IPCS INCHEM Home

    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.

    REFERENCES

    Anon. (1969) Mainly on Coumarin, Food and Cosmet. Toxicology, 7,
         681

    Anon. (1975) Some naturally occurring substances. Coumarin, IARC
         Monograph, 10, 113

    Cohen, A. J. (1979) Critical review of the toxicity of coumarin with
         special references to interspecies differences in metabolism and
         hepatotoxic response and their significance to man, Fd Cosmet.
         Toxicol., 17, 277-289

    De La Iglesia, F. A., McGuire, E. J. & Feuer, G. (1975) Coumarin and 4
         methyl-coumarin induced changes in the hepatic endoplasmic
         reticulum studied by quantitative stereology, Toxicology, 4,
         305-314

    Evans, J. G., Gaunt, I. F. & Lake, B. G. (1979) Two-year toxicity
         study on coumarin in the baboon, Fd Cosmet. Toxicol., 17,
         187-193

    FDA (1979) Memorandum from U.S. FDA dated March 19, 1979. Review of
         Liver Slides and/or Data from Griepentrog Study, Hagan Rat
         Studies and FDA Dog Studies (p. 176). Submitted to WHO/FAO

    Feuer, G. (1974) The metabolism and biological action of coumarin,
         Prog. Med. Chem., 10, 85-158

    Feuer, G. et al. (1979) Effect of drugs on proquesterone metabolism in
         the female cat, Toxicology, 12, 197-209

    Feuer, G., Golberg, L. & Gibson, K. I. (1966) Liver response tests.
         VII. Coumarin metabolism in relation to the inhibition of
         rat-liver glucose 6-phosphatase, Fd Cosmet. Toxicol., 4,
         157-167

    Grasso, P. et al. (1974) Liver response tests. IX. Cytopathological
         changes in the enlarged but histologically normal rat liver, Fd
         Cosmet. Toxicol., 12, 341-350

    Griepentrog, F. (1973) Pathological-anatomical results on the effect
         of coumarin in animal experiments, Toxicology, 1, 93-102

    Grigg, G. W. (1972) Effects of coumarin, pyronine Y, 6,9-dimethyl-2
         methylthiopurine, and caffeine on excision repair and
         recombination repair in Escherichia coli, J. of Gen.
         Microbiology, 70 221-230

    Grote, W. & Guenther, R. (1971) Test of a coumarin-rutin combination
         for teratogenicity by examination of fetal skeleton
         Arzneim.-Forsch., 21, 2016-2022

    Grote, W. & Weinmann, I. (1973) Examination of the active substances
         coumarin and rutin in a teratogenic trial with rabbits,
         Arzneim.-Forsch., 23, 1319-1320

    Hagan, E. C. et al. (1967) Food flavourings and compounds of related
         structure. II. Subacute and chronic toxicity, Fd Cosmet,
         Toxicol., 5, 141-157

    Hazelton, L. W. et al. (1956) Toxicity of Coumarin, J. Pharm. Expl.
         Ther., 118, 348-358

    IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals
         to Man, 10, 113-119

    Jenner, P. M. et al. (1964) Food Flavouring and compounds of related
         structure. I. Acute oral toxicity, Fd Cosmet. Toxicol., 2,
         327-343

    Kaighen, M. & Williams, R. T. (1961) The metabolism of [3-14C]
         coumarin, J. Med. Pharm. Chem., 2, 25-43

    Lake, B.G. et al. (1980) Studies on the hepatoxicity and metabolism of
         coumarin in the rat (proceedings), Biochem. Soc. Trans., 8,
         96-97

    Mead, J. A. R., Smith, J. N. & Williams, R. T. (1958) Studies in
         detoxication. 72. The metabolism of coumarin and 0-coumaric acid,
         Biochem. J., 68, 67-74

    Nievel, J. C., Anderson, J. & Bray, P. (1976) Biochemical changes in
         liver and blood underlying parenchymal damage of rat liver
         induced by a dose dependent effect of drugs before and after
         development of liver enlargement and nodular hyperplasia,
         Biochem. Soc. Trans., 4, 932-933

    Ritschel, W. A. et al. (1976) Pharmacokinetics of coumarin upon i.v.
         administration in man, Arzneim.-Forsch., 26, 1382-1387

    Ritschel, W. A. et al. (1977) Pharmacokinetics of coumarin and its
         7-hydroxymetabolites upon intravenous and personal administration
         of coumarin in man, European J. Clin. Pharmacol., 12, 457-461

    Ritschel, W. A., Cacini, W. & Hardt, T. J. (1980) Preliminary results
         on the total radioactivity distribution upon parenteral
         administration of 14-C-coumarin to DBF 1/2 mice,
         Arzneim.-Forsch., 30, 260-263

    Roll, R. V. & Bär, F. (1967) Effect of coumarin (0-hydroxycinnamic
         acid lactone) on pregnant mice, Arzneim.-Forsch, 17, 97-100.

    Scheline, R. R. (1968) Role of the intestinal microflora in the
         metabolism of coumarin in rats, Acta Pharmacol. Toxicol., 26,
         325-331

    Seidel, V. G. & Kreuser, E. D. (1979) Studies on the effect of
         coumarin on the liver of DBA/2J- and CH3/HeJ-mice,
         Arzneim.-Forsch.,  29, 1134-1140

    Shani, J. et al. (1974) Hypoglycemic effect of Trigonella foenum
         greacum and Lupinus termis (Leguminosae) seeds and their major
         alkaloids in alloxan-diabetic and normal rats, Arch. Int.
         Pharmacodyn. Ther., 210, 27-37

    Shilling, W. H., Crampton, R. F. & Longland, R. C. (1969) Metabolism
         of coumarin in man, Nature, 221, 664-665

    Waller, A. R. & Chasseaul, L. F. (1981) The metabolic rate of 14C
         Coumarin in baboon, Fd. Cosmet. Toxicol., 19, 1-6.

    Williams, R. T., Millburn, P. & Smith, R. L. (1965) The influence of
         enterohepatic circulation on toxicity of drugs, Ann. N.Y.
         Acad. Sci., 123, 110-124
    


    See Also:
       Toxicological Abbreviations
       Coumarin (ICSC)
       Coumarin (IARC Summary & Evaluation, Volume 10, 1976)
       Coumarin  (IARC Summary & Evaluation, Volume 77, 2000)