Coumarin

146.145

146.14

202-086-7

A4VZ22K1WT

1105

755852|8774

2811

DTXSID7020348

C397

Orthorhombic, rectangular plates|Colorless, crystals, flakes, or powder|White crystals

2932999099

26.3

1.4

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)

0.935 g/cm³ @ Temp: 20 °C

71 °C

301.71 °C

150°C

1.595

H2O: 1.7 g/L (20 ºC);Solubility in water: poor

Refrigerator

Vapour pressure, kPa at 106°C: 0.13

LD50 orally in rats, guinea pigs: 680, 202 mg/kg (Jenner)

Pleasant, fragrant odor resembling that of vanilla beans.

Bitter undertone; nut-like flavor on dilution

122.2 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

1 g dissolves in 400 ml cold, 50 ml boiling water|The lactone is easily hydrolyzed to the corresponding salts of coumarinic acid or o-hydroxy-cis-cinnamic acid.

Insoluble in water.

Esters, Sulfate Esters, Phosphate Esters, Thiophosphate Esters, and Borate Esters

COUMARIN is sensitive to exposure to light. It is also sensitive to heat. This chemical is incompatible with strong acids, strong bases and oxidizers. It is hydrolyzed by hot concentrated alkalis. It can be halogenated, nitrated and hydrogenated (in the presence of catalysts). (NTP, 1992)

III

6.1

UN 2811 6.1/PG 3

1

R20/21/22;R36/37/38;R40

S36-S36/37-S26

GN4200000

Xn:Harmful

Separated from food and feedstuffs.

Converted to a dimer on long exposure to light.

P301 + P310

H301

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.|Incineration: Coumarin should be combined with paper or other flammable material. An alternate procedure is to dissolve the solid in a flammable solvent and spray the soln into the fire chamber.

(a) Coumarin is the chemical 1,2-benzopyrone, C9H6O2. It is found in tonka beans and extract of tonka beans, among other natural sources, and is also synthesized. It has been used as a flavoring agent. (b) Food containing any added coumarin as such or as a constituent of tonka beans or tonka extract is deemed to be adulterated under the act, based upon an order published in the Federal Register of March 5, 1954 (19 FR 1239).

DHHS/NTP; Toxicology & Carcinogenesis Studies of Coumarin in F344/N Rats and B6C3F1 Mice (Gavage Studies) Technical Report Series No. 422 (1993) NIH Publication No. 93-3153|Cole MS et al; Surgery 103 (3): 271-7 (1988). Coumarin necrosis, a review of the literature.|Comp PC; Drug Saf 8 (2): 128-35 (1993). A review of coumarin induced skin necrosis.|Pelkonen O et al; J Cancer Res Clin Oncol 120: S30-1 (1994). Review of the regulation of coumarin 7-hydroxylation in man.

UN 2811 6.1/PG 3

This chemical is combustible. (NTP, 1992)|Combustible.

|Warning|H302 (89.69%): Harmful if swallowed [Warning Acute toxicity, oral]|P260, P261, P264, P270, P272, P280, P301+P312, P302+P352, P314, P321, P330, P333+P313, P363, and P501|Aggregated GHS information provided by 2854 companies from 45 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.|Danger|H301: Toxic if swallowed [Danger Acute toxicity, oral]|P264, P270, P301+P310, P321, P330, P405, and P501|H302: Harmful if swallowed [Warning Acute toxicity, oral]|P260, P264, P270, P301+P312, P314, P330, and P501

Fires involving this material can be controlled with a dry chemical, carbon dioxide or Halon extinguisher. A water spray may also be used. (NTP, 1992)|Use water spray, foam, powder, carbon dioxide.

Excerpt from ERG Guide 154 [Substances - Toxic and/or Corrosive (Non-Combustible)]: As an immediate precautionary measure, isolate spill or leak area in all directions for at least 50 meters (150 feet) for liquids and at least 25 meters (75 feet) for solids. SPILL: Increase, in the downwind direction, as necessary, the isolation distance shown above. FIRE: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. (ERG, 2016)

SMALL SPILLS AND LEAKAGE: Should a spill occur while you are handling this chemical, FIRST REMOVE ALL SOURCES OF IGNITION, then you should dampen the solid spill material with 60-70% ethanol and transfer the dampened material to a suitable container. Use absorbent paper dampened with 60-70% ethanol to pick up any remaining material. Seal the absorbent paper, and any of your clothes, which may be contaminated, in a vapor-tight plastic bag for eventual disposal. Solvent wash all contaminated surfaces with 60-70% ethanol followed by washing with a soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned. STORAGE PRECAUTIONS: You should protect this material from exposure to light. Keep it away from oxidizing materials and store it under refrigerated temperatures. (NTP, 1992)

MINIMUM PROTECTIVE CLOTHING: If Tyvek-type disposable protective clothing is not worn during handling of this chemical, wear disposable Tyvek-type sleeves taped to your gloves. RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with a combination filter cartridge, i.e. organic vapor/acid gas/HEPA (specific for organic vapors, HCl, acid gas, SO2 and a high efficiency particulate filter). (NTP, 1992)

SLIGHT, WHEN EXPOSED TO HEAT OR FLAME.

SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants.|...Substitution of less irritating substances, ...redesign of operations...prevent contact, provision of a physical barrier against contact, proper washing facilities, work clothing and storage facilities, protective clothing, and barrier creams. Medical control... .

Personal protection: particulate filter respirator adapted to the airborne concentration of the substance. Carefully collect remainder. Then store and dispose of according to local regulations.

Separated from food and feedstuffs.

Evaporation at 20 °C is negligible; a nuisance-causing concentration of airborne particles can, however, be reached quickly.

The substance is irritating to the skin.

This substance is possibly carcinogenic to humans.

NO open flames.

PREVENT DISPERSION OF DUST!

Use ventilation.

Protective gloves. Protective clothing.

Wear face shield.

Coumarin was detected in fine particle emissions from fireplace combustion of northeastern US woods at the following concns: 0.077, 0.049, 0.359, 0.110, 0.080, and 0.067 mg/g organic carbon from the residential fireplace burning of red maple, northern red oak, paper birch, eastern white pine, eastern hemlock, and balsam fir, respectively(1).

RURAL/REMOTE: The concn of coumarin over the southern North Atlantic Ocean (20 m high) was 0.10 ng/cu m(1).

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.[

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/

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

/ACCIDENTAL POISONINGS/ Coumarin, contained in sweetclover hay (melilotus spp), is converted to dicoumarin by molds under certain conditions. This compound interferes with prothrombin synthesis and results in hemorrhagic disease when molded sweetclover hay is ingested over period of time.

Toxicity and carcinogenicity studies were conducted by administering coumarin (97% pure) in corn oil by gavage to groups of male and female F344/N rats and B6C3F1 mice for ... 2 yr. 2-YEAR STUDY IN RATS: Groups of 60 male and 60 female rats were admin coumarin in corn oil by gavage at doses of 0 25, 50, or 100 mg/kg body weight. ... 2-YEAR STUDY IN MICE: Groups of 70 male and 70 female mice were admin coumarin in corn oil by gavage at doses of 0 50, 100, or 200 mg/kg body weight for up to 2 yr. ... CONCLUSIONS: Under the conditions of these 2 yr gavage studies there was some evidence of carcinogenic activity of coumarin in male F344/N rats based on increased incidences of renal tubule adenomas. There was equivocal evidence of carcinogenic activity of coumarin in female F344/N rats based on a marginally increased incidence of renal tubule adenomas. There was some evidence of carcinogenic activity of coumarin in male B6C3F1 mice based on the increased incidence of alveolar/bronchiolar adenomas. There was clear evidence of carcinogenic activity of coumarin in female B6C3F1 mice based on increased incidences of alveolar/bronchiolar adenomas, alveolar/bronchiolar carcinomas, and hepatocellular adenomas. The marginally increased incidences of squamous cell papillomas of the forestomach in male and female mice receiving 50 mg/kg may have been related to coumarin administration.

Some individuals have been identified as poor metabolizers of... coumarin..., which /is/ metabolized by CYP2A6... . However, the incidence of each of these phenotypes is apparently <1% of the populations examined to date.

REPORTED IN TONKA BEAN (DIPTERYX ODORATA) SEED, THE FLOWERS OF MELILOTUS OFFICIALIS, THE LEAVES OF MELILOTUS ALBUS, IN LIATRIS ODORATISSIMA, ASPERULA ODOROSA, WILD VANILLA (ACHLYS TRIPHYLLA), LAVENDER OIL, & SEVERAL VARIETIES OF ORCHID.|...FOUND IN EDIBLE PLANTS SUCH AS STRAWBERRIES, BLACKCURRENTS, APRICOTS, & CHERRIES...|Coumarin is a naturally occurring compound found in a large number of plants belonging to many different families, including tonka beans, lavender oil, woodruff (Asperula species), cassia, meliot and sweet clover (Melilotus)(1,2).

Coumarin's production and use as a fragrance ingredient in soaps, detergents, lotions, perfumes, tobacco, household products(1) and as a pharmaceutical flavoring(2) may result in its release to the environment through various waste streams(SRC).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 140(SRC), determined from a log Kow of 1.39(2) and a regression-derived equation(3), indicates that coumarin is expected to have high mobility in soil(SRC). Volatilization of coumarin from moist soil surfaces is not expected to be an important fate process(SRC) based upon a Henry's Law constant of 9.9X10-8 atm-cu m/mole(SRC), derived from its vapor pressure, 9.8X10-4 mm Hg(4), and water solubility, 1,900 mg/l(5). Coumarin is not expected to volatilize from dry soil surfaces(SRC) based upon a vapor pressure of 9.8X10-4 mm Hg(4). Coumarin is confirmed to be biodegradable according to the standard test of the Japanese Ministry of Industry and Trade (MITI) that employs a mixed inoculum obtained from freshwater, soil, and sludge(6). Therefore, biodegradation may be an important environmental fate process in soil(SRC).|AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 140(SRC), determined from a log Kow of 1.39(2) and a regression-derived equation(3), indicates that coumarin is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon a Henry's Law constant of 9.9X10-8 atm-cu m/mole(SRC), derived from its vapor pressure, 9.8X10-4 mm Hg(3), and water solubility, 1,900 mg/l(4). According to a classification scheme(5), a BCF <10 in golden orfe(6), suggests the potential for bioconcentration in aquatic organisms is low(SRC). The lactone is hydrolyzed by alkalies to the corresponding salts of coumarinic acid or o-hydroxy-cis-cinnamic acid(8); however, no data are available concerning the hydrolysis of coumarin under environmental conditions. Coumarin is confirmed to be biodegradable according to the standard test of the Japanese Ministry of Industry and Trade (MITI) that employs a mixed inoculum obtained from freshwater, soil, and sludge(7). Therefore, biodegradation may be an important environmental fate process in water(SRC).|ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), coumarin, which has a vapor pressure of 9.8X10-4 mm Hg at 25 °C(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase coumarin is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 29 hrs(SRC), calculated from its rate constant of 1.3X10-11 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Particulate-phase coumarin may be removed from the air by wet and dry deposition(SRC). 59.2% of the initial concn of coumarin was mineralized to CO2 when exposed to UV radiation >290 nm for 17 hr(4).

The rate constant for the vapor-phase reaction of coumarin with photochemically-produced hydroxyl radicals has been estimated as 1.3X10-11 cu cm/molecule-sec at 25 °C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 29 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). The rate constant for the vapor-phase reaction of coumarin with ozone has been estimated as 2.1X10-17 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(2). This corresponds to an atmospheric half-life of about 13 hrs at an atmospheric concentration of 7X10+11 ozone molecules per cu cm(3). The lactone is hydrolyzed by alkalies to the corresponding salts of coumarinic acid or o-hydroxy-cis-cinnamic acid(4); however, no data are available concerning the hydrolysis of coumarin under environmental conditions. In a photomineralization test in which coumarin was adsorbed on silica gel and exposed to UV radiation >290 nm for 17 hr, 59.2% of the test compound was mineralized to CO2(5). A coumarin dimer is formed under prolonged exposure to sunlight or UV radiation(4).

The BCF in golden orfe was <10 after 3 days exposure(1). According to a classification scheme(2), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC). The BCF of coumarin in green algae (Chlorella sp.) after exposure to 50 ug/l of coumarin for 24 hr was 42(1).

The Koc of coumarin is estimated as 140(SRC), using a log Kow of 1.39(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that coumarin is expected to have high mobility in soil.

The Henry's Law constant for coumarin is 9.9X10-8 atm-cu m/mole(SRC), derived from its vapor pressure, 9.8X10-4 mm Hg(1), and water solubility, 1,900 mg/l(2). This Henry's Law constant indicates that coumarin is expected to be essentially nonvolatile from water surfaces(3). Coumarin is not expected to volatilize from dry soil surfaces(SRC) based upon its vapor pressure(1).

NIOSH (NOES Survey 1981-1983) has statistically estimated that 239,705 workers (110,313 of these are female) are potentially exposed to coumarin in the US(1). Occupational exposure to coumarin may occur through inhalation and dermal contact with this compound at workplaces where coumarin is produced or used(SRC). Monitoring data indicate that the general population may be exposed to coumarin via inhalation and dermal contact and ingestion via consumer products containing coumarin(SRC).

In 387 expired air samples from 54 normal subjects, 63.1% contained coumarin(1). The geometric mean concentration was 1.0(1). As part of EPA's National Human Adipose Tissue Survey, 46 composite adipose fat samples in FY82 were analyzed(2). One of these samples, from an over 45 yr age group from the northeast, contained coumarin.

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.

...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.

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/

SYMPTOMS: Exposure to this compound may cause narcosis. It may also cause irritation and liver damage. (NTP, 1992)

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop. SKIN: IMMEDIATELY flood affected skin with water while removing and isolating all contaminated clothing. Gently wash all affected skin areas thoroughly with soap and water. IMMEDIATELY call a hospital or poison control center even if no symptoms (such as redness or irritation) develop. IMMEDIATELY transport the victim to a hospital for treatment after washing the affected areas. INHALATION: IMMEDIATELY leave the contaminated area; take deep breaths of fresh air. IMMEDIATELY call a physician and be prepared to transport the victim to a hospital even if no symptoms (such as wheezing, coughing, shortness of breath, or burning in the mouth, throat, or chest) develop. Provide proper respiratory protection to rescuers entering an unknown atmosphere. Whenever possible, Self-Contained Breathing Apparatus (SCBA) should be used; if not available, use a level of protection greater than or equal to that advised under Protective Clothing. INGESTION: DO NOT INDUCE VOMITING. If the victim is conscious and not convulsing, give 1 or 2 glasses of water to dilute the chemical and IMMEDIATELY call a hospital or poison control center. Be prepared to transport the victim to a hospital if advised by a physician. If the victim is convulsing or unconscious, do not give anything by mouth, ensure that the victim's airway is open and lay the victim on his/her side with the head lower than the body. DO NOT INDUCE VOMITING. IMMEDIATELY transport the victim to a hospital. OTHER: Since this chemical is a known or suspected carcinogen you should contact a physician for advice regarding the possible long term health effects and potential recommendation for medical monitoring. Recommendations from the physician will depend upon the specific compound, its chemical, physical and toxicity properties, the exposure level, length of exposure, and the route of exposure. (NTP, 1992)

Fresh air, rest.

Remove contaminated clothes. Rinse and then wash skin with water and soap.

First rinse with plenty of water for several minutes (remove contact lenses if easily possible), then refer for medical attention.

/EPIDEMIOLOGY STUDIES/ To study the late effects of prenatal exposure to coumarins, physical, neurological, and mental development were assessed. In a pilot study 21 index (I) children and 17 controls (C) were examined at the age 8-10 years. No statistical significant differences were found between the index and control group in this small study. Nevertheless, an indication seemed to be present for a possible effect of prenatal exposure to coumarins. Five children showed minor neurological dysfunction (MND); the two children with the more serious variant (NOS = neurologial optimality score 42-48) had both been exposed to coumarins. The distribution of the IQ-scores corresponded with the distribution of the scores in the Dutch standardization sample. There were 3 children with an IQ less than 80. All three had been exposed to oral anticoagulants during pregnancy in the 2nd and 3rd (n = 2), or in the 3rd trimester only. One child with severe abnormalities, namely hypoplasia of both optic nerves, cerebral palsy and retardation, had been exposed during the 2nd and 3rd trimester of pregnancy.

1,2-benzopyrone

The substance can be absorbed into the body by inhalation of its aerosol, through the skin and by ingestion.

MAY BE ABSORBED! Redness. Pain.

All other chemical product and preparation manufacturing|2H-1-Benzopyran-2-one: ACTIVE|Commercially, in detergents, soaps, and cosmetics, and as flavoring agent for cattle medicines.|Use in foods not permitted in USA.|... Is widely distributed in the plant kingdom but most of it has been produced synthetically for many years for commercial use.

AOAC Official Method 955.31: Vanillin, ethyl vanillin, and coumarin in vanilla extract; chromatographic method.|Citrus peel oils were examined by high-performance liquid chromatography for their coumarin and psoralen content. Resolution and identification was carried out on micro CN, C-18, and porasil columns. Coumarins and psoralens were detected at 320 and 305 nm.|AOAC Official Method 976.12: Coumarin in wines; gas chromatographic method.

Pharmaceuticals -> Animal Drugs -> Approved in Taiwan|Cosmetics -> Masking