Toxicological evaluation of some food
additives including anticaking agents,
antimicrobials, antioxidants, emulsifiers
and thickening agents
WHO FOOD ADDITIVES SERIES NO. 5
The evaluations contained in this publication
were prepared by the Joint FAO/WHO Expert
Committee on Food Additives which met in Geneva,
25 June - 4 July 19731
World Health Organization
Geneva
1974
1 Seventeenth Report of the Joint FAO/WHO Expert Committee on
Food Additives, Wld Hlth Org. techn. Rep. Ser., 1974, No. 539;
FAO Nutrition Meetings Report Series, 1974, No. 53.
NITRITE, POTASSIUM AND SODIUM SALTS
Explanation
These compounds have been evaluated for acceptable daily intake
by the Joint FAO/WHO Expert Committee on Food Additives (see Annex 1,
Refs No. 6 and No. 9) in 1961 and 1964.
Since the previous evaluation, additional data have become
available and are summarized and discussed in the following monograph.
The previously published monograph has been expanded and is reproduced
in its entirety below.
BIOLOGICAL DATA
BIOCHEMICAL ASPECTS
Sodium nitrite is readily absorbed from the gut and rapidly
disappears from the bloodstream. 30-40% of absorbed nitrite is
excreted unchanged in the urine, the fate of 60-70% is not accurately
known. It can combine with myoglobin to form nitrosomyoglobin and with
haemoglobin to form methaemoglobin (MAFF, 1962).
Following absorption of nitrites, the most important biochemical
reaction that occurs is the conversion of haemoglobin to
methaemoglobin. There is some controversy concerning the molar ratios
involved in this reaction. Making an extreme assumption, it may be
stated that 1 g of sodium nitrite could convert as much as 1855 g of
haemoglobin to methaemoglobin (Lehman, 1958).
The sub-acute hazard of nitrites rests on the amount of
methaemoglobin formed and on the ability of the body to reconvert this
methaemoglobin back to haemoglobin.
Inorganic nitrite is oxidized to nitrate by tissue homogenates.
The reaction depends on catalase content and is mediated by probably a
D amino acid oxidase or xanthine oxidase system linked with catalase.
Hydrogen peroxide formed by the oxidation is used by the catalase for
the coupled oxidation of nitrite (Heppel & Porterfield, 1949). Nitrite
oxidizes in vivo haemoglobin in preference to glutathione which is
protected by pentose cycles and prevents Heinz bodies formation in
human erythrocytes (Harley & Robin, 1962).
Rats given for two to three weeks a diet deficient in vitamin A
to deplete liver stores were then given for six days 0.3% sodium
nitrite in the diet and on the third and fourth day vitamin A or
carotene orally or s.c.. Assay of liver levels on the sixth day showed
reduced storage of vitamin A following oral but not s.c. vitamin A
dosing. Nitrite is known to degrade carotene under acid conditions and
may have caused this by direct action (Emerick & Olson, 1962).
Calves receiving 4 ppm (0.0004%) nitrite in drinking-water alone
or with E. coli or with a thyroid depressant showed interference
with carotene utilization in all experiments (McIlwain & Schipper,
1963). Chicks receiving 0.4% potassium nitrite showed growth
depression, reduced vitamin A storage in liver and enlargement of the
thyroid gland despite dietary supplementation with vitamin A (Sell &
Roberts, 1963). When chicks were given doses of 18-60 mg/kg/day of
sodium nitrite over a few days the liver showed inhibition of vitamin
A accumulation even if fed vitamin A-rich diets (Brüggemann & Tiews,
1964).
TOXICOLOGICAL STUDIES
Special studies on nitrosamines
A. Carcinogenesis and nitrosamines
Since the discovery of the carcinogenic property of
dimethylnitrosamine (Magee & Barnes, 1956), many other nitrosamines
have been found to induce malignant tumours in various species of
laboratory animals (Magee & Barnes, 1967). There is growing concern
with regard to certain nitrosamines as etiological agents for cancer
in the human environment (Lijinsky & Epstein, 1970). It is generally
accepted that the use of nitrite as a food preservative may be
associated with the formation of nitrosamines in foods as well as in
the animal organism. The nitrosamines vary in their carcinogenic
potential. They can induce malignant tumours at very low levels, such
as 2 ppm (0.0002%) in the diet of rats (Terracini et al., 1967),
equivalent to daily doses of 0.1 mg/kg bw. A single oral dose of
30 mg/kg bw of nitrosamine proved to be carcinogenic in the rat
(Druckrey et al., 1969). Tumours of the trachea developed in the
offspring of hamsters treated either during pregnancy or lactation
with nitrosamine (Mohr & Althof, 1971).
1. In vitro nitrosamine formation
Nitrosamines are formed when sodium nitrite and various secondary
amines are incubated with human gastric juice at pH 1.3 (Sander,
1967). DEN (diethylnitrosamine) was detected when diethylamine and
sodium nitrite were incubated with gastric juices from man, rat,
rabbit, cat and dog. Human and rabbit juices (pH 1-2) produced more
DEN than the less acidic gastric juice (pH 4-5) of the rat (Sen et
al., 1969). Dimethylamine and sodium nitrite incubated together in the
molecular proportion 1:4 with the bacterial flora of the rat intestine
under anaerobic condition at pH7 gave rise to dimethylnitrosamine
(DMN). DMN formation was enhanced by the addition of glucose and
riboflavin, but suppressed by neomycin (Klubes et al., 1972). Ender &
Ceh (1971) reported the formation of various nitrosamines when nitrite
was incubated with alkylamines, heterocyclic amines, biogenic amines,
certain amino acids and proteins from meat and fish respectively.
Nitrosamine formation increased greatly at high incubation
temperatures and at lower pH-values.
2. In vivo nitrosamine formation
Diphenylnitrosamine, at levels ranging from 0.5 to 11 µg/l, was
detected in stomach contents of 11 out of 35 patients, following the
intragastric administration of a test solution containing 300 mg
sodium nitrate, 10 mg diphenylamine, 100 mg sodium-bicarbonate and
1000 mg glucose (Sander & Seif, 1969). Synthesis of nitrosopiperidine
from nitrite or nitrate and piperidine in the gastrointestinal tract
of the rat was observed (Alam et al., 1971a, 1971b). Intragastric
injection of sodium nitrite and sarcosine resulted in the detection of
nitroso-sarcosine in the stomach wall of mice (Friedman, 1972).
3. Carcinogenesis with the simultaneous administration of
nitrite and various amines
Sander & Bürkle (1969) reported the occurrence of oesophageal and
hepatic tumours in rats fed N methyl-benzylamine or morpholine mixed
with sodium nitrite in the diet. Sodium nitrite in the drinking-water
given together with piperazine, morpholine and N-methylamine
respectively to mice led to a highly significant increase of lung
tumours (Greenblatt et al., 1971). Similarly the administration of
methylurea or ethylurea with sodium nitrite resulted in the induction
of lung adenomas in mice (Mirvish, 1971).
Rats fed dimethylurea and 0.3% sodium nitrite for 36 days
developed tumours of CNS, heart, thymus, kidney or thyroid in all
animals (Sander, 1970). Mice given either methylurea (5360 ppm
(0.536%)) or ethylurea (6360 ppm (0.636%)) with 1 g/l sodium nitrite
for six months showed more lung adenomas in test animals (Mirvish et
al., 1972). Concurrent administration of 0.1% sodium nitrite and 0.5%
proline, hydroxyproline or arginine for 26 weeks produced no increase
in lung adenomas (Greenblatt & Lijinsky, 1972).
4. Nitrosamines in foods
Of the unprocessed foods analysed, only mushrooms were shown to
contain dimethylnitrosamine at levels ranging from 0.4 to 30 µg/kg
(Ender & Ceh, 1968). The same authors analysed different smoked fish
and meat products and found dimethylnitrosamine at levels of 0.5 to
15 µg/kg. Eighteen samples of smoked, and five of canned fish were
analysed after cooking with or without sodium nitrite (up to 200 ppm
(0.02%)). The results indicated that certain kinds of fish, especially
those rich in amines, formed dimethylnitrosamine at levels ranging
from 2.5 to 45 µg/kg during cooking with nitrite (Sen et al., 1970).
Fifty-one samples of a variety of meat products contained 5 µg/kg or
less dimethylnitrosamine (Fazio et al., 1971). Dimethylnitrosamine was
found at levels of 10-80 µg/kg in five out of 59 samples of prepared
meat products (Sen, 1972). Analyses of 40 samples of frankfurters from
eight large producers in the United States of America revealed the
presence of dimethylnitrosamine at levels of 2-84 µg/kg only in a
small proportion of samples (Wasserman et al., 1972). Crosby et al.
(1972) while analysing various bacons, fish and miscellaneous food
products, found that frying or baking of fish products almost doubled
their very low or undetectable dimethylnitrosamine content. Sen et al.
(1973) reported that various samples of side bacon when fried
contained 4-25 µg/kg nitrosopyrrolidine; without frying
nitrosopyrrolidine was undetectable.
B. Teratogenesis and nitrosamines
A single i.v. dose of N-nitrosomethylurea to pregnant rats
led to increased foetal deaths and reabsorptions and to malformations
in those surviving (von Kreybig, 1965). It has been shown that
N-nitrosomethylurea and N-nitrosoethylurea were potent teratogens and
carcinogens in rats (Druckrey et al., 1966).
C. Mutagenesis and nitrosamines
Chromosomal aberrations and gene mutations were observed
following the administration of N1-nitro-N-nitrosomethylguanidine and
N-nitrosomethylurea (Magee & Barnes, 1967). Malling (1971) found that
both dimethylnitrosamine and diethylnitrosamine were active mutagens
in the mouse liver-microsome system. Four carcinogenic nitrosamines,
dimethylnitrosamine, N-nitrosomethylurea, N-nitroso-methylurethane and
N methyl-N-nitro-N-nitrosoguanidine proved to be effective in
producing cell killing, chromatid breaks and chromatid rearrangements
in Chinese hamster ovary cells (Kao & Puck, 1971).
1. Comments on studies reported
From the studies referred to and others in the literature it is
evident that (a) nitrosamines are potent carcinogens in several
species of animals, (b) nitrosamines can be formed when nitrites
and secondary amines are incubated with human gastric juice,
(c) nitrosamine formation has been detected in in vivo studies and
(d) nitrosamines have been reported in several foods. While there are
indications of a dose-response relationship in nitrosamine-induced
tumour development, a no-effect level for several nitrosamines has not
as yet been established. It must be remembered that the possibility of
nitrosamine formation in foods or in the animal organism does not
depend solely on added nitrite or nitrate. Nitrates occur naturally
in many foods and nitrite has been detected in saliva at levels of
5-10 ppm (0.0005-0.001%).
The role played by nitrites in food preservation is important
and the ability to inhibit the growth and toxin formation of
C. botulinum must be weighed against the potential risk associated
with their role in nitrosamine formation. The whole question of
nitrosamine formation and effects is under active investigation in
several countries. One promising area of this investigation involves
the use of ascorbic acid as a blocking agent in nitrosation of amines.
Special studies on reproduction and teratogenicity
Rat
The F1b generations of rats raised from parents fed from day 40,
meat heat-processed with 0, 200, 1000 and 4000 ppm (0.0%, 0.02%, 0.1%,
and 0.04%) sodium nitrite were sacrificed on day 21 and examined.
Three control groups were used. Fertility, preimplantation loss and
resorptions were in no way affected by nitrite. No difference from
controls was seen regarding litter size, sex ratio and mean pup
weight. No significant malformations were noted (Carstensen &
Hasselager, 1972).
Two groups of 12 pregnant rats received either 2000 or 3000 mg/l
sodium nitrite in their drinking-water, a group of seven pregnant rats
was the control. Anaemia was found in pregnant animals and there was
greater mortality of newborn in the groups with nitrite (30% and 53%
compared with 6% in controls). Treated pups also gained weight more
slowly but had no methaemoglobinaemia. Nitrites were shown to pass the
placental barrier (Gruener & Shuval, 1971).
Guinea-pig
Groups of three to four pregnant guinea-pigs were given 50 mg/kg
or 60 mg/kg sodium nitrite s.c. once. Normal pregnancies ensued at the
lower level. At the higher dose fetal mortality and abortion occurred
within one to four days (Sinha & Sleight, 1971).
Groups were given 300 to 10 000 ppm (0.03-1%) nitrite in their
diet. Male fertility was unimpaired as all groups conceived. Food,
water consumption, weight gain were normal except animals on
10 000 ppm (1%) which showed very reduced weight gain. No live births
occurred at and above 5000 ppm (0.5%) and maternal deaths, abortions,
fetal resorptions and mummification were seen. Histology showed
degenerative placental lesions and inflammation of the uterus and
cervix. No significant alterations in serum nitrite, blood urea or
serum potassium were seen but haemoglobin was slightly reduced at
higher levels. Methaemoglobin did not exceed 20% (Sleight & Atallah,
1968).
Cattle
Cows, pregnant two months, were given nitrite in their diet to
produce 40-50% methaemoglobinaemia until they calved or aborted. Only
one abortion occurred, the rest had normal pregnancies. No gross
pathology was seen (Winter & Hokanson, 1964).
Acute toxicity
LD50
Animal Route (mg/kg bw) Reference
Mouse oral 220 Greenberg et al., 1945
Mouse - female oral 175 Lehman, 1958
Rat - female oral 85 Lehman, 1958
Sodium nitrite has been used for therapeutic purposes as a
vasodilating agent in dosages of 30-120 mg.
The acute effects of nitrite include vasodilatation, lowering
of blood pressure, reduction of vitamin A stores in the liver and
disturbances of thyroid function. Dogs given a single dose of
1-2 mg/kg sodium nitrite in sausage showed a rise in respiration and
heart rate, changes in ECG, methaemoglobinaemia within one to two
hours, a rise in serum sodium, fall in serum potassium and a rise in
SGOT (Myasnikov & Pravosudov, 1966).
Short-term studies
Mouse
When mice were given sodium nitrite in their drinking-water at 0,
100, 1000, 1500 and 2000 mg/l their motor activity decreased
especially at the highest level (Gruener & Shuval, 1971).
Rat
Rats given 0, 100, 300 and 2000 mg/l sodium nitrite in their
drinking-water for two months showed in their EEG increased
frequencies of background waves at the highest level and slightly
reduced frequencies at lower levels. At all levels there were
paroxysmal outbursts not seen in pretreatment period. After four
months observation following treatment only the animals at the
100 mg/l level returned to normal EEGs, all higher levels continued to
show EEG abnormalities (Gruener & Shuval, 1971). Rats given in their
drinking-water for 200 days nitrite at levels of intake of 170 and
340 mg/kg/day showed methaemoglobinaemia, raised haematocrit, no Heinz
bodies, raised spleen weights in females, raised heart weights in
males, some changes in liver weight in females and in kidney weights
of both sexes (Musil, 1966).
Rats were fed a sodium nitrite supplement for a period up to
168 days. One rat received a total of 167 mg of sodium nitrite in
121 days. This represents 93 ppm (0.0093%) in the daily diet. No
effects on growth or on the weights of important organs were noted
(Tarr & Carter, 1942).
Cat
In a similar experiment with cats, one animal received a total of
about 4100 mg of sodium nitrite during a period of 105 days. This
represents approximately 390 ppm (0.039%) in the daily diet. No
effects on the growth rate or on the weight of important organs were
noted. No histopathological examination has been reported on any
animal fed with nitrite (Tarr & Carter, 1942).
Long-term studies
Rat
The continuous administration of sodium nitrite in the drinking-
water at the rate of 100 mg/kg bw daily over the whole life span and
in three successive generations (95 rats) resulted in spite of the
high dosage (67% of the acute LD50) in only a slight inhibition of
growth (10-20%) and in a shortening of the median life-span from 740
to 640 days. Reproduction was normal. Neither the blood picture nor
the organs showed any ill effects. The number of tumours observed in
the test group (one thymoma and one hepatoma) was not greater than in
the control group. Cumulative toxic effects were not observed (Lehman,
1958).
Six groups of 30 male and 30 female rats were given standard diet
(control) or 40% meat (control) or 40% meat heat-processed with 0.5%
sodium nitrite, 0.5% sodium nitrate and 1% gluconodeltalactone, 0.02%
sodium nitrite and 1% gluconodeltalactone for 116 weeks. Body weight
was lower in the group with 0.5% sodium nitrite with or without GDL.
Food intake was not affected anywhere. Behaviour was normal in all
groups. Mortality rose equally in all groups after 18 months. No
adverse effects on haematology were seen except that red cell counts
were lower in the nitrite groups. BSP, SGPT and drug-metabolizing
enzymes showed no evidence of liver damage. Spontaneous tumour
incidence was high but no significant rise in organ tumours likely
to be caused by nitrosamines appeared. DNA of liver cells nuclei was
not increased, the ratio diploid/tetraploid cells was normal and
alpha-fetoproteins in serm showed no evidence of liver tumours. The
diet with 40% meat treated with 0.5% nitrite is equivalent to 20 ppb
nitrosamines (= 1 mg/kg per day) (Van Logten et al., 1972). The F1A
generations of rats raised from parents fed from day 40 with meat
heat-processed with 0, 200, 1000 and 4000 ppm (0.0, 0.02, 0.1 and
0.4%) sodium nitrite have been kept on diets containing 46% similarly
treated meat as the sole protein source. The groups consist of 340,
120, 120 and 132 males and females and the minimum age so far is
583 days (Poulsen, 1973).
Rats were fed 0.2% sodium nitrite for 18 months without adverse
effects (Lijinsky, 1971). In another study five groups of eight male
rats were given tap water or 5 mg/kg, 50 mg/kg, 100 mg/kg and
150 mg/kg sodium nitrite in their drinking-water for 24 months. There
were no significant differences regarding growth, haemoglobin levels,
blood glucose, pyruvate and lactate, methaemoglobin was about 5%, 10%
and 20% in the highest levels and slightly raised for two months only
at the 5 mg/kg level. Histopathology showed bronchopneumonia in a
dose-related manner (non-SPF animals) and the highest group showed
loci of myocardial degeneration. In all test groups but especially at
the highest level the coronary vessels were thin and dilated (Gruener
& Shyval, 1971).
Long-term feeding studies in rats with nitrite-cured meat are in
progress in the FDA (FDA, 1972).
OBSERVATIONS IN MAN
Many cases have been reported of accidental poisoning resulting
from the presence of sodium nitrite in food products. From this
information it is possible to deduce that the oral lethal dose in man
varies from 0.18 to 2.5 g, the lower figures being those for children
and old people (Naidu & Venkratrao, 1945; Greenberg et al., 1945;
Schmidt et al., 1949; Schrader & Gessner, 1943).
Comments:
Though in the long-term studies cited only a slight inhibition of
growth occurred, the dose causing this effect appears to give the best
approximation to the threshold dose level. Food for babies less than
six months should not contain added nitrite.
From the studies referred to and others in the literature it is
evident that: (a) nitrosamines are potent carcinogens in several
species of animals; (b) nitrosamines can be formed when nitrites and
secondary amines are incubated at pH 1-3 (as exists in human gastric
juice); (c) nitrosamine formation from nitrites and amines occurs
in vivo; (d) nitrosamines have been reported as reaction products of
nitrites and components of foods; while there are indications of a
dose-response relationship in nitrosamine-induced tumour development,
a no-effect level for several nitrosamines has not yet been
established.
It must be remembered that the possibility of nitrosamine
formation in foods or in the animal organism does not depend solely
on added nitrite. Some nitrate occurs naturally in many foods and may
be converted to nitrite by microorganisms. Nitrite has also been
detected as a normal constituent of saliva at levels of 5-10 ppm
(0.0005-0.001%).
The role played by nitrites in food preservation is important
and the ability to inhibit the growth and toxin formation of
Clostri-dum botulinum must be weighed against the potential risk
associated with their role in nitrosamine formation. The whole
question of nitrosamine formation and effects is under active
investigation in several countries. One promising area of this
investigation involves the use of ascorbic acid as a blocking agent in
nitrosation of amines.
EVALUATION
Level causing no toxicological effect
From consideration of the long-term studies it can be concluded
that this level will be somewhat below 100 mg/kg bw per day.
Estimate of acceptable daily intake for man*
0-0.2 mg/kg bw.**
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See Also:
Toxicological Abbreviations