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EUGENOL

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Eugenol is a local anesthetic. It is used in dental products.

Specific Substances

    1) 2-Methoxy-4(2-propenyl)phenol
    2) 4-Allyl-2-Methoxyphenol
    3) Caryophyllic Acid
    4) CAS 97-53-0
    5) EUGEN (FOR USE IN DENTAL TREATMENT)
    6) EUGENIC (FOR USE IN DENTAL TREATMENT)

Available Forms Sources

    A) FORMS
    1) CLOVE OIL consists of 85 to 87% eugenol (Anon, 1987).
    2) Clove cigarettes ("kreteks" - brand name) made from the dried flower bud of Eugenia caryophyllata thumb, contain 30 to 40% clove buds. The clove oil content in dry clove buds is approximately 15% wt/vol; thus 1 gram of dry clove buds contains 120 to 130 mg of eugenol (Anon, 1988).
    a) The average amount of eugenol was reported to be 13 mg per cigarette, as determined by standardized machine smoking conditions for three commercial brands of clove cigarettes without filter tips (LaVoie et al, 1986). Approximately 7 mg of eugenol is inhaled while smoking a clove cigarrette (Anon, 1992).
    B) USES
    1) DENTAL PRODUCTS: Eugenol is widely used in dental products, being incorporated into impression pastes, peridontal dressings, cement, endodontic sealers, fillings, and dressings for dry sockets (Barkin et al, 1984).
    2) FLAVORING: Eugenol is also used as a flavoring in foods and pharmaceuticals, and in the manufacture of textiles (Anon, 1988).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Eugenol is a local anesthetic. It is widely used in dental products, being incorporated into impression pastes, periodontal dressings, cement, endodontic sealers, fillings, and dressings for dry sockets. Eugenol is also used as a flavoring in foods and pharmaceuticals, and in the manufacture of textiles. Other forms include clove oil and clove cigarettes.
    B) TOXICOLOGY: Eugenol is a phenolic compound with the ability to quickly and effectively penetrate nerve bundles to serve as a painkiller. Dermal exposure to eugenol-containing products may result in irritation and inflammation. Eugenol inhibits mitochondrial respiration in vitro in a dose-dependent fashion, causing uncoupled oxidative phosphorylation and cellular injury.
    C) EPIDEMIOLOGY: Patients may be exposed to eugenol by occupational contact, or inadvertent ingestion of eugenol containing products. Patients can also get inhalational exposure by smoking clove cigarettes. Severe poisoning is extremely rare.
    D) WITH THERAPEUTIC USE
    1) Contact dermatitis, direct tissue damage, and allergic reactions have occurred following therapeutic use of dental products containing eugenol.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Eugenol containing products can be irritating to the skin, lungs, conjunctiva, and gastrointestinal tract.
    2) SEVERE TOXICITY: Vomiting, metabolic acidosis, CNS depression, seizures, hepatotoxicity, hypoglycemia, and disseminated intravascular coagulation have been reported in children following clove oil ingestions. Clove cigarette smoking may cause nausea, vomiting, exacerbation of chronic bronchitis or asthma attacks, pneumonia, bronchitis, hemoptysis, respiratory failure, and acute lung injury. It is unclear how much of these effects are produced by eugenol and how much by other components of the cigarettes.
    0.2.3) VITAL SIGNS
    A) WITH POISONING/EXPOSURE
    1) Hypothermia was reported following exposure to a clove oil solution containing 81% eugenol.
    0.2.20) REPRODUCTIVE
    A) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.
    0.2.21) CARCINOGENICITY
    A) Limited evidence, from animal models, suggests that eugenol may possess carcinogenic potential.

Laboratory Monitoring

    A) Monitor pulse oximetry and/or arterial blood gases, chest radiograph, and pulmonary function tests in patients with respiratory signs/symptoms.
    B) In severe poisoning cases, monitor electrolytes, renal and hepatic function tests, serum glucose, complete blood count and coagulation studies as indicated.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. In patients with significant ingestions of concentrated eugenol, endoscopy should be performed 12 to 24 hours post-ingestion to assess severity. Monitor the patient for respiratory distress. If a cough or breathing difficulty develops, evaluate for respiratory tract irritation, bronchitis, and pneumonitis.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Treat severe metabolic acidosis (pH less than 7.1) with sodium bicarbonate 1 to 2 mEq/kg. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur.
    C) DECONTAMINATION
    1) PREHOSPITAL: Due to the irritant nature of this substance and theoretical risk of aspiration pneumonitis, prehospital gastrointestinal decontamination is not advised.
    2) HOSPITAL: Due to the irritant nature of this substance, relatively benign clinical course in most cases involving systemic absorption, risk of aspiration, and the role of GI endoscopy in concentrated eugenol ingestions, activated charcoal is not routinely recommended.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with significant CNS depression, severe allergic reactions, and pulmonary toxicity.
    E) ANTIDOTE
    1) None
    F) ACUTE LUNG INJURY
    1) Supplemental oxygen; PEEP and mechanical ventilation may be needed.
    G) HYPERSENSITIVITY REACTION
    1) MILD/MODERATE: Antihistamines with or without inhaled beta agonists, corticosteroids or epinephrine.
    2) SEVERE: Administer oxygen, aggressive airway management, antihistamines, epinephrine, corticosteroids, ECG monitoring, and IV fluids.
    H) ENHANCED ELIMINATION PROCEDURE
    1) It is unknown if hemodialysis, hemoperfusion and plasmapheresis are likely to be useful following an oral exposure.
    I) PATIENT DISPOSITION
    1) OBSERVATION CRITERIA: Mildly symptomatic patients or asymptomatic patients with large exposures should be observed for 6 hours for signs of toxicity.
    2) ADMISSION CRITERIA: Patients with significant symptoms should be admitted for treatment and monitoring. Patients with respiratory failure should be admitted to an ICU setting.
    3) CONSULT CRITERIA: Contact a regional poison center or medical toxicologist for any patient with severe toxicity. In case of concentrated eugenol ingestion, consult a gastroenterologist or surgeon for endoscopy to assess severity of mucosal injury. For patients with eye exposure, consult an ophthalmologist for assistance of ophthalmic examination if needed.
    J) PITFALLS
    1) Failure to detect airway compromise and provide proper airway management. Failure to detect/recognize severe allergic reaction.
    K) PHARMACOKINETICS
    1) Little is known about the metabolic pathways of eugenol in humans. In a rat study, most eugenol was excreted unchanged in the urine. Approximately 1% of eugenol is demethylated.
    L) DIFFERENTIAL DIAGNOSIS
    1) Acute asthmatic attack, COPD with acute exacerbation, chlorine gas exposure, ammonia gas exposure, and irritant exposure.
    0.4.3) INHALATION EXPOSURE
    A) Administer 100% humidified supplemental oxygen, perform endotracheal intubation, and provide assisted ventilation as required. Administer inhaled beta adrenergic agonists and systemic steroids if bronchospasm develops.
    0.4.4) EYE EXPOSURE
    A) Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persists after 15 minutes of irrigation, an ophthalmologic examination should be performed.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) Remove contaminated clothing and wash exposed area extremely thoroughly with soap and water. A physician may need to examine the area if irritation or pain persists.

Range Of Toxicity

    A) TOXICITY: A specific toxic dose has not been established. CHILD: A 2-year-old child developed metabolic acidosis, hypoglycemia, disseminated intravascular coagulation, hepatotoxicity, and generalized seizures after ingesting 5 to 10 mL of clove oil, containing 70% to 90% eugenol. INFANT: Metabolic acidosis, elevated urine specific gravity, proteinuria, and ketonuria were noted in a 7-month-old after ingestion of 1 teaspoon of clove oil (500 mg/kg of eugenol).

Clinical Effects

Summary Of Exposure

    A) USES: Eugenol is a local anesthetic. It is widely used in dental products, being incorporated into impression pastes, periodontal dressings, cement, endodontic sealers, fillings, and dressings for dry sockets. Eugenol is also used as a flavoring in foods and pharmaceuticals, and in the manufacture of textiles. Other forms include clove oil and clove cigarettes.
    B) TOXICOLOGY: Eugenol is a phenolic compound with the ability to quickly and effectively penetrate nerve bundles to serve as a painkiller. Dermal exposure to eugenol-containing products may result in irritation and inflammation. Eugenol inhibits mitochondrial respiration in vitro in a dose-dependent fashion, causing uncoupled oxidative phosphorylation and cellular injury.
    C) EPIDEMIOLOGY: Patients may be exposed to eugenol by occupational contact, or inadvertent ingestion of eugenol containing products. Patients can also get inhalational exposure by smoking clove cigarettes. Severe poisoning is extremely rare.
    D) WITH THERAPEUTIC USE
    1) Contact dermatitis, direct tissue damage, and allergic reactions have occurred following therapeutic use of dental products containing eugenol.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Eugenol containing products can be irritating to the skin, lungs, conjunctiva, and gastrointestinal tract.
    2) SEVERE TOXICITY: Vomiting, metabolic acidosis, CNS depression, seizures, hepatotoxicity, hypoglycemia, and disseminated intravascular coagulation have been reported in children following clove oil ingestions. Clove cigarette smoking may cause nausea, vomiting, exacerbation of chronic bronchitis or asthma attacks, pneumonia, bronchitis, hemoptysis, respiratory failure, and acute lung injury. It is unclear how much of these effects are produced by eugenol and how much by other components of the cigarettes.

Vital Signs

    3.3.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Hypothermia was reported following exposure to a clove oil solution containing 81% eugenol.
    3.3.3) TEMPERATURE
    A) WITH POISONING/EXPOSURE
    1) CASE REPORT: HYPOTHERMIA: A 67-year-old man with a history of alcohol abuse and hypertension presented to the emergency department after using a clove oil solution containing 81% eugenol and alcohol to relieve a toothache (it is not clear if he ingested or applied the solution to his teeth or gums). Upon arrival he was hypothermic with a temperature of 34 degrees C (93.2 degrees F). Examination also showed a Glasgow Coma Scale score of 5 and hypertension. Arterial blood gas analysis showed metabolic acidosis. Laboratory results showed a blood alcohol concentration of 1.62%. He received supportive treatment after being intubated and transferred to the intensive care unit. He was fully awake and extubated within 10 hours. One day after admission he was discharged (Dyrbye et al, 2012).

Heent

    3.4.3) EYES
    A) ANESTHESIA: Permanent right infraorbital anesthesia and anhydrosis have been reported following the spillage of clove oil during application to the right upper second premolar (Isaacs, 1983).
    B) IRRITATION (ANIMAL STUDIES): Rabbit eye tests where 0.2 mL were instilled in eyes produced moderate irritation and redness in 30 minutes, severe fulminating inflammation in 8 hr, and only mild inflammation by 36 hr (Jurecko, 1974).
    3.4.6) THROAT
    A) BURNS: Mucous membrane burns may occur (Barkin et al, 1984).
    B) DENTAL PRODUCT EFFECTS: When used in dentistry, eugenol has shown 3 distinct types of toxicity (Barkin et al, 1984):
    1) Direct tissue damage
    2) Contact dermatitis
    3) Allergic reactions

Cardiovascular

    3.5.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) VASCULAR DISORDER
    a) Deaths in animals have been due to peripheral vascular collapse.
    2) OTHER
    a) In vitro studies of guinea-pig papillary muscle have demonstrated that eugenol inhibits calcium influx in a dose-dependent fashion (Sensch et al, 1993).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) ACUTE LUNG INJURY
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Pulmonary edema developed in a 32-year-old woman who injected IV an unknown amount of clove oil (Kirsch et al, 1990).
    b) CASE REPORT: Clove cigarette smoking was associated with high-altitude pulmonary edema in a 29-year-old woman. A burning occurred after smoking clove cigarettes. Five days later the patient spent 2 days at an altitude of 2440 to 3350 meters (8,000 to 11,000 feet), then pulmonary edema developed (Hackett et al, 1985).
    B) PLEURAL EFFUSION
    1) WITH POISONING/EXPOSURE
    a) Clove cigarette smoking has been associated with pleural effusion (Anon, 1991).
    C) RESPIRATORY FAILURE
    1) WITH POISONING/EXPOSURE
    a) Clove cigarette smoking has been associated with respiratory insufficiency (Anon, 1991).
    D) ACUTE RESPIRATORY INFECTIONS
    1) WITH POISONING/EXPOSURE
    a) Respiratory tract infections have been associated with clove cigarette smoking (Anon, 1991).
    E) HEMOPTYSIS
    1) WITH POISONING/EXPOSURE
    a) Clove cigarette smoking has been associated with hemoptysis and bronchospasm (Anon, 1991).
    F) DIFFICULTY SWALLOWING
    1) WITH POISONING/EXPOSURE
    a) Eugenol is a local anesthetic and may impair the swallowing reflex. This impaired reflex was blamed for a fatal case of aspiration pneumonitis (Guidotti & Laing, 1992).
    b) The local anesthetic effect of eugenol may contribute to deeper inhalation of clove cigarette smoke (Anon, 1991). Exposure to clove cigarette smoke was no more toxic than regular cigarette smoke after 14 days in rats (Clark, 1990).
    G) DYSPNEA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 34-year-old woman developed maculopapular erythema, a cough, and dyspnea approximately 1 month after using a mop spray containing several chemicals including eugenol while working for a cleaning company. The erythema occurred at areas exposed to the spray. Her respiratory and dermal symptoms worsened following successive exposures to the spray, but resolved within 2 hours following administration of antihistamines and bronchodilators. Patch testing with European standard series and fragrances was negative, and skin prick testing of various airborne allergens, latex, eugenol 2%, clove, and cinnamon, was only positive for Artemisia vulgaris pollen. However, a specific bronchial challenge with eugenol at a concentration of 1:1000 resulted in a 17% decrease in FEV1 with dyspnea and cough 8 hours later. Maculopapular erythema of the face, chest, back, and arms occurred 12 hours after challenge. Despite removal from her workplace and continuous therapy with antihistamines, bronchodilators, and inhaled corticosteroids, the patient experienced daily wheezing, dyspnea, cough, and skin lesions due to other environmental exposures (eg, perfumes, fresheners, cleaning products), with symptoms only controlled following the addition of deflazacort 6 mg every 48 hours (Lopez-Saez et al, 2015).
    3.6.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) PULMONARY EDEMA
    a) DOGS: Pulmonary edema developed in dogs following IV injection of high dose eugenol (Sticht & Smith, 1971).
    b) RATS: Lung congestion, interstitial hemorrhages, acute emphysema, and acute pulmonary edema developed in rats following intratracheal or IP administration (LaVoie et al, 1986) (Wright et al, 1995).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM DEFICIT
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 67-year-old man with a history of alcohol abuse and hypertension presented to the emergency department after using a clove oil solution containing 81% eugenol and alcohol to relieve a toothache (it is not clear if he ingested or applied the solution to his tooth or gums). At presentation his Glasgow Coma Scale score was 5. Examination showed that he was also hypertensive and hypothermic. Neurologic exam showed hyperreactive symmetrical reflexes and a positive Babinski response on the left foot. Arterial blood gas analysis revealed metabolic acidosis. Further analysis showed a blood alcohol concentration of 1.62%. He was intubated and admitted to the intensive care unit where he received supportive treatment. He was fully awake and extubated within 10 hours. He was discharged 1 day later (Dyrbye et al, 2012).
    b) CASE REPORT: CNS depression developed in a 7-month-old following ingestion of 1 teaspoon of clove oil; however, the child had been suffering from a GI disorder with diarrhea (contracted in Mexico) for several days prior to clove oil ingestion (Lane et al, 1991).
    B) ABSENCE OF SENSATION
    1) WITH POISONING/EXPOSURE
    a) Local analgesia may occur (Anon, 1988) (Anon, 1991).
    b) CASE REPORT: Permanent infraorbital anesthesia, occurred in a 24-year-old woman after spillage of clove oil used for a tooth ache (Isaacs, 1983).
    C) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Generalized seizures were reported in a 2-year-old boy after accidentally ingesting 5 to 10 mL of clove oil (Brown et al, 1992; Hartnoll et al, 1993).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) ATAXIA
    a) DOGS: Ataxia occurred in dogs given 5 grams of eugenol. Two of these animals (10 kg) died (Lauber & Hollander, 1950). Other tested animals developed lower limb paralysis, coma, and death after large doses (Sober et al, 1950).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) VOMITING
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 7-month-old vomited once after ingesting 1 teaspoon of clove oil. No evidence of burns or mucosal injury was found upon oropharyngeal examination and endoscopy (Lane et al, 1991).
    3.8.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) ANOREXIA
    a) RATS: Exposure of rats to 0.77 to 2.58 mg/L of air for 4 hours resulted in significant reduction (80%) in food consumption for 14 days after exposure (Clark, 1988).
    2) VOMITING
    a) DOGS: Vomiting occurred in dogs given 2.5 to 5 grams of eugenol by stomach tube (Lauber & Hollander, 1950).
    3) GASTROENTERITIS
    a) RATS and guinea pigs given 150 mg of eugenol orally showed desquamation of the epithelium of the stomach and punctiform hemorrhages in the pyloric and glandular areas (Hartiala et al, 1966).
    b) DOGS given a 5% W/V emulsion of eugenol developed degenerative and reparative changes in the gastric mucous barrier (Hollander & Goldfischer, 1949).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) ABNORMAL LIVER FUNCTION
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Hepatic encephalopathy occurred in a 2-year-old boy following ingestion of 5 to 10 mL of clove oil (70% to 90% eugenol) (Brown et al, 1992; Hartnoll et al, 1993).
    B) HEPATIC FAILURE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 3-month-old infant developed fulminant hepatic failure, coagulopathy, and hypoglycemia after ingesting approximately 8 mL of clove oil. Thirty-five hours after ingestion, the patient's AST was greater than 10,000 units/liter and, at 38 hours postingestion, her INR and ALT peaked at 3.86 and 8761 units/liter, respectively. Intravenous N-acetylcysteine therapy was initiated approximately 32 hours postingestion and continued until approximately 84 hours postingestion (after the patient's INR had decreased to less than 2.0). The patient recovered and was discharged home 5 days postingestion (Eisen et al, 2004).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) ALBUMINURIA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Elevated urine specific gravity, proteinuria, and ketonuria occurred in a 7-month-old following ingestion of 1 teaspoon of clove oil. The child had been suffering from a GI disorder with diarrhea (contracted in Mexico) for several days prior to the exposure (Lane et al, 1991).

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) ACIDOSIS
    1) WITH POISONING/EXPOSURE
    a) PEDIATRIC
    1) CASE REPORT: A large anion-gap metabolic acidosis occurred in a 7-month-old after ingesting 1 teaspoon of clove oil (Lane et al, 1991).
    2) CASE REPORT: Metabolic acidosis (pH 7.32, PO2 22.7 kPa, PCO2 3.5 kPa, and base excess -10.7) was reported in a 2-year-old boy who developed seizures after ingesting 10 mL of clove oil. Self-ventilation on 30% oxygen corrected the acidosis (Brown et al, 1992).
    b) ADULT
    1) CASE REPORT: A 67-year-old man with a history of alcohol abuse and hypertension presented to the emergency department with a Glasgow Coma Scale score of 5 after using a clove oil solution containing 81% eugenol and alcohol to relieve a toothache (it is not clear if he ingested or applied the solution to his teeth or gums). Arterial blood gas analysis showed metabolic acidosis (pH 7.24; CO2 41.25 mmHg; HCO3 17.2 mmol/L). Laboratory results showed a blood alcohol concentration of 1.62%. He received supportive treatment after being intubated and transferred to the intensive care unit. He was fully awake and extubated within 10 hours. One day after admission he was discharged (Dyrbye et al, 2012).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) DISSEMINATED INTRAVASCULAR COAGULATION
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Disseminated intravascular coagulopathy was reported in a 2-year-old boy who ingested 5 to 10 mL of clove oil (70% to 90% eugenol) (Brown et al, 1992; Hartnoll et al, 1993).
    1) CASE REPORT: A 3-month-old infant developed fulminant hepatic failure, coagulopathy, and hypoglycemia after ingesting approximately 8 mL of clove oil. Thirty-eight hours after ingesting the clove oil, the patient's INR peaked at 3.86. Intravenous N-acetylcysteine therapy was initiated approximately 32 hours postingestion and continued until approximately 84 hours postingestion (after the patient's INR had decreased to less than 2.0). The patient recovered and was discharged home 5 days postingestion (Eisen et al, 2004).
    B) PLATELET ADHESION
    1) WITH POISONING/EXPOSURE
    a) IN-VITRO STUDIES
    1) Acetyl eugenol inhibits chemically-induced aggregation of isolated human platelets (Srivastava & Malhotra, 1991).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) CHEMICAL BURN
    1) WITH THERAPEUTIC USE
    a) A chemical burn due to eugenol has been reported (Isaacs, 1983).
    B) SKIN IRRITATION
    1) WITH THERAPEUTIC USE
    a) Transient, mild inflammation and erythema have been reported following application. These effects usually dissipate within a few hours.
    b) Eugenol was cytotoxic in experiments involving application to labial mucosa (Barkin et al, 1984; Lindquist & Otteskog, 1981).
    C) CONTACT DERMATITIS
    1) WITH THERAPEUTIC USE
    a) Contact dermatitis and allergic reactions can occur, particularly with repeated exposure. Contact mucositis can occur from eugenol-containing mouth washes and other dental products (Kozam & Mantell, 1978; Audicana et al, 1991; Vilaplana et al, 1991; Kanerva et al, 1998).
    1) These reactions are generally not serious, resulting only in erythema and pain in those tissues contacting the eugenol (Barkin et al, 1984).
    b) Tests have shown that eugenol is inflammatory, and the commercial eugenol which has impurities is even more inflammatory (Webb & Bussell, 1981).
    c) CASE REPORT: A 34-year-old woman developed maculopapular erythema, a cough, and dyspnea approximately 1 month after using a mop spray containing several chemicals including eugenol while working for a cleaning company. The erythema occurred at areas exposed to the spray. Her respiratory and dermal symptoms worsened following successive exposures to the spray, but resolved within 2 hours following administration of antihistamines and bronchodilators. Patch testing with European standard series and fragrances was negative, and skin prick testing of various airborne allergens, latex, eugenol 2%, clove, and cinnamon, was only positive for Artemisia vulgaris pollen. However, a specific bronchial challenge with eugenol at a concentration of 1:1000 resulted in a 17% decrease in FEV1 with dyspnea and cough 8 hours later. Maculopapular erythema of the face, chest, back, and arms occurred 12 hours post-challenge. Despite removal from her workplace and continuous therapy with antihistamines, bronchodilators, and inhaled corticosteroids, the patient experienced daily wheezing, dyspnea, cough, and skin lesions due to other environmental exposures (eg, perfumes, fresheners, cleaning products), with symptoms only controlled following the addition of deflazacort 6 mg every 48 hours (Lopez-Saez et al, 2015).
    D) ERYTHEMA MULTIFORME
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 47-year-old man developed erythema and pruritus on his shoulders, arms and back approximately 10 days after receiving a massage using an oil containing laurel oil. He had been referred to a dermatology clinic after an increase in lesions and a lack of response to a topical lotion containing methylprednisolone and systemic antihistamines. A punch skin biopsy was performed. Based on his physical exam, including urticarial plaques, atypical targetoid papules with desquamation, and histopathology findings, the patient was diagnosed with erythema multiforme-like allergic contact dermatitis. A course of systemic corticosteroids was begun with gradual resolution of symptoms (Uzuncakmak et al, 2015).
    E) URTICARIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Chronic disseminated urticaria was reported in a 22-year-old woman after use of a dental cement containing eugenol (Grade & Martens, 1989).
    F) ANHIDROSIS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Infraorbital anhidrosis and permanent local anesthesia at the site of contact was reported in a 24-year-old woman who had spilled oil of clove (Isaacs, 1983).
    G) PHOTOSENSITIVITY
    1) WITH POISONING/EXPOSURE
    a) Photodermatitis was reported in a patient following 2 episodes of exposure to eugenol-containing products. Patch testing of a fragrance mix containing isoeugenol was positive, but photopatch testing of nutmeg oil, containing eugenol and isoeugenol, was negative (Fernandez de Corres et al, 1996).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ANAPHYLACTOID REACTION
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Anaphylaxis occurred in a patient after a pulp cap with eugenol (McCarter, 1966).
    B) ULCERATIVE STOMATITIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A patient who had a eugenol temporary restoration experienced irritation and erythema within 24 hours.
    1) By the third day there was complete sloughing of oral mucosa, bilateral loss of papillae on the tongue and ulceration of the vermilion border. Facial swelling occurred.
    2) The patient was given 100 mg of Solumedrol(R) and 50 mg of IM diphenhydramine. The patient was continued on oral prednisone 10 mg. The oral mucosa improved over 2 weeks and it took 2 to 3 months for the tongue papillae to heal (Barkin et al, 1984).
    b) Similar, but less serious reactions have been reported by others (Mitchell, 1982).

Reproductive

    3.20.1) SUMMARY
    A) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the teratogenic potential of this agent.

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) Limited evidence, from animal models, suggests that eugenol may possess carcinogenic potential.
    3.21.3) HUMAN STUDIES
    A) CARCINOMA
    1) Limited evidence, from animal studies, suggests that eugenol may possess carcinogenic potential (Guidotti et al, 1989).

Genotoxicity

    A) MICRONUCLEI INDUCTION - Increased micronuclei were determined in polychromatic erythrocytes of mice following 400 or 600 mg/kg eugenol (57 to 87% of the LD50), IP. These doses greatly exceed the doses which are typically expected in human exposures (Ellahuene et al, 1994).
    B) ABSENCE OF MUTAGENICITY - Ames tests using S. typhimurium strains TA 98 and TA 100 were negative for eugenol-containing root canal sealers (Stea et al, 1994).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor pulse oximetry and/or arterial blood gases, chest radiograph, and pulmonary function tests in patients with respiratory signs/symptoms.
    B) In severe poisoning cases, monitor electrolytes, renal and hepatic function tests, serum glucose, complete blood count and coagulation studies as indicated.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with significant symptoms should be admitted for treatment and monitoring. Patients with respiratory failure should be admitted to an ICU setting.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Contact a regional poison center or medical toxicologist for any patient with severe toxicity. In case of concentrated eugenol ingestion, consult a gastroenterologist or surgeon for endoscopy to assess severity of mucosal injury. For patients with eye exposure, consult an ophthalmologist for assistance of ophthalmic examination if needed.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Mildly symptomatic patients or asymptomatic patients with large exposures should be observed for 6 hours for signs of toxicity.

Monitoring

    A) Monitor pulse oximetry and/or arterial blood gases, chest radiograph, and pulmonary function tests in patients with respiratory signs/symptoms.
    B) In severe poisoning cases, monitor electrolytes, renal and hepatic function tests, serum glucose, complete blood count and coagulation studies as indicated.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Due to the irritant nature of this substance and theoretical risk of aspiration pneumonitis, prehospital gastrointestinal decontamination is not advised.
    6.5.2) PREVENTION OF ABSORPTION
    A) Due to the irritant nature of this substance, relatively benign clinical course in most cases involving systemic absorption, risk of aspiration, and the role of GI endoscopy in concentrated eugenol ingestions, activated charcoal is not routinely recommended.
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive. In patients with significant ingestions of concentrated eugenol, endoscopy should be performed 12 to 24 hours post-ingestion to assess severity. Monitor the patient for respiratory distress. If a cough or breathing difficulty develops, evaluate for respiratory tract irritation, bronchitis, and pneumonitis.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. Treat severe metabolic acidosis (pH less than 7.1) with sodium bicarbonate 1 to 2 mEq/kg. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur.
    B) MONITORING OF PATIENT
    1) Monitor pulse oximetry and/or arterial blood gases, chest radiograph, and pulmonary function tests in patients with respiratory signs/symptoms.
    2) In severe poisoning cases, monitor electrolytes, renal and hepatic function tests, serum glucose, complete blood count and coagulation studies as indicated.
    C) ENDOSCOPIC PROCEDURE
    1) Endoscopy should be performed 12 to 24 hours postingestion of concentrated eugenol, to assess severity. The esophagoscope should not be passed beyond the circumferential first burn to avoid risk of perforation.
    D) ACIDOSIS
    1) METABOLIC ACIDOSIS: Treat severe metabolic acidosis (pH less than 7.1) with sodium bicarbonate, 1 to 2 mEq/kg is a reasonable starting dose(Kraut & Madias, 2010). Monitor serum electrolytes and arterial or venous blood gases to guide further therapy.
    E) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    F) ACUTE LUNG INJURY
    1) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
    2) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).
    a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)
    3) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
    4) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
    5) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
    6) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
    7) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).
    G) HYPERSENSITIVITY REACTION
    1) SUMMARY
    a) Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta adrenergic agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.
    2) BRONCHOSPASM
    a) ALBUTEROL
    1) ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007). CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 mg/kg (up to 10 mg) every 1 to 4 hours as needed, or 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    3) CORTICOSTEROIDS
    a) Consider systemic corticosteroids in patients with significant bronchospasm.
    b) PREDNISONE: ADULT: 40 to 80 milligrams/day. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 to 2 divided doses divided twice daily (National Heart,Lung,and Blood Institute, 2007).
    4) MILD CASES
    a) DIPHENHYDRAMINE
    1) SUMMARY: Oral diphenhydramine, as well as other H1 antihistamines can be used as indicated (Lieberman et al, 2010).
    2) ADULT: 50 milligrams orally, or 10 to 50 mg intravenously at a rate not to exceed 25 mg/min or may be given by deep intramuscular injection. A total of 100 mg may be administered if needed. Maximum daily dosage is 400 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    3) CHILD: 5 mg/kg/24 hours or 150 mg/m(2)/24 hours. Divided into 4 doses, administered intravenously at a rate not exceeding 25 mg/min or by deep intramuscular injection. Maximum daily dosage is 300 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    5) MODERATE CASES
    a) EPINEPHRINE: INJECTABLE SOLUTION: It should be administered early in patients by IM injection. Using a 1:1000 (1 mg/mL) solution of epinephrine. Initial Dose: 0.01 mg/kg intramuscularly with a maximum dose of 0.5 mg in adults and 0.3 mg in children. The dose may be repeated every 5 to 15 minutes, if no clinical improvement. Most patients respond to 1 or 2 doses (Nowak & Macias, 2014).
    6) SEVERE CASES
    a) EPINEPHRINE
    1) INTRAVENOUS BOLUS: ADULT: 1 mg intravenously as a 1:10,000 (0.1 mg/mL) solution; CHILD: 0.01 mL/kg intravenously to a maximum single dose of 1 mg given as a 1:10,000 (0.1 mg/mL) solution. It can be repeated every 3 to 5 minutes as needed. The dose can also be given by the intraosseous route if IV access cannot be established (Lieberman et al, 2015). ALTERNATIVE ROUTE: ENDOTRACHEAL ADMINISTRATION: If IV/IO access is unavailable. DOSE: ADULT: Administer 2 to 2.5 mg of 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube. CHILD: DOSE: 0.1 mg/kg to a maximum of 2.5 mg administered as a 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube (Lieberman et al, 2015).
    2) INTRAVENOUS INFUSION: Intravenous administration may be considered in patients poorly responsive to IM or SubQ epinephrine. An epinephrine infusion may be prepared by adding 1 mg (1 mL of 1:1000 (1 mg/mL) solution) to 250 mL D5W, yielding a concentration of 4 mcg/mL, and infuse this solution IV at a rate of 1 mcg/min to 10 mcg/min (maximum rate). CHILD: A dosage of 0.01 mg/kg (0.1 mL/kg of a 1:10,000 (0.1 mg/mL) solution up to 10 mcg/min (maximum dose 0.3 mg) is recommended for children (Lieberman et al, 2010). Careful titration of a continuous infusion of IV epinephrine, based on the severity of the reaction, along with a crystalloid infusion can be considered in the treatment of anaphylactic shock. It appears to be a reasonable alternative to IV boluses, if the patient is not in cardiac arrest (Vanden Hoek,TL,et al).
    7) AIRWAY MANAGEMENT
    a) OXYGEN: 5 to 10 liters/minute via high flow mask.
    b) INTUBATION: Perform early if any stridor or signs of airway obstruction.
    c) CRICOTHYROTOMY: Use if unable to intubate with complete airway obstruction (Vanden Hoek,TL,et al).
    d) BRONCHODILATORS are recommended for mild to severe bronchospasm.
    e) ALBUTEROL: ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007).
    f) ALBUTEROL: CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    8) MONITORING
    a) CARDIAC MONITOR: All complicated cases.
    b) IV ACCESS: Routine in all complicated cases.
    9) HYPOTENSION
    a) If hypotensive give 500 to 2000 milliliters crystalloid initially (20 milliliters/kilogram in children) and titrate to desired effect (stabilization of vital signs, mentation, urine output); adults may require up to 6 to 10 L/24 hours. Central venous or pulmonary artery pressure monitoring is recommended in patients with persistent hypotension.
    1) VASOPRESSORS: Should be used in refractory cases unresponsive to repeated doses of epinephrine and after vigorous intravenous crystalloid rehydration (Lieberman et al, 2010).
    2) DOPAMINE: Initial Dose: 2 to 20 micrograms/kilogram/minute intravenously; titrate to maintain systolic blood pressure greater than 90 mm Hg (Lieberman et al, 2010).
    10) H1 and H2 ANTIHISTAMINES
    a) SUMMARY: Antihistamines are second-line therapy and are used as supportive therapy and should not be used in place of epinephrine (Lieberman et al, 2010).
    1) DIPHENHYDRAMINE: ADULT: 25 to 50 milligrams via a slow intravenous infusion or IM. PEDIATRIC: 1 milligram/kilogram via slow intravenous infusion or IM up to 50 mg in children (Lieberman et al, 2010).
    b) RANITIDINE: ADULT: 1 mg/kg parenterally; CHILD: 12.5 to 50 mg parenterally. If the intravenous route is used, ranitidine should be infused over 10 to 15 minutes or diluted in 5% dextrose to a volume of 20 mL and injected over 5 minutes (Lieberman et al, 2010).
    c) Oral diphenhydramine, as well as other H1 antihistamines, can also be used as indicated (Lieberman et al, 2010).
    11) DYSRHYTHMIAS
    a) Dysrhythmias and cardiac dysfunction may occur primarily or iatrogenically as a result of pharmacologic treatment (epinephrine) (Vanden Hoek,TL,et al). Monitor and correct serum electrolytes, oxygenation and tissue perfusion. Treat with antiarrhythmic agents as indicated.
    12) OTHER THERAPIES
    a) There have been a few reports of patients with anaphylaxis, with or without cardiac arrest, that have responded to vasopressin therapy that did not respond to standard therapy. Although there are no randomized controlled trials, other alternative vasoactive therapies (ie, vasopressin, norepinephrine, methoxamine, and metaraminol) may be considered in patients in cardiac arrest secondary to anaphylaxis that do not respond to epinephrine (Vanden Hoek,TL,et al).
    H) EXPERIMENTAL THERAPY
    1) N-ACETYLCYSTEINE/CASE REPORT: A 3-month-old infant developed fulminant hepatic failure, coagulopathy, and hypoglycemia after ingesting approximately 8 mL of clove oil. Thirty-five hours after ingestion, the patient's AST was greater than 10,000 units/liter and, at 38 hours post-ingestion, her INR and ALT peaked at 3.86 and 8761 units/liter, respectively. Intravenous N-acetylcysteine therapy was initiated approximately 32 hours post-ingestion and continued until approximately 84 hours post-ingestion (after the patient's INR had decreased to less than 2.0). The patient recovered and was discharged home 5 days post-ingestion (Eisen et al, 2004). The intravenous N-acetylcysteine dosing regimen initiated was the standard 20-hour protocol typically used for acetaminophen poisoning. Please refer to the ACETAMINOPHEN-ACUTE management for further information.
    a) Animal studies indicate that eugenol in rat hepatocytes causes depletion of hepatic glutathione and conjugation of eugenol with glutathione, sulphate, and glucuronic acid, resulting in hepatotoxicity similar to that of acetaminophen-induced hepatotoxicity (Eisen et al, 2004).

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DERMAL DECONTAMINATION
    1) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Enhanced Elimination

    A) ENHANCED ELIMINATION PROCEDURE
    1) It is unknown if hemodialysis, hemoperfusion and plasmapheresis are likely to be useful following an oral exposure.

Range Of Toxicity

Summary

    A) TOXICITY: A specific toxic dose has not been established. CHILD: A 2-year-old child developed metabolic acidosis, hypoglycemia, disseminated intravascular coagulation, hepatotoxicity, and generalized seizures after ingesting 5 to 10 mL of clove oil, containing 70% to 90% eugenol. INFANT: Metabolic acidosis, elevated urine specific gravity, proteinuria, and ketonuria were noted in a 7-month-old after ingestion of 1 teaspoon of clove oil (500 mg/kg of eugenol).

Maximum Tolerated Exposure

    A) INFANT
    1) Metabolic acidosis, elevated urine specific gravity, proteinuria, and ketonuria were noted in a 7-month-old after ingestion of 1 teaspoon of clove oil (500 mg/kg of eugenol).
    a) No evidence of mucosal injury was noted after oropharyngeal examination and endoscopy.
    b) Chest x-ray revealed evidence of aspiration; however, the child vomited once and was lavaged.
    c) All effects resolved in 48 hours (Lane et al, 1991).
    B) CHILD
    1) A 2-year-old child developed metabolic acidosis, hypoglycemia, disseminated intravascular coagulation, hepatotoxicity, and generalized seizures after ingesting 5 to 10 mL of clove oil, containing 70% to 90% eugenol (Hartnoll et al, 1993; Brown et al, 1992).
    C) DERMAL
    1) An 8% ointment applied to 25 humans for 48 hours was mildly irritating in all subjects (Opdyke, 1975a). A 20% clove oil preparation was irritating and produced erythema in 2 of 25 subjects (Opdyke, 1975b).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (ORAL)MOUSE:
    1) 3000 mg/kg (Hagen et al, 1965)
    B) LD50- (INTRATRACHEAL)RAT:
    1) 11 mg/kg (Hagen et al, 1965)
    C) LD50- (ORAL)RAT:
    1) 2680 mg/kg (Hagen et al, 1965)
    2) 1930 mg/kg (Sober et al, 1950)

Pharmacology Toxicology

Toxicologic Mechanism

    A) Eugenol is a phenolic compound with the ability to quickly and effectively penetrate nerve bundles to serve as an anodyne (Gurney, 1965).
    1) Studies using 100% eugenol on rabbit labial mucosa show denaturation of cytoplasmic proteins, loss of cell boundaries, cell necrosis, edema, and striated muscle dissolution (Kozam & Mantell, 1978).
    2) Another study showed eugenol in concentrations of 0.05 to 100% extinguished the impulse transmission capability of nerves within three hours (Kozam, 1977).
    3) It has been suggested that eugenol anesthetizes the back of clove-cigarette smoker's throats and trachea, permitting deeper inhalation. Eugenol may produce irritation through hypersensitivity or direct irritant effects.
    B) Eugenol inhibited mitochondrial respiration dose dependently in vitro and uncoupled oxidative phosphorylation causing cell injury (Cotmore et al, 1979).
    C) Eugenol inhibits prostaglandin synthesis in animals studied (Bennett et al, 1988).
    D) Eugenol and isoeugenol exhibit antibacterial and antifungal activity (Kurita et al, 1981; Boonchird & Flegel, 1982; Thomas et al, 1980).
    E) Eugenol inhibits platelet aggregation, with about the same effectiveness of indomethacin (Laekeman et al, 1990).

Physicochemical

Physical Characteristics

    A) Eugenol has an odor of clove.

Molecular Weight

    A) 164.2

Animal Toxicology

Clinical Effects

    11.1.3) CANINE/DOG
    A) PULMONARY EDEMA was seen in dogs given injections of large doses (Sticht & Smith, 1971).
    B) ATAXIA was seen in dogs given 5 g of eugenol. Two of the animals died (Lauber & Hollander, 1950).
    C) GASTROENTERITIS - Dogs given a 5% W/V emulsion developed degenerative and reparative changes of the gastric mucous barrier (Hollonder & Goldfischer, 1949). Vomiting has been reported with 2.5 to 5 mL (given via a stomach tube) (Lauber & Hollander, 1950).

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