COUMARIN
Explanation
Coumarin has not previously been evaluated by the Joint FAO/WHO
Expert Committee on Food Additives.
Coumarin (2-H-1-benzopyran-2-one) occurs in the fruits, roots,
bark, stalks, leaves, and branches of a wide variety of plants
including tonka bean, cassie, lavender, lovage, yellow sweet clover,
deer tongue, and woodruff (Grigg, 1977-78). It is used as a flavouring
agent in food; as a fixative and enhancer for the odour of essential
oils in perfumes; in toilet soaps, toothpastes and hair preparations;
in tobacco products to enhance and fix the natural taste, flavour and
aroma; and in industrial products to mask disagreeable odours
(International Agency for Research on Cancer, 1976).
BIOLOGICAL DATA
BIOCHEMICAL ASPECTS
Metabolism
Female rabbits dosed orally with 50 mg/kg of 3-14C-coumarin
excreted over 80% of the label in the urine in 24 hours. No label was
found in the expired air and only a small amount in the faeces. Major
metabolites were 3-hydroxycoumarin, 0-hydroxyphenylacetic acid and
7-hydroxycoumarin. The hydroxycoumarins were excreted mainly as
conjugates. In female albino rats given 100 mg/kg of the
3-14C-coumarin, it was reported that urinary and faecal excretion
each accounted for about 50% of the label. The main urinary metabolite
was 0- hydroxyphenylacetic acid, and it was reported that more
extensive ring openings reactions occurred in the rat than in the
rabbit (Kaichen & Williams, 1961).
Wistar and Carshalton rats given 200 mg/kg of coumarin orally
excreted 70% of the label in the urine and 10% in the faeces within 48
hours of dosing. The material was rapidly absorbed, radioactivity
appeared in the serum liver and kidney within 5 minutes of dosing. The
major metabolites noted in the liver serum and urine were 3,4, and
7-hydroxycoumarin, 0-coumaric acid, and 2-hydroxyphenylpropionic acid
(Feuer et al., 1966).
Conjugates of the 3,7, and 8-hydroxycoumarins were isolated from
the urine of the ferret, rabbit, guinea-pig and mouse following oral
administration of coumarin (Mead et al., 1958).
It was reported that in biliary cannulated rats 50% of orally
administered or injected coumarin appears in the bile as metabolites
in which the ring has been opened (Williams et al., 1965).
Absorption, distribution and excretion
The primary urinary metabolite in male albino rats given
100 mg/kg of coumarin by gavage or i.p. injection was
O-hydroxyphenylacetic acid. Melilotic acid was found in the urine at
about 5% to 10% of the level of O-hydroxyphenylacetic acid. Studies
with rat caecal flora indicated that the melilotic acid may have been
formed intestinally (Scheline, 1968).
DBA/2/lac adult male mice were given 14C-coumarin by retro-
orbital injection. Peak levels of radioactivity were observed in the
blood, brain, heart, muscle and spleen 2.5 minutes after dosing. Liver
and kidney had the highest levels with the peak occurring after 10
minutes. Blood and brain concentrations were equal. It appeared that
coumarin itself crosses the blood-brain barrier, but not its
metabolites. The decrease of radioactivity with time fit a two
compartment level for the brain, heart, lung, muscle and spleen, and a
one compartment level for the blood, liver and kidney (Ritschel et
al., 1980).
Orally administered (14C) coumarin was rapidly absorbed and
excreted by the baboon. Ninety per cent. of the dose was absorbed
within 45 minutes. Excretion was primarily in the urine (76% in six
hours and 81% in 24 hours). The major urinary excretion products were
free or conjugated 7-hydroxycoumarin. Less than 1% of the dose was
excreted as 0-hydroxyphenylacetic acid (Wallar & Chasseaul, 1981).
Four male and four female human volunteers were given 200 mg each
of coumarin in capsule. Most of the dose was excreted in the first 24
hours, primarily as 7-hydroxycoumarin (69-92% of the administered
dose), 0-hydroxyphenylacetic acid accounted for 1 to 6% of the dose.
Control and second day urines contained no significant amounts of the
two metabolites (Shilling et al., 1969). The biological half life of
coumarin in man was calculated to be 1.81, 1.45, and 1.49 hours
following i.v. administration of doses of 0.125, 0.2 and 0.25 mg/kg,
respectively (Ritschel et al., 1976).
Blood concentration-time profiles calculated after oral or i.v.
administration of 0.25 mg/kg of coumarin to four male and two female
adult humans indicated that the data were best described by an open
two-compartment model with a large distribution to the peripheral
compartment (Ritschel et al., 1977). This pharmacokinetic model
suggests that the major site of metabolism of coumarin is the liver,
and the glucuronidation of the metabolites may occur at several sites,
including the liver, intestinal wall and other tissues (Ritschel et
al., 1977).
Effects on enzymes and other biochemical parameters
An oral dose of 1 mmol/kg (146 mg/kg> of coumarin dissolved in
arachis oil administered daily for seven days to virgin female Wistar
rats resulted in a decrease in serum progesterone levels (Feuer et
al., 1979).
Coumarin administered by gavage at a dose of 250 or 1000 mg/kg to
female albino rats Hebrew University Sabra strain was reported to
cause hypoglycaemia which lasted about 24 hours. The high dose was
fatal to 30 to 47% of the rats within 5 hours (Shani et al., 1974).
Compounds with the coumarin structure are well known for their
anticoagulant activity. Coumarin per se shows very little of this
activity, compared to other coumarin derivatives. The correlation
between chemical structure and anticoagulant activity has been
discussed by Feuer (Feuer, 1974).
TOXICOLOGICAL STUDIES
Special studies on hepatotoxicity
Groups of six male rats were given doses of 15, 45, 135 or
405 mg/kg of coumarin daily for seven days by oral intubation. The
substance was administered as a 2% solution in arachis oil. There was
no increase in relative liver weight at the two lower doses, however,
there was a dose related increase at the two highest doses.
Histological changes occurred at the highest dose only and consisted
of fatty change and vacuolar degeneration in the centrilobular
hepatocytes. A centrilobular loss of G6P and analine hydroxylase
occurred at the two highest doses. Lysosomal and ultrastructural
changes also occurred at the two highest doses, the latter consisted
of hypertrophy and dilatation of the rough endoplasmic reticulum in
centrilobular hepatocytes, increases in the size of lysosomes and the
number of autophagic vacuoles. Dose related depression in cytochrome
P-450 and amidopyrine demethylase also occurred at the two highest
doses (Grasso et al., 1974).
Male Sprague Dawley rats were administered by intubation either 0
or 375 mg/kg of coumarin in a corn oil vehicle. After 24 hours, the
animals were sacrificed and the livers were observed to be
significantly enlarged. Markers of the hepatic mixed function oxidase
system such as ethyl morphine N-demethylase, 7-ethoxycoumarin
O-de-ethylase and cytochrome P-450 were significantly decreased by
coumarin treatment. Examination of liver sections from animals treated
with 125 to 750 mg/kg of coumarin showed dose related centrilobular
necrosis. Studies on the NADDH specific metabolism of 3-14C-coumarin
by washed rat hepatic microsome showed binding of labelled metabolites
to microsomal protein. Bound label could not be washed out with either
5% trichloroacetic acid or 80% methanol. Within two hours after
coumarin administration, hepatic reduced glutathione stores were
depleted (Lake et al., 1980).
Male Wistar rats were given by gavage either 0 or 1 mmol
(145 mg/kg bw) of coumarin dissolved in arachis oil daily for seven
days. The animals were sacrificed 24 hours after the last dose and
liver samples were prepared for light and electron microscopy. There
was a 33% reduction in the number of hepatocytes and about a 40%
increase in the mean volume of the hepatocytes in the dosed rats. The
mean smooth endoplasmic reticulum membrane area per g of liver
significantly decreased in the coumarin treated animals (De La Iglesia
et al., 1975).
Coumarin was fed for 32 weeks in the diet at 0.5% to DBA/2 mice
and at 1% to CH3/HeJ mice. Minimal increases in serum glutamate-
oxalate transminase, gamma-glutamyltransferase and sorbitol
dehydrogenase activities were noted, but no gross or microscopic liver
lesions were reported (Seidel & Kreuser, 1979).
Female Wistar rats were given by gavage 146 mg/kg of coumarin
daily for up to three months. After two days of treatment, sorbitol
dehydrogenase activity was increased in the liver and there was
swelling of mitochondria (Nievel et al., 1976).
Special studies on mutagenicity
Coumarin was found to inhibit Uvr repair of ultraviolet lesions
in E. coli. Caffeine was also inhibitory in this system (Grigg,
1972).
Special studies on teratogenicity
Groups of pregnant mice were fed 0, 0.05, 0.10 or 0.25% coumarin
in the diet on days 6 to 17 of pregnancy. There was no increase in
malformations at any dose but there was delayed ossification and
increased stillbirths in the high dose group (Roll & Bar, 1967).
A group of 17 pregnant Gottingen miniature pigs were given a
preparation containing coumarin and troxerutin on days 6 to 30 of
pregnancy. The dose amounted to 25 mg/kg of coumarin and 150 mg/kg/day
of troxerutin. A control group of six animals was tested. No
embryotoxic or foetotoxic effects were noted (Grote et al., 1977).
Studies carried out on the same coumarin-rutim preparation in rabbits
and rats were also negative (Grote & Gunther, 1971; Grote & Welamann,
1973).
Acute toxicity
LD50
Animal Route (mg/kg bw) References
Rat Oral 680 Jenner et al., 1964
Guinea-pig Oral 202 Jenner et al., 1964
Rat Oral 290 (propylene Hazelton et al., 1956
glycol vehicle)
Oral 520 (corn oil Hazelton et al., 1956
vehicle)
Short-term studies
Rat
Groups of three male and three female Osborne Mendel rats were
fed 0 or 10 000 ppm (0 or 1%) of coumarin in the diet for four weeks.
Marked growth retardation, testicular atrophy and slight to moderate
liver damage was noted. The liver damage consisted of dead and dying
cells, a decrease in oxyphillia and cytoplasm in the centrolobular
cells and a proliferation of bile ducts. In a similar study, the same
dose of coumarin was fed up to eight weeks to 10 animals per sex, per
group. None of the animals given coumarin survived beyond week 8;
liver damage similar to that reported above was also seen (Hagan et
al., 1967).
Groups of 10 male and 10 female Osborne Mendel rats were
administered 0 or 1000 ppm (0 or 0.1%) of coumarin in the diet for 14
weeks. Another study took place with five male and five female rats
given the same dose regimen for 28 weeks. In both studies, no adverse
effects were seen with respect to growth, gross or microscopic
pathology and relative organ weights. A similar study by the same
workers with six male and six female rats given 0 or 2500 ppm (0 or
0.25%) of coumarin for 29 weeks showed growth retardation and slight
macroscopic liver mottling in the dosed males. Histopathology
indicated slight midzonal fatty changes in the dosed animals of both
sexes, but more marked in the males (Hagan et al., 1967).
Groups of five male Carworth Farms strain albino rats were fed a
lab chow diet containing 0, 200 or 1000 ppm (0, 0.02 or 0.1%) of
coumarin. After 60 days, one rat from each group was sacrificed for
gross pathology. At 90 days, all animals were sacrificed for gross and
microscopic pathology. No mortality occurred in the study. Growth was
significantly retarded in the 1000 ppm (0.1%) group and feed
consumption was also reduced. At autopsy, slight mottling of liver and
kidney surface were noted in the dosed rats but no compound-related
histopathological changes were reported. No significant compound-
related changes were observed in relative organ weights. In another
study, groups of 12 male and 13 female rats (Carworth strain) were
pair fed diets containing 0, 50, 250 and 2500 ppm (0, 0.005, 0.025 and
0.25%) of coumarin. Each male and female rat was fed daily the average
quantity of food consumed by the male or female group eating the least
quantity on the previous day. After 60 days on test, one animal from
each group was chosen for gross pathology. After 90 days on test, all
animals were sacrificed for gross and microscopic pathology. A
significant depression in feed efficiency occurred in the high dose
females and a trend towards liver damage was also observed in the high
dose group. The high dose male and female sacrificed at 60 days had
mottled and spotted livers. Two high dose rats which died after 83
days on test showed spotty areas on the liver, one also had
discoloration of the kidney. Another animal from the 2500 ppm (0.25%)
group died at day 48 showing nodular haemorrhagic lungs. After 90
days, autopsy of the survivors at 2500 ppm (0.25%) showed 15 with
mottled or spotted liver surfaces. Significantly higher liver to body
weight ratios were noted in the high dose groups. Upon histopathology,
marked degenerative changes were noted in the livers of four rats, and
eight animals showed similar but less severe changes. Fatty
metamorphosis was noted in three animals examined for this trait. No
histological changes were observed in other organs and no liver
histopathology in other organs and no liver histopathology was noted
in the other dose groups (Hazelton et al., 1956).
Dog
One male and one female dog were given 100 mg/kg of coumarin by
capsule six days per week for up to 16 days. The male was killed in
extremis after nine days and the female was found dead on day 16.
Marked emaciation and slight dehydration and jaundice were noted.
Macroscopically the livers were yellow coloured and had a nutmeg
appearance. Microscopically there was marked disorganization of the
lobular pattern, moderate increase in the size of the liver cells,
vacuolation, a large amount of diffusely distributed fat, focal
necrosis, fibrosis and very slight to moderate bile duct
proliferation. The spleen was pale coloured, the bone marrow was thin
and fatty and the gall bladder moderately distended. Similar studies
were carried out in groups of two male and one or two female dogs
given 50 mg/kg for 35 to 277 days, 25 mg/kg for 133 to 330 days, and
10 mg/kg for 297 to 350 days. At 50 mg/kg, one animal died at 35 days,
the other two animals were sacrificed at 45 and 277 days. Emaciation
was noted in the animals and jaundice was noted in the two females.
Liver changes were similar to those noted at 100 mg/kg as described
above. Large amounts of haemosiderin were noted in the spleen and the
bone marrow was pale. At 25 mg/kg, moderate emaciation and jaundice
were observed in one female. Liver changes similar to those noted
above were seen in one animal while less severe changes were noted in
the others. Moderate haemosiderosis was observed and the gall bladder
was moderately distended in two animals. No definite effect of
treatment was reported at 10 mg/kg (Hagan et al., 1967).
A group of seven female and two male mongrel dogs received in
capsule form 100 mg/kg daily of samples of coumarin from several
different sources for 11 to 70 days. One female dog received 500 mg/kg
of coumarin daily for two days and another female served as a control.
The animal receiving 500 mg/kg died on the second day. At 100 mg/kg,
there were clinical signs of toxicity within 11 days. They included
vomiting, anorexia, weight loss, salivation, depression,
incoordination and jaundice. Increased bromosulfalein retention,
elevated icterus index and prolonged prothrombin times were also
observed. Urinary analyses were positive for protein, sugar, occult
blood and bile in all dosed dogs. Recovery from clinical signs in 40
to 60 days were observed in two dogs in which coumarin treatment was
halted after eight days. Gross pathology of the dosed dogs showed
jaundice of the sclera, gums and body connective tissue and altered
colour in the liver. There were also gross haemorrhagic areas observed
in the gall bladder, urinary bladder, perirenal adipose tissue and
pleura. Histopathology of the liver showed marked swelling of cells,
granularity of and swelling of the cytoplasm, rupturing of cell
membranes, pycnosis, karyorrhexes and cytolysis. Bile duct and liver
cell regeneration was also observed. Histological changes in the
kidney included swelling and granularity of the ephithelial cells of
the convoluted tubules. The changes were reported to be compatible
with bile nephrosis (Hazelton et al., 1956).
Long-term studies
Rat
Groups of six male and six female Osborne-Mendel rata were fed 0,
1000, 2500 or 5000 ppm (0, 0.1, 0.25 or 0.5%) of coumarin and 3% of
corn oil in the diet for two years. Another group of six males and six
females received 2500 ppm (0.25%) of coumarin but no corn oil. Two
control groups were used, one group had 3% corn oil added to the diet.
In the group given 5000 ppm (0.5%) coumarin, there was growth
retardation with normal food utilization (measured only the first
year), and haemoglobin levels were reduced. Macroscopically, the liver
was enlarged and distorted by well-delineated masses. There were pin
point foci. Microscopically, the liver showed focal proliferation of
bile ducts of a typical appearance, with associated fibrosis
(cholangiofibrosis) in the masses. There was also a slight degree of
fatty metamorphosis, slight variation in cell size, very slight
proliferation of normal size bile ducts and minimal focal necrosis. In
the two groups given 2500 ppm (0.25%) coumarin, there was slight
damage of the type seen at 5000 ppm (0.5%), but no cholangiofibrosis
was noted. There was no effect seen at 1000 ppm (0.1%) (Hagan et al.,
1967).
Groups of 20 or 25 male and 20 or 25 female rats were fed 0,
1000, 2500, 5000 or 6000 ppm (0, 0.1, 0.25, 0.5 or 0.6%) of coumarin
in the diet for up to two years. An additional group of 32 males was
fed 6000 ppm (0.6%) coumarin. It was reported that 12 of 14 rats from
the 5000 ppm (0.5%) group developed bile duct carcinomas and five of
the 25 surviving animals fed 6000 ppm (0.6%) also developed bile duct
carcinomas. There were no tumours of this type reported in the
controls. Reduced food intake occurred at the 6000 ppm (0.6%) level
(coumarin intake equivalent to an intake of 3500 ppm (0.35%) for a
normal diet). Benign bile duct adenomas or bile duct proliferation was
reported in the 1000 or 2500 ppm (0.1 or 0.25%) groups (Griepentrog,
1973). The diagnosis of bile duct carcinomas in this study has been
questioned because (1) cytological changes in bile duct are not
regarded as unequivocal evidence of carcinogenesis and (2) the lack of
metastasis to other tissues (FDA, 1975; Cohen, 1980).
Baboon
Groups of four to eight male baboons of several species were fed
0, 2.5, 7.5, 22.5 or 67.5 mg/kg of coumarin in the diet for two years.
Liver biopsies were taken at six or ten months. At 16 months, one
animal each from the 0, 22.5 and 67.5 mg/kg group were sacrificed. At
18 months, all animals in the 25 mg/kg group were sacrificed along
with four from the 7.5 mg/kg group, and one of the animals in the
22.5 mg/kg group was moved to the 67.5 mg/kg group. The remaining
animals were sacrificed at 24 months. The individual body weights of
the animals varied widely at the beginning because of the varying ages
and species of the baboons making weight changes difficult to
evaluate. Nevertheless, there seemed to be no compound-related body
weight changes. Relative liver weights were increased in the high dose
animals only. No treatment-related effects on liver histology were
observed in the six to 10 month biopsy specimens. No biliary
hyperplasia or fibrosis was seen at any dose. Marked dilatation of the
endoplasmic reticulum was seen upon ultrastructural examination of the
liver in three of the high dose animals. The authors stated such
changes are generally accepted as evidence of early cell damage. No
significant treatment-related changes in liver enzymes were observed
(Evans et al., 1979).
Comments
Orally administered coumarin is rapidly absorbed and metabolized.
There are major differences in the matabolism of coumarin, by the
different animal species studied in man. In the rat, the major urinary
metabolite is 0-hydroxyphenylacetic acid (12-27%), with minor
amounts of 7-hydroxycoumarin (0.3-0.5%), 0-coumaric acid and
3,4,7-hydroxycoumarin. Urinary excretion accounts for 47-60% of the
administered dose, and faecal excretion for 32-38%. Similarly, in the
dog, 0-hydroxyphenylacetic acid is the major urinary metabolite with
only about 10% of the dose excreted as 7-hydroxycoumarin. In
contrast, in the baboon and man, the major urinary metabolite is
7-hydroxycoumarin, 0-hydroxyphenylacetic acid accounting for 1-6% of
the dose. Excretion of the metabolites in man and the baboon is almost
entirely in the urine (80-100% of the administered dose).
In rats and dogs, coumarin is hepatotoxic, but this effect has
not been observed in the baboon.
Although one lifetime feeding study in rats fed coumarin at 5000
to 6000 ppm (0.5 to 0.6%) of the diet was stated to be associated with
the occurrence of bile duct carcinomas, some doubt has been expressed
of this diagnosis. In addition, another lifetime feeding study in the
rat at 5000 ppm (0.5%) of the diet showed cholangiofibrosis in the
liver, but there was no evidence of bile duct carcinomas. These
conflicting reports prevent any definitive statement on the
carcinogenicity of coumarin to the rat. The significance of the
observed liver damage in rats, to man is also not clearly established,
since coumarin is metabolized quite differently in the rat as compared
to man, and the hepatoxic potential of the metabolites have not been
established. In addition, coumarin is not hepatoxic to the baboon,
which metabolizes coumarin similarly to man, but quite different from
the rat.
EVALUATION
No ADI established.
FURTHER WORK OR INFORMATION
Lifetime feeding studies in the rat.
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See Also:
Toxicological Abbreviations
Coumarin (ICSC)
Coumarin (IARC Summary & Evaluation, Volume 10, 1976)
Coumarin (IARC Summary & Evaluation, Volume 77, 2000)