Absorption, Distribution and Excretion
A species difference has been reported for the excretion of an oral dose of (14)C-coumarin. Within 4 days rats excreted 47% of the label in the urine and 39% in the feces, whereas rabbits excreted 92% in the urine and negligible amount in the feces.
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 feces.
The reason for the considerable fecal excretion of (14)C /after oral administration of (14)C-coumarin/ in rat... may represent unabsorbed material.
Twenty-four hr after an IP dose to rats of... (14)C-coumarin, 38% had been excreted in the urine, 13% in the feces, 30% was excreted in the air as (14)C-carbon dioxide and 9% of the remainder was mainly present in the cecum.
For more Absorption, Distribution and Excretion (Complete) data for COUMARIN (14 total), please visit the HSDB record page.

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Metabolism / Metabolites
...Recombinant human and rat CYP1A forms and recombinant human CYP2E1 readily catalyzed CE /coumarin-3,4-epoxide/ production. Coinhibition with CYP1A1/2 and CYP2E1 antibodies blocked CE formation by 38, 84, and 67 to 92% (n=3 individual samples) in mouse, rat, and human hepatic microsomes, respectively. Although CYP1A and 2E forms seem to be the most active catalysts of CE formation in liver, studies conducted with the mechanism-based inhibitor 5-phenyl-pentyne demonstrated that CYP2F2 is responsible for up to 67% of CE formation in whole mouse lung microsomes. In contrast to the CE pathway, coumarin 3-hydroxylation is a minor product of coumarin in liver microsomes from mice, rats, and humans and is catalyzed predominately by CYP3A and CYP1A forms, confirming that CE and 3-hydroxycoumarin are formed via distinct metabolic pathways.
...To examine species differences in CYP2A function, liver microsomes from nine mammalian species (rat, mouse, hamster, rabbit, guinea pig, cat, dog, cynomolgus monkey and human were tested for their ability to catalyze the 7 alpha- and 15 alpha-hydroxylation of testosterone and the 7-hydroxylation of coumarin. Antibody against rat CYP2Al recognized one or more proteins in liver microsomes from all mammalian species examined. However, liver microsomes from cat, dog, cynomolgus monkey, and human catalyzed negligible rates of testosterone 7 alpha- and/or 15 alpha-hydroxylation, whereas rat and cat liver microsomes catalyzed negligible rates of coumarin 7-hydroxylation. Formation of 7-hydroxycoumarin accounted for a different proportion of the coumarin metabolites formed by liver microsomes from each of the various species examined. 7-Hydroxycoumarin was the major metabolite (>70%) in human and monkey, but only a minor metabolite (<1%) in rat. The 7-hydroxylation of coumarin by human liver microsomes was catalyzed by a single, high-affinity enzyme (Km 0.2-0.6 uM, which was markedly inhibited (>95%) by antibody against rat CYP2Al. The rate of coumarin 7-hydroxylation varied approximately 17-fold among liver microsomes from 22 human subjects. This variation was highly correlated (r2=0.956) with interindividual differences in the levels of CYP2A6... . These results indicate that CYP2A6 is largely or entirely responsible for catalyzing the 7-hydroxylation of coumarin in human liver, microsomes. Treatment of monkeys with phenobarbital or dexamethasone increased coumarin 7-hydroxylase activity, whereas treatment with beta-naphthoflavone caused a slight decr. In contrast to rats and mice, the expression of CYP2A enzymes in cynomolgus monkeys and humans was not sexually differentiated. Despite their structural similarity to coumarin, the anticoagulants dicumarol and warfarin do not appear to be substrates for CYP2A6. ...
/The rat can/ hydroxylate coumarin in the 3-position. As can... the rabbit... .
The hepatic enzyme system, coumarin-7-hydroxylase, responsible for a high proportion of the hydroxylation of coumarin in cats, guinea pigs, hamsters, rabbits, and especially in man, is absent from the livers of ferrets, mice and rats. Rat liver contains an inhibitor of this enzyme.
For more Metabolism/Metabolites (Complete) data for COUMARIN (15 total), please visit the HSDB record page.
Coumarin has known human metabolites that include 3-Hydroxycoumarin, 7-Hydroxycoumarin, and Coumarin 3,4-epoxide.

Toxicity Summary
IDENTIFICATION: Coumarin occurs in fruits, roots, bark, stalks, leaves and branches of a wide variety of plants including Tonka bean, cassie, levender, lovage, yellow sweet clover, deer tongue and woodruff. It is used as a flavoring agent in food; a fixative and enhancer for the odor of essential oils in perfumes; in toilet soaps, toothpastes and in hair preparations; in tobacco products to enhance and fix the natural taste, flavor and aroma; and in industrial products to mask disagreeable odors. HUMAN EXPOSURE: Four male and four female volunteers were given 200 mg each of coumarin in a capsule. Most of dose was excreted in the first 24 hr, primarily as 7-hydroxycoumarin and another metabolic product O-hydroxyphenylacetic acid. Blood concentration time profiles calculated after oral or iv administration of coumarin to four male and two female adults indicated an open two compartment model. The major site of metabolism is the liver and the glucuronidation of the metabolites may occur at several sites, including the liver and intestinal wall along with other tissues. ANIMAL STUDIES: Coumarin administered to female Albino rats caused hyperglycemia which lasted about 24 hr. An oral dose of coumarin dissolved in Arachis oil administered daily for seven dats to virgin female Wistar rats resulted in a decrease in serum progesterone levels. Groups of six male rats were given coumarin in Arachis oil daily for seven days by oral intubation. There was no increase in relative liver weight at lower doses; however, there was a dose related increase at the highest dose tested. Histological changes at the highest dose consisted of fatty change abd vacuolar degeneration in the centrilobular hepatocytes. A centrilobular loss of G6P and aniline hydroxylase resulted at the two highest doses. Lysosomal and ultrastructural changes also occurred at the two highest doses; the latter consisted of hypertrophy and dilation of the rough endoplasmic reticulium in centrilobular hepatocytes, increases in the size of lysosomes and the number of autophagic vacoules. Dose related depression in cytochrome p-450 and aminopyridine demethylase also occurred at the two highest dose levels. Coumarin was fed for 32 weeks in the diet to DBA/2 mice and to CH3/HeJ mice. Minimal increases in serum glutamate oxalate transferase, gamma-glutamyl transferase and sorbitol dehydrogenase activities were noted, but no gross or microscopic liver lestions were reported. Coumarin was found to inhibit Uvr repair of ultraviolet induced lesions in Escherichia coli. Groups of pregnant mice were fed in the diet on days 6-17 of pregnancy. No increase in malformations at any dose was noted although delayed ossification and increased still births at the high dose group was found. Groups of three male and three female Orsborne-Mendel rats were fed coumarin in the diet for four weeks. Marked growth retardation, testicular atrophy and slight to moderate liver damage was noted. Liver damage consisted of dead and dying cells, a decrease in oxyphillia and cytoplasm in the centrilobular cells and proliferation of bile ducts. One male and one female dog were given coumarin by capsures 6 days/wk for up to 16 days. The male was sacrificed in extremis after nime days and the female was found dead on day 16. The livers were yellow colored and had a nutmeg appearance. Microscopically there was marked disorganization of the lobular pattern, moderate increase in the size of liver cells, vacoulation, a large amount of diffusely distributed fat, focal necrosis, fibrosis and a very slight to moderate bile duct proliferation. The spleen was pale colored and the bone marrow was thin and fatty and the gall bladder moderately distended. Groups of 4 to 8 male baboons of several species were fed coumarin in the diet for two years. No changes in body weight were noted. Relative liver weights were increased in the high dose animals. No treatment related effects on liver histology were observed in six to ten month biopsy specimens. No biliary hyperplasia or fibrosis was seen at any dose. Marked dilation of the endoplasmic reticulum was seen upon sultrastructural examination of the liver in three high dose animals.[

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Interactions
Coumarin was a moderate inhibitor of 7,12-dimethylbenz(a)anthracene-induced neoplasia of rat mammary gland. It also inhibited benzo(a)pyrene-induced neoplasia of mouse forestomach.
The possibility that pretreatment with coumarin would inhibit the genotoxicity of benzo(a)pyrene was investigated in ICR mice. Male and female mice weighing 21 to 24 g were given coumarin in olive oil at doses of 65 g/kg or 139 mg/kg body weight by oral gavage. Controls received only olive oil. The animals were treated daily for 1 week with 1 day of no treatment at midweek. After the six treatments the animals were given benzo(a)pyrene injections (150 mg/kg in olive oil). At various times (12-72 hr) after the BP injection, ... bone marrow smears were examined for the presence of micronuclei in polychromatic erythrocytes. ... Pretreatment with coumarin alone did not cause formation in polychromatic erythrocytes in both males and females. In male animals treated with coumarin prior to benzo(a)pyrene treatment there was a statistically significant reduction in the number of micronucleated polychromatic erythrocytes. To clarify that this reduction was not due to a phase shift in the start of micronuclei production studies were conducted at several time intervals after benzo(a)pyrene injection. Again there was no micronuclei induction by coumarin alone and there was a significant reduction in benzo(a)pyrene induced micronuclei when male mice were pretreated with coumarin. This protective effect of coumarin pretreatment was not seen in female animals.
The following drugs ... may increase ... response to coumarin or indandione derivatives: alcohol (acute intoxication), allopurinol, aminosalicylic acid, amiodarone, anabolic steroids, chloral hydrate, chloramphenicol, cimetidine, clofibrate, co-trimoxazole, danazol, dextrothyroxine sodium, diazoxide, diflunisal, disulfiram, erythromycin, ethacrynic acid, fenoprofen calcium, glucagon, ibuprofen, indomethacin, influenza virus vaccine, isoniazid, meclofenamate, mefenamic acid, methylthiouracil, metronidazole, miconazole, nalidixic acid, neomycin (oral), pentoxifylline, phenylbutazone, propoxyphene, propylthiouracil, quinidine, quinine, salicylates, streptokinase, sulfinpyrazone, sulfonamides, sulindac, tetracyclines, thiazides, thyroid drugs, tricyclic antidepressants, urokinase, vitamin E. /Coumarin & indandione derivatives/
The following drugs ... may ... decrease ... response to coumarin or indandione derivatives: alcohol (chronic alcoholism), barbiturates, carbamazepine, corticosteroids, corticotropin, ethchlorvynol, glutethimide, griseofulvin, mercaptopurine, methaqualone, oral contraceptives containing estrogen, rifampin, spironolactone, vitamin K. /Coumarin & indandione derivatives/

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Non-Human Toxicity Values
LD50 Rat oral 293 mg/kg
LD50 Mouse oral 196 mg/kg
LD50 Mouse ip 220 mg/kg
LD50 Mouse subcutaneous 242 mg/kg
LD50 Guinea pig oral 202 mg/kg

[1]. Biomed Chromatogr. 2011 Jul;25(7):7

Coumarin appears as colorless crystals, flakes or colorless to white powder with a pleasant fragrant vanilla odor and a bitter aromatic burning taste. (NTP, 1992)
Coumarin is a chromenone having the keto group located at the 2-position. It has a role as a fluorescent dye, a plant metabolite and a human metabolite.
Coumarin has been reported in Caragana frutex, Eupatorium japonicum, and other organisms with data available.
Coumarin is o hydroxycinnamic acid. Pleasant smelling compound found in many plants and released on wilting. Has anticoagulant activity by competing with Vitamin K.
Coumarin is a chemical compound/poison found in many plants, notably in high concentration in the tonka bean, woodruff, and bison grass. It has a sweet scent, readily recognised as the scent of newly-mown hay. It has clinical value as the precursor for several anticoagulants, notably warfarin. --Wikipedia. Coumarins, as a class, are comprised of numerous naturally occurring benzo-alpha-pyrone compounds with important and diverse physiological activities. The parent compound, coumarin, occurs naturally in many plants, natural spices, and foods such as tonka bean, cassia (bastard cinnamon or Chinese cinnamon), cinnamon, melilot (sweet clover), green tea, peppermint, celery, bilberry, lavender, honey (derived both from sweet clover and lavender), and carrots, as well as in beer, tobacco, wine, and other foodstuffs. Coumarin concentrations in these plants, spices, and foods range from <1 mg/kg in celery, 7000 mg/kg in cinnamon, and up to 87,000 mg/kg in cassia. An estimate of human exposure to coumarin from the diet has been calculated to be 0.02 mg/kg/day. Coumarin is used as an additive in perfumes and fragranced consumer products at concentrations ranging from <0.5% to 6.4% in fine fragrances to <0.01% in detergents. An estimate for systemic exposure of humans from the use of fragranced cosmetic products is 0.04 mg/kg BW/day, assuming complete dermal penetration. The use of coumarin as a food additive was banned by the FDA in 1954 based on reports of hepatotoxicity in rats. Due to its potential hepatotoxic effects in humans, the European Commission restricted coumarin from naturals as a direct food additive to 2 mg/kg food/day, with exceptions granting higher levels for alcoholic beverages, caramel, chewing gum, and certain 'traditional foods'. In addition to human exposure to coumarin from dietary sources and consumer products, coumarin is also used clinically as an antineoplastic and for the treatment of lymphedema and venous insufficiency. Exposure ranges from 11 mg/day for consumption of natural food ingredients to 7 g/day following clinical administration. Although adverse effects in humans following coumarin exposure are rare, and only associated with clinical doses, recent evidence indicates coumarin causes liver tumors in rats and mice and Clara cell toxicity and lung tumors in mice. The multiple effects as well as the ongoing human exposure to coumarin have resulted in a significant research effort focused on understanding the mechanism of coumarin induced toxicity/carcinogenicity and its human relevance. These investigations have revealed significant species differences in coumarin metabolism and toxicity such that the mechanism of coumarin induced effects in rodents, and the relevance of these findings for the safety assessment of coumarin exposure in humans are now better understood. In October 2004, the European Food Safety Authority (EFSA, 2004) reviewed coumarin to establish a tolerable daily intake (TDI) in foods. EFSA issued an opinion indicating that coumarin is not genotoxic, and that a threshold approach to safety assessment was most appropriate. EFSA recommended a TDI of 0 to 0.1 mg/kg BW/day. Including dietary contributions, the total human exposure is estimated to be 0.06 mg/kg/day. As a pharmaceutical, coumarin has been used in diverse applications with a wide variety of dosing regimens. Unlike coumadin and other coumarin derivatives, coumarin has no anti-coagulant activity. However, at low doses (typically 7 to 10 mg/day), coumarin has been used as a 'venotonic' to promote vein health and small venule blood flow. Additionally, coumarin has been used clinically in the treatment of high-protein lymphedema of various etiologies. (A7913).
See also: Cinnamon (part of); Chinese Cinnamon (part of); Chinese Cinnamon Leaf Oil (part of) ... View More ...

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Mechanism of Action
Coumarin and some of its metabolites have been shown to inhibit glucose-6-phosphatase in liver and in liver microsomal preparation. It interferes with excision repair processes on ultra-violet-damaged DNA and with host cell reactivation of ultra-violet-irradiated phage T1 in E coli WP2.
Both 4-hydroxycoumarin derivatives and indandiones (also known as oral anticoagulants) are antagonists of vitamin K. Their use as rodenticides is based on the inhibition of the vitamin K-dependent step in the synthesis of a number of blood coagulation factors. The vitamin K-dependent proteins ...in the coagulation cascade... are the procoagulant factors II (prothrombin), VII (proconvertin), IX (Christmas factor) and X (Stuart-Prower factor), and the coagulation-inhibiting proteins C and S. All these proteins are synthesized in the liver. Before they are released into the circulation the various precursor proteins undergo substantial (intracellular) post-translational modification. Vitamin K functions as a co-enzyme in one of these modifications, namely the carboxylation at well-defined positions of 10-12 glutamate residues into gamma-carboxyglutamate (Gla). The presence of these Gla residues is essential for the procoagulant activity of the various coagulations factors. Vitamin K hydroquinone (KH2) is the active co-enzyme, and its oxidation to vitamin K 2,3-epoxide (KO) provides the energy required for the carboxylation reaction. The epoxide is than recycled in two reduction steps mediated by the enzyme KO reductase... . The latter enzyme is the target enzyme for coumarin anticoagulants. Their blocking of the KO reductase leads to a rapid exhaustion of the supply of KH2, and thus to an effective prevention of the formation of Gla residues. This leads to an accumulation of non-carboxylated coagulation factor precursors in the liver. In some cases these precursors are processed further without being carboxylated, and (depending on the species) may appear in the circulation. At that stage the under-carboxylated proteins are designated as descarboxy coagulation factors. Normal coagulation factors circulate in the form of zymogens, which can only participate in the coagulation cascade after being activated by limited proteolytic degradation. Descarboxy coagulation factors have no procoagulant activity (i.e. they cannot be activated) and neither they can be converted into the active zymogens by vitamin K action. Whereas in anticoagulated humans high levels of circulating descarboxy coagulation factors are detectable, these levels are negligible in warfarin-treated rats and mice. /Anticoagulant rodenticides/

C9H6O2

146.15

146.036

C, 73.97; H, 4.14; O, 21.89

91-64-5

Coumarin-d4;185056-83-1

323

White to off-white solid powder

1.2±0.1 g/cm3

298.0±0.0 °C at 760 mmHg

68-73 °C(lit.)

118.3±16.1 °C

0.0±0.6 mmHg at 25°C

1.595

1.39

0

2

0

11

196

0

O=C1C=CC2C(=CC=CC=2)O1

ZYGHJZDHTFUPRJ-UHFFFAOYSA-NZYGHJZDHTFUPRJ-UHFFFAOYSA-N

InChI=1S/C9H6O2/c10-9-6-5-7-3-1-2-4-8(7)11-9/h1-6H

2H-1-Benzopyran-2-one

Coumarin; NSC 8774; NSC-8774; NSC8774

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : 29 ~100 mg/mL (198.43 ~684.28 mM )
Ethanol : ~29 mg/mL
H2O : ~4 mg/mL (~27.37 mM)

Solubility in Formulation 1: ≥ 3 mg/mL (20.53 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 30.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 3 mg/mL (20.53 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 30.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 3 mg/mL (20.53 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 30.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 8.33 mg/mL (57.00 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication (<60°C).

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 (Please use freshly prepared in vivo formulations for optimal results.)