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4-AMINODIPHENYL

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) 4-Aminodiphenyl is prepared from diazoaminobenzene. It is a known carcinogen.

Specific Substances

    A) No Synonyms were found in group or single elements
    1.2.1) MOLECULAR FORMULA
    1) C12-H11-N

Available Forms Sources

    A) SOURCES
    1) 4-Aminodiphenyl is a component of tobacco smoke and is an indoor air pollutant (Clayton & Clayton, 1993; Luceri et al, 1993).
    B) USES
    1) 4-Aminodiphenyl is used in organic research (Lewis, 1993). It was previously used as a rubber antioxidant (Budavari, 1989; (Hathaway et al, 1991). It is no longer produced commercially in the US or in most other countries because of its carcinogenic activity (HSDB, 1995).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) 4-Aminodiphenyl is toxic by ingestion, inhalation, and skin absorption. Some references state that 4-aminodiphenyl may induce METHEMOGLOBINEMIA, while others do not mention this effect.
    B) 4-Aminodiphenyl exposure is associated with a high incidence of bladder cancer in humans. In experimental animals, it has produced bladder and liver tumors.
    1) 4-Aminodiphenyl appears to be one of the most potent of the known bladder carcinogens.
    C) 4-Aminodiphenyl is no longer produced on a commercial scale. Because of demonstrated carcinogenicity in experimental animals and humans, contact by all routes should be avoided.
    0.2.4) HEENT
    A) 4-Aminodiphenyl is an eye irritant.
    0.2.6) RESPIRATORY
    A) Exposure may produced dyspnea.
    0.2.7) NEUROLOGIC
    A) Headache, dizziness, lethargy, and ataxia may occur.
    0.2.9) HEPATIC
    A) Some aromatic amines are hepatotoxins, but this has not been shown for 4-aminodiphenyl.
    0.2.10) GENITOURINARY
    A) Acute hemorrhagic cystitis may occur.
    0.2.13) HEMATOLOGIC
    A) Methemoglobinemia has been induced by 4-aminodiphenyl in dogs, but this effect has not been reported in humans.
    0.2.14) DERMATOLOGIC
    A) 4-Aminodiphenyl is an irritant.
    B) Some aromatic amines are skin sensitizers, but this has not been shown for 4-aminodiphenyl.
    0.2.19) IMMUNOLOGIC
    A) Aromatic amines can be skin and respiratory sensitizers, but this has not been shown for 4-aminodiphenyl.
    0.2.20) REPRODUCTIVE
    A) 4-Aminodiphenyl crosses the placenta in humans and rats. It is present in breast milk of rats, and DNA adducts can be detected in livers of rats nursing from treated dams.
    0.2.21) CARCINOGENICITY
    A) 4-Aminodiphenyl is an OSHA-regulated human carcinogen.

Laboratory Monitoring

    A) If patient is cyanotic, obtain CBC, electrolytes, arterial blood gases, chest x-ray, EKG, and methemoglobin level.
    B) Obtain a measured O2 saturation on blood gases; calculated saturation is inaccurate in the setting of methemoglobinemia.
    C) If patient is not cyanotic but has had significant exposure, methemoglobin level may be drawn as a baseline.
    D) METHEMOGLOBIN LEVELS WILL BE ARTIFICIALLY LOW IF BLOOD IS
    1) NOT ANALYZED RAPIDLY (FEW HOURS). Bedside determination can be made by placing a drop of blood on filter paper with a control drop of blood nearby. With greater than 15% methemoglobinemia, the affected blood will have a chocolate brown color in comparison with the control blood.
    E) If chronic cyanosis is not due to pulmonary disease, especially if family history of cyanosis is present, hemoglobin electrophoresis, methemoglobin reductase level, and/or G-6-PD activity may be indicated.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) EMESIS: Ipecac-induced emesis is not recommended because of the potential for CNS depression and seizures.
    B) 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.
    C) 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.
    D) 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.
    E) Monitor oxygenation, methemoglobin levels, hemoglobin, hematocrit, plasma free hemoglobin, urinalysis, and perhaps other indices of hemolysis.
    F) Patients with methemoglobinemia should be administered supplemental oxygen.
    G) Transfusion of blood or packed red blood cells may be required if hemolysis is extensive.
    H) HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid. If hypotension persists, administer dopamine (5 to 20 mcg/kg/min) or norepinephrine (ADULT: begin infusion at 0.5 to 1 mcg/min; CHILD: begin infusion at 0.1 mcg/kg/min); titrate to desired response.
    I) If CNS and respiratory depression occur, ensure airway patency and adequacy of oxygenation and ventilation.
    J) 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.
    K) Extracorporeal enhanced elimination has not been shown to be effective. If renal failure occurs secondary to hemolysis, treatment with hemodialysis may be required. Exchange transfusion and hyperbaric oxygen may be useful in severe or unresponsive cases.
    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).
    2) Treat dermal irritation or burns with standard topical therapy. Patients developing dermal hypersensitivity reactions may require treatment with systemic or topical corticosteroids or antihistamines.

Range Of Toxicity

    A) The minimum lethal human dose to this agent has not been delineated.
    B) The maximum tolerated human exposure to this agent has not been delineated.

Clinical Effects

Summary Of Exposure

    A) 4-Aminodiphenyl is toxic by ingestion, inhalation, and skin absorption. Some references state that 4-aminodiphenyl may induce METHEMOGLOBINEMIA, while others do not mention this effect.
    B) 4-Aminodiphenyl exposure is associated with a high incidence of bladder cancer in humans. In experimental animals, it has produced bladder and liver tumors.
    1) 4-Aminodiphenyl appears to be one of the most potent of the known bladder carcinogens.
    C) 4-Aminodiphenyl is no longer produced on a commercial scale. Because of demonstrated carcinogenicity in experimental animals and humans, contact by all routes should be avoided.

Heent

    3.4.1) SUMMARY
    A) 4-Aminodiphenyl is an eye irritant.
    3.4.3) EYES
    A) IRRITATION - 4-Aminodiphenyl is an eye irritant (Lewis, 1992; NIOSH, 1995).

Respiratory

    3.6.1) SUMMARY
    A) Exposure may produced dyspnea.
    3.6.2) CLINICAL EFFECTS
    A) DYSPNEA
    1) Dyspnea has been listed as a symptom of exposure (NIOSH, 1995). Dyspnea may be either direct as a result of respiratory irritation or indirect as a consequence of oxygen deprivation from methemoglobinemia.

Neurologic

    3.7.1) SUMMARY
    A) Headache, dizziness, lethargy, and ataxia may occur.
    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM DEFICIT
    1) Headache, dizziness, lethargy, and ataxia may occur (NIOSH, 1995). These may be secondary to induction of methemoglobinemia.

Hepatic

    3.9.1) SUMMARY
    A) Some aromatic amines are hepatotoxins, but this has not been shown for 4-aminodiphenyl.
    3.9.2) CLINICAL EFFECTS
    A) TOXIC HEPATITIS
    1) HEPATOTOXICITY - Some aromatic amines are hepatotoxic (ILO, 1983). This has not been shown for 4-aminodiphenyl, however.

Genitourinary

    3.10.1) SUMMARY
    A) Acute hemorrhagic cystitis may occur.
    3.10.2) CLINICAL EFFECTS
    A) HEMORRHAGIC CYSTITIS
    1) ACUTE HEMORRHAGIC CYSTITIS - Dysuria and acute hemorrhagic cystitis have been listed as symptoms of overexposure (NIOSH, 1995).

Hematologic

    3.13.1) SUMMARY
    A) Methemoglobinemia has been induced by 4-aminodiphenyl in dogs, but this effect has not been reported in humans.
    3.13.2) CLINICAL EFFECTS
    A) METHEMOGLOBINEMIA
    1) Methemoglobinemia has been induced by 4-aminodiphenyl in dogs, but has not been reported in exposed humans (Radomski & Brill, 1970; RTECS, 1995).

Dermatologic

    3.14.1) SUMMARY
    A) 4-Aminodiphenyl is an irritant.
    B) Some aromatic amines are skin sensitizers, but this has not been shown for 4-aminodiphenyl.
    3.14.2) CLINICAL EFFECTS
    A) SKIN IRRITATION
    1) 4-Aminobiphenyl is an irritant. Its effects are similar to those of benzidine (Lewis, 1992).
    B) HYPERSENSITIVITY REACTION
    1) SENSITIZATION - Some aromatic amines are skin sensitizers (ILO, 1983). This has not been proven for 4-aminodiphenyl, however.

Immunologic

    3.19.1) SUMMARY
    A) Aromatic amines can be skin and respiratory sensitizers, but this has not been shown for 4-aminodiphenyl.
    3.19.2) CLINICAL EFFECTS
    A) ACUTE ALLERGIC REACTION
    1) SENSITIZATION - Some aromatic amines are skin and respiratory sensitizers (ILO, 1983). Neither has been proven for 4-aminodiphenyl, however.
    2) Respiratory sensitization to aromatic amines is usually less frequent than dermal sensitization (ILO, 1983).

Reproductive

    3.20.1) SUMMARY
    A) 4-Aminodiphenyl crosses the placenta in humans and rats. It is present in breast milk of rats, and DNA adducts can be detected in livers of rats nursing from treated dams.
    3.20.3) EFFECTS IN PREGNANCY
    A) PLACENTAL BARRIER
    1) Hemoglobin adducts of 4-aminodiphenyl were elevated in fetuses of smoking mothers, compared with non-smoking pairs (Coghlin et al, 1991). This result shows that 4-aminodiphenyl crosses the human placenta.
    2) 4-Aminodiphenyl-DNA adducts were detected in various tissues of mouse fetuses after the pregnant mice were treated orally with 800 mcmol/kg on day 18 of gestation (Lu et al, 1986).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) 4-Aminodiphenyl was detected in the breast milk of nursing rats, and its DNA adducts were present in livers of nursing pups (LaVoie et al, 1989).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS92-67-1 (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: 4-Aminobiphenyl
    b) Carcinogen Rating: 1
    1) The agent (mixture) is carcinogenic to humans. The exposure circumstance entails exposures that are carcinogenic to humans. This category is used when there is sufficient evidence of carcinogenicity in humans. Exceptionally, an agent (mixture) may be placed in this category when evidence of carcinogenicity in humans is less than sufficient but there is sufficient evidence of carcinogenicity in experimental animals and strong evidence in exposed humans that the agent (mixture) acts through a relevant mechanism of carcinogenicity.
    3.21.2) SUMMARY/HUMAN
    A) 4-Aminodiphenyl is an OSHA-regulated human carcinogen.
    3.21.3) HUMAN STUDIES
    A) CARCINOMA
    1) 4-Aminodiphenyl is an OSHA-regulated human carcinogen (OSHA, 1992).
    2) 4-Aminodiphenyl is a confirmed human carcinogen (ACGIH, 1991). It has been linked with bladder cancers in epidemiologic studies (Clayton & Clayton, 1993; ILO, 1983). It appears to be one of the most potent known bladder carcinogens (ACGIH, 1991).
    3) In pioneering studies by Case et al in 1954, 55 out of 315 workers exposed to 4-aminodiphenyl developed bladder cancer (ILO, 1983).
    4) In a group of 171 workers exposed to 4-aminodiphenyl for periods of 1.5 to 19 years, 11 percent developed bladder tumors, with latency of 5 to 19 years (Melick et al, 1955; (Hathaway et al, 1991) ACGIH, 1991).
    5) There were 35 histologically confirmed cases of bladder tumors in a group of 503 workers; 24 additional workers had positive cytology (Koss et al, 1969; (Hathaway et al, 1991) ACGIH, 1991).
    6) Increased mortality rates from bladder cancer, soft tissue sarcomas, and respiratory cancer were seen in a group of 754 workers who were exposed to 4-aminodiphenyl and who also developed chloracne from exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in an industrial accident in 1949. No soft tissue sarcomas were seen in the group exposed to TCDD alone (Collins et al, 1993).
    3.21.4) ANIMAL STUDIES
    A) CARCINOMA
    1) 4-Aminodiphenyl has induced bladder cancers in dogs and tumors at other sites in rabbits and mice (Clayton & Clayton, 1993).
    2) Bladder papillomas and carcinomas were seen in dogs fed 1 mg/kg 4-aminodiphenyl, 5 days per week for life (Walpole et al, 1952; (Hathaway et al, 1991) ACGIH, 1991).
    3) All 4 dogs ingesting 0.3 grams of 4-aminodiphenyl 3 times/week developed fatal urinary bladder carcinomas (Deichmann et al, 1958; (Hathaway et al, 1991) ACGIH, 1991).
    a) A single, near-fatal dose was not carcinogenic in dogs after 5 years, however (Deichmann & MacDonald, 1968; ACGIH, 1991).
    4) Mammary gland and intestinal tumors developed in rats given a total dose of 3.6 to 5.8 grams/kg intraperitoneally (Walpole et al, 1952; (Hathaway et al, 1991) ACGIH, 1991).
    5) Hepatomas were induced in 19 out of 20 male mice, and 6 of 23 female mice, given 3 subcutaneous injections of 200 mcg of 4-aminodiphenyl during the newborn period (Gorrod et al, 1968; (Hathaway et al, 1991) ACGIH, 1991).

Genotoxicity

    A) 4-Aminodiphenyl can form DNA and hemoglobin adducts. It has induced unscheduled DNA synthesis, mutations in microorganisms and cultured mammalian cells, and chromosome aberrations and sister chromatid exchanges in mice.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) If patient is cyanotic, obtain CBC, electrolytes, arterial blood gases, chest x-ray, EKG, and methemoglobin level.
    B) Obtain a measured O2 saturation on blood gases; calculated saturation is inaccurate in the setting of methemoglobinemia.
    C) If patient is not cyanotic but has had significant exposure, methemoglobin level may be drawn as a baseline.
    D) METHEMOGLOBIN LEVELS WILL BE ARTIFICIALLY LOW IF BLOOD IS
    1) NOT ANALYZED RAPIDLY (FEW HOURS). Bedside determination can be made by placing a drop of blood on filter paper with a control drop of blood nearby. With greater than 15% methemoglobinemia, the affected blood will have a chocolate brown color in comparison with the control blood.
    E) If chronic cyanosis is not due to pulmonary disease, especially if family history of cyanosis is present, hemoglobin electrophoresis, methemoglobin reductase level, and/or G-6-PD activity may be indicated.
    4.1.2) SERUM/BLOOD
    A) ACID/BASE
    1) Arterial blood gases should be drawn in all cyanotic patients; significant disparity between the calculated and measured percentage of O2 saturation values may be due to methemoglobin.
    2) pO2 is usually normal, even in the presence of severe methemoglobinemia.
    3) Metabolic acidosis is secondary to tissue hypoxia and mandates immediate treatment.
    a) METABOLIC ACIDOSIS - Methemoglobin is incapable of reversibly binding oxygen. Metabolic acidosis occurs when the methemoglobin level is high enough to result in tissue hypoxia (generally >50%).
    b) Partial respiratory compensation for the metabolic acidosis usually occurs.
    4) HYPOXIA - The pO2 and O2 saturation percentages are usually normal, even in severe methemoglobinemia, reflecting normal pulmonary function.
    a) pO2 is a measurement of the partial pressure of oxygen in plasma and is not a direct measurement of oxygen bound to hemoglobin, and O2 saturation when CALCULATED is merely extrapolated from the pO2 and assumes normal hemoglobin is present.
    b) Therefore, in disease states in which hemoglobin is abnormal (eg, methemoglobinemia, carbon monoxide poisoning), CALCULATED oxygen saturations are extremely unreliable. However, if oxygen saturations are MEASURED directly, then a discrepancy between measured and calculated oxygen saturations will be seen.
    c) Whenever there is a marked difference between measured and calculated O2 saturations, methemoglobinemia or carbon monoxide poisoning should be suspected.
    d) Hypoxia may result from loss of respiratory drive if the patient is comatose.
    B) HEMATOLOGIC
    1) If patient is cyanotic, obtain methemoglobin level.
    a) If patient is not cyanotic but has ingested or been exposed to a methemoglobin-inducing substance, methemoglobin level may be drawn as baseline.
    1) Methemoglobinemia may not develop for several hours (e.g, 1 to 10) after exposure to some chemicals. A period of observation of asymptomatic individuals may be advisable following 4-aminodiphenyl exposure, as biochemical transformation may be required before methemoglobinemia can be induced.
    2) The methemoglobin level, expressed as a percentage of total hemoglobin, is essential both in making the diagnosis and grading the severity. (NOTE - The methemoglobin level will be reduced if blood sample is not analyzed rapidly (few hours) by endogenous methemoglobin reductase.) The development of methemoglobinemia may be delayed with some chemical exposures.
    3) Serial levels should be obtained because continued absorption of the inducing agent may occur for up to 24 hours (Hall, 1986).
    4) Patients may be asymptomatic shortly after exposure. Methemoglobinemia may not develop for several hours (e.g, 1 to 10) after exposure to some chemicals. A period of observation of asymptomatic individuals may be advisable following 4-aminodiphenyl exposure, as biochemical transformation may be required before methemoglobinemia can be induced.
    5) Chronic familial methemoglobinemia should prompt a search for an abnormal hemoglobin or enzyme deficiency. Hemoglobin electrophoresis, methemoglobin reductase activity, and G-6-PD activity may be diagnostic.
    6) METHEMOGLOBIN LEVEL - Diagnostic; levels >15% usually produce symptoms; cyanosis may be present with level of 15%. Methemoglobin levels will be reduced if blood sample is not analyzed rapidly (few hours) by endogenous methemoglobin reductase. The development of methemoglobinemia may be delayed with some chemical exposures.
    2) If patient is cyanotic, obtain CBC.
    3) Hemoglobin should be obtained to determine effective hemoglobin concentration. Anemic patients may have greater symptoms and require treatment at lower methemoglobin levels.
    C) BLOOD/SERUM CHEMISTRY
    1) Obtain electrolytes in cyanotic patients.
    4.1.3) URINE
    A) URINALYSIS
    1) Urinalysis may show brown or black discoloration, casts, and protein.
    2) Hematuria may indicate advanced development of bladder cancer (ILO, 1983).
    B) OTHER
    1) Monitor urinary cytology on desquamated urinary epithelial cells. NOTE - There is a high proportion of false positive results with this test (ILO, 1983).
    a) A total of 35 out of 59 individuals with positive urinary cytology eventually developed bladder carcinoma (ILO, 1983).
    4.1.4) OTHER
    A) OTHER
    1) OXYGEN SATURATION
    a) PULSE OXIMETRY - A disparity between the oxygen saturation calculated from PaO2 values and pulse oximetry readings may provide an important clue to the presence of methemoglobinemia.
    1) Pulse oximetry overestimates oxygen saturation and should not be used to reflect arterial oxygen content or tissue oxygen delivery, but SpO(2) reading must be interpreted correctly (Watcha, 1989; Bardoczky, 1990; Barker, 1989; Rieder, 1989).
    2) Treatment of methemoglobinemia should be guided by direct measurements of oxyhemoglobin using a cooximeter and not on the basis of measurements using pulse oximetry or on estimates of saturations calculated from the PaO2 and the oxyhemoglobin dissociation curve (Watcha, 1989).
    2) ECG
    a) Cardiac monitoring is recommended, especially in patients with underlying diseases known to increase susceptibility.
    b) In patients with methemoglobinemia, sinus tachycardia is frequently present and may be secondary to anxiety, tissue hypoxia, or acidosis. If acidosis and tissue hypoxia are severe enough, ischemic changes, ventricular arrhythmias, and cardiac arrest may result.
    3) OTHER
    a) Positive urinary cytology is an indication for cytoscopic examination of the bladder (ILO, 1983).

Radiographic Studies

    A) CHEST RADIOGRAPH
    1) Obtain chest X-ray if patient is cyanotic or in the case of significant inhalation exposure.

Methods

    A) MULTIPLE ANALYTICAL METHODS
    1) BEDSIDE TEST - As methemoglobin levels approach 15% to 20%, the blood turns chocolate brown; a drop of the patient's blood placed on filter paper can be compared with that of a control to make the diagnosis while awaiting definitive serum levels.
    a) Both sample and control blood are placed on filter paper and exposed to room air; the control blood will be red, while the blood containing large amounts of methemoglobin (>15%) will be dry and deep chocolate brown.
    b) In clinical practice, physicians may delay diagnosis of methemoglobinemia by over-relying on their bedside acumen in detecting chocolate-brown blood. Subtle changes in the appearance of sampled blood may be easily missed if the clinician is not looking specifically for them, and the chocolate-brown color is difficult to identify (Henretig, 1988).
    1) In an asymptomatic but cyanotic patient in whom methemoglobinemia is suspected, none of the bedside techniques commonly recommended are completely reliable; diagnosis should be pursued with a spectrophotometric analysis.
    2) BUBBLING OXYGEN involves bubbling 100% oxygen through a sample of venous blood. While normal hemoglobin will turn bright red, methemoglobin will not.
    3) POTASSIUM CYANIDE - Venous blood containing significant methemoglobin concentrations diluted by 1:100 with deionized water will turn bright pink with the addition of a crystal of potassium cyanide, secondary to production of cyanohemoglobin (Done, 1976).

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) Any cyanotic or dyspneic patient with clinically significant methemoglobinemia, or any patient with a methemoglobin level >20%, should be admitted to the intensive care unit, even if improvement has occurred after appropriate emergency department management.
    B) Patients with significant exposure should be admitted because the substance may be absorbed or metabolized slowly and cause delayed methemoglobin formation.
    C) Patients with altered mental status should be observed continuously on an inpatient basis because of the possibility of mixed ingestion of toxic substances. Sudden deterioration may occur in cases of toxic ingestion.
    D) 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.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients may be asymptomatic shortly after exposure. The development of severe methemoglobinemia may be delayed several hours because of metabolism to active forms of methemoglobin inducers.
    B) Observation of asymptomatic or mildly symptomatic individuals may be advisable, biochemical transformation may be required before methemoglobinemia can be induced (Smith, 1991).
    6.3.3) DISPOSITION/INHALATION EXPOSURE
    6.3.3.1) ADMISSION CRITERIA/INHALATION
    A) All patients demonstrating cyanosis with symptoms, or methemoglobin levels greater than 20 percent, should be admitted. In less severe cases of methemoglobinemia, the possibility of continued absorption of the toxin must be ruled out before the patient may be safely discharged. Signs and symptoms of toxicity may also be delayed if biochemical transformation of the chemical is required before methemoglobinemia results. When doubt exists, it is probably best to admit the patient.

Monitoring

    A) If patient is cyanotic, obtain CBC, electrolytes, arterial blood gases, chest x-ray, EKG, and methemoglobin level.
    B) Obtain a measured O2 saturation on blood gases; calculated saturation is inaccurate in the setting of methemoglobinemia.
    C) If patient is not cyanotic but has had significant exposure, methemoglobin level may be drawn as a baseline.
    D) METHEMOGLOBIN LEVELS WILL BE ARTIFICIALLY LOW IF BLOOD IS
    1) NOT ANALYZED RAPIDLY (FEW HOURS). Bedside determination can be made by placing a drop of blood on filter paper with a control drop of blood nearby. With greater than 15% methemoglobinemia, the affected blood will have a chocolate brown color in comparison with the control blood.
    E) If chronic cyanosis is not due to pulmonary disease, especially if family history of cyanosis is present, hemoglobin electrophoresis, methemoglobin reductase level, and/or G-6-PD activity may be indicated.

Oral Exposure

    6.5.2) PREVENTION OF ABSORPTION
    A) EMESIS/NOT RECOMMENDED
    1) EMESIS: Ipecac-induced emesis is not recommended because of the potential for CNS depression and seizures.
    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) 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.
    D) 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) OXYGEN
    1) INDICATIONS - 100% oxygen should be administered to all cyanotic patients until the methemoglobin level is below 20% and the patient is in no respiratory distress.
    2) The lack of clinical response to administration of 100% oxygen is diagnostic of methemoglobinemia.
    a) With a normal circulation, the inhalation of 100% oxygen rapidly improves peripheral cyanosis (nail beds, mucous membranes, distal extremities) associated with cardiovascular or pulmonary disease. In patients with methemoglobinemia, cyanosis does not improve when 100% oxygen is administered.
    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 15%.
    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.
    5) METHYLENE BLUE/PRECAUTIONS
    a) METHEMOGLOBINEMIA - Although methylene blue has been reported to itself cause methemoglobin formation up to about 7% of total hemoglobin (Whitwam et al, 1979; Goluboff & Wheaton, 1961; Nadler et al, 1934), this hypothesis has been disputed (Stossel & Jennings, 1966; Rentsch & Wittekind, 1967) and the amounts said to be induced are clinically insignificant (Hall et al, 1986).
    b) HEMOLYSIS - Repeated large doses (up to 15 milligrams/kilogram) may cause hemolysis (Jaffe, 1979; Harvey & Keitt, 1983) particularly in the presence of G-6-PD deficiency. The dangers of repeated appropriate doses of methylene blue (1 to 2 milligrams/kilogram) are uncertain, but it is recommended that with rare exceptions the total dosage should not exceed 7 milligrams/kilogram (Wintrobe, 1974; Harvey & Keitt, 1983). Methylene blue may be ineffective in patients with G-6-PD deficiency (Rosen et al, 1971).
    c) OTHER - reported adverse effects from high doses of methylene blue include chest pain, dyspnea, anxiety, and tremors (Nadler et al, 1934).
    d) FALSE POSITIVE CO-OXIMETER RESULTS - Methylene blue may cause a false positive methemoglobin level when measuring arterial blood gases using a co-oximeter (Kirlangitis et al, 1990).
    C) HEMOLYSIS
    1) Transfusion of blood or packed red blood cells may be required.
    a) Urine alkalinization with sodium bicarbonate and maintenance of an adequate urine output may help to prevent renal damage from RBC breakdown products.
    b) Monitor serum potassium and calcium levels during therapy with sodium bicarbonate. Bicarbonate also presents a significant sodium and osmolar load.
    D) SUPPORT
    1) Frequent vital sign monitoring and support of vital functions (pulse, blood pressure, respirations) may be required.
    E) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    F) AIRWAY MANAGEMENT
    1) If CNS and respiratory depression occur, ensure airway patency and adequacy of oxygenation and ventilation. Endotracheal intubation, supplemental oxygenation, and assisted ventilation could be required.
    G) 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) OXYGEN
    1) INDICATIONS - 100% oxygen should be administered to all cyanotic patients until the methemoglobin level is below 20% and the patient is in no respiratory distress.
    2) The lack of clinical response to administration of 100% oxygen is diagnostic of methemoglobinemia.
    a) With a normal circulation, the inhalation of 100% oxygen rapidly improves peripheral cyanosis (nail beds, mucous membranes, distal extremities) associated with cardiovascular or pulmonary disease. In patients with methemoglobinemia, cyanosis does not improve when 100% oxygen is administered.
    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 15%.
    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.
    5) METHYLENE BLUE/PRECAUTIONS
    a) METHEMOGLOBINEMIA - Although methylene blue has been reported to itself cause methemoglobin formation up to about 7% of total hemoglobin (Whitwam et al, 1979; Goluboff & Wheaton, 1961; Nadler et al, 1934), this hypothesis has been disputed (Stossel & Jennings, 1966; Rentsch & Wittekind, 1967) and the amounts said to be induced are clinically insignificant (Hall et al, 1986).
    b) HEMOLYSIS - Repeated large doses (up to 15 milligrams/kilogram) may cause hemolysis (Jaffe, 1979; Harvey & Keitt, 1983) particularly in the presence of G-6-PD deficiency. The dangers of repeated appropriate doses of methylene blue (1 to 2 milligrams/kilogram) are uncertain, but it is recommended that with rare exceptions the total dosage should not exceed 7 milligrams/kilogram (Wintrobe, 1974; Harvey & Keitt, 1983). Methylene blue may be ineffective in patients with G-6-PD deficiency (Rosen et al, 1971).
    c) OTHER - reported adverse effects from high doses of methylene blue include chest pain, dyspnea, anxiety, and tremors (Nadler et al, 1934).
    d) FALSE POSITIVE CO-OXIMETER RESULTS - Methylene blue may cause a false positive methemoglobin level when measuring arterial blood gases using a co-oximeter (Kirlangitis et al, 1990).
    C) 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).
    D) 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) IRRITATION SYMPTOM
    1) Treat dermal irritation or burns with standard topical therapy. Patients developing dermal hypersensitivity reactions may require treatment with systemic or topical corticosteroids or antihistamines.
    B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Enhanced Elimination

    A) EXCHANGE TRANSFUSION
    1) Exchange transfusion has not been shown to be effective in decreasing blood levels of 4-aminodiphenyl or of methemoglobin in the case of 4-aminodiphenyl overdose.
    2) In cases of significantly elevated methemoglobin where methylene blue therapy is unsuccessful, exchange transfusion may be considered.
    B) HYPERBARIC OXYGEN
    1) Hyperbaric oxygen therapy can be used to ensure adequate oxygenation while preparations are being made for exchange transfusion in serious cases.

Range Of Toxicity

Summary

    A) The minimum lethal human dose to this agent has not been delineated.
    B) The maximum tolerated human exposure to this agent has not been delineated.

Minimum Lethal Exposure

    A) GENERAL/SUMMARY
    1) The minimum lethal human dose to this agent has not been delineated.

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) The maximum tolerated human exposure to this agent has not been delineated.
    B) CASE REPORTS
    1) Of 171 workers exposed to 4-aminodiphenyl for 1.5 to 19 years, 11% had bladder tumors. The tumors appeared 5 to 19 years after initial exposure (Hathaway et al, 1991).
    2) In a study of 503 exposed workers, there were 35 histologically confirmed bladder carcinomas and an additional 24 men with positive cytology (Hathaway et al, 1991).

Workplace Standards

    A) ACGIH TLV Values for CAS92-67-1 (American Conference of Governmental Industrial Hygienists, 2010):
    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) 4-Aminodiphenyl
    a) TLV:
    1) TLV-TWA:
    2) TLV-STEL:
    3) TLV-Ceiling:
    b) Notations and Endnotes:
    1) Carcinogenicity Category: A1
    2) Codes: L, Skin
    3) Definitions:
    a) A1: Confirmed Human Carcinogen: The agent is carcinogenic to humans based on the weight of evidence from epidemiologic studies.
    b) L: Exposure by all routes should be carefully controlled to levels as low as possible.
    c) Skin: This refers to the potential significant contribution to the overall exposure by the cutaneous route, including mucous membranes and the eyes, either by contact with vapors or, of likely greater significance, by direct skin contact with the substance. It should be noted that although some materials are capable of causing irritation, dermatitis, and sensitization in workers, these properties are not considered relevant when assigning a skin notation. Rather, data from acute dermal studies and repeated dose dermal studies in animals or humans, along with the ability of the chemical to be absorbed, are integrated in the decision-making toward assignment of the skin designation. Use of the skin designation provides an alert that air sampling would not be sufficient by itself in quantifying exposure from the substance and that measures to prevent significant cutaneous absorption may be warranted. Please see "Definitions and Notations" (in TLV booklet) for full definition.
    c) TLV Basis - Critical Effect(s): Bladder and liver cancer
    d) Molecular Weight: 169.23
    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 CAS92-67-1 (National Institute for Occupational Safety and Health, 2007):
    1) Listed as: 4-Aminodiphenyl
    2) REL:
    a) TWA:
    b) STEL:
    c) Ceiling:
    d) Carcinogen Listing: (Ca) NIOSH considers this substance to be a potential occupational carcinogen (See Appendix A in the NIOSH Pocket Guide to Chemical Hazards).
    e) Skin Designation: Not Listed
    f) Note(s): See Appendix A
    3) IDLH: Not Listed

    C) Carcinogenicity Ratings for CAS92-67-1 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): A1 ; Listed as: 4-Aminodiphenyl
    a) A1 :Confirmed Human Carcinogen: The agent is carcinogenic to humans based on the weight of evidence from epidemiologic studies.
    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): 1 ; Listed as: 4-Aminobiphenyl
    a) 1 : The agent (mixture) is carcinogenic to humans. The exposure circumstance entails exposures that are carcinogenic to humans. This category is used when there is sufficient evidence of carcinogenicity in humans. Exceptionally, an agent (mixture) may be placed in this category when evidence of carcinogenicity in humans is less than sufficient but there is sufficient evidence of carcinogenicity in experimental animals and strong evidence in exposed humans that the agent (mixture) acts through a relevant mechanism of carcinogenicity.
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Ca ; Listed as: 4-Aminodiphenyl
    a) Ca : NIOSH considers this substance to be a potential occupational carcinogen (See Appendix A in the NIOSH Pocket Guide to Chemical Hazards).
    5) MAK (DFG, 2002): Category 1 ; Listed as: 4-Aminobiphenyl
    a) Category 1 : Substances that cause cancer in man and can be assumed to make a significant contribution to cancer risk. Epidemiological studies provide adequate evidence of a positive correlation between the exposure of humans and the occurence of cancer. Limited epidemiological data can be substantiated by evidence that the substance causes cancer by a mode of action that is relevant to man.
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS92-67-1 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Listed as: 4-Aminodiphenyl; see 29 CFR 1910.1011
    2) Table Z-1 for 4-Aminodiphenyl; see 29 CFR 1910.1011:
    a) 8-hour TWA:
    1) ppm:
    a) Parts of vapor or gas per million parts of contaminated air by volume at 25 degrees C and 760 torr.
    2) mg/m3:
    a) Milligrams of substances per cubic meter of air. When entry is in this column only, the value is exact; when listed with a ppm entry, it is approximate.
    3) Ceiling Value:
    4) Skin Designation: No
    5) Notation(s): Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) References: RTECS, 1994
    1) LD50- (ORAL)MOUSE:
    a) 205 mg/kg
    2) LD50- (ORAL)RAT:
    a) 500 mg/kg

Pharmacology Toxicology

Toxicologic Mechanism

    A) Aromatic amines require metabolic activation to form ultimate mutagens and carcinogens. The active species are often hydroxylamines (ILO, 1983).
    1) 4-Aminodiphenyl is activated to a mutagenic form by microsomes in human uroepithelial cells (Hatcher et al, 1993).
    B) 4-Aminodiphenyl may require metabolic activation to form the active species for inducing methemoglobinemia.

Physicochemical

Physical Characteristics

    A) Colorless crystals that discolor to lavender when exposed to air (ACGIH, 1991).
    B) floral odor (NIOSH, 1994)

Ph

    1) No information found at the time of this review.

Molecular Weight

    A) 169.24 (RTECS , 1994)

References

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