CARBOFURAN

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

Specific Substances

1) 2,2-Dimethyl-7-coumaranyl N-methyl-carbamate
2) 2,2-dimethyl-2,3-dihydro-7-benzofuranylmethylcarbamate
3) 2,3-Dihydro-2,2-dimethylbenzofuranyl-7-N-methylcarbamate
4) 2,3-Dihydro-2,2-dimethyl-7-benzofuran-7-yl methylcarbamate
5) 2,3-Dihydro-2,2-dimethyl-7-benzofuranylmethylcarbamate
6) 7-Benzofuranol, 2,3-dihydro-2,2-dimethyl-,methylcarbamate
7) Bay 70143
8) Carbamic acid, methyl-, 2,2-dimethyl-2,3-dihydrobenzofuran-7-yl ester
9) Carbamic acid, methyl-, 2,3-dihydro-2,2-dimethyl-7-benzofuranyl ester
10) Carbofuran
11) Chinufur
12) Curaterr
13) D 1211
14) ENT 27,164
15) FMC 10242
16) Furadan
17) Furadan 3G
18) Furodan
19) Karbofuranu
20) Methyl carbamic acid 2,3-dihydro-2,2-dimethyl-7-benzofuranyl ester
21) NIA 10242
22) Niagara 10242
23) Niagara NIA-10242
24) OMS 864
25) Yaltox
26) CAS 1563-66-2
27) CARBOFURAN MIXTURE, LIQUID

1.2.1) MOLECULAR FORMULA
1) C12-H15-N-O3

Available Forms Sources

1) Pure carbofuran is a white crystalline solid. It is available in a technical grade (98% pure, in the form of a tan crystalline solid), as granules (at 2%, 3%, 5%, or 10%), as a wettable powder (at 50%, 75% or 80%), as a flowable paste (at 4 lb/gal or 48%) (Baron, 1991; CHRIS, 2000; Hayes, 1982a; Hayes & Laws, 1991a).
2) Carbofuran can be dissolved in a liquid carrier to form a water emulsifiable liquid. It is available in a seed treater form (AAR, 1998a; Baron, 1991; CHRIS, 2000).

1) It can be produced by the reaction of o-nitropehnol, methyallyl chloride, and methyl isocyanate, involving steps of dehydrochlorination, nitro reduction, diazotisation, hydration, and isocyanate addition (Ashford, 1994).

a) It can be prepared by cyclization and rearrangement of 2-methallyloxyphenol to form 7-hydroxybenzofuran, followed by esterification to from the carbamate (HSDB, 2000).
b) It can be generated by Claisen rearrangement and cyclization of 2-methallyloxy-1-nitrobenzene to 2,3-dihydro-2,2-dimethyl-7-nitrobenzofuran, followed by reduction, diazotiation, and concentration to form the phenol (HSDB, 2000).

1) Carbofuran is used as a broad-spectrum systemic insecticide, miticide, acaricide, and nematocide (ACGIH, 1991a; Budavari, 2000; Lewis, 1998; OHM/TADS, 2000).

a) Carbofuran is used as an agricultural systemic insecticide on sunflowers, fruits (such as strawberries and bananas), tobacco, beet, sorghum, oilseed rape, peanuts, potatoes, lucerne, groundnuts, soya beans, sugar cane, rice, cotton, coffee, cucurbits, lavender, mushrooms, corn, alfalfa, and other field crops. It is also used on ornamentals and forest trees (ACGIH, 1991a; Hartley & Kidd, 1987a; Lewis, 1997).
b) Carbofuran is also used as a pesticide in household products (Lewis, 1998).

Overview

Life Support

Clinical Effects

0.2.1)

A) The following are symptoms from carbamate insecticides in general, which are due to the anticholinesterase activity of this class of compounds. All of these effects may not be documented for carbofuran, but could potentially occur in individual cases.
B) USES: Carbofuran, a carbamate insecticide, is used as a systemic carbamate acaricide, insecticide, and nematicide. It is applied to soil to control insects and nematodes in ornamental plants, trees, and crops.
C) TOXICOLOGY: Carbamate insecticides competitively inhibit pseudocholinesterase and acetylcholinesterase, preventing hydrolysis and inactivation of acetylcholine. Acetylcholine accumulates at nerve junctions, causing malfunction of the sympathetic, parasympathetic, and peripheral nervous systems and some of the CNS. Clinical signs of cholinergic excess develop.
D) EPIDEMIOLOGY: Exposure to carbamate insecticides is common, but serious toxicity is unusual in the US. Common source of severe poisoning in developing countries. Toxicity generally less severe than with organophosphates.
E) 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.

0.2.3)

A) WITH POISONING/EXPOSURE

1) Hypoventilation and tachycardia or bradycardia may occur.

0.2.4)

A) WITH POISONING/EXPOSURE

1) Blurred vision, miosis, and eye irritation may commonly occur. Mydriasis may occur.

0.2.5)

A) WITH POISONING/EXPOSURE

1) Either bradycardia or tachycardia may occur.

0.2.6)

A) WITH POISONING/EXPOSURE

1) Copious secretions, respiratory insufficiency, and pulmonary edema may develop in serious poisonings.
2) Tachypnea, dyspnea, laryngeal irritation, aspiration pneumonitis, and bronchospasm may occur.

0.2.7)

A) WITH POISONING/EXPOSURE

1) Headache, blurred vision, tremor, seizures, paresis, mental depression, coma, delayed neuropathies, various dystonias, weakness, and muscle twitching may be noted.

0.2.8)

A) Nausea, vomiting, diarrhea, and abdominal cramping may be noted.

0.2.13)

A) WITH POISONING/EXPOSURE

1) Hemoglobin, total red blood cell count, platelets, erythrocyte sedimentation rate, and hematocrit were decreased in an animal study.

0.2.14)

A) WITH POISONING/EXPOSURE

1) Diaphoresis may be noted. Cyanosis may occur following severe respiratory depression.

0.2.20)

A) Teratogenic lesions, and adverse effects during pregnancy may occur.
B) Carbofuran did not appear in the milk of cows fed the pesticide for an extended period of time.
C) Carbofuran has been shown to cross the placental barrier in human poisoning cases.
D) No information about possible male reproductive effects was found in available references at the time of this review.

0.2.21)

A) At the time of this review, no studies were found on the possible carcinogenic effects of carbofuran in humans.

Laboratory Monitoring

Treatment Overview

0.4.2)

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: Activated charcoal is contraindicated because of possible respiratory depression and seizures and risk of aspiration. 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)

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)

A) Irrigate exposed eyes with water or normal saline. Systemic toxicity is unlikely to develop from ocular exposure alone.

0.4.5)

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)

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

Clinical Effects

Summary Of Exposure

Vital Signs

3.3.1)

A) WITH POISONING/EXPOSURE

1) Hypoventilation and tachycardia or bradycardia may occur.

3.3.2)

A) WITH POISONING/EXPOSURE

1) Diaphragmatic weakness may lead to respiratory depression (Gosselin et al, 1984; Gupta, 1994).
2) Tachypnea was a commonly observed sign, occurring in 54% of patients (n=13) dermally exposed to carbofuran (Satar et al, 2005)

3.3.5)

A) WITH POISONING/EXPOSURE

1) Either tachycardia or bradycardia may be noted (Satar et al, 2005; Hayes, 1982).

Heent

3.4.1)

A) WITH POISONING/EXPOSURE

1) Blurred vision, miosis, and eye irritation may commonly occur. Mydriasis may occur.

3.4.3)

A) WITH POISONING/EXPOSURE

1) Miosis and blurred vision may occur (Satar et al, 2005; Plunkett, 1976). Miosis is characteristic of severe and moderately severe poisonings, and may appear late (Aaron & Howland, 1998; Yang et al, 2000; Huang et al, 1998).
2) Dimming of vision and a burning sensation of the eyes may be noted (CHRIS, 1991).
3) Pupil dilation may occur as a nicotinic effect and may be present in up to 10% of patients (Aaron & Howland, 1998).

Cardiovascular

3.5.1)

A) WITH POISONING/EXPOSURE

1) Either bradycardia or tachycardia may occur.

3.5.2)

A) BRADYCARDIA

1) WITH POISONING/EXPOSURE

a) Either bradycardia or tachycardia may occur (Hayes, 1982). Muscarinic effects may include bradycardia (Aaron & Howland, 1998).

B) TACHYARRHYTHMIA

1) WITH POISONING/EXPOSURE

a) Nicotinic effects may include tachycardia and hypertension (Aaron & Howland, 1998; Yang et al, 2000).
b) INCIDENCE: Tachycardia was a commonly observed sign, occurring in 62% of patients (n=13) who were dermally exposed to carbofuran (Satar et al, 2005).

Respiratory

3.6.1)

A) WITH POISONING/EXPOSURE

3.6.2)

A) TACHYPNEA

1) WITH POISONING/EXPOSURE

a) INCIDENCE: Tachypnea was a commonly observed sign, occurring in 54% of patients (n=13) dermally exposed to carbofuran (Satar et al, 2005).

B) APNEA

1) WITH POISONING/EXPOSURE

a) The usual cause of death is respiratory failure as a result of respiratory muscle weakness and central depression of the respiratory drive (Aaron & Howland, 1998). Respiratory failure and coma were reported in a 23-year-old man following an intentional ingestion of 100 mL of carbofuran (Yang et al, 2000).
b) Respiratory depression, dyspnea and rales may be noted (Morgan, 1989).

C) ACUTE LUNG INJURY

1) WITH POISONING/EXPOSURE

a) Bronchospasm, chest tightness, and pulmonary edema may occur (Morgan, 1989).

1) CASE REPORT: A 26-year-old ingested a fatal quantity of carbofuran (up to 155 grams). Autopsy revealed acute visceral congestion and pulmonary edema. Death was reported due to anoxia as a result of respiratory paralysis from cholinesterase inhibition (Ferslew et al, 1992).
2) CASE REPORT: Patel (1993) reports a fatal case of suicidal ingestion of a carbamate insecticide with gross pulmonary edema present at autopsy. Death was presumed due to apnea from excessive uninhibited cholinergic activity (Patel, 1993).
3) CASE REPORT: A pregnant girl presented to the emergency department with symptoms of pulmonary edema following an ingestion of carbofuran. Fetal demise occurred before the second day (Klys et al, 1989).

b) Increased bronchial secretions may occur secondary to muscarinic effects (Aaron & Howland, 1998).
c) Laryngeal irritation, violent coughing, diaphoresis, 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).

D) PULMONARY ASPIRATION

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).

Neurologic

3.7.1)

A) WITH POISONING/EXPOSURE

1) Headache, blurred vision, tremor, seizures, paresis, mental depression, coma, delayed neuropathies, various dystonias, weakness, and muscle twitching may be noted.

3.7.2)

A) CENTRAL NERVOUS SYSTEM DEFICIT

1) WITH POISONING/EXPOSURE

a) Headache, blurred vision, miosis, tremor, paresis, and muscle twitching may be noted (Gosselin et al, 1984) CHRIS, 1991).
b) INCIDENCE: Headaches were reported in 46% of patients (n=13) following dermal exposure to carbofuran (Satar et al, 2005).

B) COMA

1) WITH POISONING/EXPOSURE

a) In severe poisoning, respiratory depression, mental confusion, lassitude, dizziness, incoordination, coma, and seizures may occur (Plunkett, 1976; Tobin, 1970; Gosselin et al, 1984). Coma and respiratory failure were reported in a 23-year-old man after ingestion of 100 mL of carbofuran (Yang et al, 2000).

C) SEIZURE

1) WITH POISONING/EXPOSURE

a) Seizures or dystonias may occur in severe poisonings. Children may be more susceptible to seizures than adults; in one series 2 children poisoned by carbamates had seizures (Zweiner & Ginsburg, 1988).

D) SPASMODIC MOVEMENT

1) WITH POISONING/EXPOSURE

a) Muscle fasciculations may develop as a nicotinic effect (Baron, 1991; Ekins & Geller, 1994).
b) Fasciculations occurred in 2 of 13 patients following dermal exposure to carbofuran (Satar et al, 2005).

E) SECONDARY PERIPHERAL NEUROPATHY

1) WITH POISONING/EXPOSURE

a) Various peripheral neuropathies have been reported after carbamate use. The symptoms are similar to those seen with organophosphates. Delayed axonal peripheral neuropathy has been described in one patient who ingested 500 mg/kg of carbaryl (Dickoff et al, 1987).
b) Carbofuran-induced delayed sensorimotor neuropathy, with notable paresthesia and difficulty walking, was reported in a 23-year-old man following an intentional ingestion of 100 mL of carbofuran. Recovery, which began at one week post-ingestion, continued for 4 months, although deep tendon reflexes continued to remain absent in the lower extremities (Yang et al, 2000).

F) MUSCLE WEAKNESS

1) WITH POISONING/EXPOSURE

a) Acute muscle weakness may occur as a nicotinic effect (Baron, 1991). Protracted malaise and weakness may occur after apparent recovery from carbamate poisoning (Garber, 1987).
b) INCIDENCE: Dizziness and weakness were reported in 23% and 31% of patients (n=13), respectively, following dermal exposure to carbofuran. The patients recovered following supportive care (Satar et al, 2005).

G) INTERMEDIATE SYNDROME

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 53-year-old man presented 2 hours after ingesting 250 g of carbofuran in a suicide attempt. He was conscious with fasciculations, excessive salivation and constricted pupils, a heart rate of 68 bpm and a blood pressure of 100/70 mmHg. Gastric lavage was performed, continuous atropine infusion was started and crystalline penicillin was given to cover any possible aspiration. He did not receive pralidoxime. On hospital day 3, he developed dyspnea, weakness of the neck flexors, shallow respirations at minutes and a drop in oxygen saturation, symptoms clinically characteristic of intermediate syndrome. On hospital day 5, ventilator-associated pneumonia was suspected and he was treated with third-generation cephalosporins, in spite of which his condition steadily deteriorated. He developed septic shock unresponsive to vasopressors and antibiotics and died on hospital day 8 (Paul & Mannathukkaran, 2005).

3.7.3)

A) ANIMAL STUDIES

1) ENZYME ABNORMALITY

a) Multiple intraperitoneal doses of furdan in mice caused a significant decrease in acetylcholinesterase activity and a significant increase in acetylcholine, gamma-amino-butyric acid, epinephrine, norepinephrine, dopamine, and 5-hydroxytryptamine concentrations (HSDB , 2000).

2) COMA

a) CAT: A cat poisoned with carbofuran presented with hindleg stiffness, profuse salivation and vomiting, and severe tonoclonic spasms. Following respiratory depression and cyanosis, the cat became comatose and was subsequently euthanized (McCoy et al, 1994).

Gastrointestinal

3.8.1)

A) Nausea, vomiting, diarrhea, and abdominal cramping may be noted.

3.8.2)

A) CHOLINERGIC CRISIS

1) WITH POISONING/EXPOSURE

a) Increased salivation, lacrimation, urinary incontinence, diarrhea, gastrointestinal cramping, and emesis (SLUDGE syndrome) may occur within 30 minutes after exposure. The syndrome may be indistinguishable from that seen following organophosphate poisoning (Gosselin et al, 1984; Plunkett, 1976; Tobin, 1970; Aaron & Howland, 1998; Huang et al, 1998).
b) INCIDENCE: Nausea, vomiting, and increased salivation were reported in 85%, 69%, and 46% of patients (n=13), respectively, following dermal exposure to carbofuran. Symptoms resolved with supportive care (Satar et al, 2005).

Hematologic

3.13.1)

A) WITH POISONING/EXPOSURE

1) Hemoglobin, total red blood cell count, platelets, erythrocyte sedimentation rate, and hematocrit were decreased in an animal study.

3.13.3)

A) ANIMAL STUDIES

1) BLOOD DYSCRASIA

a) HEMATOLOGIC ABNORMALITIES: Multiple intraperitoneal doses of furdan in mice caused a significant decrease in hemoglobin content, total red blood cell count, platelets, erythrocyte sedimentation rate, and hematocrit. Total white blood cells were increased and clotting time was prolonged; there was an increase in neutrophils and basophils and a decrease in the lymphocyte count (HSDB , 2000).

Dermatologic

3.14.1)

A) WITH POISONING/EXPOSURE

1) Diaphoresis may be noted. Cyanosis may occur following severe respiratory depression.

3.14.2)

A) EXCESSIVE SWEATING

1) WITH POISONING/EXPOSURE

a) Intense sweating, a muscarinic effect, may occur (Gupta, 1994; Plunkett, 1976; Huang et al, 1998).

B) CYANOSIS

1) WITH POISONING/EXPOSURE

a) Cyanosis, a result of significant respiratory depression, may occur following severe intoxications (Aaron & Howland, 1998).

C) STEVENS-JOHNSON SYNDROME

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 63-year-old farmer presented with a sensation of burning over his face and extremities and multiple erythematous papules and bullae with dermal denudation on his face, neck, and back 2 days after occupational dermal exposure to a carbofuran insecticide. A skin biopsy confirmed the suspected diagnosis of Stevens-Johnson syndrome. With supportive treatment including systemic corticosteroids and topical emollients, the patient gradually recovered and was discharged 2 weeks post-presentation (Lim et al, 2010).

3.14.3)

A) ANIMAL STUDIES

1) LACK OF EFFECT

a) SENSITIZATION: Skin sensitization reaction was not noted in guinea pigs (Baron, 1991).

Musculoskeletal

3.15.3)

A) ANIMAL STUDIES

1) ENZYME ABNORMALITY

a) Studies in rats administered sublethal doses of carbofuran demonstrated that overt toxic signs (muscle fasciculations and seizures) correlated well with reduced levels of ATP and phosphocreatine (PC) in hemidiaphragm muscle. In contrast, levels of AMP and creatine (CR) remained essentially unchanged. A significantly higher activity of creatine kinase was observed in the serum (Gupta et al, 1991; Gupta, 1994).

Immunologic

3.19.3)

A) ANIMAL STUDIES

1) IMMUNE SYSTEM DISORDER

a) Results of a study in pregnant mice that received carbofuran throughout gestation suggest that prenatal exposure may result in moderate disturbances of serum concentrations of immunoglobulins in apparently normal mice (HSDB , 2000).

2) LACK OF EFFECT

a) No statistically significant alterations on induced cellular or humoral immune responses were noted in rabbits exposed to carbofuran (Street & Sharma, 1975).

Reproductive

3.20.1)

3.20.2)

A) CONGENITAL ANOMALY

1) Carbofuran caused teratogenic lesions in chick embryos (Gosselin et al, 1984).
2) Alterations of the normal pattern of fetal rat brain acetylcholinesterase isoenzymes were noted when the dams were given intragastric doses of 2.5 mg/kg of carbofuran (Cambon et al, 1980).

a) Administration of carbofuran to pregnant rats significantly depressed acetylcholinesterase activity in the brains of both the dams and fetuses by one hour after treatment and this effect lasted for about 24 hours (Cambon et al, 1979).
b) In many instances, fetal brain acetylcholinesterase was more severely affected than maternal enzyme activity (Cambon et al, 1979).

3) Teratogenic effects have been noted in the offspring of pregnant mice and rats exposed to carbofuran (RTECS , 2000; Anon, 1978).
4) Teratogenic lesions in chick embryos have been produced (Gosselin et al, 1984). N-nitroso derivatives of carbofuran and its metabolites are mutagenic and carbofuran is a suspected carcinogen (Nelson et al, 1981) CHRIS, 1991).

B) SKELETAL MALFORMATION

1) Pre-implantation mortality and post-implantation mortality have been observed in rat studies. Biochemical and metabolic effects on the newborn; specific developmental abnormalities in the immune, reticuloendothelial, and musculoskeletal systems; delayed effects on the newborn; fetotoxicity; and fetal death have been observed in mouse studies (RTECS , 2000).

C) LACK OF EFFECTS

1) Carbofuran was not fetotoxic or teratogenic in rats or mice (Courtney, 1985; Cranmer, 1978). It did not cause birth defects in rats, dogs, or rabbits (McCarthy, 1971).

3.20.3)

A) PLACENTAL BARRIER

1) Carbofuran has been shown to cross the placental barrier in human poisoning cases (Sancewicz-Pach et al, 1997; Klys et al, 1989).
2) ANIMAL STUDIES - Carbofuran had postnatal effects on the immune system in mice (Cranmer, 1979; Barnet, 1980).

B) ABORTION

1) Two cases of carbofuran poisoning in pregnant women resulted in fetal death (at 18 weeks of pregnancy) and spontaneous abortion (at 12 weeks of pregnancy) (Sancewicz-Pach et al, 1997).

a) A woman 18 weeks pregnant ingested carbofuran to commit suicide. The mother recovered from the poisoning but there was fetal demise. Postmortem examination revealed a macerated, intrauterine-dead fetus with no congenital defects (Klys et al, 1989).

C) ANIMAL STUDIES

1) Carbofuran resulted in enhanced pre-implantation losses when administered at a dose of 0.4 or 0.8 mg/kg orally in rats on days 1-5 of pregnancy (Jayatunga et al, 1998).
2) In Swiss albino mice, carbofuran 1.3 mg/kg/day dosed for 30 days caused a significant decrease in the number of estrous cycles and duration of proestrus, estrus, and metestrus. There was a concomitant significant increase in the diestrus phase. The same dose for mice treated for 5, 10, and 20 days caused no significant change in the number or duration of the estrous cycle (Baligar & Kaliwal, 2003).
3) ENZYME ABNORMALITY

a) ANIMAL STUDIES

1) Carbofuran administration caused significantly depressed acetylcholinesterase activity in the brains of pregnant rats (Cambon et al, 1979). When given to rats at a dose of 0.05 to 2.5 mg/kg during pregnancy, it inhibited fetal cholinesterase (Cambon et al, 1980; Declume, 1980) more so than the maternal enzyme (Cambon et al, 1979).
2) A transplacental effect on activity of acetylcholinesterase has been observed in the day 18 rat fetus (HSDB , 2000).
3) IMMUNOGLOBULINS - Results of a study in pregnant mice who received carbofuran throughout gestation suggest that prenatal exposure may result in moderate disturbances of serum concentrations of immunoglobulins in apparently normal mice (HSDB , 2000).

3.20.4)

A) BREAST MILK

1) Dairy cattle fed 0.5 to 3 grams of carbofuran mixed with corn silage for 28 to 56 days developed typical symptoms of mild intoxication and had 3-hydroxycarbofuran (a metabolite), but no carbofuran itself, in the milk (Miles et al, 1971).

3.20.5)

A) ANIMAL STUDIES

1) Carbofuran did not affect fertility in mice (Cranmer, 1978).

Carcinogenicity

3.21.1)

A) IARC Carcinogenicity Ratings for CAS1563-66-2 (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)

A) At the time of this review, no studies were found on the possible carcinogenic effects of carbofuran in humans.

3.21.4)

A) CARCINOMA

1) Carbofuran was not carcinogenic in mice (Hayes & Laws, 1991).

Genotoxicity

1) Carbofuran induced chromosome damage in human cells in culture, but its end metabolite was inactive.
2) Using the mutations in microorganisms system, mutations were detected in bacteria (S. typhimurium and other microorganisms). Using the mutations in mammalian somatic cells system, mutations were observed in hamster lung cells. Carbofuran was negative in another mutagenicity assay.
3) Mutagenic N-nitroso derivatives of carbofuran could be formed under conditions found in the human stomach.

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Monitor vital signs frequently. Obtain serial ECGs and Institute continuous cardiac and pulse oximetry monitoring.
B) Monitor for respiratory distress (i.e. bronchorrhea, bronchospasm) and for clinical evidence of cholinergic excess (i.e. 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 (i.e. forced vital capacity, expiratory volume in 1 second, negative inspiratory force) in symptomatic patients; may help anticipate need for intubation.
F) Obtain a chest x-ray in all symptomatic patients.

4.1.2)

A) BLOOD/SERUM CHEMISTRY

1) Cholinesterase levels can be done by specialized toxicology laboratories, but are not generally useful in sublethal exposures due to the rapid hydrolysis of the carbamylated acetylcholinesterase. Unless the patient has had extraordinary exposure to an N-methyl carbamate compound (such as carbofuran), 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.
2) In symptomatic patients, the red blood cell and serum cholinesterase activity correlated in 20 of 24 patients (Zweiner & Ginsburg, 1988).
3) The degree of intoxication may be strongly correlated to the depression of acetylcholinesterase activity (Case, 1974; Palmer & Schlinke, 1973).

4.1.3)

A) URINARY LEVELS

1) One technique for assessing absorption of the principal N-methyl carbamate compounds is measurement of specific phenolic metabolites in urine. These are alpha-naphthol (from carbaryl), isopropoxyphenol (from propoxur), carbofuranphenol (from carbofuran), and certain others.

4.1.4)

A) OTHER

1) ECG

a) Monitor ECG for significant bradycardia or tachyarrhythmias.

Radiographic Studies

1) If respiratory depression or pulmonary edema occur, monitor chest x-ray.

Methods

1) Cholinesterase levels can be done by specialized toxicology laboratories. Unless the patient has had extraordinary exposure to an N-methyl carbamate compound (such as carbofuran), 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).
2) Carbofuran may be detected and measured in various biological fluids by thin layer chromatography and UV light (Ferslew et al, 1992).

Treatment

Life Support

Patient Disposition

6.3.1)

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

Oral Exposure

6.5.1)

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) 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)

A) SUMMARY

1) Activated charcoal should be administered if ingestion has been recent. Seizures may occur; protect the airway.

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)

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.
6) Obtain a chest x-ray in all symptomatic patients.

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).

b) INDICATIONS: After adequate atropinization, pralidoxime may be indicated in the following situations (Consensus, 1986).

1) Life-threatening symptoms such as severe muscle weakness, fasciculations, paralysis, or decreased respiratory effort.
2) Continued excessive requirements of atropine.
3) Concomitant organophosphate and carbamate exposure.

2) INCREASED TOXICITY WITH USE

a) 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).
b) 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. A total of 5 animals were studied (Natoff & Reiff, 1973).

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, 1992).
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 emergency department 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).
2) LD50 data for pralidoxime alone (no carbaryl) in rats was not done in this study.

5) CASE SERIES

a) OBIDOXIME: Twenty-six 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.

1) 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).

6) 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.

7) 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).

8) 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).

9) 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, 2010; 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) CARBOFURAN

1) Specific carbamate recommendations include:
2) CARBOFURAN: In a case of voluntary acute carbofuran poisoning, pancuronium bromide with assisted ventilation and diazepam were used to treat a persistent nicotinic myoclonic state (Poirier et al, 1987).

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) EXPERIMENTAL THERAPY

1) CIMETIDINE: Additional studies are needed to determine the clinical significance of these findings.
2) 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) They did not measure serial cholinesterase levels in the human volunteer, which would have made the study more believable. The exact mechanism of carbaryl metabolism is unknown.

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)

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)

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)

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

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

Abstracts

Case Reports

1) INHALATION: Significant occupational exposure can occur: a worker who attempted to clean a piece of equipment which had been used to apply carbofuran granules was hospitalized in a coma but presumably recovered after 3 days of treatment (Maddy & Edmiston, 1988).
2) ORAL: In a case of voluntary acute carbofuran poisoning, pancuronium bromide with assisted ventilation and diazepam were used to treat a persistent nicotinic myoclonic state; rhabdomyolysis was not observed (Poirer et al, 1987).
3) ORAL: A fatal case of carbofuran ingestion is reported. A 26-year-old man intentionally ingested 155 grams and was found dead. Autopsy revealed acute visceral congestion and pulmonary edema. Death was attributed to anoxia due to respiratory paralysis (Ferslew et al, 1992).
4) ORAL: A 17-year-old pregnant girl ingested carbofuran in a suicide attempt. She presented to the emergency department unconscious with symptoms of pulmonary edema. Following therapy with atropine (10 to 15 mg in 24 hours) the patient recovered. The fetus, however, perished and was delivered as a stillbirth with no congenital anomalies present (Klys et al, 1989).

Range Of Toxicity

Summary

Minimum Lethal Exposure

1) A suicidal ingestion of 155 grams of carbofuran proved fatal to a 26-year-old man. Death was attributed to anoxia due to respiratory paralysis (Ferslew et al, 1992).
2) Between 7 drops and 1 teaspoon of carbofuran may be fatal to humans. It is considered extremely toxic (OHM/TADS , 2000).

1) The 30-day empirical minimum lethal dosage is 0.2 mg/kg/day for mallards and 4.2 mg/kg/day for pheasants (HSDB , 2000).
2) After 17 g/kg of carbofuran was applied to the skin of rabbits for 20 days intermittently, death occurred (RTECS , 2000).
3) After 1960 mg/kg of carbofuran was administered orally to chickens for 2 weeks continuously, death occurred (RTECS , 2000).
4) Although carbofuran is not irritating to rabbit eyes, ocular exposure has caused death in rabbits (Hayes & Laws, 1991).

Maximum Tolerated Exposure

1) The World Health Organization (WHO) has classified carbofuran as pesticide class IB (highly hazardous) (World Health Organization, 2006).

1) Workers exposed to a concentration of nearly 0.1 mg/m(3) per day have not demonstrated adverse effects (ACGIH, 1986).
2) Workers wearing respirators in areas with air concentrations of 0.007 to 0.642 mg/m(3) did not report any symptoms (Tobin, 1970).
3) A woman developed acetylcholinesterase activity inhibition of 50% to 80% of normal following oral exposure to 60 mg of carbofuran. All symptoms resolved and complete recovery was noted within 72 hours (Izmirova et al, 1981).
4) A 23-year-old man was admitted to the hospital in a coma, and with respiratory failure, miosis, tachycardia, and hypertension a few hours after ingesting approximately 100 mL carbofuran. He survived, but he exhibited carbofuran-induced delayed sensorimotor neuropathy which continued for 4 months after exposure (Yang et al, 2000).
5) Grain farmers exposed dermally to 1,262 mcg/kg of carbofuran exhibited no acute adverse effects during the exposure and for 4 days post-exposure. The farmers were reported to excrete approximately 28 mcg/kg of carbofuran in their urine. No ChE inhibition was reported (Hussain et al, 1990).
6) Twenty-five pesticide industry workers exposed acutely to airborne carbofuran concentrations ranging from 0.018 to 1.115 mg/m(3) experienced acute toxicity, with onset ranging from 0.5 to 3 hours (mean, 1.5 hours). Most recovered within 2 to 3 hours following removal from exposure. In 24 cases, blood ChE activities were inhibited (Huang et al, 1998).

1) 4.5 mg/kg of carbofuran is the minimum toxic dose for cattle and sheep (Lewis, 1998).
2) In Rhesus monkeys, slight cholinesterase depression occurred with exposure to 0.86 mg/m(3) of carbofuran in the form of 75% wettable powder (ACGIH, 1991).
3) Dogs ingesting 500 ppm of carbofuran in their diet for 1 year showed a loss in body weight (which was associated with food retension), loose stools, testicular degeneration, weight reduction of the brain and heart, inflammation in the lungs, and depression of plasma acetylcholinesterase activity, hematocrit, hemoglobin, and erythrocyte count, with concurrent changes in electrolyte values (Hayes & Laws, 1991).
4) Rats given carbofuran in their diet at 100 ppm for 2 years showeda loss in body weight and a moderate reduction of acetylcholinesterase activities in plasma, erythrocytes, and brain (Hayes & Laws, 1991).
5) In rats, carbofuran inhibits acetylcholinesterase in maternal tissues to a lesser degree than the fetal tissues (HSDB , 2000).
6) Dermal application of carbofuran at 1000 mg/kg caused minimal symptoms in rats with no deaths (HSDB , 2000).
7) Rats ingesting 100 ppm of carbofuran through their diet were reported having no increase in birth defects in their offspring; however, the offspring survival rate decreased (HSDB , 2000).
8) Mice treated with multiple IP doses of carbofuran at 0.25 mg/kg caused significant decrease in lymphocyte count hemoglobin content, red blood cells total count, platelet count, erythrocyte sedimentation rate, and hematocrit value; increase in white blood cells total count, neutrophil count, and basophil count; bone marrow depression; and splenic hyperplasia (HSDB , 2000).

Serum Plasma Blood Concentrations

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) CASE REPORTS

a) Ferslew et al (1992) reported serum carbofuran levels of 29.3 mcg/mL with a greater than 92% inhibition of cholinesterase activity in a fatal case of a 155 gram suicidal ingestion.
b) Out of 24 acute toxic occupational airborne exposures to carbofuran, whole blood ChE was reported to range from 31% to 50% in 4 cases, from 51% to 70% in 18 cases, above 70% in one case and below 30% in another case. In most cases, recovery of inhibited ChE activities occurred within 2 to 4 hours, and in a few cases within 10 hours or more (Huang et al, 1998).

2) ANIMAL DATA

a) RATS - The depression of acetylcholinesterase activity was correlated with plasma levels of carbofuran and its metabolite, 3-hydroxycarbofuran, after injection or ingestion in rats (Ferguson et al, 1984).

Workplace Standards

1) Editor's Note: The listed values are recommendations or guidelines developed by ACGIH(R) to assist in the control of health hazards. They should only be used, interpreted and applied by individuals trained in industrial hygiene. Before applying these values, it is imperative to read the introduction to each section in the current TLVs(R) and BEI(R) Book and become familiar with the constraints and limitations to their use. Always consult the Documentation of the TLVs(R) and BEIs(R) before applying these recommendations and guidelines.

a) Adopted Value

1) Carbofuran

a) TLV:

1) TLV-TWA: 0.1 mg/m(3)
2) TLV-STEL:
3) TLV-Ceiling:

b) Notations and Endnotes:

1) Carcinogenicity Category: A4
2) Codes: BEI(A), IFV
3) Definitions:

a) A4: Not Classifiable as a Human Carcinogen: Agents which cause concern that they could be carcinogenic for humans but which cannot be assessed conclusively because of a lack of data. In vitro or animal studies do not provide indications of carcinogenicity which are sufficient to classify the agent into one of the other categories.
b) BEI(A): The BEI notation is listed when a BEI is also recommended for the substance listed. Biological monitoring should be instituted for such substances to evaluate the total exposure from all sources, including dermal, ingestion, or non-occupational. Substances identified as Acetylcholinesterase Inhibiting Pesticides are part of this notation.
c) IFV: Inhalable fraction and vapor.

c) TLV Basis - Critical Effect(s): Cholinesterase inhibition
d) Molecular Weight: 221.30

1) For gases and vapors, to convert the TLV from ppm to mg/m(3):

a) [(TLV in ppm)(gram molecular weight of substance)]/24.45

2) For gases and vapors, to convert the TLV from mg/m(3) to ppm:

a) [(TLV in mg/m(3))(24.45)]/gram molecular weight of substance

e) Additional information:

B) NIOSH REL and IDLH Values for CAS1563-66-2 (National Institute for Occupational Safety and Health, 2007):

1) Listed as: Carbofuran
2) REL:

a) TWA: 0.1 mg/m(3)
b) STEL:
c) Ceiling:
d) Carcinogen Listing: (Not Listed) Not Listed
e) Skin Designation: Not Listed
f) Note(s):

3) IDLH: Not Listed

C) Carcinogenicity Ratings for CAS1563-66-2 :

1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): A4 ; Listed as: Carbofuran

2) EPA (U.S. Environmental Protection Agency, 2011): Not Assessed under the IRIS program. ; Listed as: Carbofuran
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 ; Listed as: Carbofuran
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 CAS1563-66-2 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):

1) Not Listed

Toxicity Information

7.7.1)

A) References: ACGIH, 1991 EPA, 1988 Hartley & Kidd, 1987 Hayes, 1982 HSDB, 2000 ) OHM/TADS, 2000 RTECS, 2000

1) LD50- (ORAL)HUMAN:

a) 11 mg/kg (OHM/TADS, 2000)

2) LD50- (SKIN)HUMAN:

a) 10,000 mg/kg (OHM/TADS, 2000)

3) LD50- (ORAL)MOUSE:

a) 14.4 mg/kg (EPA, 1988)
b) 2 mg/kg

4) LD50- (INHALATION)RAT:

a) >0.026 mg/L for 1H (EPA, 1988)
b) 0.075 - 0.108 mg/L for 4H (EPA, 1988)

5) LD50- (OCULAR)RAT:

a) 21.5 mg/kg -- in the form of 25% wettable powder (HSDB, 2000)
b) 18 mg/kg -- in the form of 75% wettable powder (HSDB, 2000)

6) LD50- (ORAL)RAT:

a) Male, 8.7 mg/kg (ACGIH, 1991)
b) Female, 8 mg/kg (ACGIH, 1991)
c) 132 mg/kg -- in the form of 10% granule (Hayes, 1982)
d) 19 mg/kg -- in the form of 75% wettable powder (ACGIH, 1991; Hayes, 1982)
e) 8.2 - 14.1 mg/kg -- in the technical grade (Hartley & Kidd, 1987; Hayes, 1982)
f) 5.3 mg/kg (OHM/TADS, 2000)
g) 5 mg/kg
h) 3.8 - 34.5 mg/kg (EPA, 1988)

7) LD50- (SKIN)RAT:

a) 1350 mg/kg -- in the form of 4 lb/gal flowable powder (HSDB, 2000)
b) 120 mg/kg

Pharmacology Toxicology

Toxicologic Mechanism

1) The inhibitory effect of carbofuran on cholinesterase enzymes is due to carbamylation of the esteratic sites on the enzyme molecule. The chemical bond is much more labile than that characterizing the phosphorylation by organophosphate insecticides.

a) In general, this feature tends to make poisonings by carbofuran less prolonged than poisonings by organophosphates, but clinical manifestations may be as acutely severe (Aaron & Howland, 1998).

2) INJECTION - Following injection of 50 mcg/kg in rats, acetylcholinesterase activity was depressed by 83 percent in two minutes (Ferguson et al, 1984).
3) ORAL EXPOSURE - With oral exposure, acetylcholinesterase activity was depressed by 37 percent within 15 minutes of ingestion (Ferguson et al, 1984). Recovery of acetylcholinesterase activity parallels carbofuran elimination (Ferguson et al, 1984).

Physicochemical

Physical Characteristics

Molecular Weight

Other

1) Odorless for pure material (CHRIS , 2000; HSDB , 2000)

Animal Toxicology

References

General Bibliography

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FeedBack

CARBOFURAN

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Summary Of Exposure

Vital Signs

Heent

Cardiovascular

Respiratory

Neurologic

Gastrointestinal

Hematologic

Dermatologic

Musculoskeletal

Immunologic

Reproductive

Carcinogenicity

Genotoxicity

Monitoring Parameters Levels

Radiographic Studies

Methods

Life Support

Patient Disposition

Monitoring

Oral Exposure

Inhalation Exposure

Eye Exposure

Dermal Exposure

Enhanced Elimination

Case Reports

Summary

Minimum Lethal Exposure

Maximum Tolerated Exposure

Serum Plasma Blood Concentrations

Workplace Standards

Toxicity Information

Toxicologic Mechanism

Physical Characteristics

Molecular Weight

Other

General Bibliography