WORLD HEALTH ORGANIZATION
WHO Food Additives Series 1972, No. 1
TOXICOLOGICAL EVALUATION OF SOME
ENZYMES, MODIFIED STARCHES AND
CERTAIN OTHER SUBSTANCES
The evaluations contained in this publication were prepared by the
Joint FAO/WHO Expert Committee on Food Additives which met in Rome,
16-24 June 19711
World Health Organization
Geneva
1972
1 Fifteenth Report of the Joint FAO/WHO Expert Committee on Food
Additives, Wld Hlth Org. techn. Rep. Ser., 1972, No. 488; FAO
Nutrition Meetings Report Series, 1972, No. 50.
The monographs contained in the present volume are also issued by the
Food and Agriculture Organization of the United Nations, Rome, as FAO
Nutrition Meetings Report Series, No. 50A
(c) FAO and WHO 1972
HEXAMETHYLENETETRAMINE
Biological data
Biochemical aspects
Under acid conditions, or in the presence of proteins,
hexamethylenetetramine (HMT) decomposes gradually yielding ammonia mid
formaldehyde (Hutschenreuter, 1956).
Because of these chemical and biochemical properties it is pertinent
to consider biochemical information on formaldehyde and its metabolite
formic acid in relation to the toxicological evaluation of HMT.
Formaldehyde and formic acid occur in fresh unpreserved codfish muscle
(Amano & Yamada, 1964), also in honey, roasted foods and some fruits
(Malorny, 1969a).
Formaldehyde and formic acid are excreted in the urine of dogs and
cats fed a meal of fish not treated with preservatives, the source of
the substances being trimethylamine oxide occurring naturally in fish
muscle (Malorny & Rieforock. 1962; Malorny et al., 1963; Schassan,
1963). The concentration of free formaldehyde in the urine of these
dogs and cats given unpreserved fish was 1 to 5 times higher than that
found in human subjects who had consumed fish preserved with
hexamethylenetetramine. Humans fed almost exclusively on unpreserved
fish did not show an increase in the excretion of formaldehyde or
formic acid (Malorny & Rieforock, 1962). Formic acid present in the
diet is mostly metabolized by man, only 25 mg is excreted daily in the
urine (Malorny, 1969b).
Hexamethylenetetramine liberated free formaldehyde in the stomach
(Malorny & Rieforock, 1963).
Intravenous infusion in dogs of formaldehyde, 35 mg/kg as a 0.6 per
cent. solution during 8 to 10 minutes, was carried out. Two minutes
after completion of the infusion there was no increase in formaldehyde
but a high increase in the formic acid level in the blood. The formic
acid level decreased by 50 per cent. in 1 hour, by 75 per cent. after
2 hours, and was back to normal after 4 hours. In vitro human blood
oxidizes 30 per cent. formaldehyde (0.7 mg to 1 ml blood) to formic
acid within 4 hours. Addition of methylene blue (0.05 per cent. to
0,2 per cent.) results in a complete oxidation of the formaldehyde
(Malorny et al., 1964).
Similar maximal plasma concentrations of formic acid were found after
intravenous injection of equimolar solutions of formaldehyde, formic
acid, or sodium formate, and the elimination constants and biological
half-lives of formic acid in these different cases were also similar
(Malorny et al., 1965). In another study, it was found that
elimination of formic acid from the body is much more rapid in rats
than in dogs, the biological half-lives being about 12 min and 77 min
respectively, while those of the guinea-pig are 12 min, rabbit 32 min
and for the cat the value is 67 min. The rate of oxidation of
formaldehyde to formic acid is comparable in all these species, with a
half-life of only 1 min (Rieforock, 1965).
The kinetics of the absorption of formaldehyde by erythrocytes and its
conversion to formic acid were studied in rabbits, guinea pigs, rats
and cats. The elimination of formic acid was proportional to the
concentration present but formaldehyde had the same biological
half-life of 1 min irrespective of species. Using 3 different i.v.
infusion rates (8, 2 or 0.5 mi/min) for formaldehyde showed that only
at 0.5 ml/min there was no free formaldehyde present in the blood but
only formic acid. Formic acid was eliminated from erythrocytes,
plasma, liver. kidney, testes, muscle and brain in an exponential
manner. The half-life varied with species but was always shortest in
the liver. No relation to catalase activity of the blood was
established. Pre-treatment of the cat with folic acid reduces the
half-life for formic acid. Treatment with methotrexate, a folic acid
inhibitor, prolongs the half-life in the dog from 61 to 480 min
Malorny, 1966).
Formaldehyde, administered orally to dogs, was rapidly absorbed and
converted to formic acid. No formaldehyde was detected in the plasma
and only traces occurred transiently in the erythrocytes. In cats the
production of formic acid and influx of lactic acid into the blood
caused a temporary acidosis. When formaldehyde was added to human
blood in vitro it was rapidly absorbed on to the erythrocytes and
then oxidized to formate. Both NAD and NADP-independent formaldehyde
dehydrogenase and catalase appeared to be involved in this oxidation,
so that both erythrocytes and the liver played an important role in
the rapid detoxication of orally and parenterally-administered
formaldehyde (Malorny et al., 1965).
The elimination of formate is folic acid dependent, since in the cat
daily injections of folic acid for several days before giving formate
have been shown to reduce the biological half-life of formate
considerably, from 67 min without folic acid pretreatment to 46 min
after 4 days' treatment and 17 min after 10 days' treatment
(Rieforock, 1965). Interference with liver function prolongs the
biological half-life of formic acid in rabbits from 35 to 130 min
(Malorny, 1969a). In vitro experiments with liver homogenate showed
that after 30 min 31.6 per cent., 3.9 per cent. and 8.0 per cent. of
formaldehyde was found in the case of rat, guinea-pig and rat liver
respectively (Neugebauer, 1967).
Experiments with 14C-labelled formaldehyde given by stomach tube to
rats and mice showed that 5 min after application the radioactivity
was distributed over the total body. After 12 hours, approximately 40
per cent. had been expired as 14CO2, 10 per cent. had been excreted
in the urine and 1 per cent. in the faeces. The homogenized whole
animals contained 20 per cent. of the radioactivity after 24 hours and
10 per cent. after 96 hours (Buss of al., 1964).
When female rats were given 70 mg/kg of 14C-labelled formaldehyde
intraperitoneally, 82 per cent. was detected as 14CO2 and the urine
contained 13-14 per cent. of the isotope in the form of methionine,
serine and a formaldehyde-cysteine adduct (Neely, 1964).
The yellow discoloration observed in rats treated with oral or i.m.
HMT was shown to be due to a reaction between formaldehyde in the
urine and kynurenine in the rat hair (Kewitz & Welsch, 1966).
Twelve human volunteers received orally 1.48-2.96 g sodium formate.
They excreted on average 13 mg formic acid/24 hours from control diet
and only 23 per cent./24 hours of the additional formic acid. Most of
the additional load was excreted within 6 hours and all had been
eliminated after 12 hours. No cumulation was observed. Excretion of
formate is accompanied by alkaline urinary pH and mild diuresis. The
biological half-life of orally administered sodium formate was found
to be 46 min as determined by plasma levels in 3 volunteers. Four to
7 per cent. of the administered dose was excreted in 24 hours. No
metabolic acidosis was found in man because of rapid metabolism of the
formate anion but the excess of bicarbonate is excreted as alkaline
urine. Formic acid is absorbed rapidly from the stomach in
undissociated form (Malorny, 1969b).
Special studies
Both HMT (Auerbach, 1951) and formaldehyde (Rapoport, 1946) have been
shown to act as mutagens in Drosophilia. Stumm-Tegethoff (1964) has
demonstrated that formic acid, present as an impurity in formaldehyde,
is the causative agent in producing the mutagenic effect in
Drosophilia melanogaster. Nafei & Auerbach (1964) have shown that
mutations only occur in the larval spermatocytes and that the
conditions necessary for the change only exist for a short time.
Acute toxicity
Animal Route LD50 (mg/kg Reference
body-weight)
Mouse Oral
(formic acid) 1 100 Malorny, 1968a
(Sod. formate) 11 200 "
(Pot. formate) 5 500 "
(Amm. formate) 2 250 "
(Calc. formate) 1 920 "
Intravenous
(formic acid) 145 "
(Sod. formate) 807 "
(Pot. formate) 95 "
(Amm. formate) 410 "
(Calc. formate) 154 "
Rat i.v. (HMT) 9 200 Malorny et al., 1965
One group of 14 6-week old male and female rats were given a single
intravenous injection of 10 g HMT/kg body-weight as an 80 per cent.
aqueous solution. All animals survived without evidence of toxic
effect. Two groups of 5 adult rats were given 10 or 20 g HMT/kg
body-weight as an 80 per cent. aqueous solution by oral intubation.
All animals survived (Della Ports, 1966).
Short-term studies
Mouse
Groups of 13 mice were treated daily by cutaneous application 10 per
cent. HMT in chloroform, 1.5 per cent. aqueous formaldehyde, and
chloroform alone, for 300 days. No malignant tumours were found in
any group (Kewitz, 1966).
One group of 5 male and 5 female rats was given by gavage 400 mg HMT
daily for 90 days. A second group of 5 male and 5 female rats was
given daily intramuscular injections of 200 mg HMT for 90 days. A
third group of 15 male and 15 female rats was given repeated oral
doses of 400 mg HMT by gavage over 333 days. No adverse effects were
noted in any group except for a citrus-yellowish discoloration of the
fur (Brendel. 1964).
Cat
One male and 3 female cats were fed approximately 15 000 ppm of
formaldehyde (375 mg/kg/day) and two males and three females were fed
approximately 50 000 ppm of HMT (1250 mg/kg/day) for 2 years. The
control group consisted of 3 males and 3 females. One female in the
formaldehyde group died in the seventh month of pleuritis and a female
of the HMT group died in the twenty-third month of a pyogenic
infection of the nasal cavity and paranasal sinuses. No effect of
formaldehyde or MT was found on food consumption, weight gain or
appearance. Preliminary microscopic examination of tissues from test
and control animals show no changes attributable to formaldehyde or
HMT (Kewitz, 1966).
Long-term studies
1. Oral administration
Mice
Sixteen groups of 30, 50 or 100 males and an equal number of females
of CTM, SWR or C3Hf strain mice received in their drinking-water
either 0, 0.5, 1 or 5 per cent. hexamethylenetetramine over 60 weeks.
The group receiving 5 per cent. was treated for 30 weeks only. After
the end of treatment animals were observed for the remainder of their
lifetimes. The coats of treated mice showed no discoloration. The
group on 5 per cent. HMT showed slightly reduced growth rate and
survival and the SWR group on 1 per cent. showed also slight growth
retardation. Gross and histopathology did not show any pathological
lesions related to treatment. As regards tumour incidence there was
no significant difference between treated and control groups (Della
Porta et al.p 1968).
Groups of 30 male and 30 female NMRI/Han albino mice were fed 0 per
cent. and 1 per cent. of HMT and 0.15 per cent. formaldehyde for 2
years. Benign and malignant tumours were found in a total of 43
animals: 20 in the HMT group, 12 in the formaldehyde group and 11 in
the control group. Except for 1 control male and 2 males receiving
HMT all tumours occurred in females. Twenty-nine of 36 malignant
tumours were subcutaneous carcinomas and adeno carcinomas. The author
concluded from the data that the possibility of an increased tumour
incidence effect by HMT could not be ruled out. A further study was
instituted using groups of 50 female mice at levels of 0 per cent.,
0.1 per cent., 0.5 per cent. and 1 per cent. hexamethylenetetramine,
which, after 31 weeks, showed no difference in tumour incidence
between the groups (Kewitz, 1966).
Rat
Four groups of 48 male and 48 female rats received for 104 weeks
either 0 or 1 per cent. HMT in their drinking-water while another 2
groups of 12 male and 12 female rats received 5 per cent. in their
drinking-water for only 2 weeks. The coat of treated rats showed a
yellowish discoloration due to a reaction between formaldehyde present
in the urine and kynurenine in the rat hair. Fifty per cent. of the
rats given the high dose level died within the 2 weeks of
administration, the remainder survived for 104 weeks. Growth,
mortality experience, gross and histopathology of the treated animals
showed no specific changes due to administration of HMT. Tumour
incidence was essentially similar in controls and treated animals at 1
per cent. level and lower than in controls at the 5 per cent. level
(Della Porta et al., 1968).
Two groups of 16 male and 16 female rats were given either 0 or 0.16
per cent. HMT in their diet and were observed over 28-30 months.
General health and behaviour as tested by activity in the revolving
drum at 1, 3, 7 and 14 months showed no significant differences
between controls and test groups. Body-weights of male rats were
slightly lower in the treated animals. Mortality experience was
similar for all groups. The addition of HMT had no effect on
palatability of the diet. Organ weights showed no gross differences
and tumour incidence was not different between controls and test
animals, although not all rats were examined by autopsy. Separate
mating of the test and control groups revealed no differences in
fertility as measured by numbers of pups produced. The young showed
no difference in activity as measured by the revolving drum, nor did
they show any abnormalities or differences in body-weight. Organ
weights and gross and histopathology were unremarkable. Some test
rats showed yellowish staining of hair (Natvig et al., 1971).
2. Subcutaneous administration
Mice
Two groups of 39 male and 44 female CTM mice received 5 subcutaneous
injections on 5 alternate days of 5 g/kg HMT, a 30 per cent. aqueous
solution, beginning on day 10 of age. They were observed for 100
weeks. No pathological findings related to treatment were noted nor
was there any difference from controls regarding tumour incidence
(Della Porta et al,, 1968).
Rat
Twenty rats were given subcutaneous doses of 1 ml of a 0.4 per cent.
aqueous solution of formaldehyde, in the dorsal region, weekly for 15
months. Half the animals died during the experiment without
developing tumours; of the remaining 10, 4 showed sarcomas 3-5 months
after cessation of treatment. Two of these tumours developed at the
site of injection and were diagnosed as spindlecell sarcomas. One
tumour developed in the liver (male, 21 months) with metastases to the
colon; the other was in the colon (female, 21 months) (Watanabe of
al., 1953; Watanabe et al., 1954).
Twenty rats were injected subcutaneously on the left dorsal side once
or twice weekly with 1-2 ml solution of hexamethylene-tetramine, using
at first a concentration of 9.23 per cent. but, after the middle of
the experiment, a concentration of 35-40 per cent. In addition,
shortly before each injection of hexamethylenetetramine, an injection
of 0.5 ml 0.1 per cent. formic acid was given on the right dorsum. Of
14 survivors, 8 showed tumours at the sites of injection of
hexamethylenetetramine. At the sites of formic acid injection small
ulcers sometimes formed but no subcutaneous thickening or nodules. Of
the 8 tumours 7 were sarcomas and 1 syringadenoma (Watanabe &
Sugimotop 1955).
Groups of 15 male and 15 female albino rats were injected
subcutaneously with 1 ml of 40 per cent. HMT solution and 1 ml of 0.1
per cent. formaldehyde solution weekly for 1-1/2 years. Control
groups of 7 males and 7 females and 8 males and 8 females were
similarly injected with doses of sodium chloride or sucrose
(equiosmotic with 40 per cent. hexamethylenetetramine) for 1-1/2
years, by which time the last animal had died. In the HMT group, 1
injection-site spindle-cell sarcoma, 1 distal spindle-cell sarcoma, 1
alveolar mammary carcinoma and 1 fibrosarcoma, in addition to 2 benign
tumours were seen. In the formaldehyde group, 2 malignant tumours and
3 benign fibro-adenomas were seen. In the control group, 1 blastoma
(in a sodium chloride-injected animal) was found (Kewitz, 1966).
Two groups of 20 male and 20 female rats received 5 subcutaneous
injections of 5 g/kg HMT as 30 per cent. aqueous solution on alternate
days starting at day 10 of age and were observed for 104 weeks. No
treatment-related abnormalities were seen regarding growth, mortality,
gross or histopathology or tumour incidence. The test animals had a
lower tumour incidence than the controls (Della Porta et al., 1968).
Reproduction studies
Rat
In a 5-generation study lasting 3-1/2 years, a total of 80, 80 and 245
rats were fed 0, 5 and 50 mg/kg daily of HMT in the drinking-water.
Animals, including pregnant dams, were selected from each group at
half-yearly intervals, starting at 1-1/2 years, for pathological
study. No changes attributable to HMT were found in test animals or
foetuses and placentas at either level. Tumours were observed on 3 of
48 animals at the high dose level (Malorny, 1966b).
Groups of 10 male and 10 female rats were fed 0 ppm, 400 ppm, 800 ppm
and 1600 ppm of hexamethylenetetramine in a normal basic diet for 2
years. The 10 pairs were mated at the age of 20 weeks, 28 weeks and
35 weeks. No effect was found at all levels on growth, 2-year
survival, reproduction and viability of offspring. Post-sacrifice
examination of survivors (organs examined and type of examination not
stated) disclosed no specific pathological changes (Berglund, 1966).
Twelve female and 6 male Wistar rats were given 1 per cent. HMT in the
drinking-water starting 2 weeks before mating. The females were kept
under treatment during pregnancy and lactation. A similar untreated
group of 12 females and 6 males served as control. Twelve treated
females and 11 controls became pregnant and gave birth to 124 and 118
babies respectively; no malformations were noted. From these animals,
24 for each sex were continued on the 1 per cent. HMT up to the
twentieth week of age or were kept untreated. The body-weight of
treated animals was significantly lower than that of the controls,
only up to the ninth week of age for the males and up to the
thirteenth week for the females. At the end of the treatment both
groups were sacrificed; the weight of organs was identical in the
treated and control animals; there was no gross or histological
pathology. In a second experiment, rats were given 1 per cent. HMT in
the drinking-water for 3 successive generations, up to the age of 40
weeks in the F1 and F2 groups and of 20 weeks for F3. The 3
groups were composed of 13 male and 7 female, 15 male and 11 female,
12 male and 12 female, respectively. In addition, a group of 16 male
and 16 female descendants of 2 per cent. HMT-treated parents were
given 2 per cent. HMT for 59 weeks. A group of 48 males and 48
females served as untreated controls. All groups were kept under
observation for over 2 years. No evidence of carcinogenicity was
found in any of the HMT-treated groups (Della Porta et al., 1970).
A 5-generation study using 8 male and 24 female rats as P generation
is in progress using 8 controls. Test animals received 0.2 per cent.
calcium formate in their drinking-water. No abnormalities were
detected regarding growth and fertility. No disturbances of organ
function or retinal or fundal abnormalities were noted. Gross and
histopathology of 250 rats from 3 generations revealed no abnormal
findings related to the administration of calcium formate. Tumour
incidence was no different from controls. Pregnancy and foetuses as
well as numbers of pups per litter were similar to controls. No
malformations or placental changes were detected. Similar groups were
given 0.4 per cent. calcium formate in their drinking-water for 2
generations and will be continued. No abnormalities, including
histopathology, related to the test substances have been seen.
Dog
A group of 2 male and 4 female mongrel dogs was fed from 1250 to 1875
ppm of HMT and a group of 4 males and 4 females was fed from 125 to
375 ppm of formaldehyde for 32 months. The control group consisted of
2 males and 1 female. Groups formed from litters of these animals
were also fed test diets; 3 males and 2 females were fed 1250 ppm of
HMT, 3 males and 2 females were fed 375 ppm of formaldehyde and 2
animals of each sex served as a control group for 22 months. At the
end of the test period, the test animals were placed on a normal diet
and the controls on 1250 ppm of HMT for 1 year. No effect of
formaldehyde or HMT was found on food consumption, growth,
reproduction or litter numbers and weights or in monthly observations
on blood chemistry and cell total and differential counts, and
periodic urine examinations.
However, of 30 litters in the HMT group, 66.7 per cent. were noted as
unusual in that there were stillborn and eaten animals as well as 5
cases of defective animals born; in the formaldehyde group, 60 per
cent. of 34 litters were noted as unusual, with 10 cases of defective
animals. Of 16 litters in the control group, 7.7 per cent. were noted
as unusual, with no malformations (Kewitz, 1966).
According to a preliminary report, groups of 8 pregnant female beagle
dogs received from the fourth to fifty-sixth day after mating either
0, 0.0125 per cent. and 0.0375 per cent. of formalin or 0.06 per cent.
and 0.125 per cent. of HMT in their food. Many litters are still in
the pre-weaned stage at present. So far no adverse effects have been
reported with regard to rate of pregnancy and duration, behaviour and
weight of the mothers or litter size, pup weight, incidence of
congenital defects or survival to weaning of the pups (Tierfarm,
1969).
Chick embryo
Two hundred fertilized chicken eggs were injected with 5 mg HMT after
96 hours incubation. The distribution of GMT and formaldehyde was
determined between the sixth and nineteenth day of incubation in the
various components of the egg. HMT is continuously metabolized. No
toxic effect was noted in the chick embryos examined (Pilz, 1967).
Formaldehyde was injected in another experiment into fertilized eggs.
There was rapid oxidation to formic acid. After 48 hours some 90 per
cent. had been converted to formic acid. The remaining formaldehyde
was probably bound to the albumin and the shell proteins. Injected
sodium formate is metabolized at a much slower rate but had
disappeared by the twelfth day of incubation. Practically no
formaldehyde metabolism occurs in the extra-embryonal components but
embryonic liver and erythrocytes rapidly oxidize formaldehyde to
formic acid (Lange. 1968).
Sodium formate did not show any toxic or teratogenic effect when
submitted to the chick embryo test (Malorny, 1969a),
Comments
As the toxicological effects of hexamethylenetetramine (HMT) appear to
be due to the liberation of formaldehyde and its oxidation product,
formic acid, much work has been done on formaldehyde and formates as
well as on hexamethylenetetramine (HMT). The metabolic studies point
to rapid conversion of formaldehyde to formate and then to water and
carbon dioxide particularly by the liver and the erythrocytes. Very
little formate is excreted by man in his urine after its oral
ingestion. Only one of many long-term studies in mice conflicts with
other studies in this species as well as in the rat. These long-term
studies point to a dietary level of 1 per cent. hexamethylenetetramine
(HMT) as causing no effect in rodents. The initial observations from
a teratogenicity study in dogs revealed no adverse effects on the
foetuses and the neonates. Other reproduction studies in rats using
dietary levels from 0.1-1 per cent. hexamethylenetetramine (HMT)
revealed no adverse effects. The probability of carcinogenic
potential suggested by the production of local sarcomata in rats at
the site of repeated injections appears to be excluded as a result of
the findings in adequate studies using oral administration. In
addition, the experiments on pregnant and lactating rats indicate the
absence of carcinogenic effects in the offspring.
EVALUATION
Level causing no toxicological effect in rats
1 per cent. (10 000 ppm) in the diet equivalent to 500 mg/kg
body-weight/day.
Estimate of acceptable daily intake for man mg/kg body-weight
Temporary acceptance 0-5
Further work required by 1972
Report on the completed teratogenicity study in dogs.
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