BENZOIC ACID AND ITS CALCIUM, POTASSIUM AND SODIUM SALTS
Explanation
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.
BIOLOGICAL DATA
BIOCHEMICAL ASPECTS
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,
1931).
TOXICOLOGICAL STUDIES
Special studies on carcinogenicity
Mouse
See under long-term studies (Hosino, 1951).
Rat
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
Mouse
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
Rat
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,
1971).
Chicken
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
LD50
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
Mouse
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).
Rat
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,
1948).
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,
1929).
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).
Guinea-pig
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).
Dog
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
Mouse
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).
Rat
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).
OBSERVATIONS IN MAN
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,
1959).
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).
Comments
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.
EVALUATION
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