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THIOFANOX

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

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    A) FORMS
    1) Thiofanox is a carbamate compound. It is a colorless solid with a pungent odor, which is soluble in aromatic and chlorinated hydrocarbon solvents and sparingly soluble in water and aliphatic hydrocarbons (HSDB , 1993).
    B) SOURCES
    1) Thiofanox and other carbamate pesticides are cholinesterase inhibitors. Unlike the organophosphates, the carbamates cause reversible acetylcholinesterase inhibition. Their effects are generally similar to those of the organophosphates, but are not as severe and resolve more quickly (Morgan, 1989).
    2) Thiofanox is a HIGHLY TOXIC substance.
    3) Little information was found on the effects of thiofanox itself. This review is based on the properties of carbamates in general. Effects attributed specifically to thiofanox are noted.
    C) USES
    1) Thiofanox is used as a systemic insecticide and acaricide (EPA, 1985).

Therapeutic Toxic Class

    A) Thiofanox is a carbamate compound.

Specific Substances

    A) No Synonyms were found in group or single elements
    1.2.1) MOLECULAR FORMULA
    1) C9-H18-N2-O2-S

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: Thiofanox is a carbamate compound. It is used as a systemic insecticide and acaricide. Thiofanox is not registered for use in the US.
    B) TOXICOLOGY: Thiofanox, like other carbamate pesticides, is a cholinesterase inhibitor. Unlike organophosphates, carbamates cause reversible inhibition of acetylcholinesterase; their effects are similar to those of the organophosphates, but are not as severe and disappear more quickly.
    C) EPIDEMIOLOGY: Exposure to carbamate insecticides is common, but serious toxicity is unusual in the US. Common source of severe poisoning in developing countries. Toxicity is generally less severe than with organophosphates.
    D) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE POISONING: MUSCARINIC EFFECTS: Can include bradycardia, salivation, lacrimation, diaphoresis, vomiting, diarrhea, urination, and miosis. NICOTINIC EFFECTS: Tachycardia, hypertension, mydriasis, and muscle cramps may develop.
    2) SEVERE POISONING: MUSCARINIC EFFECTS: Bronchorrhea, bronchospasm, and acute lung injury. NICOTINIC EFFECTS: Muscle fasciculations, weakness, and respiratory failure. CENTRAL EFFECTS: CNS depression, agitation, confusion, delirium, coma, and seizures. Hypotension, ventricular dysrhythmias, metabolic acidosis, pancreatitis, and hyperglycemia can also develop.
    3) CHILDREN: May have different predominant signs and symptoms than adults (more likely CNS depression, stupor, coma, flaccidity, dyspnea, and seizures). Children may also have fewer muscarinic and nicotinic signs of intoxication (ie, secretions, bradycardia, fasciculations, and miosis) as compared with adults.
    4) INHALATION EXPOSURE: Vapors rapidly produce mucous membrane and upper airway irritation and bronchospasm, followed by systemic muscarinic, nicotinic, and central effects if exposed to significant concentrations.
    0.2.4) HEENT
    A) Pinpoint pupils may be seen.
    0.2.5) CARDIOVASCULAR
    A) Bradycardia or tachycardia may occur.
    B) Electrocardiographic (T-wave) changes have been reported in exposed workers.
    0.2.6) RESPIRATORY
    A) Dyspnea, rales, and pulmonary edema may occur.
    B) Aspiration pneumonitis from hydrocarbon vehicles may occur.
    C) Laryngeal irritation and associated cough is common following inhalation of carbamate dusting powders.
    0.2.7) NEUROLOGIC
    A) Blurred vision, miosis, tremor, muscle twitching, convulsions, mental confusion, and coma may occur.
    B) Delayed peripheral neuropathy similar to that seen with organophosphates has been described in one case.
    C) Dystonic reaction may occur following parenteral injection.
    0.2.8) GASTROINTESTINAL
    A) Nausea, vomiting, diarrhea, and abdominal cramping may be noted.
    B) Acute pancreatitis has been reported following carbamate intoxication.
    0.2.13) HEMATOLOGIC
    A) Reversible inhibition of cholinesterases is the hallmark of carbamate poisoning.
    B) Disseminated intravascular coagulation has been reported.
    0.2.18) PSYCHIATRIC
    A) Memory loss, agitation, altered cognitive functions, and lowered verbal intelligence have occurred.
    0.2.20) REPRODUCTIVE
    A) At the time of this review, no data were available to assess the teratogenic human potential of this agent.
    B) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.
    C) ANIMAL STUDIES - CARBARYL a related compound, has been embryotoxic, fetotoxic, and teratogenic, and has affected both male and female fertility in laboratory animals.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, no data were available to assess the carcinogenic potential of this agent.

Laboratory Monitoring

    A) Monitor vital signs frequently. Obtain serial ECGs and institute continuous cardiac and pulse oximetry monitoring.
    B) Monitor for respiratory distress (ie, bronchorrhea, bronchospasm) and for clinical evidence of cholinergic excess (ie, salivation, vomiting, urination, defecation, miosis).
    C) Determine plasma and/or red blood cell cholinesterase activities (plasma is generally more sensitive, but red cell correlates somewhat better with clinical signs and symptoms). Depression in excess of 50% of baseline is generally associated with cholinergic effects; in severe poisoning, cholinesterase activity may be depressed by 90% of baseline. Correlation between cholinesterase levels and clinical effects in milder poisonings may be poor.
    D) Monitor electrolytes and serum lipase in patients with significant poisoning.
    E) Monitor pulmonary function (ie, forced vital capacity, expiratory volume in 1 second, negative inspiratory force) in symptomatic patients; may help anticipate need for intubation.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TOXICITY
    1) A patient who is either asymptomatic or presents with mild clinical symptoms (i.e. normal vitals, pulse oximetry and an acetylcholinesterase greater than 80% of lower reference range), and remains stable for 12 hours can be discharged. Obtain appropriate psychiatric evaluation if an intentional exposure.
    B) MANAGEMENT OF MODERATE TO SEVERE TOXICITY
    1) Immediate assessment and evaluation. Airway management is likely to be necessary. Simple decontamination (i.e. skin and gastrointestinal, removal of contaminated clothes). Administer antidotes: atropine for muscarinic manifestations (e.g. salivation, diarrhea, bronchorrhea), pralidoxime for severe toxicity with nicotinic manifestations (e.g. weakness, fasciculations). Treat seizures with benzodiazepines. Admit to intensive care with continuous monitoring, titration of antidotes, ventilation, and inotropes as needed. Consult a medical toxicologist and/or poison center.
    C) DECONTAMINATION
    1) PREHOSPITAL: INGESTION: Activated charcoal is contraindicated because of possible respiratory depression and seizures and risk of aspiration. DERMAL: Remove contaminated clothing, wash skin with soap and water. Universal precautions and nitrile gloves to protect personnel.
    2) HOSPITAL: INGESTION: Activated charcoal for large ingestions. Consider nasogastric tube for aspiration of gastric contents, or gastric lavage for recent large ingestions, if patient is intubated or able to protect airway. DERMAL: Remove contaminated clothing. Wash skin thoroughly with soap and water. Universal precautions and nitrile gloves to protect staff from contamination. Systemic toxicity can result from dermal exposure. OCULAR: Copious eye irrigation.
    D) AIRWAY MANAGEMENT
    1) Immediately assess airway and respiratory function. Endotracheal intubation may be necessary because of respiratory muscle weakness or bronchorrhea. Avoid succinylcholine for rapid sequence intubation as prolonged paralysis may result. Monitoring pulmonary function (FVC, FEV1, NIF) may help anticipate need for intubation.
    E) ANTIDOTES
    1) There are two primary classes of antidotes: ATROPINE is used to antagonize muscarinic effects. OXIMES (pralidoxime in the US, or obidoxime in some other countries) are used to reverse neuromuscular blockade. Use of oximes is usually indicated for patients with severe toxicity and are used in conjunction with atropine.
    a) ATROPINE
    1) Atropine is used to treat muscarinic effects (e.g. salivation, lacrimation, defecation, urination, bronchorrhea). ADULT: 1 to 3 mg IV; CHILD: 0.02 mg/kg IV. If inadequate response in 3 to 5 minutes, double the dose. Continue doubling the dose and administer it IV every 3 to 5 minutes as needed to dry pulmonary secretions. Once secretions are dried, maintain with an infusion of 10% to 20% of the loading dose every hour. Monitor frequently for evidence of cholinergic effects or atropine toxicity (e.g. delirium, hyperthermia, ileus) and titrate dose accordingly. Large doses (hundreds of milligrams) are sometimes required. Atropinization may be required for hours to days depending on severity.
    b) PRALIDOXIME
    1) Treat moderate to severe poisoning (fasciculations, muscle weakness, respiratory depression, coma, seizures) with pralidoxime in addition to atropine; most effective if given within 48 hours. Administer for 24 hours after cholinergic manifestations have resolved. May require prolonged administration. ADULT DOSE: A loading dose of 30 mg/kg (maximum: 2 grams) over 30 minutes followed by a maintenance infusion of 8 to 10 mg/kg/hr (up to 650 mg/hr). ALTERNATE ADULT DOSE: 1 to 2 grams diluted in 100 mL of 0.9% sodium chloride infused over 15 to 30 minutes. Repeat initial bolus dose in 1 hour and then every 3 to 8 hours if muscle weakness or fasciculations persist (continuous infusion preferred). In patients with serious cholinergic intoxication, a continuous infusion of 500 mg/hr should be considered. Intravenous dosing is preferred; however, intramuscular administration may be considered. A continuous infusion of pralidoxime is generally preferred to intermittent bolus dosing to maintain a target concentration with less variation. CHILD DOSE: A loading dose of 20 to 40 mg/kg (maximum: 2 grams/dose) infused over 30 to 60 minutes in 0.9% sodium chloride. Repeat initial bolus dose in 1 hour and then every 3 to 8 hours if muscle weakness or fasciculations persist (continuous infusion preferred). ALTERNATE CHILD DOSE: 25 to 50 mg/kg (up to a maximum dose of 2 g), followed via continuous infusion of 10 to 20 mg/kg/hr. In patients with serious cholinergic intoxication, a continuous infusion of 10 to 20 mg/kg/hr up to 500 mg/hr should be considered.
    F) SEIZURES
    1) IV benzodiazepines are indicated for seizures or agitation, diazepam 5 to 10 mg IV, lorazepam 2 to 4 mg IV; repeat as needed.
    G) HYPOTENSIVE EPISODE
    1) IV fluids, dopamine, norepinephrine.
    H) BRONCHOSPASM
    1) Inhaled ipratropium or glycopyrrolate may be useful in addition to intravenous atropine.
    I) PATIENT DISPOSITION
    1) HOME CRITERIA: Patients with unintentional trivial exposures who are asymptomatic can be observed in the home or in the workplace.
    2) OBSERVATION CRITERIA: Patients with deliberate or significant exposure and those who are symptomatic should be sent to a health care facility for evaluation, treatment and observation for 6 to 12 hours. Onset of toxicity is variable; most patients will develop symptoms within 6 hours. Patients that remain asymptomatic 12 hours after an ingestion or a dermal exposure are unlikely to develop severe toxicity. Cholinesterase activity should be determined to confirm the degree of exposure.
    3) ADMISSION CRITERIA: All intentional ingestions should be initially managed as a severe exposure. Determine cholinesterase activity to assess if a significant exposure occurred. Patients who develop signs or symptoms of cholinergic toxicity (e.g. muscarinic, nicotinic OR central) should be admitted to an intensive care setting.
    4) CONSULT CRITERIA: Consult a medical toxicologist and/or poison center for assistance with any patient with moderate to severe cholinergic manifestations.
    J) PITFALLS
    1) Inadequate initial atropinization. Patients with severe toxicity require rapid administration of large doses, titrate to the endpoint or drying pulmonary secretions.
    2) Monitor respiratory function closely, pulmonary function testing may provide early clues to the development of respiratory failure.
    3) Some component of dermal exposure occurs with most significant overdoses, inadequate decontamination may worsen toxicity.
    4) Patients should be monitored closely for 48 hours after discontinuation of atropine and pralidoxime for evidence of recurrent toxicity or intermediate syndrome.
    K) TOXICOKINETICS
    1) Well absorbed across the lung, mucous membranes (including gut), and skin; significant toxicity has been reported after all these routes of exposure.
    2) Most patients who develop severe toxicity have signs and symptoms within 6 hours of exposure, onset of toxicity is rarely more than 12 hours after exposure.
    3) Recurrence of toxicity after apparent improvement has been described.
    L) PREDISPOSING CONDITIONS
    1) Patients with chronic occupational exposure to carbamate insecticides may have chronically depressed cholinesterase activity and may develop severe toxicity after smaller acute exposures.
    2) Dermal absorption is enhanced in young children due to larger surface area to volume ratio and more permeable skin.
    M) DIFFERENTIAL DIAGNOSIS
    1) Gastroenteritis, food poisoning, asthma, myasthenic crisis, cholinergic excess from medications.
    0.4.3) INHALATION EXPOSURE
    A) Remove from exposure and administer oxygen if respiratory distress develops.
    B) Inhaled ipratropium or glycopyrrolate may be useful in addition to intravenous atropine for bronchorrhea and bronchospasm. Inhaled beta agonists may be useful for bronchospasm unresponsive to anticholinergics.
    C) Monitor for the development of cholinergic toxicity and treat as in oral exposure.
    0.4.4) EYE EXPOSURE
    A) Irrigate exposed eyes with water or normal saline. Systemic toxicity is unlikely to develop from ocular exposure alone.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) Systemic effects can occur from dermal exposure to carbamate insecticides. Remove contaminated clothing, wash skin thoroughly with soap and water. Use universal precautions and nitrile gloves to protect staff from contamination.
    2) Monitor for the development of cholinergic toxicity and treat as in oral exposure.
    0.4.6) PARENTERAL EXPOSURE
    A) Monitor for the development of compartment syndrome, tissue necrosis, cellulitis, and thrombophlebitis in addition to systemic cholinergic toxicity (which may be prolonged) after subcutaneous, intramuscular or intravenous injection.

Range Of Toxicity

    A) TOXICITY: The World Health Organization (WHO) has classified thiofanox, technical grade, as pesticide class IB (highly hazardous). Acute toxicity depends strongly on kinetics of absorption (ie, sudden absorption of low toxicity compound may have a greater effect than gradual absorption of a higher toxicity compound).

Clinical Effects

Summary Of Exposure

    A) USES: Thiofanox is a carbamate compound. It is used as a systemic insecticide and acaricide. Thiofanox is not registered for use in the US.
    B) TOXICOLOGY: Thiofanox, like other carbamate pesticides, is a cholinesterase inhibitor. Unlike organophosphates, carbamates cause reversible inhibition of acetylcholinesterase; their effects are similar to those of the organophosphates, but are not as severe and disappear more quickly.
    C) EPIDEMIOLOGY: Exposure to carbamate insecticides is common, but serious toxicity is unusual in the US. Common source of severe poisoning in developing countries. Toxicity is generally less severe than with organophosphates.
    D) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE POISONING: MUSCARINIC EFFECTS: Can include bradycardia, salivation, lacrimation, diaphoresis, vomiting, diarrhea, urination, and miosis. NICOTINIC EFFECTS: Tachycardia, hypertension, mydriasis, and muscle cramps may develop.
    2) SEVERE POISONING: MUSCARINIC EFFECTS: Bronchorrhea, bronchospasm, and acute lung injury. NICOTINIC EFFECTS: Muscle fasciculations, weakness, and respiratory failure. CENTRAL EFFECTS: CNS depression, agitation, confusion, delirium, coma, and seizures. Hypotension, ventricular dysrhythmias, metabolic acidosis, pancreatitis, and hyperglycemia can also develop.
    3) CHILDREN: May have different predominant signs and symptoms than adults (more likely CNS depression, stupor, coma, flaccidity, dyspnea, and seizures). Children may also have fewer muscarinic and nicotinic signs of intoxication (ie, secretions, bradycardia, fasciculations, and miosis) as compared with adults.
    4) INHALATION EXPOSURE: Vapors rapidly produce mucous membrane and upper airway irritation and bronchospasm, followed by systemic muscarinic, nicotinic, and central effects if exposed to significant concentrations.

Vital Signs

    3.3.2) RESPIRATIONS
    A) Tachypnea may occur following inhalation of carbamate dusting powders, but is not necessarily related to severity of ensuing symptoms (Alcorn & Hughes, 1980).
    B) WITH POISONING/EXPOSURE
    1) Tachypnea may occur following inhalation of carbamate dusting powders, but is not necessarily related to severity of ensuing symptoms (Alcorn & Hughes, 1980).
    3.3.3) TEMPERATURE
    A) WITH POISONING/EXPOSURE
    1) HYPOTHERMIA: In a pediatric case series (n=54) of anticholinesterase (carbamate and organophosphate) poisonings, hypothermia was reported in 7% and hyperthermia was reported in 6% of the children (Verhulst et al, 2002).

Heent

    3.4.1) SUMMARY
    A) Pinpoint pupils may be seen.
    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) MIOSIS and blurred vision may occur. Miosis, a muscarinic effect, is characteristic of severe and moderately severe poisonings, but may appear late (Waseem et al, 2010; Hoffmann et al, 2008; Tsatsakis et al, 2001; Tracqui et al, 2001; Park et al, 2000; Flesch et al, 1999; Covaci et al, 1999) .
    a) INCIDENCE: Miosis was the most common symptom seen (57%) in a retrospective observational study of 54 children admitted to a pediatric intensive care unit following anticholinesterase (carbamate and organophosphate) poisoning (Verhulst et al, 2002a).
    2) MYDRIASIS: Pupil dilation may occur as a nicotinic effect and may be present in up to 10% of patients (Aaron & Howland, 1998).
    3.4.6) THROAT
    A) WITH POISONING/EXPOSURE
    1) Excessive salivation and bronchial secretions are common following severe carbamate poisoning (Waseem et al, 2010; Park et al, 2000).

Cardiovascular

    3.5.1) SUMMARY
    A) Bradycardia or tachycardia may occur.
    B) Electrocardiographic (T-wave) changes have been reported in exposed workers.
    3.5.2) CLINICAL EFFECTS
    A) BRADYCARDIA
    1) WITH POISONING/EXPOSURE
    a) Muscarinic effects may commonly include bradycardia (Covaci et al, 1999; Park et al, 2000; Tsatsakis et al, 2001).
    B) TACHYCARDIA
    1) WITH POISONING/EXPOSURE
    a) Nicotinic effects may include sinus tachycardia (Tracqui et al, 2001; Aaron & Howland, 1998).
    C) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) Hypotension has been reported following carbamate insecticide poisoning due to weakened cardiac contractility (Park et al, 2000).
    b) INCIDENCE: In a pediatric case series (n=54) of anticholinesterase (carbamate and organophosphate) poisonings, 9% developed hypotension (Verhulst et al, 2002).
    D) ELECTROCARDIOGRAM ABNORMAL
    1) WITH POISONING/EXPOSURE
    a) Sinus tachycardia with ST segment depression may occur early in the course of poisoning. Repolarization abnormalities may occur and are generally transient (Tracqui et al, 2001).
    b) CASE REPORT: Severe ST depression was reported in one pediatric carbamate poisoning (Sofer et al, 1989).
    E) HYPERTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) Nicotinic effects may include hypertension (Tracqui et al, 2001; Aaron & Howland, 1998).
    b) In a pediatric case series (n=54) of anticholinesterase (carbamate and organophosphate) poisonings, hypertension was reported in 20% of the children (Verhulst et al, 2002).

Respiratory

    3.6.1) SUMMARY
    A) Dyspnea, rales, and pulmonary edema may occur.
    B) Aspiration pneumonitis from hydrocarbon vehicles may occur.
    C) Laryngeal irritation and associated cough is common following inhalation of carbamate dusting powders.
    3.6.2) CLINICAL EFFECTS
    A) DYSPNEA
    1) WITH POISONING/EXPOSURE
    a) Dyspnea is a common manifestation of carbamate insecticide exposure (Uludag et al, 2001; Ragoucy-Sengler et al, 2000). Chest tightness, bronchospasm, increased pulmonary secretions, and rales may develop secondary to muscarinic effects (Markowitz, 1992).
    1) PEDIATRIC CASE SERIES: Dyspnea was reported in 7 of 8 children with carbamate poisoning (Sethi et al, 1989; Morgan, 1989a).
    B) RESPIRATORY FAILURE
    1) WITH POISONING/EXPOSURE
    a) Respiratory depression and rales may be noted. Dyspnea was reported in 7 of 8 children with carbamate poisoning (Sofer et al, 1989).
    b) Usual cause of death is respiratory failure as a result of respiratory muscle weakness and central depression of the respiratory drive (Aaron & Howland, 1998; Park et al, 2000).
    1) CASE SERIES: Respiratory failure was reported in 2 of 13 (15%) patients with carbamate poisoning in one series (Tsao et al, 1990).
    C) SPUTUM ABNORMAL - AMOUNT
    1) WITH POISONING/EXPOSURE
    a) INCREASED BRONCHIAL SECRETIONS may occur secondary to muscarinic effects (Waseem et al, 2010; Tracqui et al, 2001; Covaci et al, 1999) and be significant requiring frequent suctioning.
    D) IRRITATION SYMPTOM
    1) WITH POISONING/EXPOSURE
    a) Laryngeal irritation, violent coughing, and tachypnea occur frequently following inhalation of carbamate dusting powders and may not necessarily be associated with systemic signs and symptoms of carbamate poisoning (Alcorn & Hughes, 1980).
    E) BRONCHOSPASM
    1) WITH POISONING/EXPOSURE
    a) Bronchospasm and chest tightness may occur (Morgan, 1993).
    F) ACUTE LUNG INJURY
    1) WITH POISONING/EXPOSURE
    a) Acute lung injury (pulmonary edema) is a potential clinical manifestation of severe carbamate poisoning and is attributed to the muscarinic action of the insecticide. Contributing factors to the development of pulmonary edema include bradycardia and weakened cardiac contraction from an accumulation of acetylcholine on the cardiovascular system. Hypoxia may develop due to increasing capillary permeability (Park et al, 2000; Tsatsakis et al, 2001).
    G) PNEUMONITIS
    1) WITH POISONING/EXPOSURE
    a) Aspiration pneumonitis may occur after ingestion of carbamates in hydrocarbon vehicles. A complication of prolonged intubation and mechanical ventilation following pulmonary effects of poisoning is aspiration pneumonia (Aaron & Howland, 1998).
    b) Interstitial pneumonitis may occur following carbamate insecticide poisonings. A case of ingestion was reported in a 41-year-old woman, which resulted in pulmonary edema that resolved and was followed by interstitial pneumonitis as shown on high resolution CT and pathological examinations. The patient recovered following symptomatic care (Park et al, 2000).
    c) A cross-sectional study of occupational risk factors for farmer's lung (n=50,000 farmers and spouses, controlled for age, state and smoking status) or hypersensitivity pneumonitis concluded that carbamate insecticides were associated with hypersensitivity pneumonitis (OR=1.32, 95% CI=1.03-1.68) (Hoppin et al, 2007).
    H) ACUTE RESPIRATORY INSUFFICIENCY
    1) WITH POISONING/EXPOSURE
    a) Respiratory depression along with acute pulmonary edema is usually the immediate cause of death from acute exposures to N-methyl carbamates such as thiofanox (Morgan, 1993).

Neurologic

    3.7.1) SUMMARY
    A) Blurred vision, miosis, tremor, muscle twitching, convulsions, mental confusion, and coma may occur.
    B) Delayed peripheral neuropathy similar to that seen with organophosphates has been described in one case.
    C) Dystonic reaction may occur following parenteral injection.
    3.7.2) CLINICAL EFFECTS
    A) DEFICIENCY OF ACETYLCHOLINESTERASE
    1) WITH POISONING/EXPOSURE
    a) Reversible carbamylation of acetylcholinesterase is the hallmark of poisoning by carbamates. This causes accumulation of acetylcholine at neuroeffector and myoneural junctions, as well as in autonomic ganglia and the brain (Morgan, 1993).
    B) COMA
    1) WITH POISONING/EXPOSURE
    a) CNS depression leading to coma may occur after severe poisonings, with decreased or absent tendon and brainstem reflexes (Ratner et al, 1983; Umehara et al, 1991; Flesch et al, 1999; Park et al, 2000; Tsatsakis et al, 2001; Tracqui et al, 2001).
    1) CASE SERIES (PEDIATRIC): In one series, 8 of 8 children with carbamate poisoning developed severe CNS depression with stupor and coma (Sethi et al, 1989).
    C) TREMOR
    1) WITH POISONING/EXPOSURE
    a) Tremor, paresis, and muscle twitching may be noted (Morgan, 1993).
    D) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) In severe poisoning convulsions may occur.
    1) Children may be more susceptible to seizures than adults; in one series 2 children poisoned by carbamates had seizures (Zweiner & Ginsburg, 1988). In another series, 8 of 8 children with carbamate poisoning developed severe CNS depression with stupor and coma (Sofer et al, 1989).
    b) CASE SERIES: In a pediatric series of 54 anticholinesterase (carbamate and organophosphate) poisonings, 30% developed seizures (Verhulst et al, 2002).
    E) MUSCLE WEAKNESS
    1) WITH POISONING/EXPOSURE
    a) Protracted malaise and weakness may occur after apparent recovery from carbamate poisoning (Garber, 1987).
    F) DECREASED MUSCLE TONE
    1) WITH POISONING/EXPOSURE
    a) Hypotonia is a common nicotinic effect of carbamate insecticide poisoning (Ragoucy-Sengler et al, 2000; Tsatsakis et al, 2001).
    G) SPASMODIC MOVEMENT
    1) WITH POISONING/EXPOSURE
    a) Muscle fasciculations may develop as a nicotinic effect (Waseem et al, 2010; Hoffmann et al, 2008; Ragoucy-Sengler et al, 2000; Flesch et al, 1999; Burgess et al, 1994; Ekins & Geller, 1994).
    H) HEADACHE
    1) WITH POISONING/EXPOSURE
    a) Headache, blurred vision, miosis, tremor, paresis, and muscle twitching may be noted (Morgan, 1993).

Gastrointestinal

    3.8.1) SUMMARY
    A) Nausea, vomiting, diarrhea, and abdominal cramping may be noted.
    B) Acute pancreatitis has been reported following carbamate intoxication.
    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH POISONING/EXPOSURE
    a) Nausea and vomiting are common muscarinic signs (Topacoglu et al, 2007; Ratner et al, 1983; Burgess et al, 1994; Lifshitz et al, 1994).
    B) DIARRHEA
    1) WITH POISONING/EXPOSURE
    a) Diarrhea is common (Ratner et al, 1983; Burgess et al, 1994; Lifshitz et al, 1994; Lifshitz et al, 1999).
    C) ABDOMINAL PAIN
    1) WITH POISONING/EXPOSURE
    a) Abdominal pain and cramping may develop (Sargin et al, 1992).
    D) EXCESSIVE SALIVATION
    1) WITH POISONING/EXPOSURE
    a) Salivation may occur as a cholinergic crisis effect following intentional ingestions (Waseem et al, 2010; Park et al, 2000; Flesch et al, 1999).
    E) ACUTE PANCREATITIS
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES
    1) In a prospective case study of 17 children with documented organophosphate or carbamate insecticide poisoning, 5 were diagnosed with acute pancreatitis. All of the 5 had significantly elevated serum levels of immunoreactive trypsin and 4 had a significant increase in serum amylase levels. Clinical manifestations were mild. One case was a documented carbamate poisoning (Weizman & Sofer, 1992).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) HYPERBILIRUBINEMIA
    1) WITH POISONING/EXPOSURE
    a) In a case series of 49 carbamate insecticide poisonings, 9 patients (11%) developed elevated serum bilirubin concentrations. Mean total serum bilirubin was reported to be 69.05 micromols/liter, while the mean indirect serum bilirubin concentration was 45.2 micromols/liter (Saadeh, 2001).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) INCONTINENCE
    1) WITH POISONING/EXPOSURE
    a) Urinary incontinence was seen in 7% of children (n= 54) admitted to a pediatric intensive care unit following severe anticholinesterase (carbamate and organophosphate) insecticide poisoning (Verhulst et al, 2002a).
    B) RENAL FUNCTION TESTS ABNORMAL
    1) WITH POISONING/EXPOSURE
    a) Renal biochemical abnormalities in a study of patients (n=84) following acute poisoning with carbamate insecticides or organophosphates included azotemia (BUN greater than 6.7 mmol/L) (21%), hematuria (17%), glycosuria (15%) and proteinuria (5%) (Saadeh, 2001).

Hematologic

    3.13.1) SUMMARY
    A) Reversible inhibition of cholinesterases is the hallmark of carbamate poisoning.
    B) Disseminated intravascular coagulation has been reported.
    3.13.2) CLINICAL EFFECTS
    A) DEFICIENCY OF CHOLINESTERASE
    1) WITH POISONING/EXPOSURE
    a) Thiofanox and other carbamates reversibly inhibit serum pseudocholinesterase and erythrocyte acetylcholinesterase. Reactivation occurred within two hours (Chin et al, 1980).
    b) Erythrocyte acetylcholinesterase was inhibited more than plasma pseudocholinesterase (Chin et al, 1980).
    B) DISSEMINATED INTRAVASCULAR COAGULATION
    1) WITH POISONING/EXPOSURE
    a) Disseminated intravascular coagulation caused by another carbamate, propoxur, has been reported (Misra et al, 1987).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) EXCESSIVE SWEATING
    1) WITH POISONING/EXPOSURE
    a) Diaphoresis may commonly develop as a muscarinic effect (Waseem et al, 2010; Park et al, 2000; Burgess et al, 1994; Morgan, 1993).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS39196-18-4 (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) Not Listed
    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, no data were available to assess the carcinogenic potential of this agent.
    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the carcinogenic potential of this agent.

Genotoxicity

    A) At the time of this review, no data were available to assess the mutagenic or genotoxic potential of this agent.

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) SPASMODIC MOVEMENT
    1) WITH POISONING/EXPOSURE
    a) Fasciculations and tremor are cholinergic effects (Morgan, 1993).

Reproductive

    3.20.1) SUMMARY
    A) At the time of this review, no data were available to assess the teratogenic human potential of this agent.
    B) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.
    C) ANIMAL STUDIES - CARBARYL a related compound, has been embryotoxic, fetotoxic, and teratogenic, and has affected both male and female fertility in laboratory animals.
    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.
    B) ANIMAL STUDIES
    1) The potential of carbaryl, a related compound, to produce developmental toxicity has been studied in numerous mammalian species utilizing a wide variety of study designs and routes of administration. Structural malformations have been produced in animals only at exposure levels obviously toxic to the pregnant animal. Doses tested often approach the LD50 (Cranmer, 1986).
    3.20.3) EFFECTS IN PREGNANCY
    A) CASE REPORT
    1) RELATED COMPOUND
    a) A 17-year-old pregnant woman (18 weeks gestation) ingested carbofuran, a related carbamate, to commit suicide. She arrived at a health care facility 2 hours after ingestion. She was treated with carbon gastric lavage and intensive symptomatic care. Fetal pulse was not audible on the second day of admission. Neither heart tones nor fetal movement could be detected by ultrasonography. Induction of delivery because of still pregnancy occurred on the seventh day of hospital admission. Postmortem examination of the fetus revealed a macerated, intrauterine-dead female, of age 4 to 5 lunar months, with no congenital defects. Concentration of carbofuran in the kidney, liver, and brain of the fetus was comparable with the concentration in the mother's blood (Klys et al, 1989).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs frequently. Obtain serial ECGs and institute continuous cardiac and pulse oximetry monitoring.
    B) Monitor for respiratory distress (ie, bronchorrhea, bronchospasm) and for clinical evidence of cholinergic excess (ie, salivation, vomiting, urination, defecation, miosis).
    C) Determine plasma and/or red blood cell cholinesterase activities (plasma is generally more sensitive, but red cell correlates somewhat better with clinical signs and symptoms). Depression in excess of 50% of baseline is generally associated with cholinergic effects; in severe poisoning, cholinesterase activity may be depressed by 90% of baseline. Correlation between cholinesterase levels and clinical effects in milder poisonings may be poor.
    D) Monitor electrolytes and serum lipase in patients with significant poisoning.
    E) Monitor pulmonary function (ie, forced vital capacity, expiratory volume in 1 second, negative inspiratory force) in symptomatic patients; may help anticipate need for intubation.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) CHOLINESTERASE LEVELS: If a blood sample can be obtained and analyzed within a short time after acute exposure to a carbamate such as thiofanox, determination of plasma pseudocholinesterase and/or red blood cell acetylcholinesterase activity may be useful in confirming exposure. A rapid method of analysis should be used, because the carbamylated enzyme is rapidly reactivated both in vivo and in vitro (Morgan, 1993).
    a) Depression of cholinesterase levels often does not correlate with severity of clinical symptoms, however.
    b) Cholinesterase levels can be done by specialized toxicology laboratories. Unless the patient has had extraordinary exposure to an N-methyl carbamate compound, it is unlikely that blood cholinesterase activities will be depressed. Nonetheless, there is some merit in ordering cholinesterase levels to assess the approximate magnitude of toxicant absorption. In symptomatic patients, the red blood cell and serum cholinesterase activity correlated in 20 of 24 patients (Zweiner & Ginsburg, 1988).
    c) Serial monitoring of plasma pseudocholinesterase and erythrocyte acetylcholinesterase levels, in conjunction with reversal of clinical signs and symptoms, may be useful in determining when an occupationally-exposed person may return to work. In general, elevation of cholinesterase to 70% of pre-exposure value is considered sufficient recovery.
    4.1.3) URINE
    A) URINARY LEVELS
    1) Detection of phenolic derivatives of carbamates may be useful to confirm exposure to specific compounds, but is not sufficiently reliable for biological monitoring (Kuhr & Dorough, 1976).

Radiographic Studies

    A) CHEST RADIOGRAPH
    1) Chest x-ray should be obtained in all symptomatic patients. The major cause of morbidity and mortality in carbamate insecticide poisonings is respiratory failure and associated pulmonary edema.
    B) CT RADIOGRAPH
    1) High resolution CT (HRCT) has been used in the follow-up of carbamate poisoning with pulmonary edema. HRCT demonstrated diffuse bilateral reticular opacities with parenchymal distortion and multifocal areas of ground glass attenuation and consolidation associated with traction bronchiectasis on both lungs. HRCT and pathologic findings revealed interstitial pneumonitis after resolution of pulmonary edema in one case (Park et al, 2000).

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) All intentional ingestions should be initially managed as a severe exposure. Determine cholinesterase activity to assess if a significant exposure occurred. Patients who develop signs or symptoms of cholinergic toxicity (e.g. muscarinic, nicotinic OR central) should be admitted to an intensive care setting.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Patients with unintentional trivial exposures who are asymptomatic can be observed in the home or in the workplace.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a medical toxicologist and/or poison center for assistance with any patient with moderate to severe cholinergic manifestations.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with deliberate or significant exposure and those who are symptomatic should be sent to a health care facility for evaluation, treatment and observation for 6 to 12 hours. Onset of toxicity is variable; most patients will develop symptoms within 6 hours. Patients that remain asymptomatic 12 hours after an ingestion or a dermal exposure are unlikely to develop severe toxicity. Cholinesterase activity should be determined to confirm the degree of exposure.

Monitoring

    A) Monitor vital signs frequently. Obtain serial ECGs and institute continuous cardiac and pulse oximetry monitoring.
    B) Monitor for respiratory distress (ie, bronchorrhea, bronchospasm) and for clinical evidence of cholinergic excess (ie, salivation, vomiting, urination, defecation, miosis).
    C) Determine plasma and/or red blood cell cholinesterase activities (plasma is generally more sensitive, but red cell correlates somewhat better with clinical signs and symptoms). Depression in excess of 50% of baseline is generally associated with cholinergic effects; in severe poisoning, cholinesterase activity may be depressed by 90% of baseline. Correlation between cholinesterase levels and clinical effects in milder poisonings may be poor.
    D) Monitor electrolytes and serum lipase in patients with significant poisoning.
    E) Monitor pulmonary function (ie, forced vital capacity, expiratory volume in 1 second, negative inspiratory force) in symptomatic patients; may help anticipate need for intubation.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) PREHOSPITAL: Activated charcoal is contraindicated because of possible respiratory depression, seizures, and risk of aspiration. Remove contaminated clothing and wash skin with soap and water. Universal precautions and nitrile gloves to protect personnel. Vomiting should be contained and treated as hazardous material. Rescue personnel should avoid dermal exposure to vomiting because of the risk of intoxication.
    B) ANTIDOTE: There are two primary classes of antidotes: ATROPINE (muscarinic antagonist); OXIMES (pralidoxime in the US, or obidoxime in some other countries) to reverse neuromuscular blockade. Use of oximes is generally indicated for patients with severe toxicity and are used in conjunction with atropine.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) Gastric lavage or activated charcoal should be administered if ingestion has been recent. Seizures may occur; protect the airway.
    2) Transfer to a medical facility for oral decontamination.
    B) 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).
    C) GASTRIC LAVAGE
    1) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).
    a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.
    2) PRECAUTIONS:
    a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
    b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.
    3) LAVAGE FLUID:
    a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
    b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
    c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.
    4) COMPLICATIONS:
    a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
    b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).
    5) CONTRAINDICATIONS:
    a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Monitor vital signs frequently. Obtain serial ECGs and institute continuous cardiac and pulse oximetry monitoring.
    2) Monitor for respiratory distress (ie, bronchorrhea, bronchospasm) and for clinical evidence of cholinergic excess (ie, salivation, vomiting, urination, defecation, miosis).
    3) Determine plasma and/or red blood cell cholinesterase activities (plasma is generally more sensitive, but red cell correlates somewhat better with clinical signs and symptoms). Depression in excess of 50% of baseline is generally associated with cholinergic effects; in severe poisoning, cholinesterase activity may be depressed by 90% of baseline. Correlation between cholinesterase levels and clinical effects in milder poisonings may be poor.
    4) Monitor electrolytes and serum lipase in patients with significant poisoning.
    5) Monitor pulmonary function (ie, forced vital capacity, expiratory volume in 1 second, negative inspiratory force) in symptomatic patients; may help anticipate need for intubation.
    B) ATROPINE
    1) SUMMARY
    a) Atropine is used to treat muscarinic effects (e.g. salivation, lacrimation, defecation, urination, bronchorrhea).
    2) DOSE
    a) ADULT: 1 to 3 mg IV; CHILD: 0.02 mg/kg IV. If inadequate response in 3 to 5 minutes, double the dose. Continue doubling the dose and administering it IV every 3 to 5 minutes as needed to dry pulmonary secretions. Once secretions are dried, maintain with an infusion of 10% to 20% of the loading dose every hour. Monitor frequently for evidence of cholinergic effects or atropine toxicity (e.g., delirium, hyperthermia, ileus) and titrate dose accordingly. Large doses (hundreds of milligrams) are sometimes required. Atropinization may be required for hours to days depending on severity (Roberts & Aaron, 2007).
    3) MAINTAIN ATROPINIZATION: For hours or days, depending on estimated toxicity and dose of toxicant. Following a massive exposure, hundreds of milligrams of atropine may be needed. In one adult case, a total atropine dose of 970 milligrams was required (Nelson et al, 2001).
    4) ATROPINE INFUSION: An atropine drip may be compounded using the powdered form of the drug or using the 20 mL multidose vial. Use preservative-free atropine. In one adult case, an atropine drip was started at 6 mg/hr, then titrated up to 9 mg/hr in order to prevent recurrent bronchorrhea. This was continued for 5 days until a total dose of 970 mg had been administered (Nelson et al, 2001).
    5) ATROPINE WITHDRAWAL: Done gradually by lengthening interval between doses. Check lung bases for rales, and observe patient for return of cholinergic signs. Increase atropine dosage promptly if there are indications of relapse.
    6) PRESERVATIVE TOXICITY: Many parenteral atropine preparations are preserved with benzyl alcohol or chlorobutanol. High dose atropine therapy may result in excipient toxicity if these formulations are used. Preservative-free atropine injection is available.
    7) SUCTIONING: Careful suctioning of oral and tracheal secretions may be necessary until atropinization is achieved.
    C) PRALIDOXIME
    1) INDICATIONS
    a) USE IS CONTROVERSIAL: Critical reviews of the use of oximes in carbamate poisoning have been published (Pelfrene, 1986; Kurtz, 1990). Clinical experience in humans has not consistently confirmed the value of pralidoxime in carbamate poisoning.
    1) A consensus of experts concluded that 6 of 10 had or would use pralidoxime in conjunction with atropine for specific indications listed below. Four of 10 would not use pralidoxime. One expert presented anecdotal experience in two patients who appeared to worsen after receiving pralidoxime(Consensus, 1986).
    2) INDICATIONS: After adequate atropinization, pralidoxime may be indicated in the following situations (Consensus, 1986).
    a) Life-threatening symptoms such as severe muscle weakness, fasciculations, paralysis, or decreased respiratory effort.
    b) Continued excessive requirements of atropine.
    c) Concomitant organophosphate and carbamate exposure.
    b) INCREASED TOXICITY WITH USE
    1) In one human case report of carbaryl poisoning, pralidoxime was implicated in contributing to toxicity, but the patient appeared to be inadequately atropinized (Farago, 1969).
    2) ANIMAL STUDIES: In laboratory animals, when pralidoxime was given alone or an alternate oxime (obidoxime) was given with atropine, an increase in carbaryl toxicity (but not other carbamates) was seen (Natoff & Reiff, 1973). A total of 5 animals were studied.
    3) NO INCREASED TOXICITY WITH USE
    a) Pralidoxime was used in 5 of 13 patients with carbamate poisoning in one series, with no adverse outcome (Tsao et al, 1990).
    4) EFFICACIOUS USE
    a) CASE REPORT: Progressive weakness due to severe aldicarb poisoning, with a plasma cholinesterase 6% of normal, responded to administration of pralidoxime 4 grams over 10 hours (Burgess et al, 1994).
    b) CASE REPORT: Pralidoxime stopped muscle fasciculations in a severe carbamate poisoning caused by methomyl in a 52-year-old man. A total of 16 grams pralidoxime (2 grams in the ED and 0.5 gm/hr for 28 hours) and 18 mg atropine were given. Rapid and pronounced clinical improvement occurred (Ekins & Geller, 1994).
    c) ANIMAL STUDY: In laboratory animals, pralidoxime in combination with atropine decreased toxicity of various carbamates, including carbaryl. A total of 5 animals were studied (Natoff & Reiff, 1973).
    d) ANIMAL STUDY: In another study involving 6 animals, pralidoxime alone was effective in isolan and dimetilan, but not with carbaryl (Sanderson, 1961).
    e) ANIMAL STUDY: A study of effectiveness of atropine, pralidoxime, and HI-6 against carbaryl intoxication in rats demonstrated a decrease LD50 (intraperitoneally) when pralidoxime was used alone compared to control (39.4 milligrams/kilogram pralidoxime vs 69.9 milligrams/kilogram control).
    1) Pralidoxime used with atropine decreased the LD50 compared to atropine alone, but was still above control (244 milligrams/kilogram atropine + pralidoxime vs 460 milligrams/kilogram atropine vs 69.9 milligrams/kilogram control) (Harris et al, 1989).
    5) CASE SERIES
    a) OBIDOXIME: 26 children were administered IV atropine and obidoxime during the first 5 hours of suspected organophosphate poisoning. Obidoxime was given in 2 doses of 6 mg/kg each, the first on admission and the second 3 to 4 hours later.
    b) Marked clinical improvement occurred within 2 to 4 hours and all children had recovered completely by 24 hours. Subsequently, all 26 children were confirmed to have carbamate poisoning. As rapid improvement within 24 hours is described in most reported cases of carbamate poisoning, there was no clear effect from obidoxime therapy. Secondary complications of oxime-related adverse effects were not observed (Lifshitz et al, 1994).
    2) DOSE
    a) PRALIDOXIME DOSE
    1) ADULT: A loading dose of 30 mg/kg (maximum: 2 grams) over 30 minutes followed by a maintenance infusion of 8 to 10 mg/kg/hr (up to 650 mg/hr) (Howland, 2011). In vitro studies have recommended a target plasma concentration of close to 17 mcg/mL necessary for pralidoxime to be effective, which is higher than the previously suggested concentration of at least 4 mcg/mL (Howland, 2011; Eddleston et al, 2002). ALTERNATE ADULT: An alternate initial dose for adults is 1 to 2 grams diluted in 100 mL of 0.9% sodium chloride infused over 15 to 30 minutes. Repeat initial bolus dose in 1 hour and then every 3 to 8 hours if muscle weakness or fasciculations persist (continuous infusion preferred). In patients with serious cholinergic intoxication, a continuous infusion of 500 mg/hr should be considered. In patients with acute lung injury, a 5% solution may be administered by a slow IV injection over at least 5 minutes (Howland, 2006). Intravenous dosing is preferred; however, intramuscular administration may be considered using a 1-g vial of pralidoxime reconstituted with 3 mL of sterile water for injection or 0.9% sodium chloride for injection, producing a solution containing 300 mg/mL (Howland, 2011). An initial intramuscular pralidoxime dose of 1 gram or up to 2 grams in cases of very severe poisoning has also been recommended (Haddad, 1990; S Sweetman , 2002).
    2) CHILD: A loading dose of 20 to 40 mg/kg (maximum: 2 grams/dose) infused over 30 to 60 minutes in 0.9% sodium chloride (Howland, 2006; Schexnayder et al, 1998). Repeat initial bolus dose in 1 hour and then every 3 to 8 hours if muscle weakness or fasciculations persist (continuous infusion preferred). ALTERNATE CHILD: An alternate loading dose of 25 to 50 mg/kg (up to a maximum dose of 2 g), followed via continuous infusion of 10 to 20 mg/kg/hr. In patients with serious cholinergic intoxication, a continuous infusion of 10 to 20 mg/kg/hr up to 500 mg/hr should be considered (Howland, 2006).
    3) Presently, the ideal dose has NOT been established and dosing is likely based on several factors: type of OP agent (ie, diethyl OPs appear to respond more favorably to oximes, while dimethyl OPs seem to respond poorly) which may relate to a variation in the speed of ageing, time since exposure, body load, and pharmacogenetics (Eddleston et al, 2008)
    4) CONTINUOUS INFUSION
    a) A continuous infusion of pralidoxime is generally preferred to intermittent bolus dosing to maintain a target concentration with less variation (Howland, 2011; Eddleston et al, 2008; Roberts & Aaron, 2007; Gallagher et al, 1989; Thompson, 1987). In an open label, randomized study of moderately severe organophosphate poisoned patients treated with high dose continuous infusions required less atropine, were less likely to be intubated and had shorter duration of ventilatory support than patients treated with intermittent bolus doses. HIGH DOSE CONTINUOUS INFUSION: In this study, an initial 2 g bolus (pralidoxime chloride or iodide) was given, followed by 1 g over an hour every hour for 48 hours. Followed by 1 g every 4 hours until the patient could be weaned from mechanical ventilation. The response to therapy was beneficial in patients exposed to either a dimethyl or diethyl organophosphate pesticide (Pawar et al, 2006).
    b) Infusion over a period of several days may be necessary and is generally well tolerated (Namba et al, 1971).
    5) MAXIMUM DOSE
    a) The maximum recommended dose for pralidoxime is 12 grams in 24 hours for adults (S Sweetman , 2002); based on WHO, this dose may be exceeded in severely poisoned adults (Tang et al, 2013).
    6) DURATION OF INTRAVENOUS DOSING
    a) Dosing should be continued for at least 24 hours after cholinergic manifestations have resolved (Howland, 2006). Prolonged administration may be necessary in severe cases, especially in the case of poisoning by lipophilic organophosphates (Wadia & Amin, 1988). Observe patients carefully for recurrent cholinergic manifestations after pralidoxime is discontinued.
    3) ADVERSE EFFECTS
    a) SUMMARY
    1) Minimal toxicity when administered as directed; adverse effects may include: pain at injection site; transient elevations of CPK, SGOT, SGPT; dizziness, blurred vision, diplopia, drowsiness, nausea, tachycardia, hyperventilation, and muscular weakness (Prod Info PROTOPAM(R) CHLORIDE injection, 2006). Rapid injection may produce laryngospasm, muscle rigidity and tachycardia (Prod Info PROTOPAM(R) CHLORIDE injection, 2006).
    b) MINIMAL TOXICITY
    1) When administered as directed, pralidoxime has minimal toxicity (Prod Info PROTOPAM(R) CHLORIDE injection, 2006). Up to 40.5 grams have been administered over seven days (26 grams in the first 54 hours) without ill effects (Namba et al, 1971).
    2) One child developed delirium, visual hallucinations, tachycardia, mydriasis, and dry mucous membranes (Farrar et al, 1990). The authors were uncertain if these effects were related to 2-PAM or organophosphate poisoning per se.
    c) NEUROMUSCULAR BLOCKADE
    1) High doses have been reported to cause neuromuscular blockade, but this would not be expected to occur with recommended doses (Grob & Johns, 1958).
    d) VISUAL DISTURBANCES
    1) Oximes have produced visual disturbances (eg, blurred vision, diplopia) (Prod Info PROTOPAM(R) CHLORIDE injection, 2006).
    2) Transient increases in intraocular pressure may occur (Ballantyne B, 1987).
    e) ASYSTOLE
    1) Pralidoxime administered intravenously at an infusion rate of 2 grams over 10 minutes was associated with asystole in a single reported case, which occurred about 2 minutes after initiation of the infusion (Scott, 1986). A cause and effect relationship was not established.
    f) WEAKNESS
    1) Mild weakness, blurred vision, dizziness, headache, nausea, and tachycardia may occur if the rate of pralidoxime infusion exceeds 500 milligrams/minute (Jager & Stagg, 1958).
    g) ATROPINE SIDE EFFECTS
    1) Concomitant administration of pralidoxime may enhance the side effects of atropine administration (Hiraki et al, 1958). The signs of atropinization may occur earlier than anticipated when the agents are used together (Prod Info PROTOPAM(R) CHLORIDE injection, 2006).
    h) CARDIOVASCULAR
    1) Transient dose-dependent increases in blood pressure have occurred in adults receiving 15 to 30 milligrams/kilogram of 2-PAM (Calesnick et al, 1967). Increases in systolic and diastolic blood pressure have been observed in healthy volunteers given parenteral doses of pralidoxime (Prod Info PROTOPAM(R) CHLORIDE injection, 2006).
    2) Electrocardiographic changes and marked hypertension were observed at doses of 45 milligrams/kilogram (Calesnick et al, 1967).
    4) PHARMACOKINETICS
    a) HALF-LIFE: Pralidoxime is relatively short-acting with an estimated half-life of 75 minutes (Prod Info PROTOPAM(R) CHLORIDE injection, 2006). One report found that the effective half-life of pralidoxime chloride was longer in poisoned individuals than in healthy volunteers. This was attributed to a reduced renal blood flow in the poisoned patients (Jovanovic, 1989).
    5) AVAILABLE FORMS
    a) VIALS
    1) Each 20-mL vial contains 1 gram of pralidoxime chloride (Prod Info PROTOPAM(R) Chloride injection, 2010)
    b) SELF-INJECTOR
    1) Each auto-injector contains 600-mg of pralidoxime chloride in 2 mL of a sterile solution containing 20 mg/mL benzyl alcohol, 11.26 mg/mL glycine in water for injection (Prod Info PRALIDOXIME CHLORIDE intramuscular injection, 2003).
    c) CONVERSION FROM AUTOINJECTOR TO IV SOLUTION
    1) In one study, the conversion of intramuscular pralidoxime (from a MARK I Injector) to an IV solution resulted in a stable and sterile solution for up to 28 days. It is suggested that this conversion may be used in a mass casualty situation when additional IV doses of pralidoxime are needed. The following method may be used to transfer the syringe content: (Corvino et al, 2006).
    a) Avoid a shattered glass incident by using a biological safety cabinet.
    b) Double-glove and use a 30 mL empty sterile glass vial.
    c) Sterilize the vial diaphragm with alcohol.
    d) To vent the vial, insert a 1 1/2 inch 21 gauge IV needle bent to 90 degrees.
    e) Obtain the pralidoxime syringe from the kit and place it over the top of the vial diaphragm.
    f) Keep the syringe perpendicular to the vial and grasp the barrel of the syringe and press down firmly until the needle is deployed, and allow the syringe contents to enter into the vial.
    g) Use 5 pralidoxime injectors for one vial, which will be 10 mL in each vial.
    h) A 19 gauge 1.5 inch 5 micro filter needle is used with the 5 or 10 mL syringe to withdraw the pralidoxime solution from the 30 mL vial.
    i) Each vial (10 mL) is used to prepare either 250 mL, 0.9% sodium chloride injection IV bag at 8 mg/mL OR 100 mL, 0.9% sodium chloride injection IV bag to yield a final pralidoxime concentration of 10 mg/mL; 3.33 mL should be added into a 100 mL bag and 6.66 mL should be added into a 250 mL bag.
    d) OTHER SALTS
    1) Pralidoxime mesylate (P2S) in the United Kingdom (UK License holder, Department of Health).
    2) Pralidoxime methisulfate (Contrathion(R)) available in Greece (from IFET), Turkey (from Keymen), Brazil (from Sanofi-Aventis), Italy (from Sanofi-Aventis) and France (from SERB).
    D) 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).
    E) EXPERIMENTAL THERAPY
    1) CIMETIDINE has been investigated in isolated perfused rat liver and in one human volunteer for its ability to alter the metabolism of carbaryl. Cimetidine prolonged the half-life of carbaryl in this model (Ward et al, 1988).
    a) The investigators did not measure serial cholinesterase levels in the human volunteer, which would have increased validity. The exact mechanism of carbaryl metabolism is unknown. Additional studies are needed to determine the clinical significance of these findings.
    2) DIPHENHYDRAMINE: Al-Baggou and Mohammad (1999) reported antagonism of methomyl- induced toxicosis by diphenhydramine the rat model. When diphenhydramine was administered to rats (20 mg/kg SubQ.) immediately following methomyl (6 mg/kg i.p.), cholinergic toxicity was decreased, with prevention of seizures, gasping and death by 100% in comparison to controls (methomyl- saline group). The actions of diphenhydramine may be attributed to antimuscarinic and possibly antinicotinic effects. Further studies are needed to test the antidotal efficacy of diphenhydramine in poisonings with other carbamate insecticides. No reports on efficacy in humans were available. (Al-Baggou & Mohammad, 1999).
    3) MEMANTINE: In a rat study, memantine, a NMDA receptor antagonist and atropine pretreatment, produced attenuation of carbofuran induced changes in acetylcholinesterase and radical oxygen species formation. The authors concluded that memantine protected against neuronal oxidative injury and dendritic changes (Gupta et al, 2007).
    4) N-ACETYLCYSTEINE: In a rat study, n-acetylcysteine had a protective effect on carbofuran induced alterations in calcium homestasis and neurobehavioral function (Kamboj & Sandhir, 2007).

Inhalation Exposure

    6.7.1) DECONTAMINATION
    A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
    B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.

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) CLOTHING
    1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. Rescue personnel and bystanders should avoid direct contact with contaminated skin, clothing, or other objects (Burgess et al, 1999). Since contaminated leather items cannot be decontaminated, they should be discarded (Simpson & Schuman, 2002).

Enhanced Elimination

    A) EXTRACORPOREAL ELIMINATION
    1) ENHANCED ELIMINATION is NOT RECOMMENDED.
    2) Enhanced elimination, especially hemoperfusion, is not indicated or useful (Personal Communication, 1995).

Range Of Toxicity

Summary

    A) TOXICITY: The World Health Organization (WHO) has classified thiofanox, technical grade, as pesticide class IB (highly hazardous). Acute toxicity depends strongly on kinetics of absorption (ie, sudden absorption of low toxicity compound may have a greater effect than gradual absorption of a higher toxicity compound).

Minimum Lethal Exposure

    A) PESTICIDE CLASSIFICATION
    1) The World Health Organization (WHO) has classified thiofanox, technical grade, as pesticide class IB (highly hazardous) (World Health Organization, 2006).
    2) Based on its acute oral toxicity in rats, thiofanox would be considered in HIGHLY TOXIC group of carbamates.

Maximum Tolerated Exposure

    A) SUMMARY
    1) The maximum tolerated human exposure to this agent has not been delineated.
    B) PEDIATRIC
    1) Note that CHILDREN MAY EXHIBIT DIFFERENT PREDOMINANT SIGNS of organophosphate poisoning from adults. In studies of children poisoned by organophosphate or carbamate compounds, the major symptoms in most of them were CNS depression, stupor, flaccidity, dyspnea, and coma. Other classical signs of organophosphate poisoning, such as miosis, fasciculations, bradycardia, excessive salivation and lacrimation, and gastrointestinal symptoms, were infrequent (Sofer et al, 1989) Lifshitz et al., 1999).
    2) Children tend to be more sensitive to organophosphates than adults (Zwiener & Ginsburg, 1988).
    C) CASE REPORTS
    1) ADULT
    a) Three workers at a pesticide-formulating plant developed symptoms of organophosphate poisoning associated with each worker wearing a uniform that was contaminated with 76% parathion and then laundered. The uniform had been laundered three times before the third worker wore it and he still developed nausea, vomiting, and red cell cholinesterase activity of 75% of normal (Clifford & Nies, 1989).

Workplace Standards

    A) ACGIH TLV Values for CAS39196-18-4 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS39196-18-4 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS39196-18-4 :
    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): Not Listed
    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 CAS39196-18-4 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) Reference: RTECS, 1999; HSDB, 1999
    1) LD50- (ORAL)RAT:
    a) 8500 mcg/kg
    b) 8.5 mg/kg
    2) LD50- (SKIN)RAT:
    a) Albino, 39 mg/kg

Physicochemical

Physical Characteristics

    A) Thiofanox is a colorless solid with a pungent odor (Sittig, 1991).

Molecular Weight

    A) 218.35 (Lewis, 1996)

References

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