With the exception of the calcium salt which has not previously
    been evaluated, benzoic acid and its potassium and sodium salts have
    been evaluated for acceptable daily intake for man by the Joint
    FAO/WHO Expert Committee on Food Additives in 1961, 1965 and 1973 (see
    Annex I, Refs. 6, 11 and 32). Toxicological monographs were issued in
    1961, 1965 and 1973 (see Annex I, Refs. 6, 13 and 33).

         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.

         At the present time no biological data or toxicological studies
    conducted with calcium and potassium benzoates are available.



    Absorption, distribution and excretion

         The liver is the main site of conjugation with glycine in both
    man and most experimental animals (rabbits, rats), with the exception
    of the dog. In sheep, where the kidney is the main site of
    biosyntheses (Snapper et al., 1924; Friedmann & Tachau, 1911), there
    is an apparent reduced capability of conjugating benzoic acid with
    glycine. Infusion of increasing amounts of benzoic acid into the rumen
    at levels up to 1.8 g/kg led to a progressive fall in conjugation and
    increasing excretion of free benzoic acid in the urine. Doses of 1.1
    and 1.8 g/kg were toxic leading to death. Potassium deficiency also
    occurred as shown by the usual symptoms of severe muscular weakness
    and tremors (Martin, 1966). For many years, a liver function test was
    used in man based on the urinary excretion of hippuric acid after a
    test dose of benzoic acid (6 g orally or 1.5-2.O g intravenously).
    Hence there exists a large amount of experience on the excretion of
    benzoic acid and hippuric acid in man. In the blood, benzoates exist
    in the free state and are not bound to proteins (Knoefel & Huang,
    1956). In the dog, the kidney clearance was estimated to be 0.90-1.89%
    (Knoefel & Huang, 1956).

         Normal urinary excretion of hippuric acid in man was estimated to
    be 1.0-1.25 g/day, equivalent to 0.7-1.7 g of benzoic acid (Stein et
    al., 1954). Other determinations of the normal excretion in man and
    rat yield values lying between 1-3 mg/kg bw (Armstrong et al., 1955).
    The maximum rate of the hippuric acid excretion after ingestion of
    benzoic acid was observed to be 17 mg/minute and for benzoyl

    glucuronic acid, 0.67 mg/minute equivalent to 24 g/day calculated as
    benzoic acid (Schachter, 1957). Up to 10 g of benzoate is
    quantitatively excreted by man (Barnes, 1959). At high intake levels,
    up to 36% sodium benzoate is conjugated with glucuronic acid and all
    metabolites eliminated completely within 14 hours (Schachter, 1957).
    Seventy-five to 80% of administered benzoic acid is eliminated by man
    in six hours (Quick, 1931). Sodium benzoate also decreases uric acid
    (Quick, 1931), urea, and ammonia excretion in man (Lewis, 1914).

         Precursors of endogenous benzoate are phenylalanine and tyrosine.
    Experiments with labelled phenylalanine showed that about 1-2% is
    metabolized by this pathway. Rabbits given 50-400 mg/kg bw per day of
    deuterio-phenylalanine for six to 12 days, humans given 14-28 mg/kg bw
    per day for four to six days, and guinea-pigs given 300 mg/kg bw per
    day for 12 days, were examined (Bernard et al., 1955). 1-14C acetate,
    however, did not produce labelled benzoic acid in rabbits and guinea-
    pigs (Bernard et al., 1955). 3-14C phenylalanine given
    intraperitoneally to rats, produced 0.6-1% of activity as urinary
    hippuric acid (Altman et al., 1954).

         1,3,4,5-tetrahydroxycyclohexanoic acid (quinic acid) may also
    serve as a precursor of benzoic acid in intermediary metabolism
    (Dickens & Pearson, 1951). Several human subjects were given 6 g
    quinic acid orally or 250 g prunes and excreted hippuric acid in
    increased amounts during the following 24 hours (Quick, 1931). When
    deuterio-benzoic acid was administered to man and rats it was excreted
    with its deuterium content unchanged. Feeding guinea-pigs, with body
    fluids enriched in D20, with hydro-aromatic compounds led to urinary
    excretion of deuterio-benzoic acid with high D content. A similarly
    prepared rat, when fed 750 mg hydroxy benzoic acid over five days,
    excreted urinary benzoic acid enriched in D. When human subjects and
    guinea-pigs were given quinic acid over several days, 47-72% was
    converted to benzoic acid and excreted in the urine (Bernard et al.,
    1955). Four rats irradiated with 700 roentgens and four controls were
    given intraperitoneally carboxyl-14C-labelled sodium benzoate and
    fasted. Irradiation had no effect on the conjugating ability but the
    irradiated rats excreted less labelled hippuric acid due to dilution
    by endogenously produced benzoic acid (Schreier et al., 1954).

         Benzoic acid inhibits pepsin digestion and sodium benzoate
    inhibits trypsin digestion of fibrin but they have no effect on
    amylase or lipase. Trypsin digestion of casein is only initially
    depressed by sodium benzoate (Kluge, 1933). Benzoic acid is a specific
    powerful inhibitor of the D-amino-acid oxidase (50% inhibition by
    10-4M) (Klein & Kamin, 1964). Concentrations in the range of 10-3M
    exert some unspecific inhibitory effects on the metabolism of fatty
    acids, e.g. on acetoacetate formation (Avigan et al., 1955).

         Benzoic acid is rapidly absorbed (Schanker et al., 1958) and
    rapidly and completely excreted in the urine (Schachter, 1957; Barnes,
    1959). One healthy man given 6, 9, 13.9, 34.7 and 69.3 mmol of sodium

    benzoate showed a complete elimination of the drug within 10-14 hours
    (Schachter, 1957). Cumulation does not occur, as shown by experiments,
    on the distribution and elimination of sodium benzoate-1-C14
    administered i.p., orally, or s.c. to the rat. Practically
    quantitative excretion occurs in the urine within one to two days,
    less than 1% of radioactivity appears in the faeces, and a few ppm
    appear in organs. All radioactivity was identified as labelled benzoic
    acid (Lang & Lang, 1956). Orally or s.c. administered labelled benzoic
    acid appeared at 90% in the urine as hippuric acid, 0.1% of
    radioactivity occurred in the expired CO2, and 2% remained in the
    carcass (Bernard et al., 1955).

         Two urinary metabolites of benzoic acid are known, namely
    hippuric acid and benzoyl-glucuronic acid. Conjugation with glycine
    and glucuronic acid occurs in preference to oxidation because benzoic
    acid strongly inhibits fatty oxidation in the liver. In man, rabbit
    and rat, benzoic acid is almost entirely excreted as hippuric acid,
    whereas dogs excrete more conjugated glucuronic acid than hippuric
    acid (Williams, 1959). Sheep are less able to excrete free benzoic
    acid in their urine (Martin, 1966). The urine of man, pig, rabbit and
    sheep contains up to 10% of benzoyl-glucuronic acid.

         The maximum urinary excretory rate achieved depends on the dose
    of benzoate given. Limiting values of hippuric acid excretion were
    approached in man at a dose of 13.9 mmol (Schachter, 1957).
    Limitations in availability of glycine account for this (Quick, 1933).
    In the rat the tolerance of large doses of benzoic acid depends on the
    addition of adequate amounts of glycine to the diet leaving sufficient
    glycine for protein synthesis. Normally preformed glycine is used
    though some is synthesized as well by the rat (Quick, 1931; Barnes,
    1959). When rats were fed 1.5% benzoic acid (as the sodium salt) in
    the diet, they excreted 95% and more of the drug as hippuric acid in
    the urine. As the benzoate in the diet was increased to 3.75%, the
    ratio of hippuric acid to total benzoic acid in the urine decreased.
    Additional glycine raised elimination to 86-99%. The only other
    derivative, found in significant amounts in the urine, was benzoyl
    glucuronide (Griffith, 1929). Dogs and rabbits excrete hippuric acid
    independent of the route of administration of benzoic acid (Quick,


    Special studies on carcinogenicity


         See under long-term studies (Hosino, 1951).


         Groups of 50 male and 52 female Fischer-344 rats (four to five
    weeks old) received diets containing 1 (500 mg/kg/day) or 2%
    (1000 mg/kg/day) sodium benzoate for a period of 18-24 months.
    Controls consisted of 25 male and 43 female rats and received basal
    diet. Food was adequately controlled to avoid excess. Tap water was
    freely offered to all animals. All surviving animals were sacrificed
    between 18 and 25 months. Autopsy was carried out in all animals,
    those dying and sacrificed, and various organ tissues were
    histopathologically examined. No adverse clinical signs directly
    attributable to the compound were observed in treated animals.
    Differences in the average body weight and mortality rate between
    treated and control groups were negligible. Although a variety of
    tumours occurred among test and control rats of each sex, tumours
    appearing in treated rats were similar in type and number to those in
    controls. No evidence of carcinogenicity in rats from sodium benzoate
    was demonstrated (Sodemoto & Enomoto, 1980).

    Special studies on mutagenicity

         Sodium benzoate at concentrations ranging from 0.05 × 102 to
    5 × 104 ppm induces an array of cytological effects on Vicia faba
    root mitotic cells involving all the stages of the mitotic cycle. The
    most remarkable of these are the inhibition of DNA synthesis and the
    induction of anaphase bridges and subsequent micronuclei (Njagi &
    Gopalan, 1982).

         Mutagenicity studies in vitro demonstrated that sodium benzoate
    induced chromosomal aberrations in rat cells and also showed a
    positive mutagenic activity in recombination (REC) assay. The Ames
    test using Salmonella was negative (Kawachi, 1975, cited by Sodemoto
    & Enomoto, 1980).

    Special studies on reproduction


         Some of the animals subjected to a 17-month study were mated and
    their reproduction studied over five generations. Only body weights
    are given in the results (Shtenberg & Ignat'ev, 1970).

    Special studies on teratogenicity


         Groups of rats (number per group not defined) were injected
    intraperitoneally with sodium benzoate at dose levels of 100, 315, or

    1000 mg/kg during days 9-11 or 12-14 of gestation. Control animals
    were treated with sodium chloride at dose levels of 90 or 100 mg/kg on
    the same days as treated groups. During both treatment periods, sodium
    benzoate caused an increase in utero deaths and reduction of foetal
    body weight in the 1000 mg/kg dose group.

    During exposure days 9-11, the foetuses of this group exhibited some
    gross malformations, types and frequency not defined (Minor & Becker,


         Sodium benzoate produced no teratogenic effects in chicken
    embryos after injection into the air cell of egg on day 4 of
    incubation at levels as high as 5 mg/egg (Verrett et al., 1980).

    Acute toxicity

    Animal       Route              (mg/kg bw)         Reference

    Rat          Oral (Na salt)      2 700           Deuel et al., 1954
                 i.v. (Na salt)      1 714 ± 124     Spector, 1956

    Rabbit       Oral (Na salt)      2 000           Spector, 1956
                 s.c. (Na salt)      2 000           Spector, 1956

    Dog          Oral (Na salt)      2 000           Spector, 1956

    Rat          Oral (Benzoic
                 acid)               2 000-2 500     Ignat'ev, 1965

         Data on the LD50 of potassium and calcium benzoates are not
    available. Benzoic acid is not acutely toxic to man (Lehman, 1908) or
    to test animals in moderate doses (Rost et al., 1913; Smyth &
    Carpenter, 1948).

         Outbreaks of poisoning affecting 28 cats have followed ingestion
    of meat containing 2.39% benzoic acid. The effects were nervousness,
    excitability, and loss of balance and vision. Convulsions occurred and
    17 cats either died or were killed. Autopsies showed damage to
    intestinal mucosa and liver. The sensitivity of the cat may be due to
    its failure to form benzoyl glucuronide and toxicity may develop with
    quantities greater than 0.45 g/kg single doses or 0.2 g/kg repeated
    doses (Bedford & Clarke, 1971).

    Short-term studies


         Mice fed 3 g sodium benzoate daily for 10 days showed a 10%
    reduction of their creatine output, probably due to depletion of the
    glycine pool (Polonowski & Boy, 1941). Groups of 50 male and 50 female
    mice were given benzoic acid at the rate of 80 mg/kg/day, sodium
    bisulfite at 160 mg/kg/day, and a mixture of the two at the same
    levels by gavage. The highest mortality, as well as reduced weight
    gain, were observed in mice given the combination. A five-day period
    of food restriction at 2.5 months produced an 85% mortality in both
    groups (Shtenberg & Ignat'ev, 1970).


         Groups of 10 rats (five males and five females) were fed sodium
    benzoate for 30 days at levels ranging from 16-1090 mg/kg bw. There
    were no observable effects on body weight, appetite or mortality, nor
    were there any histological changes in the organs (Smyth & Carpenter,

         Groups of three male and three female rats were fed 0, 2 and 5%
    sodium benzoate in the diet for 28 days. All animals on the 5% level
    died during the first two weeks showing hyperexcitability, urinary
    incontinence, and convulsions. At the 2% level, male rats showed a
    significant decrease in body weight. The food intake of male and
    female animals was decreased at the 2% level compared with controls
    (Fanelli & Halliday, 1963). Four groups of 15 rats were given 0%, 5%
    sodium benzoate and 5% benzoate + 1% glycine in their diet for three
    weeks. Body weight was reduced at the 5% level but to a lesser extent
    when 1% glycine was added. Total cholesterol content of the liver was
    unaffected but phospholipids were significantly reduced in the liver
    at the 5% level. Potassium concentration of skeletal muscle at the 5%
    level was also low. Glycine corrected the potassium and phospholipid
    deficiencies (Kowalewski, 1960). Twenty-eight young rats were given a
    diet containing 5% sodium benzoate for three weeks. Nineteen animals
    died within two weeks. Food consumption was significantly reduced and
    most animals developed severe diarrhoea. Autopsy changes were gut
    haemorrhage and nasal blood crust, but normal urine. Five adult rats
    on a similar diet died within five weeks with severe weight loss
    (Kieckebusch & Lang, 1960). Groups of four to 19 male rats were fed
    diets containing 0, 1.5, 2.0, 2.5, 3, 3.25 and 3.75% sodium benzoate
    for 40 days. Average growth was less than in controls at all levels
    but above 3%, mortality was high, food efficiency poor, and growth
    severely depressed. Addition of glycine reduced the toxic effects.
    Animals died with incoordination, tremor or convulsions, and had
    severe eye inflammation. Feeding other groups of 10-15 young male rats

    on restricted amounts of diet containing 0, 1.5, 2.0, 2.5 and 3%
    sodium benzoate revealed no differences in weight gain at the 3%
    level. Glycine addition again improved this weight loss (Griffith,

         Groups of 10 male and 10 female rats (four to five weeks old,
    weighing 110-150 g) were fed sodium benzoate in the diet at levels 0,
    0.5, 1, 2, 4, or 8% for a period of six weeks. All rats on the 8%
    level and 19 rats on the 4% level died within four weeks. A
    considerable number of animals, 19, 18, and 17 of the 2, 1 and 0.5%
    groups, respectively survived for six weeks. A significant reduction
    of body weight gain was noted only in the 8% and 4% groups. Animals
    treated with sodium benzoate showed hypersensitivity as an acute toxic
    effect, but convulsions or other symptoms were not observed. No
    morphological change at autopsy, except for atrophy of the spleen and
    lymph nodes, was found in rats from the high dose level (8% and 4%)
    which died during the study period. Survivors showed no abnormal
    morphological changes at sacrifice (Sodemoto & Enomoto, 1980).

         Ninety-day feeding tests were carried out: on groups of eight to
    10 rats on diets containing 1, 2, 4 and 8% of sodium benzoate.

         In the group on the 8% diet there were four deaths (average
    number of days to death, 13). The weight gain of the four survivors
    was two-thirds of that of the controls on an identical food intake.
    Kidney and liver weights were significantly higher than those of the
    control group. At the lower levels, no demonstrable effect was
    observed (Deuel et al., 1954).


         Experiments on groups of four animals showed that doses of
    benzoate + benzoic acid of 150 mg/kg bw given daily up to 65 days had
    no adverse effects. When the same dose was fed to scorbutic animals a
    shortening of the life-span was observed (Kluge, 1933).


         Feeding tests on 17 dogs over 250 days with sodium benzoate or
    benzoic acid at the rate of 1000 mg/kg bw had no effects on growth,
    appetite and wellbeing. Above this level, ataxia, epileptic
    convulsions, and death occurred (Rost et al., 1913).

    Long-term studies


         Parenteral administration of benzoic acid has been shown not to
    cause tumour development (Hosino, 1951). Groups of 25 male and 25
    female mice were given benzoic acid in doses of 40 mg/kg/day, sodium

    bisulfite in doses of 80 mg/kg/day and a mixture of the two at the
    same levels for 17 months. Mortality was increased in the groups
    receiving the mixture (62%) compared with the individual substance
    groups (32%) at eight months. Mortality at 17 months is not given and
    pathology is not reported (Shtenberg & Ignat'ev, 1970).


         Three groups of 20 male and 20 female rats were pair fed for
    eight weeks on diets containing O, 0.5 and 1% benzoic acid and
    thereafter fed ad libitum over four generations. Two generations
    were fed for their whole life-span, the third and fourth generations
    were autopsied after 16 weeks. No harmful effects were observed on
    growth, fertility, lactation and life-span. The post-mortem
    examination showed no abnormalities (Kieckebusch & Lang, 1960). In
    another experiment 20 male and 30 female rats were fed on a diet
    containing 1.5% benzoic acid with 13 male and 12 female rats as
    controls for 18 months. Fifteen animals died in the test group, while
    only three died in the control group. The test animals showed reduced
    body weight and food intake. Repeat experiments on groups of 20 test
    animals and 10 controls taken from another strain showed similar
    findings (Marquardt, 1960).

         Groups of 10 rats, males and females, received benzoic acid at
    40 mg/kg/day or sodium bisulfite at 80 mg/kg/day or a mixture of the
    two in the diet for 18 months. The growth was slightly reduced and the
    erythrocyte sedimentation rate was increased. Rats fed benzoic acid
    developed some tolerance to a lethal dose of the compound given
    terminally. No pathology is reported (Shtenberg & Ignat'ev, 1970).


         In man, tolerance appears to vary. 5.7 g sodium benzoate causes
    marked gastrointestinal disturbances in some (Meissner & Shepard,
    1866) while others tolerate 25-40 g (Bignami, 1924). Up to 12 g daily
    have been given therapeutically to some, without ill-effects (Senator,
    1879), yet this same amount given over five days has produced gastric
    burning and anorexia in 30% of other subjects (Waldo et al., 1949).
    (Toxic symptoms in animals are local gastrointestinal mucosal
    irritation or CNS effects with convulsions.) Acute toxicity in man is
    readily reversible and probably due to the disturbance in acid-base
    equilibrium rather than associated with any tissue damage (Barnes,

         Six men were given 0.3-0.4 g of benzoic acid in their diet for
    periods up to 62 days. No abnormalities were seen in blood picture,
    urine composition, nitrogen balance, and wellbeing (Chittenden et al.,
    1909). Nine patients receiving penicillin treatment were given 1200 mg
    of benzoic acid daily divided into eight doses over a period of five
    days in eight of the subjects and 14 days in one case. No effect was

    observed. In no case did the endogenous creatinine clearance show
    significant changes nor did routine urine analysis show any
    abnormality (Waldo et al., 1949).

         It has been reported that some patients who suffer from asthma,
    rhinitis, or urticaria undergo exacerbation of symptoms following
    ingestion of foods or beverages containing benzoates (Freedman, 1977).


         Benzoic acid is effectively and rapidly metabolized and
    eliminated by the body without apparent tissue injury. The rat seems
    closest to man as far as the metabolism of benzoate is concerned.
    Mutagenicity studies in vitro demonstrated that sodium benzoate
    produces adverse cytogenetic effects in plant and mammalian cells but
    produced negative results in the Ames test. In vivo carcinogenicity
    studies were negative. Long-term toxicity studies demonstrated that
    exposure to benzoic acid in the diet at a level of 1% (500 mg/kg) did
    not cause observable toxic effects. A teratogenicity study in rats
    with sodium benzoate is insufficient to draw meaningful conclusions.
    Sodium benzoate produced no teratogenic effects in the chicken embryo.
    In multigeneration reproduction studies with benzoic acid, no harmful
    effects were observed. The cat seems to be much more sensitive than
    other species. Allergic responses to sodium benzoate have been
    reported. Although there is no toxicological data available for
    calcium and potassium benzoate, there is no reason to believe they
    differ toxicologically from benzoic acid and sodium benzoate when used
    as food additives.


    Level causing no toxicological effect

         Rat: 1% (10 000 ppm) in the diet equivalent to 500 mg/kg bw.

    Estimate of acceptable daily intake for man

         0-5 mg/kg bw.*


    *    As the sum of benzoic acid and Na, K and Ca benzoate (expressed
         as benzoic acid).


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    See Also:
       Toxicological Abbreviations