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PIPERONYL BUTOXIDE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Piperonyl butoxide is an insecticide and acaricide which is used as a synergist (by enzyme inhibition) to increase the potency of pyrethrins and rotenone.

Specific Substances

    1) 3,4-methylenedioxy-6-propylbenzyl
    2) Butyl carbitol 6-propylpiperonyl ether
    3) butyl carbityl-6-(propyl piperonyl) ether
    4) ENT 14,250
    5) N-butyl diethyleneglycol ether
    6) NCI-c 02813
    7) NIOSH/RTECS XS 8050000
    8) NIA 5273
    9) CAS 51-03-6
    10) References: Sax, 1984
    1.2.1) MOLECULAR FORMULA
    1) C19-H30-O5

Available Forms Sources

    A) FORMS
    1) TRADE NAMES
    a) Butacide(R)
    b) Prento(R)
    c) Pybuthrin(R)

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: Piperonyl butoxide is an insecticide and acaricide which is used as a synergist (by enzyme inhibition) to increase the potency of pyrethrins and rotenone. This chemical is often combined with hydrocarbons or other insecticides.
    B) TOXICOLOGY: Piperonyl butoxide inhibits mixed function oxidase enzymes of the liver which metabolize pyrethrins and pyrethroids, with which they are combined. Acute oral or dermal exposure is unlikely to result in significant signs and symptoms of systemic toxicity or dermal irritation.
    C) EPIDEMIOLOGY: Exposures to piperonyl butoxide are common but significant toxicity is rare.
    D) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Piperonyl butoxide is minimally toxic. Skin irritation or significant percutaneous absorption is not expected following normal dermal exposure. Nausea, vomiting, anorexia, or diarrhea, eye irritation may be seen. One case of pathological laughter has been reported with human exposure.
    2) SEVERE TOXICITY: Not reported in humans. Primary sources of data are from animals which include reports of hyperexcitability, unsteadiness, anemias, liver injury, coma, seizures, and brain damage in large overdoses.
    0.2.20) REPRODUCTIVE
    A) Mixed results for teratogenicity have been obtained in animals.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, no studies were found on the possible carcinogenic activity of piperonyl butoxide in humans.

Laboratory Monitoring

    A) No specific laboratory tests are necessary unless otherwise clinically indicated.
    B) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    C) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) TREATMENT OF TOXICITY
    1) Treatment is symptomatic and supportive.
    B) DECONTAMINATION
    1) ORAL EXPOSURE: Prehospital gastrointestinal decontamination is generally not indicated; minor exposures generally do not cause toxicity. Gastrointestinal decontamination is only indicated if there is a coingestant with significant toxicity.
    2) INHALATION EXPOSURE: Move patient to fresh air. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with inhaled beta-2 agonist and corticosteroids.
    3) OCULAR EXPOSURE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia occurs, patient should be seen in a healthcare facility.
    4) DERMAL EXPOSURE: Remove contaminated clothing and wash exposed area thoroughly.
    C) AIRWAY MANAGEMENTS
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with severe respiratory distress or acute allergic reaction.
    D) ANTIDOTE
    1) None.
    E) HYPERSENSITIVITY REACTION
    1) MILD/MODERATE: Antihistamines with or without inhaled beta agonists, corticosteroids or epinephrine. SEVERE: Oxygen, aggressive airway management, antihistamines, epinephrine, corticosteroids, ECG monitoring, and IV fluids.
    F) ENHANCED ELIMINATION PROCEDURE
    1) Hemodialysis is not recommended given the low toxicity of this agent.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: Most unintentional exposures in patients who are asymptomatic may be watched at home.
    2) OBSERVATION CRITERIA: Patients with deliberate exposure, and those with more than mild symptoms or any evidence of bronchospasm or acute allergic reaction should be referred to a healthcare facility.
    3) ADMISSION CRITERIA: Patients who remain symptomatic despite adequate supportive care may require admission.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    H) PITFALLS
    1) Failure to recognize that a product may contain other dangerous insecticides.
    I) TOXICOKINETICS
    1) Absorption: Poorly absorbed orally; not appreciably absorbed from the skin. Excretion: In animals, it was rapidly excreted in the urine after oral administration; 78 to 87% of an administered dose was excreted in the feces.
    J) DIFFERENTIAL DIAGNOSIS
    1) Irritating gas exposures such as chlorine and chloramine. Also can mimic substances that can trigger bronchospasm especially in asthmatic patients.
    0.4.3) INHALATION EXPOSURE
    A) INHALATION: Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm.
    0.4.4) EYE EXPOSURE
    A) DECONTAMINATION: 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, the patient should be seen in a healthcare facility.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    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. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Range Of Toxicity

    A) TOXICITY: Piperonyl butoxide is minimally toxic; specific toxic dose has not been determined. There have been no human deaths reported due to acute exposure. No irritation or toxic effects have been observed after dermal contact. Male volunteers tolerated a single oral dose of 50 mg (0.71 mg/kg body weight) piperonyl butoxide with no signs of toxicity.

Clinical Effects

Summary Of Exposure

    A) USES: Piperonyl butoxide is an insecticide and acaricide which is used as a synergist (by enzyme inhibition) to increase the potency of pyrethrins and rotenone. This chemical is often combined with hydrocarbons or other insecticides.
    B) TOXICOLOGY: Piperonyl butoxide inhibits mixed function oxidase enzymes of the liver which metabolize pyrethrins and pyrethroids, with which they are combined. Acute oral or dermal exposure is unlikely to result in significant signs and symptoms of systemic toxicity or dermal irritation.
    C) EPIDEMIOLOGY: Exposures to piperonyl butoxide are common but significant toxicity is rare.
    D) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Piperonyl butoxide is minimally toxic. Skin irritation or significant percutaneous absorption is not expected following normal dermal exposure. Nausea, vomiting, anorexia, or diarrhea, eye irritation may be seen. One case of pathological laughter has been reported with human exposure.
    2) SEVERE TOXICITY: Not reported in humans. Primary sources of data are from animals which include reports of hyperexcitability, unsteadiness, anemias, liver injury, coma, seizures, and brain damage in large overdoses.

Heent

    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) Piperonyl butoxide may be mildly irritating, but is not damaging (Grant, 1993).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM FINDING
    1) PATHOLOGICAL LAUGHTER
    a) CASE REPORT: Pathological laughter, tremors, and a feeling of generalized numbness were reported in a 33-year-old male immediately after inhalation of an insecticide containing 1.0% technical piperonyl butoxide, 1.0% N-octyl-bicycloheptene dicarboximide, and 8.0% refined petroleum oil. The remaining neurological exam was normal. The laughter persisted for almost 2 hours until the patient complained of abdominal pain and general fatigue and was given diazepam 5 mg IV with immediate relief of symptoms (Zellers et al, 1990).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) COMA
    a) Coma was seen just before death in acutely poisoned animals (Hayes, 1982).
    2) SEIZURES
    a) Seizures were seen in rabbits given 1880 mg/kg dermally (Lehman AJ, 1952).
    3) NERVOUSNESS
    a) Hyperexcitability and unsteadiness were seen in animals following a large, single oral dose (Lehman AJ, 1952).
    4) BRAIN STEM DISORDER
    a) Rats within the first 4 days showed damage to ganglion cells of the brain stem (Sarles & Vandegrift, 1952).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) VOMITING
    1) WITH POISONING/EXPOSURE
    a) Nausea and vomiting may occur (Sax, 1984).
    B) LOSS OF APPETITE
    1) WITH POISONING/EXPOSURE
    a) Anorexia may be seen after a large single dose (Hayes, 1982).
    C) DIARRHEA
    1) WITH POISONING/EXPOSURE
    a) Diarrhea may occur (Sax, 1984).

Hepatic

    3.9.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HEPATOCELLULAR DAMAGE
    a) Liver injury may occur after single large doses.
    b) RATS killed with a single large dose showed fatty changes and hydroscopic swelling of the nucleus with cytoplasmic vacuolation (Sarles & Vandegrift, 1952).
    c) DOGS: A dog given a dose of 31 mg/kg/day developed liver injury; another dog tolerated this dose with a slightly increased liver weight (Hayes, 1982).

Hematologic

    3.13.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) ANEMIA
    a) Anemias have been seen in animal studies (Arena & Drew, 1986).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) CELLULITIS
    1) WITH POISONING/EXPOSURE
    a) Cellulitis occurred around the injection site when a commercial spray was injected subcutaneously and intravenously. The causal agent was impossible to determine (Goldberg et al, 1982).
    b) CASE REPORT: Two cases of cellulitis occurred after subcutaneous and intravenous injection of a commercial household spray containing chlorinated hydrocarbons, piperonyl butoxide, pyrethrins, carbamates, and hydrocarbons. A sterile abscess was also seen (Goldberg et al, 1982).

Reproductive

    3.20.1) SUMMARY
    A) Mixed results for teratogenicity have been obtained in animals.
    3.20.2) TERATOGENICITY
    A) CONGENITAL ANOMALY
    1) Two sisters exposed to PB and other insecticides during the first trimester of pregnancy each had a male infant with coarctation of the aorta (Hall et al, 1975). In these cases the possible contribution of the other chemicals and/or genetic factors cannot be ruled out.
    B) ANIMAL STUDIES
    1) Both positive and negative studies have been reported.
    a) RATS tolerated 84 mg/kg/day through 2 generations without effects. Rats given 300 or 1,000 mg/kg/day on gestation days 6 to 15 had no or little maternal toxicity, and no fetal anomalies (Kennedy et al, 1977).
    b) RABBITS/MICE - Teratogenic effects, including microphthalmia, have been demonstrated in one strain of mice and in a rabbit study, at doses that produced maternal toxicity.
    1) Oligodactyly, along with increased fetal deaths and lower fetal body weights, were seen in offspring of pregnant CD-1 mice given 1065 to 1800 mg/kg by gavage on day 9 of gestation (Tanaka et al, 1994).
    2) Negative teratogenic studies have been reported in other strains of mice and in rabbits (TERIS , 1991).
    c) Piperonyl butoxide was fetotoxic and teratogenic in CD-1 mice. Fetuses from dams given doses of 1065 to 1800 mg/kg by gavage on day 9 of gestation had increased early and late fetal deaths, and reduced fetal body weights. Significant increases in oligodactyly were also seen (Tanaka et al, 1994). Studies in rats at these doses on days 11 to 12 of gestation produced similar effects as well as limb deformity, but maternal weight gain was also affected at these doses (Tanaka et al, 1995).
    d) Female reproduction and postnatal growth were reduced in rats (HSDB). PB was listed as being a potential reproductive hazard in a preliminary study from the National Cancer Institute (Schwetz, 1976).
    e) In a 3-generation reproductive study in mice, piperonyl butoxide was given at levels up to 0.8% in the diet. It produced smaller litter size and weight in groups receiving higher doses. Survival of pups was reduced at the highest dose in each generation. Few differences were seen in neurobehavioral tests in the first generation, but second generation mice showed deviations in surface righting, olfactory orientation, and cliff avoidance. Piperonyl butoxide was apparently not teratogenic, but was fetotoxic. It induced neurobehavioral changes with increasing severity in subsequent generations (Tanaka et al, 1992).
    f) PB was embryotoxic and fetotoxic in mice when injected subcutaneously, and also caused eye or ear birth defects (RTECS). It was teratogenic in rabbits (Schwetz, 1976), but did not cause birth defects in mice (Schwetz, 1976) or rats (Kennedy et al, 1977) Khera et al, 1979).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    Pyrethrins with piperonyl butoxideC
    Reference: Briggs et al, 1998.

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS51-03-6 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) IARC Classification
    a) Listed as: Piperonyl butoxide
    b) Carcinogen Rating: 3
    1) The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.
    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, no studies were found on the possible carcinogenic activity of piperonyl butoxide in humans.
    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.
    3.21.4) ANIMAL STUDIES
    A) CARCINOMA
    1) Piperonyl butoxide has caused increases in tumors in rats and mice, but interpretation of the results has been difficult because the control values were low in comparison with historical controls (p 112). Similarly ambiguous results were found in a feeding study in rats where the increases in tumors were not dose-related (Cardy, 1979).
    2) Piperonyl butoxide induced liver tumors in male and female rats when given in the diet for nearly 2 years at levels up to 2.4% (Takahashi et al, 1994b). In an 18-month study in mice, some carcinogenic effects were seen at a single high dose used (Falk, 1971). Mice given 0.6% or 1.2% piperonyl butoxide in the diet for 12 months developed hepatocellular carcinomas (Takahashi et al, 1994a).
    3) One possible confounder in these studies is the ability of PB to interact with other carcinogens (Falk & Kotin, 1969) Schuller, no date). PB greatly inhibited tumor development when given with butylated hydroxytoluene (Witschi & Morse, 1985), but did not suppress dimethylnitrosamine tumorigenesis (Witschi & Morse, 1985). It increased hepatomas when given SC with either Freon 112 or Freon 113 in mice (Hayes & Laws, 1991).

Genotoxicity

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

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) No specific laboratory tests are necessary unless otherwise clinically indicated.
    B) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    C) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients who remain symptomatic despite adequate supportive care may require admission.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Most unintentional exposures in patients who are asymptomatic may be watched at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with deliberate exposure, and those with more than mild symptoms or any evidence of bronchospasm or acute allergic reaction should be referred to a healthcare facility.

Monitoring

    A) No specific laboratory tests are necessary unless otherwise clinically indicated.
    B) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    C) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ORAL EXPOSURE
    1) Piperonyl butoxide is of low toxicity. Prehospital gastrointestinal decontamination is generally not indicated. Gastrointestinal decontamination is only indicated if there is a coingestant with significant toxicity.
    B) INHALATION EXPOSURE
    1) Move patient to fresh air. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with inhaled beta-2 agonist and corticosteroids.
    C) OCULAR EXPOSURE
    1) Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia occurs, patient should be seen in a healthcare facility.
    D) DERMAL EXPOSURE
    1) Remove contaminated clothing and wash exposed area thoroughly.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) Piperonyl butoxide is of low toxicity. Prehospital gastrointestinal decontamination is generally not indicated. Gastrointestinal decontamination is only indicated if there is a coingestant with significant toxicity.
    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).
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) No specific laboratory tests are necessary unless otherwise clinically indicated.
    2) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    3) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    B) DILUTION
    1) DILUTION: If no respiratory compromise is present, administer milk or water as soon as possible after ingestion. Dilution may only be helpful if performed in the first seconds to minutes after ingestion. The ideal amount is unknown; no more than 8 ounces (240 mL) in adults and 4 ounces (120 mL) in children is recommended to minimize the risk of vomiting (Caravati, 2004).
    C) HYPERSENSITIVITY REACTION
    1) SUMMARY
    a) Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta adrenergic agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.
    2) BRONCHOSPASM
    a) ALBUTEROL
    1) ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007). CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 mg/kg (up to 10 mg) every 1 to 4 hours as needed, or 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    3) CORTICOSTEROIDS
    a) Consider systemic corticosteroids in patients with significant bronchospasm.
    b) PREDNISONE: ADULT: 40 to 80 milligrams/day. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 to 2 divided doses divided twice daily (National Heart,Lung,and Blood Institute, 2007).
    4) MILD CASES
    a) DIPHENHYDRAMINE
    1) SUMMARY: Oral diphenhydramine, as well as other H1 antihistamines can be used as indicated (Lieberman et al, 2010).
    2) ADULT: 50 milligrams orally, or 10 to 50 mg intravenously at a rate not to exceed 25 mg/min or may be given by deep intramuscular injection. A total of 100 mg may be administered if needed. Maximum daily dosage is 400 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    3) CHILD: 5 mg/kg/24 hours or 150 mg/m(2)/24 hours. Divided into 4 doses, administered intravenously at a rate not exceeding 25 mg/min or by deep intramuscular injection. Maximum daily dosage is 300 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    5) MODERATE CASES
    a) EPINEPHRINE: INJECTABLE SOLUTION: It should be administered early in patients by IM injection. Using a 1:1000 (1 mg/mL) solution of epinephrine. Initial Dose: 0.01 mg/kg intramuscularly with a maximum dose of 0.5 mg in adults and 0.3 mg in children. The dose may be repeated every 5 to 15 minutes, if no clinical improvement. Most patients respond to 1 or 2 doses (Nowak & Macias, 2014).
    6) SEVERE CASES
    a) EPINEPHRINE
    1) INTRAVENOUS BOLUS: ADULT: 1 mg intravenously as a 1:10,000 (0.1 mg/mL) solution; CHILD: 0.01 mL/kg intravenously to a maximum single dose of 1 mg given as a 1:10,000 (0.1 mg/mL) solution. It can be repeated every 3 to 5 minutes as needed. The dose can also be given by the intraosseous route if IV access cannot be established (Lieberman et al, 2015). ALTERNATIVE ROUTE: ENDOTRACHEAL ADMINISTRATION: If IV/IO access is unavailable. DOSE: ADULT: Administer 2 to 2.5 mg of 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube. CHILD: DOSE: 0.1 mg/kg to a maximum of 2.5 mg administered as a 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube (Lieberman et al, 2015).
    2) INTRAVENOUS INFUSION: Intravenous administration may be considered in patients poorly responsive to IM or SubQ epinephrine. An epinephrine infusion may be prepared by adding 1 mg (1 mL of 1:1000 (1 mg/mL) solution) to 250 mL D5W, yielding a concentration of 4 mcg/mL, and infuse this solution IV at a rate of 1 mcg/min to 10 mcg/min (maximum rate). CHILD: A dosage of 0.01 mg/kg (0.1 mL/kg of a 1:10,000 (0.1 mg/mL) solution up to 10 mcg/min (maximum dose 0.3 mg) is recommended for children (Lieberman et al, 2010). Careful titration of a continuous infusion of IV epinephrine, based on the severity of the reaction, along with a crystalloid infusion can be considered in the treatment of anaphylactic shock. It appears to be a reasonable alternative to IV boluses, if the patient is not in cardiac arrest (Vanden Hoek,TL,et al).
    7) AIRWAY MANAGEMENT
    a) OXYGEN: 5 to 10 liters/minute via high flow mask.
    b) INTUBATION: Perform early if any stridor or signs of airway obstruction.
    c) CRICOTHYROTOMY: Use if unable to intubate with complete airway obstruction (Vanden Hoek,TL,et al).
    d) BRONCHODILATORS are recommended for mild to severe bronchospasm.
    e) ALBUTEROL: ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007).
    f) ALBUTEROL: CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    8) MONITORING
    a) CARDIAC MONITOR: All complicated cases.
    b) IV ACCESS: Routine in all complicated cases.
    9) HYPOTENSION
    a) If hypotensive give 500 to 2000 milliliters crystalloid initially (20 milliliters/kilogram in children) and titrate to desired effect (stabilization of vital signs, mentation, urine output); adults may require up to 6 to 10 L/24 hours. Central venous or pulmonary artery pressure monitoring is recommended in patients with persistent hypotension.
    1) VASOPRESSORS: Should be used in refractory cases unresponsive to repeated doses of epinephrine and after vigorous intravenous crystalloid rehydration (Lieberman et al, 2010).
    2) DOPAMINE: Initial Dose: 2 to 20 micrograms/kilogram/minute intravenously; titrate to maintain systolic blood pressure greater than 90 mm Hg (Lieberman et al, 2010).
    10) H1 and H2 ANTIHISTAMINES
    a) SUMMARY: Antihistamines are second-line therapy and are used as supportive therapy and should not be used in place of epinephrine (Lieberman et al, 2010).
    1) DIPHENHYDRAMINE: ADULT: 25 to 50 milligrams via a slow intravenous infusion or IM. PEDIATRIC: 1 milligram/kilogram via slow intravenous infusion or IM up to 50 mg in children (Lieberman et al, 2010).
    b) RANITIDINE: ADULT: 1 mg/kg parenterally; CHILD: 12.5 to 50 mg parenterally. If the intravenous route is used, ranitidine should be infused over 10 to 15 minutes or diluted in 5% dextrose to a volume of 20 mL and injected over 5 minutes (Lieberman et al, 2010).
    c) Oral diphenhydramine, as well as other H1 antihistamines, can also be used as indicated (Lieberman et al, 2010).
    11) DYSRHYTHMIAS
    a) Dysrhythmias and cardiac dysfunction may occur primarily or iatrogenically as a result of pharmacologic treatment (epinephrine) (Vanden Hoek,TL,et al). Monitor and correct serum electrolytes, oxygenation and tissue perfusion. Treat with antiarrhythmic agents as indicated.
    12) OTHER THERAPIES
    a) There have been a few reports of patients with anaphylaxis, with or without cardiac arrest, that have responded to vasopressin therapy that did not respond to standard therapy. Although there are no randomized controlled trials, other alternative vasoactive therapies (ie, vasopressin, norepinephrine, methoxamine, and metaraminol) may be considered in patients in cardiac arrest secondary to anaphylaxis that do not respond to epinephrine (Vanden Hoek,TL,et al).
    D) TELEPHONE CONSULTATION
    1) The National Pesticide Information Center (NPIC) is a cooperative effort of Oregon State University and the US EPA. NPIC provides consultation to poison centers and other health care professionals for the management of pesticide poisoning. Calls regarding emergency cases requiring immediate medical response will be transferred to the Oregon Poison Center.
    a) NPIC contact information: phone: 1-800-858-7378. email: npic@ace.orst.edu Hours: 8 AM to 12 PM Pacific time Monday through Friday, excluding holidays.

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

Enhanced Elimination

    A) SUMMARY
    1) Hemodialysis is not recommended given the low toxicity of this agent.

Range Of Toxicity

Summary

    A) TOXICITY: Piperonyl butoxide is minimally toxic; specific toxic dose has not been determined. There have been no human deaths reported due to acute exposure. No irritation or toxic effects have been observed after dermal contact. Male volunteers tolerated a single oral dose of 50 mg (0.71 mg/kg body weight) piperonyl butoxide with no signs of toxicity.

Minimum Lethal Exposure

    A) The minimal toxic or lethal dose in humans is not established. There have been no deaths reported following acute exposure to piperonyl butoxide alone.

Maximum Tolerated Exposure

    A) No cases of severe irritation or toxic effects have been reported in the many exposures which occurred in development, manufacture, laboratory testing on insects, or field use.
    B) Male volunteers tolerated a single oral dose of 50 mg (0.71 mg/kg body weight) piperonyl butoxide with no signs of toxicity (HSDB , 2000).

Workplace Standards

    A) ACGIH TLV Values for CAS51-03-6 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS51-03-6 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS51-03-6 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): 3 ; Listed as: Piperonyl butoxide
    a) 3 : The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS51-03-6 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (ORAL)RAT:
    1) 7500-10,000 mg/kg (Sarles et al, 1949)
    2) 11,500 (Lehman, 1952)
    B) LD50- (SKIN)RAT:
    1) Greater than 7950 mg/kg (Gaines, 1969)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Piperonyl butoxide is an inhibitor of the liver microsomal detoxification enzymes both in vivo and in vitro (Fine & Molloy, 1964; Anders, 1968; Jaffee et al, 1968).
    B) MECHANISM OF ACTION -
    1) Piperonyl butoxide's effects on enzymes are biphasic, first inhibiting the enzymes, then increasing activity (Goldstein et al, 1973).
    2) Piperonyl butoxide is an active acaricide and has some insecticidal activity. It enhances the paralytic effect toxic to insects. It increases the effectiveness of other insecticides due to its synergistic effect (Hayes, 1982).

Toxicologic Mechanism

    A) Piperonyl butoxide inhibits the mixed function oxidase enzymes of the livers of test animals which metabolize pyrethrins and pyrethroids, therefore increasing their toxicity (Morgan, 1982).

Physicochemical

Physical Characteristics

    A) A light brown liquid with a mild odor and bitter taste (HSDB , 2000).
    B) Piperonyl butoxide is a colorless to light brown or yellow liquid (HSDB , 2000).

Molecular Weight

    A) 338.43(HSDB , 2000)

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