the diet. Similar results were reported in a study with human subjects
    (Freeland-Graves et al., 1980).

         High levels of zinc in the diets of experimental animals result
    in decreased cytochrome oxidase activity in the heart and liver, as
    well as catalase in the liver. The effect is due to interference with
    copper metabolism and is readily reversed by supplementation of the
    diet with copper (NRC, 1979).

         Diets deficient in zinc result in decreased activity of zinc-
    dependent enzymes in the tissues, which is subsequently reflected in
    changes in intermediary metabolism. However, interpretation of these
    effects is complicated because the earliest effects of zinc deficiency
    in the diet of experimental animals is decreased food intake, followed
    by cessation of growth (NRC, 1979).

    Special studies on mutagenicity

         Zinc chloride did not show any mutagenic or DNA-damaging
    capacity in a recombination-repair-deficient assay with strains of
    B. subtilis H17 (Rec+, arg-, try-) and M45 (Rec-, arg-, try-)
    (Kanematsu et al., 1980).

         Zinc sulfate produced no detectable aberrations of the bone
    marrow metaphase chromosomes of rats when administered orally at
    dosages of 2.75, 27.5 and 275 mg/kg bw (Litton Bionetics, 1973).

         No significant aberrations in the anaphase chromosomes of human
    embryonic lung cultures were noted when the cells were treated with
    0.1, 1.0 and 10 g/ml of zinc sulfate (Litton Bionetics, 1973).

         In a dominant-lethal assay, 10 male rats were assigned to each of
    5 groups. Three of the groups were given varying doses of zinc sulfate
    (2.75, 27.5 and 275 mg/kg), while the other 2 comprised positive
    (0.3 mg/kg triethylene melamine) or negative (saline) controls. The
    test compound was administered via intubation on an acute (single
    dose) or subacute (1 dose per day for 5 days) basis. Following
    treatment, the males were sequentially mated to 2 females per week for
    7 or 8 weeks. The results of this study did not detect any mutagenic
    activity of zinc sulfate (Litton Bionetics, 1973).

         Zinc sulfate produced no significant increases in mutation
    frequencies, both in vitro and in vivo, in 2 histidine auxotrophs
    of S. typhimurium (G-46 and TA-1530) and a diploid strain of
    S. cerevisiae (D-3) in a host-mediated assay. A dose-related
    increase in recombinant frequencies was noted in S. cerevisiae;
    however, this was not considered significant, because the increase in
    frequency was less than 4 times the negative control (Litton
    Bionetics, 1973).

         Zinc oxide and zinc stearate did not exhibit genetic activity in
    a series of in vitro microbial assays with S. cerevisiae (D-4) and
    S. typhimurium (TA-1535, TA-1537 and TA-1538), with and without
    activation, although dose-related increases in mutation frequencies
    were noted in mouse activation tests with strain TA-1537 (Litton
    Bionetics, 1976, 1977).

         Administration of ZnSO4 to pregnant female rats on day 20 of
    gestation resulted in the reduction of the incorporation of
    3H-thymidine into the DNA of the liver and brain of the developing
    foetus (Dreosti et al., 1981).

    Special studies on reproduction

         Groups of young rats were placed in cages and received either a
    basal diet or the basal diet plus 0.25% or 0.5% of zinc dust, zinc
    chloride, zinc oxide, zinc sulfate or zinc carbonate. After a period
    of time the animals were mated and the offspring, after weaning, were
    placed on identical dietary regimens. This was carried through for a
    subsequent generation. No toxic effects were noted, with the animals
    exhibiting normal growth, physical appearance and organ weight and
    reproductive performance (Heller & Burke, 1927).

    Special studies on teratogenicity

    Mouse

         Pregnant albino CD-1, outbred mice were dosed daily from day 6
    through day 15 of gestation with zinc sulfate at levels equivalent to
    0, 0.3, 1.4, 6.5 and 30 mg/kg bw. Body weights were recorded on days
    0, 6, 11, 15 and 17 of gestation and all animals were observed daily
    for appearance and behaviour. On day 17 all dams were subjected to
    caesarean section and the numbers of implantation sites, resorption
    sites, live and dead foetuses and pup body weights were recorded. All
    foetuses were examined grossly, while one-third underwent soft-tissue
    analysis and the remainder were examined for skeletal defects. Zinc
    sulfate had no discernible effect on nidation or on maternal or foetal
    survival or teratogenic effects (Food and Drug Research Laboratories,
    1973a).

    Hamster

         Pregnant hamsters were dosed daily from day 6 through day 10 of
    gestation with zinc sulfate at dose levels equivalent to 0.9, 4.1,
    19.0 and 88 mg/kg bw. Body weights were recorded on days 0, 8, 10 and
    14 of gestation. All animals were observed daily for appearance,
    behaviour and food intake. On day 14 all animals were subjected to
    caesarean section and the numbers of implantation and resorption
    sites, live and dead foetuses and pup weights were recorded. All
    foetuses were examined for external congenital defects, while one-
    third underwent soft-tissue analysis and the remainder were examined
    for skeletal defects. Zinc sulfate had no effect on implantation or
    maternal or foetal survival. Analysis of soft and hard tissues did not
    provide any evidence of compound-associated teratogenic effects (Food
    and Drug Research Laboratories, 1973b).

    Rat

         Pregnant Wistar albino rats were dosed daily from day 6 through
    day 15 of gestation with zinc sulfate at dose levels equivalent to
    0.4, 2.0, 9.1 and 42.5 mg/kg bw. Body weights were recorded on days 0,
    6, 11, 15 and 20 of gestation. All animals were observed daily for
    appearance, behaviour and food consumption. On day 20 all dams were
    subjected to caesarean section and the number of implantation sites,
    resportion sites, live and dead foetuses and body weights of the live
    pups were recorded. All foetuses were examined grossly for the
    presence of external congenital abnormalities. One-third of the
    foetuses underwent soft-tissue analysis, while the remaining two-
    thirds were examined for skeletal defects. The administration of zinc
    sulfate in this study had no clearly discernible effect on
    implantation or on maternal or foetal survival. The number of
    abnormalities seen in zinc-treated animals did not differ from the
    number seen in negative controls (Food and Drug Research Laboratories,
    1973c).

         Foetal viability and development were examined on day 20 of
    pregnancy in 4 adult hooded Wistar, female rats which received 20 mg
    of zinc sulfate by gavage on day 6 through day 12 of gestation. Four
    animals served as controls by receiving a similar volume of saline.
    The number of foetuses were significantly reduced in the zinc-treated
    dams, and no obvious malformations were seen in the pups which
    survived to term (Dreosti et al., 1981).

    Acute toxicity
                                                                        

                                          LD50
       Compound      Animal    Route   (mg/kg bw)   Reference
                                                                        

    Zinc sulfate     Mouse     Oral         611    Caujolle et al., 1964
                     Rat       Oral       1 374    Caujolle et al., 1964

    Zinc sulfate     Rat       Oral         750    Hahn & Schunk, 1955
      .7H2O

    Zn (OAc)2        Rat       Oral         750    Hahn & Schunk, 1955
      .7H2O          Rat       Oral       2 460    Smyth et al., 1969

    Zinc chloride    Rat       Oral         750    Hahn & Schunk, 1955
                     Rabbit    Oral         750    Hahn & Schunk, 1955

    Zinc sulfate     Rat       Oral         920    Litton Bionetics, 1973
                                                                        

    Cat

         Five cats were provided 50 g/kg bw of raw oysters which contained
    900 ppm (0.09%) zinc. The intake of oysters varied between 18 and 
    50 g/kg bw, which resulted in zinc intakes of approximately 16-45 mg/kg
    bw. No ill-effects were noted during a 24-hour observation period. Two
    weeks later the experimental regimen was repeated with the same
    result. Several months later an identical experiment was performed
    with oysters containing 1970 ppm (0.197%) zinc with no indications of
    ill-effects (Mannell, 1967).

    Short-term studies

    Rat

         Zinc was administered either as a suspension of zinc oxide or as
    solutions of zinc acetate, zinc citrate or zinc malate in daily doses
    ranging from 0.5 to 34.4 mg of zinc for periods ranging from 35 to 53
    weeks. Clinical and laboratory studies conducted during the course of
    the study included observations on general health, body weight,
    food and fluid intakes, urinalysis, haemoglobin and blood cell
    determinations, gross and microscopic examination of tissues and
    determinations of ingested zinc and of zinc content in urine, faeces,
    tissues and organs. No evidence was obtained of significant clinical,
    laboratory or gross and histological findings of damage resulting from
    ingestion of the various forms of zinc (Drinker et al., 1927a).

         Four groups of 25 Wistar rats each were maintained on diets that
    provided 0, 60, 120 or 600 mg of zinc chloride/day. The 0, 60 and
    120 mg/day dosages which were administered for 15 months produced no
    adverse effects. The highest dose group which received zinc chloride
    for 6 months showed a pronounced weight loss after 2 weeks on the test
    diet. The first mortality was also noted at this time and 13 rats
    died in the following 10 days. Six rats survived until 6 months.
    Gastrointestinal erosion and renal congestion were noted at the
    highest dose level (Wilkins, 1948).

         Weanling male Sprague-Dawley rats were housed individually and
    given free access to distilled and deionized water and were randomly
    divided into 3 groups. The zinc content, provided as zinc carbonate,
    of the diets used in these groups were 1.3, 50 and 550 ppm (0.00013,
    0.005 and 0.055%). The animals on the 55 and 550 ppm (0.0055 and
    0.055%) zinc diets received on each day an amount of diet equal to the
    diet intake of the pair-mates on the 1.3 ppm (0.00013%) zinc diet.
    After 4 weeks the animals were sacrificed and zinc levels in the
    blood, heart, lung, spleen, liver and kidney determined. The animals
    on the lowest zinc diet were considered to be on a zinc-deficient diet
    and demonstrated anorexia by the fifth day of feeding. The food
    efficiency ratio was lowest in the zinc-deficient diet as compared to
    the other zinc diets. The rats on the higher zinc diets showed similar
    weight gains and food efficiency ratios. These animals also exhibited
    higher zinc content of the heart, kidney, liver and blood than those
    on the zinc-deficient diet. Copper and magnesium content of the
    tissues analysed showed no significant alterations. However, the iron
    content of the kidney and liver was reduced in those animals on the 55
    and 550 ppm (0.0055 and 0.055%) zinc diets (Kang et al., 1977).

    Rabbit

         One litter of newborn New Zealand white rabbits received
    subcutaneous injections of 16 mg of zinc chloride between days 11 and
    17 of postnatal life. Controls received subcutaneous injections of
    hypertonic sodium chloride. The zinc-treated animals developed a
    neurological syndrome characterized by decreased spontaneous activity,
    mild ataxia, weakness of the hind legs and a diminished righting
    reflex. These were associated with gliosis in the cerebral grey and
    white matter and some pairing of astrocytic nuclei, but not with a
    reduction in brain weight or lipid content or increase in cerebral
    zinc levels. There was no evidence of neuronal loss, vascular damage
    or changes in the cerebellum or spinal cord. These effects on the
    central nervous system coincided with dilatation of the renal tubules,
    granulation of the cytoplasm of the renal tubular epithelium and
    elevated renal zinc levels (Prensky & Hillman, 1977).

    Cat

         Ten cats were fed canned salmon and milk once a day which was
    mixed with one of the following dosages of zinc oxide for periods
    ranging from 10 to 53 weeks: 33.8, 41.1, 44.0, 52.7, 64.4, 66.2,
    121.4, 265.4, 340.4 and 420.2 mg/kg bw per day. No control animals
    were used in the study. Urinalysis, haemoglobin determinations, blood
    cell counts and autopsies revealed no toxic effects in 7 of the cats.
    However, 3 of the animals did demonstrate fibrous changes in the
    pancreas (Drinker et al., 1927a).

    Dog

         Three dogs (1 male and 2 females) were administered 1 of 3 doses
    (36.1, 59.9 or 76.5 mg/kg bw) of zinc oxide on a daily basis for
    varying durations (3, 15 or 19 weeks). No control animals were
    included in the study. Urinalysis, haemoglobin determinations and
    gross pathology did not show any compound-related effects (Drinker et
    al., 1927a).

    Pig

         Groups of 6-9 weanling pigs were placed on diets which varied in
    the amount of added zinc carbonate (0, 0.05, 0.10, 0.20, 0.40 or
    0.80%) for 35-42 days. The addition of 0.1% zinc to the diet was
    determined to be the maximum level tolerated. High levels were
    associated with depressed weight gain and feed intake, arthritis,
    gastritis, catarrhal enteritis, congestion of the mesentery,
    haemorrhages in the axillary spaces, ventricles of the brain, lymph
    nodes and spleen (Brink et al., 1959).

    Long-term studies

    Mouse

         One hundred and fifty mice of the C3H strain were provided,
    ad libitum, distilled water containing zinc sulfate at a
    concentration of 500 ppm (0.05%). The control animals were provided
    with distilled water. Control and compound-treated animals were
    removed in groups of 5 every month. Plasma glucose and tissue zinc
    were determined and a histological examination of tissues was carried
    out. The last groups of mice were sacrificed at 14 months. The
    histological examination revealed hypertrophy of the adrenal cortex
    and pancreatic islets after 3 months as well as changes consistent
    with hyperactivity of the pituitary. Zinc content of the liver, spleen
    and skin, and plasma insulin and glucose concentrations were not
    altered by the zinc treatment (Aughey et al., 1977).

    Rat

         Four groups of 8 Osborne Mendel weanling rats were maintained on
    diets containing 0, 100, 500 and 1000 ppm (0, 0.01, 0.05 and 0.1%) of
    zinc sulfate for 21 months. Blood counts were made in the first 3 and
    last 5 months of the study. Bone marrow smears were made at the
    termination of the study, at which time the animals were sacrificed
    and autopsied. Microcytosis coupled with polychromasia and
    hyperchromasia were noted at all dosage levels. However, these effects
    did not persist despite the continuation of the zinc-containing diets.
    The bone marrow of zinc-treated animals showed a myeloid-erythroid
    ratio average of 1.16-1.35 as compared to a control value of 2.14.
    While the kidneys of the male rats on 500 and 1000 ppm (0.05 and 0.1%)
    were larger and more granular than those on 0 and 100 ppm (0 and
    0.01%) levels, no other gross pathological lesions associated with
    zinc administration were noted (Hagan et al., 1953).

    Dog

         Four Dalmatian puppies (10 weeks of age) received 200 mg/kg bw of
    zinc sulfate daily for 7 weeks. At the end of this period of time, the
    dosage was reduced to 100 mg/kg, because of persistent vomiting. This
    dosage was further reduced to 50 mg/kg bw, because of a similar
    problem, and continued until the end of the study 70 weeks later.
    Hypochromic anaemia was observed in all 4 of the zinc-treated dogs.
    Their bone marrows showed slight hyperplasia as compared to the
    controls with no change in the myeloid-erythroid ratio (Hagan et al.,
    1953).

    OBSERVATIONS IN MAN

         The Food and Nutrition Board of the United States (1980)
    recommendations for dietary allowances for zinc are as follows:
    infants 0-0.5 years, 2 mg, and 0.5-1.0 years, 5 mg; children 1-10
    years, 10 mg; men and women 11-51+ years, 15 mg; pregnant women,
    20 mg; and lactating women, 25 mg. Similar figures have been
    recommended by WHO/FAO (WHO, 1973).

         At this time, specific tests for zinc status in man, particularly
    marginal zinc deficiencies, have not been established. Levels of zinc
    in hair, urine and blood do not correlate well with zinc status.

    Acute effects

         Four hundred and fifty milligrams of zinc sulfate (in 200 ml
    water) is an emetic dose for an adult. However, the metallic taste of
    zinc solutions is detectable at 15 ppm (0.0015%) and is quite definite
    at 40 ppm (0.004%). These levels are higher than those found in most
    foods, but are not higher than those in some foods such as cooked meat
    and oysters. Zinc bound to food components is not available in the

    amounts analysed and would be expected to have less taste than ionic
    zinc in water. In addition, the zinc may be slowly released on
    digestion and would not cause the usual vomiting and gastrointestinal
    irritation associated with high levels of zinc. In 1 study, 4 humans
    were given oysters at a dose of 3 g/kg bw which contained 900 ppm
    (0.09%) zinc. None of the individuals noticed any ill-effects. Several
    months later the same experiment was performed with oysters containing
    1970 ppm (0.197%) zinc. In this instance 1 of the 4 individuals
    experienced nausea, severe cramps and diarrhoea (Mannell, 1967).

         Two instances of mass food poisoning have been attributed to zinc
    salts. In the first instance, between 300 and 350 people became ill.
    The major symptom was severe diarrhoea with abdominal cramping. Other
    symptoms included gross blood in their stools, tenesmus, occasional
    nausea and vomiting and 9 cases of shock. It was also shown that when
    the stools of these patients were examined excessive quantities of
    zinc were found. The average duration of illness was 18-24 hours. In
    the second episode approximately 50 individuals who consumed an
    alcoholic punch became ill. The acute symptoms included hot taste and
    dryness in the mouth, nausea, vomiting and diarrhoea. Subsequently,
    the patients reported general discomfort, muscular pain and 1 instance
    of double vision. The punch was analysed and found to contain 2200 ppm
    (0.22%) zinc. The dosage per individual was estimated to be between
    325 and 650 mg of zinc, which is equivalent to the emetic dosage range
    (Brown et al., 1964).

         Zinc toxicity has been reported in patients with impaired renal
    function undergoing dialysis with water containing high levels of
    zinc. The effects were reversed when zinc contamination of the water
    which was derived from the use of a galvanized water tank was removed
    (Petrie, 1977; Gallery et al., 1972).

    Zinc deficiency

         Zinc deficiency is associated with nutritional dwarfism which is
    characterized by growth and sexual retardation. This syndrome, which
    is common in the Middle East, is due to the diet of these individuals
    that is high in phytate which binds zinc and therefore makes it
    unavailable. A group of 19- and 20-year-old men and women who were
    suffering from this syndrome were placed in 3 experimental dietary
    groups for 6-12 months. One group received a well-balanced diet, the
    second received the same diet plus 120 mg of zinc sulfate/day, while
    the third group received the well-balanced diet alone for 6 months and
    from then on the zinc supplementation of 120 mg/day. The 2 groups
    which received the zinc supplementation demonstrated an alleviation of
    the symptoms (Halsted et al., 1972).

    Therapeutic use of zinc - wound healing

         Chronic effects due to oral ingestion of zinc salts have not been
    demonstrated. However, the use of zinc salts as an aid to wound
    healing provides information on levels of orally administered zinc
    that can be tolerated by man.

         Fourteen patients suffering from decubitus ulcers were given
    either 600 mg/day (divided into 3 doses) of zinc sulfate or a lactose
    placebo for 4 months. Urinalysis, blood counts and serum clinical
    chemistry conducted during the course of the study demonstrated no
    evidence of toxicity (Brewer et al., 1967).

         A group of patients with ulcers were divided into 2 groups of 52
    individuals each. One group served as the control and received
    660 mg/day of lactose, while the second group served as the test group
    and received 660 mg of zinc sulfate/day for 10 weeks. The healing of
    the ulcers was improved by the zinc treatment, while mild diarrhoea in
    3 patients was the only toxic effect noted (Husain, 1969). Other
    studies with patients who were treated with doses of zinc sulfate
    which ranged from 440 to 660 mg/day for the treatment of bedsores or
    leg sores also failed to demonstrate any untoward effects of the zinc
    treatment (Carruthers, 1969; Cohen, 1969).

         Thirty-four patients, 16 males and 18 females, suffering from
    sickle cell anaemia were treated 3 times daily with either 220 mg of
    lactose (placebo) or 220 mg of zinc sulfate for 6 months. It was
    determined that the healing rate was improved 3-fold by the zinc
    treatment, and that no symptoms of toxicity were associated with the
    dosage used in this study (Serjeant et al., 1970).

    Comments

         Zinc is an essential element in the nutrition of man and animals
    and has been identified as an integral part of numerous enzyme
    systems.

         The metabolism of zinc has been studied in experimental animals
    and man. A number of dietary factors interfere with the absorption of
    zinc, e.g., phytate, dietary factors and proteins. In addition,
    administration of excess zinc results in decreased zinc retention.

         Studies with experimental animals have shown that exposure to
    high levels of dietary zinc can cause anaemia as well as decreased
    levels of copper and iron absorption, and reduction in the activities
    of several important enzymes in various tissues. These effects also
    occur at lower levels of zinc exposure when the diet is deficient in
    copper. It is not known if the results of these are applicable to
    man. Zinc was not teratogenic and generally had no effect on the
    reproductive performance of test animals. It was not mutagenic in a

    number of bacterial and mammalian systems. The available long-term
    studies are insufficient to assess carcinogenicity. The required daily
    intake for adult humans is about 15 mg/day; however, the requirement
    varies with age. In addition, where cereals constitute an important
    part of the diet, a higher requirement may be needed. The average zinc
    intake via the diet and for an adult ranges from 14 to 20 mg/day
    (United States of America, United Kingdom) and is thus sufficient for
    nutritional needs. Most reports of toxic effects of zinc in man relate
    to acute effects, e.g., vomiting and diarrhoea, and are usually
    associated with the ingestion of acid drinks that have been stored in
    galvanized vessels. Certain foods such as oysters, which may contain
    very high levels of zinc, do not produce an emetic response. No
    information is available on toxic effects in man due to chronic
    excessive intake of zinc. High doses of zinc have been used
    therapeutically to promote healing of wounds. In clinical studies, up
    to 600 mg of zinc sulfate has been administered daily, in divided
    doses, for periods of several months without any reported adverse
    effects, including effects on blood counts and serum biochemistry.

    EVALUATION

         There is a wide margin between nutritionally required amounts of
    zinc and toxic levels. Clinical studies in which up to 600 mg of zinc
    sulfate (equivalent to 200 mg elemental zinc) has been administered
    daily in divided doses for a period of several months, provides a
    basis for the evaluation.

    Estimate for provisional maximum tolerable daily intake for man

    0.3-1.0 mg/kg bw.

    REFERENCES

    Aamodt, R. et al. (1975) Studies on the metabolism of Zn=65 in man,
         Fed. Proc., 34, 922

    Anderson, C. & Danylchuk, K. (1979) The effect of chronic excess zinc
         administration on the Haversian bone remodelling system and its
         possible relationship to "Itai-Itai" disease, Environ. Res.,
         20, 351-357

    Ansari, M. et al. (1975) Effects of high but non-toxic dietary zinc on
         zinc metabolism and adaptations in rats, Proc. Soc. exp. Biol.
         Med., 150, 534-536

    Aughey, E. et al. (1977) The effects of oral zinc supplementation in
         the mouse, J. comp. Pathol., 87, 1-14

    Brewer, R., Mihaldzie, N. & Dietz, A. (1967) The effect of oral zinc
         sulfate on the healing of decubitus ulcers in spinal cord injured
         patients, Proc. annu. clin. spinal Cord Inj. Conf., 16, 70-72

    Brink, M. et al. (1959) Zinc toxicity in the weanling pig, J. anim.
         Sci., 181, 836-842

    Brown, M. et al. (1964) Food poisoning involving zinc contamination,
         Arch. environ. Health, 8, 657-660

    Carruthers, R. (1969) Oral zinc sulphate in leg ulcers, Lancet, 1,
         1264

    Cabell, C. & Earle, I. (1965) Additive effect of calcium and
         phosphorus on utilization of dietary zinc, J. anim. Sci., 24,
         800-804

    Caujolle, F. et al. (1964) A comparison of the toxicities of zinc and
         cadmium sulfates, C.R. Acad. Sci. Paris, 258, 375-377

    Cerklenski, F. L. & Forbes, R. M. (1976) Influence of dietary zinc on
         lead toxicity in the rat, J. Nutr., 106, 689-696

    Cohen, C. (1969) Oral zinc sulphate in leg ulcers, Lancet, 1, 1213

    Cox, D., Schlicker, S. & Chu, R. (1969) Excess dietary zinc for the
         maternal rat, and zinc, iron, copper, calcium, and magnesium
         content and enzyme activity in maternal and fetal tissue, J.
         Nutr., 98, 459-466

    Davis, G. (1972) Competition among mineral elements relating to
         absorption by animals, Ann. N.Y. Acad. Sci., 199, 62-69

    DeSzilvay, G. (1964) The carcinogenic influence of zinc in drinking
         water, Minerva med., 55, 1504-1505

    Ditkiewicz, B., Dutkiewicz, T. & Milkowska (1979) The effect of mixed
         exposure to lead and zinc on ALA levels in urine, Int. Arch.
         occup. environ. Health, 42, 341-348

    Dreosti, I. et al. (1981) High plasma zinc levels following oral
         dosing in rats and the incorporation of 3H thymidine into
         deoxyribonucleic acid in rat fetuses, Res. Commun. chem.
         Pathol. Pharmacol., 31, 503-513

    Drinker, K., Thompson, P. & Marsh, M. (1927a) An investigation of the
         effect of long-continued ingestion of zinc, in the form zinc
         oxide, by cats and dogs together with observations upon the
         excretion and storage of zinc, Am. J. Physiol., 80, 31-64

    Drinker, K., Thompson, P. & Marsh, M. (1927b) An investigation of the
         effect upon rats of long-continued ingestion of zinc compounds,
         with special reference to the relation of zinc excretion to zinc
         intake, Am. J. Physiol., 81, 284-306

    Food and Drug Research Laboratories, Inc. (1973a) Final report -
         teratologic evaluation of zinc sulfate in mice, 26 February

    Food and Drug Research Laboratories, Inc. (1973b) Final report -
         teratologic evaluation of zinc sulfate in hamsters, 26 February

    Food and Drug Research Laboratories, Inc. (1973c) Final report -
         teratologic evaluation of zinc sulfate in rats, 26 February

    Food and Nutrition Board of United States (1980) Zinc. In: National
         Research Council Committee on Dietary Allowances, ed.
         Recommended Dietary Allowances, Washington, DC, National
         Academy of Sciences, 144-147 pp.

    Freeland-Graves, J. et al. (1980) Effect of dietary Zn/Cu ratios on
         cholesterol and HDL-cholesterol levels in women, Nutr. Rep.
         Int., 22, 285-293

    Friberg, L. et al. (1974) Cadmium in the environment, Cleveland,
         Ohio, CRC Press

    Gallery, E., Blomfield, J. & Dixon, S. R. (1972) Acute zinc toxicity
         in haemodialysis, Brit. med. J., 4, 331-333

    Giroux, E. & Henkin, R. (1972) Competition for zinc among serum
         albumin and amino acids, Biochim. Biophys Acta, 273, 64-72

    Guthrie, J. & Guthrie, O. (1974) Embryonal carcinomas in Syrian
         hamsters after intratesticular inoculation of zinc chloride
         during seasonal testicular growth, Cancer Res., 34, 2612-2614

    Hagan, E., Radomski, J. & Nelson, A. (1953) Blood and bone marrow
         effects of feeding zinc sulfate to rats and dogs, J. Am. Pharm.
         Assoc. Sci. Ed., 42, 700-702

    Hahn, F. & Schunk, R. (1955) Investigations about acute zinc
         intoxication, Nauyn-Schmiedebergs. Arch. exp. Pathol.
         Pharmacol., 226, 424-434

    Hall, A., Young, B. & Bremner, I. (1979) Intestinal metallothionein
         and the mutual antagonism between copper and zinc in the rat,
         J. inorg. Biochem., 11, 57-66

    Halme, E. (1961) On the cancer-causing effect of Zn-containing
         drinking-water, Vitalst.-Zivilisa, 6, 59-66

    Halsted, J. et al. (1972) Zinc deficiency in man, Am. J. Med., 53
         277-284

    Heller, V. & Burke, A. (1927) Toxicity of zinc, J. biol. Chem., 74
         85-93

    Henkin, R. & Aamodt, R. (1975) Zinc absorption in acrodermatitis
         enteropathica and in hypogeusia and hyposmia, Lancet, I,
         1379-1380

    Heth, D., Becker, W. & Haekstra, W. (1966) Effect of calcium,
         phosphorus and zinc on zinc-65 absorption and turnover in rats
         fed semipurified diets, J. Nutr., 88, 331-337

    Honstead, J. & Brady, D. (1967) The uptake and retention of 32P and
         65Zn from the consumption of Columbia River fish, Health
         Phys., 13, 455-463

    Husain, S. (1969) Oral zinc sulphate in leg ulcers, Lancet, II,
         1069-1073

    Kanematsu, N., Hara, M. & Kada, T. (1980) REC assay and mutagenicity
         studies on metal compounds, Mutat. Res., 77, 109-116

    Kang, H. et al. (1977) Zinc, iron, copper and magnesium concentrations
         in tissues of rats fed various amounts of zinc, Clin. Chem.,
         23, 1834-1837

    Klevay, L. (1973) Hypercholesterolemia in rats produced by an increase
         in the ratio to copper ingested, Am. J. clin. Nutr., 26,
         1060-1068

    Litton Bionetics (1973) Summary of mutagenicity screening studies,
         host-mediated assay, cytogenetics, dominant lethal assay,
         contract FDA 71-268 and 71-49, zinc sulfate

    Litton Bionetics (1976) Mutagenic evaluation of zinc oxide, USP,
         FDA 75-14

    Litton Bionetics (1977) Mutagenicity evaluation of FDA 75-72 zinc
         stearate USP 000557-05-1, FDA 75-72

    Lombeck, I. et al. (1975) Absorption of zinc in acrodermatitis
         enteropathria, Lancet, 1, 855

    Mannell, W. (1967) Effect of oysters with high zinc content on cats
         and man, BIBRA Info. Bull., 6, 432-433

    Meredith, P. & Moore, M. (1980) The in vivo effects of zinc on
         erythrocyte delta-aminolaevulinic acid dehydratase in man, Int.
         Arch., occup. Environ. Health, 45, 163-168

    Methfessel, A. & Spencer, H. (1973a) Zinc metabolism in the rat. I.
         Intestinal absorption of zinc, J. appl. Physiol., 34, 58-62

    Methfessel, A. & Spencer, H. (1973b) Zinc metabolism in the rat. II.
         Secretion of zinc into intestine, J. appl. Physiol., 34,
         63-67

    Murthy, L., Klevay, L. & Petering, H. (1974) Interrelationships of
         zinc and copper nutriture in the rat, J. Nutr., 104,
         1458-1465

    National Research Council (NRC) (1979) Zinc, Baltimore, University
         Park Press, pp. 173-268

    Nielsen, F., Sunde, M. & Hoekstra, W. (1966a) Effect of dietary amino
         acid source on the zinc-deficiency syndrome in the chick, J.
         Nutr., 89, 24-34

    Nielsen, F., Sunde, M. & Hoekstra, W. (1966b) Effect of some dietary
         synthetic and natural chelating agents on the zinc-deficiency
         syndrome in the chick, J. Nutr., 84, 35-42

    O'Dell, B. & Savage, J. (1960) Effect of phytic acid on zinc
         availability, Proc. Soc. exp. Biol. Med., 103, 304-306

    Ogiso, T. et al. (1974) Inhibitory effect of high dietary zinc on
         copper absorption in rats, Chem. Pharm. Bull., 22, 55-60

    Ogiso, T., Ogawa, N. & Muira, T. (1979) Inhibitory effect of high
         dietary zinc on copper absorption in rats. II. Binding of copper
         and zinc to cytosol proteins in the intestinal mucosa, Chem.
         Pharm. Bull., 27, 515-521

    O'Neil-Cutting, M., Bomford, A. & Munro, H. (1981) Effect of excess
         dietary zinc on tissue storage of iron in rats, J. Nutr.,
         III, 1969-1979

    Pecoud, A., Donzel, P. & Schelling, J. (1975) Effect of foodstuffs on
         the absorption of zinc sulfate, Clin. Pharm. exp. Therap.,
         17, 469-474

    Petering, H. C. (1980) The influence of dietary zinc and copper on the
         biologic effects of orally ingested lead in the rat, Ann. N.Y.
         Acad. Sci., 355, 298-308

    Petrie, J. & Row, P. (1977) Dialysis anaemia caused by subacute zinc
         toxicity, Lancet, 1, 1178-1180

    Philip, B. & Kurup, P. A. (1978) Dietary zinc and levels on collagen,
         elastin and carbohydrate components of glycoproteins of aorta,
         skin and cartilage in rats, Indian J. exp. Biol., 16, 370-372

    Prensky, A. & Hillman, L. (1977) Zinc and the developing nervous
         system: toxic effects of zinc on the central nervous system of
         the preweanling rabbit. In: Brain-fetal and infant, The Hague,
         Nijhoff Medical Division, pp. 124-136

    Reinhold, J. et al. (1973) Effects of purified phytate and phytate-
         rich bread upon metabolism of zinc, calcium, phosphorus, and
         nitrogen in man, Lancet, I, 283-288

    Richards, M. & Cousins, R. (1976) Metallothionein and its relationship
         to the metabolism of dietary zinc in rats, J. Nutr., 106,
         1591-1599

    Richmond, C. et al. (1962) Comparative metabolism of radionuclides in
         mammals. I. Uptake and retention of orally administered Zn 65 by
         four mammalian species, Health Phys., 8, 481-489

    Rosoff, B. & Spencer, H. (1965) Tissue distribution of zinc-65 in
         tumor tissue and normal tissue in man, Nature (Lond.), 207,
         652-653

    Schelling, J., Muller-Hess, S. & Thonney, F. (1973) Effect of food on
         zinc absorption, Lancet, 2, 968-969

    Serjeant, G., Galloway, R. & Gueri, M. (1970) Oral zinc sulphate in
         sickle-cell ulcers, Lancet, II, 891-893

    Slavik, M., Lovenberg, W. & Keiser, H. (1973a) Changes in serum and
         urine amino acids in patients with progressive systemic sclerosis
         treated with 6-azauridine triacetate, Biochem. Pharmacol.,
         22, 1295-1300

    Slavik, M. et al. (1973b) Alterations in metabolism of copper and zinc
         after administration of 6-azauridine triacetate, Biochem.
         Pharmacol., 22, 2349-2352

    Smith, W., Plumlee, M. & Beeson, W. (1962) Effect of source of protein
         on zinc requirement of the growing pig, J. anim. Sci., 21,
         399-405

    Smythe, H. et al. (1969) Range-finding toxicity data: List VII, Am.
         ind. Hyg. Assoc. J., 30, 470-476

    Spencer, H., Rosoff, B. & Feldstein (1965) Metabolism of zinc-65 in
         man, Radiat. Res., 24, 432-445

    Stewart, A. & Magee, A. (1964) Effect of zinc toxicity on calcium,
         phosphorus and magnesium metabolism of young rats, J. Nutr.,
         82, 282-295

    Suso, F. & Edwards, H. (1971a) Ethylenediaminetetracetate acid and
         65Zn binding by intestinal digesta, intestinal mucosa and blood
         plasma, Proc. Soc. exp. Biol. Med., 138, 157-162

    Suso, F. & Edwards, H. (1971b) Binding capacity of intestinal mucosa
         and blood plasma for zinc, Proc. Soc. exp. Biol. Med., 137,
         306-309

    Van Vleet, J., Boon, G. & Ferrans, V. (1981) Induction of lesions of
         selenium-vitamin E deficiency in weanling swine fed silver,
         cobalt, tellurium, zinc, cadmium and vanadium, Am. J. vet.
         Res., 42, 789-799

    Walters, M. & Roe, F. (1965) A study of the effect of zinc and tin
         administered orally to mice over a prolonged period, Fd.
         Cosmet. Toxicol., 3, 271-276

    World Health Organization (1973) Trace elements in human nutrition,
         WHO Tech. Rep. Ser., 532, 9-15

    Wilkins, J. (1948) A note on the toxicity of zinc chloride, Vet.
         Rec., 60, 81-84

    ANNEX I

    REPORTS AND OTHER DOCUMENTS RESULTING FROM PREVIOUS MEETINGS ON THE
    JOINT FAO/WHO EXPERT COMMITTEE ON FOOD ADDITIVES

         Documents marked with an asterisk may be obtained on request
    from: Division of Environmental Health, World Health Organization,
    1211 Geneva 27, Switzerland, or from Food Standards and Food Science
    Service, Food and Agriculture Organization of the United Nations,
    00100 Rome, Italy.

    1.   General principles governing the use of food additives (First
         report of the Expert Committee). FAO Nutrition Meetings Report
         Series, No. 15, 1957; WHO Technical Report Series, No. 129, 1957
         (out of print).

    2.   Procedures for the testing of intentional food additives to
         establish their safety for use (Second report of the Expert
         Committee). FAO Nutrition Meetings Report Series, No. 17, 1958;
         WHO Technical Report Series, No. 144, 1958 (out of print).

    3.   Specifications for identity and purity of food additives
         (antimicrobial preservatives and antioxidants) (Third report of
         the Expert Committee). These specifications were subsequently
         revised and published as Specifications for identity and purity
         of food additives, vol. I. Antimicrobial preservatives and
         antioxidants, Rome, Food and Agriculture Organization of the
         United Nations, 1962 (out of print).

    4.   Specifications for identity and purity of food additives (food
         colours) (Fourth report of the Expert Committee). These
         specifications were subsequently revised and published as
         Specifications for identity and purity of food additives, vol.
         II. Food colours, Rome, Food and Agriculture Organization of
         the United Nations, 1963 (out of print).

    5.   Evaluation of the carcinogenic hazards of food additives (Fifth
         report of the Expert Committee). FAO Nutrition Meetings Report
         Series, No. 29, 1961; WHO Technical Report Series, No. 220, 1961
         (out of print).

    6.   Evaluation of the toxicity of a number of antimicrobials and
         antioxidants (Sixth report of the Expert Committee). FAO
         Nutrition Meetings Report Series, No. 31, 1962; WHO Technical
         Report Series, No. 228, 1962.

    7.   Specifications for the identity and purity of food additives
         and their toxicological evaluation: emulsifiers, stabilizers,
         bleaching and maturing agents (Seventh report of the Expert
         Committee). FAO Nutrition Meetings Report Series, No. 25, 1964;
         WHO Technical Report Series, No. 281, 1964 (out of print).

    8.   Specifications for the identity and purity of food additives
         and their toxicological evaluation: food colours and some
         anti-microbials and antioxidants (Eighth report of the Expert
         Committee). FAO Nutrition Meetings Report Series, No. 38, 1965;
         WHO Technical Report Series, No. 309, 1965 (out of print).

    *9.  Specifications for identity and purity and toxicological
         evaluation of some antimicrobials and antioxidants. FAO
         Nutrition Meetings Report Series, No. 38A, 1965; WHO/Food
         Add/24.65.

    *10. Specifications for identity and purity and toxicological
         evaluation of food colours. FAO Nutrition Meetings Report
         Series, No. 38B, 1966; WHO/Food Add/66.25.

    11.  Specifications for the identity and purity of food additives
         and their toxicological evaluation: some antimicrobials,
         antioxidants, emulsifiers, stabilizers, flour-treatment agents,
         acids, and bases (Ninth report of the Expert Committee). FAO
         Nutrition Meetings Report Series, No. 40, 1966; WHO Technical
         Report Series, No. 339, 1966.

    12.  Specifications for the identity and purity of food additives
         and their toxicological evaluation: some emulsifiers and
         stabilizers and certain other substances (Tenth report of the
         Expert Committee). FAO Nutrition Meetings Report Series, No. 43,
         1967; WHO Technical Report Series, No. 373, 1967.

    *13. Toxicological evaluation of some antimicrobials, antioxidants,
         emulsifiers, stabilizers, flour-treatment agents, acids, and
         bases. FAO Nutrition Meetings Report Series, No. 40A, B, C;
         WHO/Food Add/67.29.

    14.  Specifications for the identity and purity of food additives
         and their toxicological evaluation: some flavouring substances
         and non-nutritive sweetening agents (Eleventh report of the
         Expert Committee). FAO Nutrition Meetings Report Series, No. 44,
         1968; WHO Technical Report Series, No. 383, 1968.

    *15. Toxicological evaluation of some flavouring substances and 
         non-nutritive sweetening agents. FAO Nutrition Meetings Report
         Series, No. 44A, 1968; WHO/Food Add/68.33.

    *16. Specification and criteria for identity and purity of some
         flavouring substances and non-nutritive sweetening agents. FAO
         Nutrition Meetings Report Series, No. 44B, 1969; WHO/Food
         Add/69.31.

    17.  Specifications for the identity and purity of food additives
         and their toxicological evaluation: some antibiotics (Twelfth
         report of the Expert Committee). FAO Nutrition Meetings Report
         Series, No. 45, 1969; WHO Technical Report Series, No. 430, 1969.

    *18. Specifications for the identity and purity of some antibiotics.
         FAO Nutrition Meetings Report Series, No. 43A, 1969; WHO/Food
         Add/69.34.

    19.  Specifications for the identity and purity of food additives
         and their toxicological evaluation: some food colours,
         emulsifiers, stabilizers, anticaking agents, and certain other
         substances (Thirteenth report of the Expert Committee). FAO
         Nutrition Meetings Report Series, No. 46, 1970; WHO Technical
         Report Series, No. 445, 1970.

    *20. Toxicological evaluation of some food colours emulsifiers,
         stabilizers, anticaking agents, and certain other substances.
         FAO Nutrition Meetings Report Series, No. 46A; WHO/Food
         Add/70.36.

    *21. Specifications for the identity and purity of some food
         colours, emulsifiers, stabilizers, anticaking agents, and
         certain other food additives. FAO Nutrition Meetings Report
         Series, No. 46B; WHO/Food Add/70.37.

    22.  Evaluation of food additives: specifications for the identity
         and purity of food additives and their toxicological
         evaluation: some extraction solvents and certain other
         substances; and a review of the technological efficacy of some
         antimicrobial agents (Fourteenth report of the Expert
         Committee). FAO Nutrition Meetings Report Series, No. 48, 1971;
         WHO Technical Report Series, No. 462, 1971.

    *23. Toxicological evaluation of some extraction solvents and
         certain other substances. FAO Nutrition Meetings Report
         Series, No. 48A, 1971; WHO/Food Add/70.39.

    *24. Specifications for the identity and purity of some extraction
         solvents and certain other substances. FAO Nutrition Meetings
         Report Series, No. 48B, 1971; WHO/Food Add/70.40.

    *25. A review of the technological efficacy of some antimicrobial
         agents. FAO Nutrition Meetings Report Series, No. 48C, 1971;
         WHO/Food Add/70.41.

    26.  Evaluation of food additives: some enzymes, modified starches,
         and certain other substances: toxicological evaluations and
         specifications and a review of the technological efficacy of
         some antioxidants (Fifteenth report of the Expert Committee).
         FAO Nutrition Meetings Report Series, No. 50, 1972; WHO Technical
         Report Series, No. 488, 1972.

    27.  Toxicological evaluation of some enzymes, modified starches,
         and certain other substances. FAO Nutrition Meetings Report
         Series, No. 50A, 1972; WHO Food Additives Series, No. 1, 1972.

    28.  Specifications for the identity and purity of some enzymes and
         certain other substances. FAO Nutrition Meetings Report Series,
         No. 50B, 1972; WHO Food Additives Series, No. 2, 1972.

    29.  A review of the technological efficacy of some antioxidants and
         synergists. FAO Nutrition Meetings Report Series, No. 50C,
         1972; WHO Food Additives Series, No. 3, 1972.

    30.  Evaluation of certain food additives and the contaminants
         mercury, lead, and cadmium (Sixteenth report of the Expert
         Committee), FAO Nutrition Meetings Report Series, No. 51, 1972;
         WHO Technical Report Series, No. 505, 1972, and corrigendum.

    31.  Evaluation of mercury, lead, cadmium, and the food additives
         amaranth, diethylpyrocarbonate, and octyl gallate. FAO
         Nutrition Meetings Report Series, No. 51A, 1972; WHO Food
         Additives Series, No. 4, 1972.

    32.  Toxicological evaluation of certain food additives with a
         review of general principles and of specifications (Seventeenth
         report of the Expert Committee). FAO Nutrition Meetings Report
         Series, No. 53, 1974; WHO Technical Report Series, No. 539, 1974,
         and corrigendum.

    33.  Toxicological evaluation of certain food additives including
         anticaking agents, antimicrobials, antioxidants, emulsifiers,
         and thickening agents. FAO Nutrition Meetings Report Series,
         No. 53A; WHO Food Additives Series, No. 5, 1974.

    34.  Evaluation of certain food additives (Eighteenth report of the
         Expert Committee). FAO Nutrition Meetings Report Series, No. 54,
         1974; WHO Technical Report Series, No. 557, 1974, and
         corrigendum.

    35.  Toxicological evaluation of some food colours, enzymes, flavour
         enhancers, thickening agents, and certain other food additives.
         FAO Nutrition Meetings Report Series, No. 54A, 1975; WHO Food
         Additives Series, No. 6, 1975.

    36.  Specifications for the identity and purity of some food
         colours, flavour enhancers, thickening agents, and certain food
         additives. FAO Nutrition Meetings Report Series, No. 54B, 1975;
         WHO Food Additives Series, No. 7, 1975.

    37.  Evaluation of certain food additives: some food colours,
         thickening agents, smoke condensates, and certain other
         substances (Nineteenth report of the Expert Committee). FAO
         Nutrition Meetings Report Series, No. 55, 1975; WHO Technical
         Report Series, No. 576, 1975.

    38.  Toxicological evaluation of some food colours, thickening
         agents, and certain other substances. FAO Nutrition Meetings
         Report Series, No. 55A; WHO Food Additives Series, No. 8, 1975.

    39.  Specifications for the identity and purity of certain food
         additives. FAO Nutrition Meetings Report Series, No. 55B, 1976;
         WHO Food Additives Series, No. 9, 1976.

    40.  Evaluation of certain food additives (Twentieth report of the
         Expert Committee). FAO Food and Nutrition Series, No. 1, 1976;
         WHO Technical Report Series, No. 599, 1976.

    41.  Toxicological evaluation of certain food additives. FAO Food
         and Nutrition Series, No. 1A, 1978; WHO Food Additives Series,
         No. 10, 1978.

    42.  Specifications for the identity and purity of certain food
         additives. FAO Food and Nutrition Series, No. 1B, 1977.

    43.  Evaluation of certain food additives (Twenty-first report of
         the Joint FAO/WHO Expert Committee on Food Additives). WHO
         Technical Report Series, No. 617, 1978.

    44.  Summary of toxicological data of certain food additives. WHO
         Food Additives Series, No. 12, 1977.

    45.  Specifications for identity and purity of some food additives,
         including antioxidants, food colours, thickeners, and others.
         FAO Nutrition Meetings Report Series, No. 57, 1977.

    46.  Specifications for identity and purity of thickening agents,
         anticaking agents, antimicrobials, antioxidants and
         emulsifiers. FAO Food and Nutrition Paper, No. 4, 1978.

    47.  Guide to specifications - General notices, general methods,
         identification tests, text solutions, and other reference
         materials. FAO Food and Nutrition Paper, No. 5, 1978.

    48.  Evaluation of certain food additives (Twenty-second report of
         the Joint FAO/WHO Expert Committee on Food Additives). WHO
         Technical Report Series, No. 631, 1978.

    49.  Summary of toxicological data of certain food additives and
         contaminants. WHO Food Additives Series, No. 13, 1978.

    50.  Specifications for the identity and purity of certain food
         additives. FAO Food and Nutrition Paper, No. 7, 1978.

    51.  Evaluation of certain food additives (Twenty-third report of
         the Joint FAO/WHO Expert Committee on Food Additives). WHO
         Technical Report Series, No. 648, 1980.

    52.  Toxicological evaluation of certain food additives. WHO Food
         Additives Series, No. 14, 1979.

    53.  Specifications for identity and purity of food colours,
         flavouring agents, and other food additives. FAO Food and
         Nutrition Paper, No. 12, 1979.

    54.  Evaluation of certain food additives (Twenty-fourth report of
         the Joint FAO/WHO Expert Committee on Food Additives). WHO
         Technical Report Series No. 653, 1980.

    55.  Toxicological evaluation of certain food additives. WHO Food
         Additives Series, No. 15, 1981.

    56.  Specifications for identity and purity of food additives
         (sweetening agents, emulsifying agents, and other food
         additives). FAO Food and Nutrition Paper, No. 17, 1980.

    57.  Evaluation of certain food additives (Twenty-fifth report of
         the Joint FAO/Expert Committee on Food Additives). WHO Technical
         Report Series, No. 669, 1981.

    58.  Toxicological evaluation of certain food additives. WHO Food
         Additives Series, No. 16, 1982.

    59.  Specifications for identity and purity of food additives
         (carrier solvents, emulsifiers and stabilizers, enzyme
         preparations, flavouring agents, food colours, sweetening
         agents and other food additives). FAO Food and Nutrition
         Paper, No. 19, 1981.

    60.  Evaluation of certain food additives and contaminants (Twenty-
         sixth report of the Joint FAO/WHO Expert Committee on Food
         Additives). WHO Technical Report Series, No. 683, 1982.

    61.  Specifications for identity and purity of food additives
         buffering agents, salts, emulsifiers, thickening agents,
         stabilizers, flavouring agents, food colours sweetening agents,
         and miscellaneous food additives. FAO Food and Nutrition Paper,
         No. 25, 1982.

        ANNEX II
    SURVEY OF PUBLICATIONS AND OTHER DOCUMENTS DIRECTLY RESULTING FROM ACTIVITIES OF THE JOINT
    FAO/WHO EXPERT COMMITTEE ON FOOD ADDITIVES
                                                                                                           

                                                       Publications                                Year of
    Meeting  Year of   Place of  Topics dealt with     or documents           Identification     publication
    No.      meeting   meeting                           resulting                codesa          or issue
                                                                                                           

    1        1956      Rome      General principles     Report only              NMRS 15            1957
                                 governing the use                               TRS 126            1957
                                 of food additives

    2        1957      Geneva    Procedures for the     Report only              NMRS 17            1958
                                 testing of                                      TRS 144            1958
                                 intentional food
                                 additives to
                                 establish their
                                 safety for use

    3        1958      Rome      Specifications for     Mimeographed             FAO                1959
                                 identity and           report
                                 purity of              Specifications           FAO-Volume I       1962
                                 antimicrobial
                                 preservatives and
                                 antioxidants

    4        1959      Rome      Specifications for     Mimeographed             FAO                1959
                                 identity and           report
                                 purity of food         Specifications           FAO-Volume II      1963
                                 colours

    5        1960      Geneva    Evaluation of the      Report only              NMRS 29            1961
                                 carcinogenic                                    TRS 220            1961
                                 hazards of food
                                 additives
                                                                                                           
    a  NMRS = FAO Nutrition Meetings Report Series; TRS = WHO Technical Report Series.

    Annex II (Con't)
                                                                                                           

                                                       Publications                                Year of
    Meeting  Year of   Place of  Topics dealt with     or documents           Identification     publication
    No.      meeting   meeting                           resulting                codesa          or issue
                                                                                                           

    6        1961      Geneva    Antimicrobials and     Report containing        NMRS 31            1962
                                 antioxidants           also                     TRS 228            1962
                                 (toxicology and        toxicological
                                 some                   monographs
                                 specifications)

    7        1963      Rome      Emulsifiers,           Report containing        NMRS 35            1964
                                 stabilizers,           toxicological            TRS 281            1964
                                 bleaching and          monographs and
                                 maturing agents        chemical
                                 (toxicology and        specifications
                                 specifications)

    8        1964      Geneva    Food colours,          Report                   NMRS 38            1965
                                 antimicrobials and                              TRS 309            1965
                                 antioxidants           Specifications           NMRS 38A           1965
                                 (toxicology and        for antimicrobials       Food Add. 24.65    1965
                                 specifications)        and antioxidants
                                                        Specifications           NMRS 38B           1966
                                                        and toxicology of        Food Add. 24.65    1966
                                                        food colours
                                                        (containing also
                                                        materials from
                                                        4th to 10th
                                                        meetings)
                                                                                                           

    a  NMRS = FAO Nutrition Meetings Report Series; TRS = WHO Technical Report Series;
       Food Add. = WHO/Food Additives.

    Annex II (Con't)
                                                                                                           

                                                       Publications                                Year of
    Meeting  Year of   Place of  Topics dealt with     or documents           Identification     publication
    No.      meeting   meeting                           resulting                codesa          or issue
                                                                                                           

    9        1965      Rome      Antimicrobials,        Report                   NMRS 40            1966
                                 antioxidants,                                   TRS 339            1966
                                 emulsifiers,           Toxicology               NMRS 40A,B,C       1967
                                 stabilizers,           and some                 Food Add. 67.29    1967
                                 flour-treating         specifications
                                 agents, acids and      (containing also
                                 bases                  materials from
                                                        10th meeting)

    10       1966      Geneva    Emulsifiers,           Report only              NMRS 43            1967           ,
                                 stabilizers and        (for monographs          TRS 373            1967
                                 certain other          see meetings 8
                                 substances             and 9)

    11       1967      Geneva    Flavouring             Report                   NMRS 44            1968
                                 substances and                                  TRS 383            1968
                                 non-nutritive          Toxicology               NMRS 44A           1968
                                 sweetening agents                               Food Add. 68.33    1967
                                                        Specifications           NMRS 44B           1969
                                                                                 Food Add. 69.31    1969

    12       1968      Geneva    Antibiotics            Report                   NMRS 45            1969
                                                                                 TRS 430            1969
                                                        Specifications           NMRS 45A           1969
                                                                                 Food Add. 69.34    1969
                                                                                                           

    a  NMRS = FAO Nutrition Meetings Report Series; TRS = WHO Technical Report Series;
       Food Add. = WHO/Food Additives.

    Annex II (Con't)
                                                                                                           

                                                       Publications                                Year of
    Meeting  Year of   Place of  Topics dealt with     or documents           Identification     publication
    No.      meeting   meeting                           resulting                codesa          or issue
                                                                                                           

    13       1969      Rome      Food colours,          Report                   NMRS 46            1970
                                 emulsifiers,                                    TRS 445            1970
                                 stabilizers,           Toxicology               NMRS 46A           1970
                                 anticaking agents,                              Food Add. 70.36    1970
                                 certain other          Specifications           NMRS 46B           1970
                                 substances                                      Food Add. 70.37    1970

    14       1970      Geneva    Extraction             Report                   NMRS 48            1971
                                 solvents,                                       TRS 462            1971
                                 certain other          Toxicology               NMRS 48A           1971
                                 substances,                                     Food Add. 70.39    1971
                                 technological          Specifications           NMRS 48B           1971
                                 efficacy of                                     Food Add. 70.40    1971
                                 antimicrobial          Efficacy                 NMRS 48C           1971
                                 agents                                          Food Add. 70.41    1971

    15       1971      Rome      Enzymes, modified      Report                   NMRS 50            1972
                                 starches, certain                               TRS 488            1972
                                 other substances,      Toxicology               NMRS 50A           1972
                                 technological                                   FAS 1              1972
                                 efficacy of            Specifications           NMRS 50B           1972
                                 antioxidants                                    FAS 2              1972
                                                        Efficacy                 NMRS 50C           1972
                                                                                 FAS 3              1972
                                                                                                           

    a  NMRS = FAO Nutrition Meetings Report Series; TRS = WHO Technical Report Series;
       Food Add. = WHO/Food Additives; FAS = WHO Food Additives Series.

    Annex II (Con't)
                                                                                                           

                                                       Publications                                Year of
    Meeting  Year of   Place of  Topics dealt with     or documents           Identification     publication
    No.      meeting   meeting                           resulting                codesa          or issue
                                                                                                           

    16       1972      Geneva    Contaminants:          Report                   NMRS 51            1972
                                 cadmium, lead,                                  TRS 505            1972
                                 mercury.               Toxicology               NMRS 51A           1972
                                 Additives:                                      FAS 4              1972
                                 amaranth,
                                 diethylpyrocarbonate
                                 and octyl gallate

    17       1973      Geneva    Certain food           Report                   NMRS 53            1974
                                 additives.                                      TRS 539            1974
                                 Review of general      Toxicology               NMRS 53A           1974
                                 principles                                      FAS 5              1974
                                                        Specificationsb          FNP 4              1978

    18       1974      Rome      Food colours,          Report                   NMRS 54            1974
                                 enzymes, flavours,                              TRS 557            1974
                                 thickening agents,     Toxicology               NMRS 54A           1975
                                 certain other food                              FAS 6              1975
                                 additives              Specifications           NMRS 54B           1975
                                                                                 FAS 7              1975
                                                                                                           

    a  NMRS = FAO Nutrition Meetings Report Series; TRS = WHO Technical Report Series;
       FAS = WHO Food Additives Series; FNP = FAO Food and Nutrition Paper.

    b  Published by FAO only.

    Annex II (Con't)
                                                                                                           

                                                       Publications                                Year of
    Meeting  Year of   Place of  Topics dealt with     or documents           Identification     publication
    No.      meeting   meeting                           resulting                codesa          or issue
                                                                                                           

    19       1975      Geneva    Food colours,          Report                   NMRS 55            1975
                                 thickening agents,                              TRS 576            1975
                                 certain other          Toxicology               NMRS 55A           1975
                                 substances                                      FAS 8              1975
                                                        Specificationsb          NMRS 55B           1976
                                                                                 FAS 9              1976

    20       1976      Rome      Certain food           Report                   FNS 1              1976
                                 additives,                                      TRS 599            1976
                                 antioxidants,          Toxicologyc              FAS 10               -
                                 sweeteners,            Specificationsb          FNS 1B             1977
                                 thickeners,                                     FAS 11             1977
                                 solvents and other
                                 food additives

    21       1977      Geneva    Certain food           Reportc                  TRS 617            1978
                                 additives,             Toxicologyc              FAS 12               -
                                 antioxidants, food     Specificationsb          NMRS 57            1977
                                 colours and
                                 thickeners
                                                                                                           

    a  NMRS = FAO Nutrition Meetings Report Series; TRS = WHO Technical Report Series;
       FAS = WHO Food Additives Series; FNS = FAO Food and Nutrition Series.

    b  Published by FAO only.

    c  Published by WHO only.

    Annex II (Con't)
                                                                                                           

                                                       Publications                                Year of
    Meeting  Year of   Place of  Topics dealt with     or documents           Identification     publication
    No.      meeting   meeting                           resulting                codesa          or issue
                                                                                                           

    22       1978      Rome      Certain food           Reportb                  TRS 631            1978
                                 additives and          Toxicologyb              FAS 13             1979
                                 contaminants,          Specificationsc          FNP 7              1978
                                 food colours,
                                 miscellaneous food
                                 additives,
                                 asbestos, lead,
                                 mercury, organic
                                 tin, and organotin
                                 compounds

    23       1979      Geneva    Food colours,          Reportb                  TRS 648            1980
                                 carrier solvents,      Toxicologyb              FAS 14             1980
                                 extraction             Specificationsc          FNP 12             1979
                                 solvents,
                                 flavours,
                                 inorganic salts
                                 and salts of
                                 organic acids
                                                                                                           

    a  TRS = WHO Technical Report Series; FAS = WHO Food Additives Series; FNP = FAO Food and
       Nutrition Paper.

    b  Published by WHO only.

    c  Published by FAO only.

    Annex II (Con't)
                                                                                                           

                                                       Publications                                Year of
    Meeting  Year of   Place of  Topics dealt with     or documents           Identification     publication
    No.      meeting   meeting                           resulting                codesa          or issue
                                                                                                           

    24       1980      Rome      Anticaking agents,     Reportb                  TRS 653            1980
                                 food                   Toxicologyb              FAS 15             1981
                                 antimicrobials,        Specificationsc          FNP 17
                                 antioxidants,
                                 emulsifiers,
                                 flavours, food
                                 colours,
                                 sweeteners,
                                 thickening agents,
                                 miscellaneous food
                                 additives

    25       1981      Geneva    Food colours,          Reportb                  TRS 669            1981
                                 flavours,              Toxicologyb              FAS 16             1982
                                 sweeteners,            Specificationsc          FNP 19             1981
                                 thickening agents,
                                 extraction
                                 solvents, carrier
                                 solvents,
                                 miscellaneous food
                                 additives
                                                                                                           

    a  TRS = WHO Technical Report Series; FAS = WHO Food Additives Series;
       FNP = FAO Food and Nutrition Paper.

    b  Published by WHO only.

    c  Published by FAO only.
        


    See Also:
       Toxicological Abbreviations
       Zinc (EHC 221, 2001)
       ZINC (JECFA Evaluation)
       Zinc (UKPID)