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P-AMINOPROPIOPHENONE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) p-Aminopropiophenone is used as an experimental cyanide and azide antidote and as an experimental radioprotective agent.

Specific Substances

    A) No Synonyms were found in group or single elements
    1.2.1) MOLECULAR FORMULA
    1) C9-H11-N-O

Available Forms Sources

    A) USES
    1) p-Aminopropiophenone is used as an experimental cyanide and azide antidote and as an experimental radioprotective agent (Budavari, 1989; (Bright & Marrs, 1986; Bright & Marrs, 1986; Bright & Marrs, 1987; Bright & Marrs, 1987; Jandorf & Bodansky, 1946; Abbanat & Smith, 1964; Carr et al, 1970; Storer, 1971).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) p-Aminopropiophenone is a methemoglobin inducing agent of relatively low toxicity.
    B) Methemoglobinemia may develop. Common clinical signs include headache, fatigue, nausea, dizziness, disorientation, syncope, and lethargy. Chocolate brown colored blood indicates a methemoglobin level of greater than 10 to 15%. Cyanosis will appear at greater than 10 to 15% methemoglobin.
    C) Hypotension and cardiac dysrhythmias may occur. Nausea and vomiting have been seen in some animal experiments.
    0.2.3) VITAL SIGNS
    A) An elevated respiratory rate may be noted. Hypotension may occur secondary to hypoxia and acidosis. Cyanosis may be evident if the methemoglobin concentration exceeds 10 to 15%.
    0.2.5) CARDIOVASCULAR
    A) Hypotension may occur secondary to hypoxia and acidosis. Cardiac dysrhythmias leading to cardiac arrest may occur.
    0.2.6) RESPIRATORY
    A) An elevated respiratory rate and dyspnea may be noted.
    0.2.7) NEUROLOGIC
    A) A variety of CNS complaints including headache, lethargy, incoordination, dizziness, fatigue, and syncope may develop.
    B) Coma or seizures may be seen.
    0.2.8) GASTROINTESTINAL
    A) Nausea and vomiting may be seen.
    0.2.11) ACID-BASE
    A) Metabolic acidosis may result.
    0.2.13) HEMATOLOGIC
    A) Blood from patients with greater than 10 to 15 percent methemoglobinemia may appear chocolate brown in color.
    1) Hemolytic anemia has not been reported, but might occur.
    0.2.14) DERMATOLOGIC
    A) Patients with greater than 10 to 15 percent methemoglobinemia may appear cyanotic.
    0.2.20) REPRODUCTIVE
    A) Fetal outcome should be unaffected by mild degrees of maternal methemoglobinemia.
    B) At the time of this review, no reproductive studies were found for p-aminopropiophenone in humans or experimental animals.
    C) No information about possible male reproductive effects was found in available references at the time of this review.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, no studies were found on the possible carcinogenic activity of p-aminopropiophenone in humans.

Laboratory Monitoring

    A) No methods for measurement of p-aminopropiophenone in biological samples were listed in available references at the time of this review.
    B) Serial methemoglobin levels should be followed for 24 hours. METHEMOGLOBIN LEVELS WILL BE REDUCED BY ENDOGENOUS METHEMOGLOBIN REDUCTASE IF BLOOD IS NOT ANALYZED RAPIDLY (FEW HOURS).
    C) ARTERIAL BLOOD GASES should be drawn in all cyanotic patients, and %O2 saturation measured if possible. A significant disparity between the calculated and measured %O2 saturation may be due to methemoglobin. Pulse oximetry may give inaccurate readings of oxyhemoglobin saturation.
    D) Obtain hemoglobin level. Anemic patients may require treatment at lower methemoglobin levels.
    E) Urinalysis may show brown or black discoloration if hemolysis has occurred, as well as casts and protein.
    F) Chest x-ray should be obtained if patients have respiratory distress.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
    B) GASTRIC LAVAGE: Consider after ingestion of a potentially life-threatening amount of poison if it can be performed soon after ingestion (generally within 1 hour). Protect airway by placement in the head down left lateral decubitus position or by endotracheal intubation. Control any seizures first.
    1) CONTRAINDICATIONS: Loss of airway protective reflexes or decreased level of consciousness in unintubated patients; following ingestion of corrosives; hydrocarbons (high aspiration potential); patients at risk of hemorrhage or gastrointestinal perforation; and trivial or non-toxic ingestion.
    C) SEIZURES: Administer a benzodiazepine; DIAZEPAM (ADULT: 5 to 10 mg IV initially; repeat every 5 to 20 minutes as needed. CHILD: 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) or LORAZEPAM (ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist. CHILD: 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).
    1) Consider phenobarbital or propofol if seizures recur after diazepam 30 mg (adults) or 10 mg (children greater than 5 years).
    2) Monitor for hypotension, dysrhythmias, respiratory depression, and need for endotracheal intubation. Evaluate for hypoglycemia, electrolyte disturbances, and hypoxia.
    D) METHEMOGLOBINEMIA
    1) Oxygen should be administered to all cyanotic patients. Cyanosis secondary to methemoglobinemia will not respond to oxygen therapy.
    2) All patients demonstrating cyanosis with symptoms or with methemoglobin levels greater than 20% should be admitted to the hospital.
    3) METHEMOGLOBINEMIA: Determine the methemoglobin concentration and evaluate the patient for clinical effects of methemoglobinemia (ie, dyspnea, headache, fatigue, CNS depression, tachycardia, metabolic acidosis). Treat patients with symptomatic methemoglobinemia with methylene blue (this usually occurs at methemoglobin concentrations above 20% to 30%, but may occur at lower methemoglobin concentrations in patients with anemia, or underlying pulmonary or cardiovascular disorders). Administer oxygen while preparing for methylene blue therapy.
    4) METHYLENE BLUE: INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules and 10 mg/1 mL (1% solution) vials. Additional doses may sometimes be required. Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection. NEONATES: DOSE: 0.3 to 1 mg/kg.
    5) Concomitant use of methylene blue with serotonergic drugs, including serotonin reuptake inhibitors (SRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), triptans, and ergot alkaloids may increase the risk of potentially fatal serotonin syndrome.
    6) Hyperbaric oxygen has been recommended as adjunctive therapy in severe cases. Exchange transfusion should be done if the methemoglobinemia is not responsive to methylene blue and is progressive in a severely symptomatic individual.
    7) Ascorbic acid may be useful in chronic congenital methemoglobinemia, but is not recommended in acutely toxic 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.
    B) At the time of this review, no information was available on whether or not p-aminopropiophenone can be absorbed and produce systemic toxicity by the inhalation route.
    C) Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    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 irrigate exposed areas with copious amounts of water. A physician may need to examine the area if irritation or pain persists.
    2) At the time of this review, no information was available on whether or not p-aminopropiophenone can be absorbed and produce systemic toxicity by the dermal route.
    3) Some chemicals can produce systemic poisoning by absorption through intact skin. Carefully observe patients with dermal exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.

Range Of Toxicity

    A) Minimum lethal human exposure is unknown.
    B) In experimental animals, induction of 95 percent methemoglobinemia by p-aminopropiophenone was fatal. Vomiting followed oral doses of 100 to 150 mg/kg.

Clinical Effects

Summary Of Exposure

    A) p-Aminopropiophenone is a methemoglobin inducing agent of relatively low toxicity.
    B) Methemoglobinemia may develop. Common clinical signs include headache, fatigue, nausea, dizziness, disorientation, syncope, and lethargy. Chocolate brown colored blood indicates a methemoglobin level of greater than 10 to 15%. Cyanosis will appear at greater than 10 to 15% methemoglobin.
    C) Hypotension and cardiac dysrhythmias may occur. Nausea and vomiting have been seen in some animal experiments.

Vital Signs

    3.3.1) SUMMARY
    A) An elevated respiratory rate may be noted. Hypotension may occur secondary to hypoxia and acidosis. Cyanosis may be evident if the methemoglobin concentration exceeds 10 to 15%.
    3.3.2) RESPIRATIONS
    A) TACHYPNEA - An elevated respiratory rate may be noted (Hall et al, 1986).
    3.3.4) BLOOD PRESSURE
    A) HYPOTENSION may occur secondary to hypoxia and acidosis (Hall et al, 1986).

Cardiovascular

    3.5.1) SUMMARY
    A) Hypotension may occur secondary to hypoxia and acidosis. Cardiac dysrhythmias leading to cardiac arrest may occur.
    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) Hypotension may occur secondary to hypoxia and acidosis (Hall et al, 1986).
    B) CONDUCTION DISORDER OF THE HEART
    1) Sinus tachycardia is common in patients with methemoglobinemia. Cardiac supraventricular and ventricular dysrhythmias leading to cardiac arrest may occur in significant cases of methemoglobinemia (Hall et al, 1986; Curry, 1982).

Respiratory

    3.6.1) SUMMARY
    A) An elevated respiratory rate and dyspnea may be noted.
    3.6.2) CLINICAL EFFECTS
    A) HYPERVENTILATION
    1) An elevated respiratory rate may be noted (Hall et al, 1986).
    B) DYSPNEA
    1) Dyspnea may be noted (Curry, 1982).

Neurologic

    3.7.1) SUMMARY
    A) A variety of CNS complaints including headache, lethargy, incoordination, dizziness, fatigue, and syncope may develop.
    B) Coma or seizures may be seen.
    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM DEFICIT
    1) A variety of CNS complaints including headache, lethargy, incoordination, dizziness, fatigue, and syncope may develop in patients with methemoglobinemia (Hall et al, 1986; Donovan, 1983; Curry, 1982).
    B) COMA
    1) Coma may be seen with higher levels of methemoglobinemia (Hall et al, 1986; Donovan, 1983; Curry, 1982).
    C) SEIZURE
    1) Seizures may develop with high levels of methemoglobinemia (Hall et al, 1986; Donovan, 1983; Curry, 1982).

Gastrointestinal

    3.8.1) SUMMARY
    A) Nausea and vomiting may be seen.
    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) Nausea and vomiting may be seen after ingestion of p-aminopropiophenone, or as a nonspecific effect of hypoxia with methemoglobinemia (Savarie et al, 1983; Hall et al, 1986).

Acid-Base

    3.11.1) SUMMARY
    A) Metabolic acidosis may result.
    3.11.2) CLINICAL EFFECTS
    A) ACIDOSIS
    1) Metabolic acidosis may result from tissue hypoxia due to decreased tissue oxygen delivery in methemoglobinemia (Hall et al, 1986).

Hematologic

    3.13.1) SUMMARY
    A) Blood from patients with greater than 10 to 15 percent methemoglobinemia may appear chocolate brown in color.
    1) Hemolytic anemia has not been reported, but might occur.
    3.13.2) CLINICAL EFFECTS
    A) METHEMOGLOBINEMIA
    1) BROWN BLOOD - Compared to a normal control, blood from patients with greater than 10 to 15 percent methemoglobinemia may appear chocolate brown in color (Hall et al, 1986; Curry, 1982).
    2) HEMOLYSIS - No information was available at the time of this review to assess whether or not p-aminopropiophenone can cause hemolysis; however, many methemoglobin-inducing compounds can also cause hemolytic anemia (Hall et al, 1986).

Dermatologic

    3.14.1) SUMMARY
    A) Patients with greater than 10 to 15 percent methemoglobinemia may appear cyanotic.
    3.14.2) CLINICAL EFFECTS
    A) CYANOSIS
    1) Patients with greater than 10 to 15 percent methemoglobinemia may appear cyanotic (Curry, 1982). This cyanosis may involve the trunk as well as the extremities, and does not clear with administration of 100 percent oxygen (Hall et al, 1986).

Reproductive

    3.20.1) SUMMARY
    A) Fetal outcome should be unaffected by mild degrees of maternal methemoglobinemia.
    B) At the time of this review, no reproductive studies were found for p-aminopropiophenone in humans or experimental animals.
    C) No information about possible male reproductive effects was found in available references at the time of this review.
    3.20.3) EFFECTS IN PREGNANCY
    A) METHEMOGLOBINEMIA
    1) There is a concern for the unborn with prenatal exposure to methemoglobin inducers. Infants may be particularly susceptible to methemoglobin formation, because fetal hemoglobin is more easily oxidized to methemoglobin than adult hemoglobin, and because fetal methemoglobin is reduced to normal hemoglobin more slowly than adult methemoglobin (Harris et al, 1979; Filer et al, 1970; Mansouri, 1985).
    2) Fetal oxygen demand is also greater than that of the adult. Therefore, THE FETUS MIGHT DEVELOP LIFE-THREATENING METHEMOGLOBINEMIA UNDER CONDITIONS WHERE THE MOTHER MAY NOT BE SERIOUSLY AFFECTED. However, the fetus may not be affected by mild degrees of maternal methemoglobinemia (Moore & Braatvedt, 1985).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS70-69-9 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, no studies were found on the possible carcinogenic activity of p-aminopropiophenone 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.

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 methods for measurement of p-aminopropiophenone in biological samples were listed in available references at the time of this review.
    B) Serial methemoglobin levels should be followed for 24 hours. METHEMOGLOBIN LEVELS WILL BE REDUCED BY ENDOGENOUS METHEMOGLOBIN REDUCTASE IF BLOOD IS NOT ANALYZED RAPIDLY (FEW HOURS).
    C) ARTERIAL BLOOD GASES should be drawn in all cyanotic patients, and %O2 saturation measured if possible. A significant disparity between the calculated and measured %O2 saturation may be due to methemoglobin. Pulse oximetry may give inaccurate readings of oxyhemoglobin saturation.
    D) Obtain hemoglobin level. Anemic patients may require treatment at lower methemoglobin levels.
    E) Urinalysis may show brown or black discoloration if hemolysis has occurred, as well as casts and protein.
    F) Chest x-ray should be obtained if patients have respiratory distress.
    4.1.2) SERUM/BLOOD
    A) HEMATOLOGIC
    1) METHEMOGLOBIN LEVELS are available in most hospitals, and are usually reported as a percent of total hemoglobin. Serial methemoglobin levels should be followed as continued absorption of the inducing agent may occur for up to 24 hours (Hall et al, 1986).
    2) HEMOGLOBIN LEVEL should be obtained to determine effective hemoglobin concentration. Anemic patients may have greater symptoms and require treatment at lower methemoglobin levels.
    B) ACID/BASE
    1) ARTERIAL BLOOD GASES should be drawn in all cyanotic patients, and %O2 saturation measured if possible. A significant disparity between the calculated and measured %O2 saturation may be due to methemoglobin. The pO2 is usually normal, even in the presence of severe methemoglobinemia. Pulse oximetry may give inaccurate readings of oxyhemoglobin saturation.
    4.1.3) URINE
    A) URINALYSIS
    1) Urine may show brown or black discoloration due to hemolysis, casts, and protein.
    4.1.4) OTHER
    A) OTHER
    1) OXYGEN SATURATION
    a) PULSE OXIMETRY - Patients with methemoglobinemia may have inaccurately measured oxygen/hemoglobin saturation by pulse oximetry (Rieder et al, 1989; Watcha et al, 1989; Barker et al, 1989).

Radiographic Studies

    A) CHEST RADIOGRAPH
    1) A chest x-ray should be obtained if patients have respiratory distress.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) No methods for measurement of p-aminopropiophenone in biological samples were listed in available references at the time of this review.
    B) Serial methemoglobin levels should be followed for 24 hours. METHEMOGLOBIN LEVELS WILL BE REDUCED BY ENDOGENOUS METHEMOGLOBIN REDUCTASE IF BLOOD IS NOT ANALYZED RAPIDLY (FEW HOURS).
    C) ARTERIAL BLOOD GASES should be drawn in all cyanotic patients, and %O2 saturation measured if possible. A significant disparity between the calculated and measured %O2 saturation may be due to methemoglobin. Pulse oximetry may give inaccurate readings of oxyhemoglobin saturation.
    D) Obtain hemoglobin level. Anemic patients may require treatment at lower methemoglobin levels.
    E) Urinalysis may show brown or black discoloration if hemolysis has occurred, as well as casts and protein.
    F) Chest x-ray should be obtained if patients have respiratory distress.

Oral Exposure

    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    B) GASTRIC LAVAGE
    1) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).
    a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.
    2) PRECAUTIONS:
    a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
    b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.
    3) LAVAGE FLUID:
    a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
    b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
    c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.
    4) COMPLICATIONS:
    a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
    b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).
    5) CONTRAINDICATIONS:
    a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.
    6.5.3) TREATMENT
    A) SUPPORT
    1) Oxygen should be administered to all cyanotic patients. Cyanosis secondary to methemoglobinemia will not respond to oxygen therapy.
    2) All patients demonstrating cyanosis with symptoms or with methemoglobin levels greater than 20% should be admitted to the hospital. In less severe cases of methemoglobinemia, the possibility of continued absorption of the toxic agent must be ruled out before the patient may be safely discharged. When doubt exists, it is probably best to admit the patient.
    B) METHEMOGLOBINEMIA
    1) Profound cyanosis may occur in individuals with methemoglobinemia who appear to be in no respiratory distress. The blood should be examined and compared to normal blood to identify chocolate-brown color, signifying a methemoglobin level of at least 10 to 15 percent.
    2) SUMMARY
    a) Determine the methemoglobin concentration and evaluate the patient for clinical effects of methemoglobinemia (ie, dyspnea, headache, fatigue, CNS depression, tachycardia, metabolic acidosis). Treat patients with symptomatic methemoglobinemia with methylene blue (this usually occurs at methemoglobin concentrations above 20% to 30%, but may occur at lower methemoglobin concentrations in patients with anemia, or underlying pulmonary or cardiovascular disorders). Administer oxygen while preparing for methylene blue therapy.
    3) METHYLENE BLUE
    a) INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules (Prod Info PROVAYBLUE(TM) intravenous injection, 2016) and 10 mg/1 mL (1% solution) vials (Prod Info methylene blue 1% intravenous injection, 2011). REPEAT DOSES: Additional doses may be required, especially for substances with prolonged absorption, slow elimination, or those that form metabolites that produce methemoglobin. NOTE: Large doses of methylene blue may cause methemoglobinemia or hemolysis (Howland, 2006). Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection (Prod Info methylene blue 1% intravenous injection, 2011; Herman et al, 1999). NEONATES: DOSE: 0.3 to 1 mg/kg (Hjelt et al, 1995).
    b) CONTRAINDICATIONS: G-6-PD deficiency (methylene blue may cause hemolysis), known hypersensitivity to methylene blue, methemoglobin reductase deficiency (Shepherd & Keyes, 2004)
    c) FAILURE: Failure of methylene blue therapy suggests: inadequate dose of methylene blue, inadequate decontamination, NADPH dependent methemoglobin reductase deficiency, hemoglobin M disease, sulfhemoglobinemia, or G-6-PD deficiency. Methylene blue is reduced by methemoglobin reductase and nicotinamide adenosine dinucleotide phosphate (NADPH) to leukomethylene blue. This in turn reduces methemoglobin. Red blood cells of patients with G-6-PD deficiency do not produce enough NADPH to convert methylene blue to leukomethylene blue (do Nascimento et al, 2008).
    d) DRUG INTERACTION: Concomitant use of methylene blue with serotonergic drugs, including serotonin reuptake inhibitors (SRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), triptans, and ergot alkaloids may increase the risk of potentially fatal serotonin syndrome (U.S. Food and Drug Administration, 2011; Stanford et al, 2010; Prod Info methylene blue 1% IV injection, 2011).
    4) TOLUIDINE BLUE OR TOLONIUM CHLORIDE (GERMANY)
    a) DOSE: 2 to 4 mg/kg intravenously over 5 minutes. Dose may be repeated in 30 minutes (Nemec, 2011; Lindenmann et al, 2006; Kiese et al, 1972).
    b) SIDE EFFECTS: Hypotension with rapid intravenous administration. Vomiting, diarrhea, excessive sweating, hypotension, dysrhythmias, hemolysis, agranulocytosis and acute renal insufficiency after overdose (Dunipace et al, 1992; Hix & Wilson, 1987; Winek et al, 1969; Teunis et al, 1970; Marquez & Todd, 1959).
    c) CONTRAINDICATIONS: G-6-PD deficiency; may cause hemolysis.
    C) HYPERBARIC OXYGEN THERAPY
    1) If the patient is not responsive to methylene blue, hyperbaric oxygen has been recommended as adjunctive therapy in severe cases (Donovan, 1983). In experimental animals, HBO has been shown to decrease mortality alone and in combination with methylene blue (Sheehy & Way, 1974; Goldstein & Doull, 1971).
    D) EXCHANGE TRANSFUSION
    1) Exchange transfusion should be done if the methemoglobinemia is not responsive to methylene blue and is progressive in a severely symptomatic individual. The mortality rate from methemoglobin levels greater than 70% is high, and exchange transfusion should be considered if levels approach this figure and cannot be controlled by the use of methylene blue.
    E) ASCORBIC ACID
    1) ASCORBIC ACID: Ascorbic acid administration may be useful in chronic congenital methemoglobinemia, but is not recommended in acutely toxic patients (Jaffe, 1979; Smith, 1967).
    F) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

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.
    6.7.2) TREATMENT
    A) OBSERVATION REGIMES
    1) At the time of this review, no information was available on whether or not p-aminopropiophenone can be absorbed and produce systemic toxicity by the inhalation route.
    2) Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

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).
    6.9.2) TREATMENT
    A) OBSERVATION REGIMES
    1) At the time of this review, no information was available on whether or not p-aminopropiophenone can be absorbed and produce systemic toxicity by the dermal exposure route.
    2) Some chemicals can produce systemic poisoning by absorption through intact skin. Carefully observe patients with dermal exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Range Of Toxicity

Summary

    A) Minimum lethal human exposure is unknown.
    B) In experimental animals, induction of 95 percent methemoglobinemia by p-aminopropiophenone was fatal. Vomiting followed oral doses of 100 to 150 mg/kg.

Minimum Lethal Exposure

    A) GENERAL/SUMMARY
    1) The minimum lethal human dose to this agent has not been delineated.
    B) ANIMAL DATA
    1) In experimental animals, induction of 95 percent methemoglobinemia by p-aminopropiophenone was fatal (Vandenbelt et al, 1944).

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) The maximum tolerated human exposure to this agent has not been delineated.
    B) ANIMAL DATA
    1) Experimental animals developed vomiting following oral doses of 100 to 150 mg/kg (Savarie et al, 1983).
    2) In experimental animals, induction of 87 percent methemoglobinemia by p-aminopropiophenone was survived (Vandenbelt et al, 1944).
    3) In cyanide poisoning experiments in dogs, doses of 0.2 to 0.5 mg of p-aminopropiophenone per kilogram produced peak methemoglobin levels ranging from 10 to 21 percent (Bright & Marrs, 1987; Bright & Marrs, 1987; Bright & Marrs, 1987; Bright & Marrs, 1986).
    a) Peak methemoglobin levels were noted about 60 minutes after administration of the drug (Bright & Marrs, 1986).
    b) These levels rapidly decreased when cyanide was administered, presumably due to formation of undetectable cyanmethemoglobin (Bright & Marrs, 1987; Bright & Marrs, 1987).
    1) Induced methemoglobin levels gradually declined after about 70 minutes, falling to less than 2.8 percent at 200 to 210 minutes after administration of cyanide (Bright & Marrs, 1987).

Workplace Standards

    A) ACGIH TLV Values for CAS70-69-9 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS70-69-9 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS70-69-9 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS70-69-9 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) References: (RTECS, 1996; Budavari, 1996 Marrs & Bright, 1987
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 80 mg/kg
    2) LD50- (ORAL)MOUSE:
    a) 168 mg/kg
    b) >5000 mg/kg
    3) LD50- (ORAL)RAT:
    a) 177 mg/kg
    b) 475 mg/kg
    c) 223 mg/kg

Physicochemical

Physical Characteristics

    A) p-Aminopropiophenone forms yellow crystalline needles when precipitated from water solution (Budavari, 1996; Lewis, 1996).

Molecular Weight

    A) 149.21

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