MOBILE VIEW  | 

COUMARIN

Classification   |    Detailed evidence-based information

Therapeutic Toxic Class

    A) Coumarin is a naturally occuring benzo-alphapyrone compound that is most often encountered as a food additive.

Specific Substances

    1) 1,2-benzopyrone
    2) 2-H-benzopyran-2-one
    3) 2,3-dihydrobenzofuran
    4) Benzo-alpha-pyrone
    5) Cis-O-coumarinic acid lactone
    6) Coumarinic anhydride
    7) Cumarin
    8) Tonka bean camphor
    9) Cas 91-64-5
    10) NCI-C07103
    1.2.1) MOLECULAR FORMULA
    1) C9-H6-O2

Available Forms Sources

    A) FORMS
    1) In Germany, coumarin is found in various rat poisons and rodenticides, for example Racumin(R).
    B) SOURCES
    1) Found in tonka beans (Dipteryx odorata or D. oppositifolia), lavendar oil, woodruff (Asperula sp), clover (Melilotus sp), and many other plant families.
    C) USES
    1) It is used as a flavor enhancer, especially for vanilla.
    2) Mexican vanilla
    a) A study by Sullivan (1981, 1981b) showed that of 1173 samples tested, 1054 (90%) were contaminated with coumarin.
    b) An FDA bulletin reported coumarin levels of from 400 to 1,800 parts/million in 19 samples found in Arizona (FDA release by WY Cobb, March 8, 1984).
    1) 1 ppm = 1 mg/liter
    2) A 5 to 10 mL "dose" of the strongest concentration would be 18 mg of coumarin. Doses of 200 to 500 mg have been tolerated with no ill effects, while 4 g have been taken with only moderate symptoms. The 5 to 10 mL dose would be equivalent to 0.00036 mg of warfarin (Coumadin(R)) in anticoagulant activity (Normal warfarin dose 2 to 10 mg/day).
    3) Should an individual drink 1 quart (approx 1 liter) in an abuse situation, this would still only be 400 to 1,800 mg of coumarin.
    c) Below is a list of the product names of vanilla Sullivan (1981) found contaminated. The list is not all inclusive, nor should it be construed as a permanent formula addition for a particular brand.
    1) Table I - Adulterated Mexican Vanilla Brands
    2)
    a) Alfercols Premier
    b) Alther
    c) American Food de Mexico
    d) Botica Central
    e) Bremer
    f) Cristal
    g) Dey Ley
    h) Diana
    i) El Gallito
    j) El Jarocho
    k) Empacador Artificial
    l) Escencia LRB (Lucio R Beltran)
    m) Esemcias Ligitimas de Papantta
    n) Essence de Vallille Pure (Haitian)
    o) Gallo
    p) La Corona de Oro
    q) La Favorita
    r) La Jarocha
    s) La Puresta
    t) La Pureza
    u) Leudol Inc
    v) Lubek
    w) Lubor
    x) Old San Antonio
    y) Paisa
    z) Paisa (Colorless)
    aa) Pardo
    ab) Product of Riko Mitla
    ac) Pura Premier (RM Leal)
    ad) Tropical World
    ae) Unica
    af) Vainilla de Cordoba
    ag) Zappor
    3) Table II - Mexican Vanilla Brands Inconsistently Adulterated
    4)
    a) Ciervo
    b) La Anita
    c) La Vencedora
    d) Molina
    e) Para de Ejotes
    f) Triunfo
    5) Table III - Mexican Vanilla Brands Not Found To Be Adulterated
    6)
    a) Deiman SA de CV
    b) Delicia
    c) Demesa
    d) En Rame Ofrenda
    e) Famus
    f) La Bandera
    g) Tropical
    h) Vai-Mex
    i) Vreez
    j) Zambrano

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) Coumarin is a naturally occuring benzo-alphapyrone compound that is most often encountered as a food additive. Although banned in the United States since 1954, it has been reported as a contaminant in vanilla from Mexico or other Caribbean countries.
    1) Although animal data would indicate that coumarin produces symptoms ranging from CNS depression, liver damage or paralysis to anticoagulation and kidney damage, the interspecies differences in signs and symptoms, toxic dose, and metabolites are so large that the relevance of these studies to humans is unknown.
    0.2.7) NEUROLOGIC
    A) Four grams has caused a decrease in sympathetic nerve reactivity and muscle paralysis.
    0.2.9) HEPATIC
    A) The O-hydroxyphenyl acetic acid metabolite has been shown to cause liver toxicity in rats, however human liver cells appear to be relatively resistant to coumarin toxicity.
    0.2.13) HEMATOLOGIC
    A) Coumarin is not an active anti-coagulant. It has an activity 1/50,000th that of warfarin.

Laboratory Monitoring

    A) Thin-layer chromatography is used to detect coumarin in vanilla at concentrations of 10 parts per million or greater.
    B) In rare circumstances of large ingestions international normalized ratio (INR) or prothrombin time and liver enzymes may be indicated.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
    B) Poisoning in man is a rare event. If large amounts are ingested consider:
    1) Measuring prothrombin time or INR for elevation.
    2) Monitoring liver function tests.
    3) CNS support for depression and possible muscle paralysis.

Range Of Toxicity

    A) TOXIC DOSE - Four grams were taken with no negative cardiovascular effects; however, symptoms of general weakness and illness, decreased sympathetic nerve activity, and muscle paralysis were reported.
    B) An FDA bulletin reported coumarin levels of from 400 to 1,800 parts/million in 19 vanilla samples found in Arizona.
    1) One part per million (ppm) is equal to 1 mg per liter. The strongest concentration (1,800 ppm) would be 1,800 mg/1000 mL.
    2) 5 to 10 mL dose of vanilla (amount that might be used in cooking) of the strongest concentration would be 18 mg of coumarin. Doses of 200 to 500 mg have been tolerated with no ill effects, while 4 g have been taken with only moderate symptoms. The 5 to 10 mL dose would be equivalent to 0.00036 mg of warfarin in anticoagulant activity.
    3) Should an individual drink 1 quart (usual packaging size) in an abuse situation, this would still only be 400 to 1,800 mg of coumarin.
    C) Acute ingestions of this product are unlikely to be toxic. Problems associated with chronic use are being investigated by the FDA.

Summary Of Exposure

    A) Coumarin is a naturally occuring benzo-alphapyrone compound that is most often encountered as a food additive. Although banned in the United States since 1954, it has been reported as a contaminant in vanilla from Mexico or other Caribbean countries.
    1) Although animal data would indicate that coumarin produces symptoms ranging from CNS depression, liver damage or paralysis to anticoagulation and kidney damage, the interspecies differences in signs and symptoms, toxic dose, and metabolites are so large that the relevance of these studies to humans is unknown.

Neurologic

    3.7.1) SUMMARY
    A) Four grams has caused a decrease in sympathetic nerve reactivity and muscle paralysis.
    3.7.2) CLINICAL EFFECTS
    A) NEUROPATHY
    1) SYMPATHETIC ACTIVITY - Decreases in sympathetic nerve reactivity were reported with doses of 4 g (Sethna & Shah, 1945).
    B) PARALYSIS
    1) Doses of 4 grams have paralyzed muscles in humans (Sethna & Shah, 1945).

Hepatic

    3.9.1) SUMMARY
    A) The O-hydroxyphenyl acetic acid metabolite has been shown to cause liver toxicity in rats, however human liver cells appear to be relatively resistant to coumarin toxicity.
    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) CASE SERIES - Cox et al (1989) studied 2,173 patients taking therapeutic coumarin, 25 to 2000 mg/day. Seventeen (0.37%) of these patients developed LFTs of at least double the normal maximum. Peak ALT levels in these patients ranged from 115 to 960 International Units/L.
    3.9.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HEPATOCELLULAR DAMAGE
    a) RATS - Feuer et al (1966) while working with rats discovered that the O-hydroxyphenyl acetic acid metabolite (not 7-hydroxycoumarin) was potentially hepatotoxic. Humans produce less than 6% of this metabolite.
    b) Cultured rat, human, mouse, and rabbit hepatocytes exposed to coumarin showed great differences in cytotoxic effects produced by coumarin and its metabolites. Rat hepatocytes were the most sensitive to coumarin and its derivatives, whereas human hepatocytes were the most resistant (Ratanasavanh et al, 1996).
    1) Lobular hepatic necrosis was observed in rats exposed to coumarin (Jack et al, 1996).

Hematologic

    3.13.1) SUMMARY
    A) Coumarin is not an active anti-coagulant. It has an activity 1/50,000th that of warfarin.
    3.13.2) CLINICAL EFFECTS
    A) COAG./BLEEDING TESTS ABNORMAL
    1) ANTICOAGULANT EFFECTS - Coumarin is not an active anticoagulant. Compared with 106 other derivatives (using bishydroxycoumarin as a 1.0 standard) coumarin scored 0.02 at the 500 mg dosage. This is 1/5,000th the activity of bishydroxycoumarin. Four doses of 500 mg each elicited no changes in prothrombin time (Overman et al, 1944). Doses of coumarin with potential anticoagulant activity would be 50,000 times those of warfarin (Coumadin(R)).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS91-64-5 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) IARC Classification
    a) Listed as: Coumarin
    b) Carcinogen Rating: 3
    1) The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Thin-layer chromatography is used to detect coumarin in vanilla at concentrations of 10 parts per million or greater.
    B) In rare circumstances of large ingestions international normalized ratio (INR) or prothrombin time and liver enzymes may be indicated.

Methods

    A) CHROMATOGRAPHY
    1) As little as 100 parts per millon of coumarin in vanilla is detectable by high-performance thin layer chromatography (Sherma et al, 1987). This value is below the level expected to be present in actual flavoring products.

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Thin-layer chromatography is used to detect coumarin in vanilla at concentrations of 10 parts per million or greater.
    B) In rare circumstances of large ingestions international normalized ratio (INR) or prothrombin time and liver enzymes may be indicated.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) Very large amounts of coumarin would need to be ingested to cause symptoms (possibly greater than 4 grams). In almost all cases no treatment is necessary.
    2) Gastric decontamination is rarely needed. Consider only if large amounts have been ingested.
    B) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) Poisoning in man is a rare event. If large amounts are ingested consider:
    a) Measuring prothrombin time or INR for elevation.
    b) Liver function tests.
    c) CNS support for depression and possible muscle paralysis.

Case Reports

    A) ROUTE OF EXPOSURE
    1) ORAL: In a study by Ritschel et al (1977), healthy volunteers were administered 0.25 mg/kg IV and 0.847 mg/kg orally. They found rapid oral absorption, but extensive first pass elimination. Only 4% of the dose eliminated was coumarin; the rest was 7-hydroxy coumarin or 7-hydroxy coumarin glucuronide (7-HCG).

Summary

    A) TOXIC DOSE - Four grams were taken with no negative cardiovascular effects; however, symptoms of general weakness and illness, decreased sympathetic nerve activity, and muscle paralysis were reported.
    B) An FDA bulletin reported coumarin levels of from 400 to 1,800 parts/million in 19 vanilla samples found in Arizona.
    1) One part per million (ppm) is equal to 1 mg per liter. The strongest concentration (1,800 ppm) would be 1,800 mg/1000 mL.
    2) 5 to 10 mL dose of vanilla (amount that might be used in cooking) of the strongest concentration would be 18 mg of coumarin. Doses of 200 to 500 mg have been tolerated with no ill effects, while 4 g have been taken with only moderate symptoms. The 5 to 10 mL dose would be equivalent to 0.00036 mg of warfarin in anticoagulant activity.
    3) Should an individual drink 1 quart (usual packaging size) in an abuse situation, this would still only be 400 to 1,800 mg of coumarin.
    C) Acute ingestions of this product are unlikely to be toxic. Problems associated with chronic use are being investigated by the FDA.

Therapeutic Dose

    7.2.1) ADULT
    A) GENERAL
    1) 200 milligrams were given to 8 normal volunteers with no ill effects (Shilling et al, 1969).

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) Four grams were taken with no negative cardiovascular effects, but symptoms of general weakness and illness, decreased sympathetic nerve action and muscle paralysis were reported (Sethna & Shah, 1945).

Workplace Standards

    A) ACGIH TLV Values for CAS91-64-5 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS91-64-5 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS91-64-5 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): 3 ; Listed as: Coumarin
    a) 3 : The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS91-64-5 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) References: RTECS, 1999 Budavari, 1996
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 220 mg/kg
    2) LD50- (ORAL)MOUSE:
    a) 196 mg/kg
    3) LD50- (SUBCUTANEOUS)MOUSE:
    a) 242 mg/kg
    4) LD50- (ORAL)RAT:
    a) 293 mg/kg
    b) 680 mg/kg

Toxicologic Mechanism

    A) Coumarin is a chemical of natural plant origin which has very mild anticoagulant properties, and CNS depressant activities in several animal species.

Physical Characteristics

    A) ODOR: Pleasant, sweet, like vanilla beans.
    B) TASTE: A burning sensation.

Molecular Weight

    A) 146.15

General Bibliography

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