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DINITRO PHENOL GROUP

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) This class of chemical was used as an explosive in World War I (Perkins, 1919).
    B) 2,4-Dinitrophenol was introduced in 1933 for stimulation of metabolism and promotion of weight loss (Cutting et al, 1933; Horner, 1942).
    C) Disophenol or 2,6-diiodo-4-nitrophenol demonstrates mode of action, toxicity, and toxicological signs similar to 2,4-dinitrophenol (Liao & Oehme, 1980).
    D) Reagent for the detection of potassium and ammonium ions (Budavari, 1996).
    E) Dinitrophenol has been and occasionally is still used as a spray against aphids and mites, as a fungicide and wood preservative against various molds and mildews, and sometimes as a weed killer (Gosselin et al, 1984).
    F) Intermediate for manufacturing dyes, photographical agent (ITI, 1988).

Specific Substances

    1) DNP (synonym)
    2) 2,4-DNP (synonym)
    3) 2,4-Dinitrophenol (synonym)
    4) CAS 51-28-5 (synonym for 2,4-Dinitrophenol)
    5) 2-sec-butyl-4,6-dinitrophenol (synonym)
    6) Dinitrobutylphenol (synonym)
    7) RCRA WASTE NUMBER: P020 (synonym)
    8) DINITROPHENOL (synonym)
    9) DN (DINITROCRESOL) (synonym)
    10) PHENOL, DINITRO (synonym)

Available Forms Sources

    A) USES
    1) This class of chemical was used as an explosive in World War I (Perkins, 1919).
    2) 2,4-Dinitrophenol was introduced in 1933 for stimulation of metabolism and promotion of weight loss but was taken off the market in 1938 due to adverse effects including pyrexia (Cutting et al, 1933; Horner, 1942). In the 1980's, DNP was reintroduced into the market as a "health" product as a weight-loss aid. It is reportedly still readily available through the internet and often marketed to bodybuilders as a weight-loss product (McFee et al, 2004).
    3) Reagent for the detection of potassium and ammonium ions (Budavari, 1996).
    4) Dinitrophenol has been and occasionally is still used as a spray against aphids and mites, as a fungicide and wood preservative against various molds and mildews, and sometimes as a weed killer (Gosselin et al, 1984).
    5) Intermediate for manufacturing dyes, photographical agent (ITI, 1988).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: 2,4 Dinitrophenol was first used in the early 1900s as a weight loss agent. The ban on human consumption was first issued in 1938 and then again in 2003; however, it still remains widely available on the internet, mainly marketed to bodybuilders who want to lose fat but not muscle mass. Commercially, dinitrophenol has been used as wood preserver, dye, photograph developer, and herbicide.
    B) TOXICOLOGY: DNP uncouples oxidative phosphorylation, leading to the inhibition of all energy-requiring processes and the extramitochondrial accumulation of inorganic phosphate and acts as a chemical ionophore, interfering with the cellular production of ATP. The loss of potential energy is dissipated as heat, which causes a rapid consumption of calories and failure in thermoregulatory homeostasis, leading to uncontrolled hyperthermia.
    C) EPIDEMIOLOGY: DNP was banned by the FDA for human consumption in 1938. Overdose and death from DNP was rare, almost nonexistent, until 2001, when an increase in availability from various internet sites caused a surge in abuse. In 2003, the FDA reissued the ban on human consumption; however, DNP still remains widely available on the internet.
    D) WITH POISONING/EXPOSURE
    1) OVERDOSE: Well absorbed by all routes. Death from intentional oral overdose and accidental dermal and inhalation exposure have been reported. ACUTE EFFECTS: Fever, tachypnea, diaphoresis, headache, malaise, thirst, yellow skin staining following dermal contact (urine/stool may be bright yellow or orange). SEVERE: Seizures, coma, cyanosis, pulmonary edema, metabolic acidosis, dysrhythmias (VT, VFib), and renal/hepatic injury. Concentrated solutions may cause caustic GI injury. INFREQUENT: Metabolic acidosis, methemoglobinemia, and cerebral edema. Deaths have been reported when DNP was used illicitly as a bodybuilding or weight loss supplement. ONSET: 1 to 3 mg/kg can produce acute toxicity in a few hours. The average time to death is 14 hours.
    0.2.3) VITAL SIGNS
    A) Blood pressure, pulse, respiratory rate, and temperature may all be elevated after exposure.
    0.2.20) REPRODUCTIVE
    A) Animal studies show developmental malformations involving the neurologic, ophthalmic, urologic, and skeletal systems of offsprings.
    0.2.21) CARCINOGENICITY
    A) Limited evidence of carcinogenicity is available among animals.

Laboratory Monitoring

    A) Nitrophenolic plasma levels can be obtained by an adaptation of the dinitro-o-cresol method, but acute availability of testing may be limited.
    B) Monitor fluids and electrolytes carefully. Monitor blood glucose, arterial blood gases, and liver and renal function tests in symptomatic patients.

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) 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.
    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) REDUCE FEVER - Control agitation with benzodiazepines. Monitor rectal temperature continuously. Remove patients clothing and enhance evaporative heat loss by spraying the skin with water and placing fans in the room. Use a hypothermia blanket. Immersion in ice water for patients unresponsive to other measures. Dantrolene may be effective. SALICYLATES ARE NOT RECOMMENDED - in the management of fever.
    E) ADMINISTER OXYGEN - if needed. Monitor for dysrhythmias if vital signs not stable.
    F) ADMINISTER INTRAVENOUS FLUIDS - and correct electrolyte, acid-base disturbances and to prevent dehydration associated with hyperthermia.
    1) Intravenous glucose solutions should be utilized to supply the requirements of increased metabolism.
    2) CAUTION - should be exercised in administering fluids to patients with cerebral edema.
    3) With significant exposure and impending coma, insert urinary catheters and a right heart catheter to measure output and pulmonary wedge pressure.
    G) If intubation or any procedure that reduces respiratory drive (eg, sedation) is performed, monitor arterial blood gases carefully to avoid uncompensated metabolic acidosis and severe acidemia. CAUTION: Inability to intubate or ventilate due to widespread muscle rigidity (despite suxamethonium and vecuronium administration) has been reported after 2,4-dinitrophenol poisoning. Be prepared to perform a surgical airway if necessary.
    H) 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.
    I) ENDOSCOPY: Early endoscopy allows patients without gastrointestinal injury to be medically cleared, and provides important prognostic information in patients who do have varying degrees of gastrointestinal burns. In addition, it facilitates the safe placement of enteral feeding tubes thereby shortening the period of time that patients with burns are without enteral nutritional support. Endoscopy should be performed within the first 24 hours post-ingestion, and should be avoided from 2 days to 2 weeks post-ingestion since wound tensile strength is lowest and the risk of perforation highest during this time. Endoscopy is indicated for all adults with deliberate ingestion or any signs or symptoms attributable to ingestion, and for children with stridor, vomiting, or drooling. Consider endoscopy in children with dysphagia, refusal to swallow, significant oral burns, or abdominal pain. If second or third degree burns are found, follow 10 to 20 days later with barium swallow or esophagram.
    J) PHARMACOLOGIC TREATMENT: The use of corticosteroids is controversial. Patients with first degree burns generally do well and rarely develop strictures. Corticosteroids are generally not beneficial in these patients. Some authors have advocated the use of corticosteroids for second degree, deep-partial thickness burns within 48 hours of ingestion in patients without gastrointestinal bleeding or evidence of perforation. However, no well-controlled human study has documented efficacy. Corticosteroids are generally not beneficial in patients with second degree, superficial-partial thickness burns. Some authors have recommended steroids in patients with third degree burns. A high percentage of patients with third degree burns go on to develop strictures with or without corticosteroid therapy and the risk of infection and perforation may be increased by corticosteroid use. Most authors feel that the risk outweighs any potential benefit and routine use is not recommended. Antibiotics are indicated for suspected perforation or infection and in patients receiving corticosteroids.
    K) SURGICAL OPTIONS: Initially, if severe esophageal burns are found a string may be placed in the stomach to facilitate later dilation. Insertion of a specialized nasogastric tube after confirmation of a circumferential burn may prevent strictures. Dilation is indicated after 2 to 4 weeks if strictures are confirmed; if unsuccessful, either colonic intraposition or gastric tube placement may be performed. Consider early laparotomy in patients with severe esophageal and/or gastric burns.
    L) ACUTE LUNG INJURY: Maintain ventilation and oxygenation and evaluate with frequent arterial blood gases and/or pulse oximetry monitoring. Early use of PEEP and mechanical ventilation may be needed.
    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 - Wash affected areas of skin and hair vigorously with soap and water. Dermal exposure is usually accompanied by a yellowish discoloration which does not have to be removed completely to prevent absorption.

Range Of Toxicity

    A) The fatal dose in adults is about 1 to 3 grams by mouth, 3 grams has proven fatal even in divided doses over a period of 5 days. A 20-year-old obese male died after ingesting a total of 2.4 grams DNP over 4 days (600 mg daily).
    B) Inhalation or dermal exposure may result in toxicity.

Clinical Effects

Summary Of Exposure

    A) USES: 2,4 Dinitrophenol was first used in the early 1900s as a weight loss agent. The ban on human consumption was first issued in 1938 and then again in 2003; however, it still remains widely available on the internet, mainly marketed to bodybuilders who want to lose fat but not muscle mass. Commercially, dinitrophenol has been used as wood preserver, dye, photograph developer, and herbicide.
    B) TOXICOLOGY: DNP uncouples oxidative phosphorylation, leading to the inhibition of all energy-requiring processes and the extramitochondrial accumulation of inorganic phosphate and acts as a chemical ionophore, interfering with the cellular production of ATP. The loss of potential energy is dissipated as heat, which causes a rapid consumption of calories and failure in thermoregulatory homeostasis, leading to uncontrolled hyperthermia.
    C) EPIDEMIOLOGY: DNP was banned by the FDA for human consumption in 1938. Overdose and death from DNP was rare, almost nonexistent, until 2001, when an increase in availability from various internet sites caused a surge in abuse. In 2003, the FDA reissued the ban on human consumption; however, DNP still remains widely available on the internet.
    D) WITH POISONING/EXPOSURE
    1) OVERDOSE: Well absorbed by all routes. Death from intentional oral overdose and accidental dermal and inhalation exposure have been reported. ACUTE EFFECTS: Fever, tachypnea, diaphoresis, headache, malaise, thirst, yellow skin staining following dermal contact (urine/stool may be bright yellow or orange). SEVERE: Seizures, coma, cyanosis, pulmonary edema, metabolic acidosis, dysrhythmias (VT, VFib), and renal/hepatic injury. Concentrated solutions may cause caustic GI injury. INFREQUENT: Metabolic acidosis, methemoglobinemia, and cerebral edema. Deaths have been reported when DNP was used illicitly as a bodybuilding or weight loss supplement. ONSET: 1 to 3 mg/kg can produce acute toxicity in a few hours. The average time to death is 14 hours.

Vital Signs

    3.3.1) SUMMARY
    A) Blood pressure, pulse, respiratory rate, and temperature may all be elevated after exposure.
    3.3.2) RESPIRATIONS
    A) WITH POISONING/EXPOSURE
    1) Respirations are usually increased (Lee et al, 2014; Tewari et al, 2009; Miranda et al, 2006) .
    3.3.3) TEMPERATURE
    A) WITH POISONING/EXPOSURE
    1) HYPERTHERMIA
    a) FEVER: Temperature is usually extremely elevated along with profuse diaphoresis, which are virtually always found after acute toxic exposure (Lee et al, 2014; Grundlingh et al, 2011; Miranda et al, 2006; McFee et al, 2004; Macnab & Fielden, 1998; Budavari, 1996; Bidstrup & Payne, 1951; MacBryde & Taussig, 1935).
    b) CASE REPORT: A 30-year-old man presented to the emergency department with diaphoresis, beet red skin, and yellow sclera. His body temperature peaked at 108 degrees F, and he developed rhabdomyolysis and renal failure. Following repeated administration of dantrolene and supportive care, the patient recovered without sequelae. Review of his medication history revealed that, prior to presentation, he had been taking dinitrophenol for weight loss and body building (Barker et al, 2006). The authors did not clarify if other measures including external cooling or benzodiazepines were utilized in this patient.
    3.3.4) BLOOD PRESSURE
    A) WITH POISONING/EXPOSURE
    1) Blood pressure may be elevated.
    3.3.5) PULSE
    A) WITH POISONING/EXPOSURE
    1) Pulse is commonly rapid (Lee et al, 2014; Grundlingh et al, 2011; Miranda et al, 2006).
    2) CASE REPORT - A 27-year-old woman presented with nausea, fatigue and excessive sweating after doubling the dose of the DNP-containing diet preparation she had bought over the internet. She was diaphoretic, tachycardic (140 beats/min), and hyperventilating (RR 60). One hour after admission, the patient desaturated to <90%; however, intubation was not possible due to widespread sustained muscle rigidity. She developed asystole and died despite resuscitation efforts (Tewari et al, 2009).

Heent

    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) CATARACTS may be seen after chronic exposure (Grundlingh et al, 2011; Kurt et al, 1986; Finkel, 1983).
    a) CASE SERIES: In a study of approximately 100 women, cataracts were reported as late as 13 months after the drug was discontinued (Whalman, 1936). However, once it appeared, the lesions developed rapidly with marked swelling of the lens, which predisposed the patients to glaucoma.
    b) The development of cataracts tend to be species-specific (Spencer et al, 1948, Armbrecht & Saver, 1960).
    2) SECONDARY GLAUCOMA was associated with most cases of mature cataract (Grant, 1986).
    3) SYMBLEPHARON leading to the loss of one eye was reported in one individual (Grant, 1986).
    4) PARESIS OF ACCOMMODATION improved when dinitrophenol was discontinued (Grant, 1986).
    5) NYSTAGMUS and dilated pupils have been present in moderately severe cases (Grant, 1986).
    6) Ophthalmoplegia developed (left sixth cranial nerve) in a 6-year-old boy poisoned with dinitrophenol (Macnab & Fielden, 1998).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) CONDUCTION DISORDER OF THE HEART
    1) WITH POISONING/EXPOSURE
    a) Sinus tachycardia, ventricular tachycardia, and ventricular fibrillation may occur (Grundlingh et al, 2011; Ellenhorn & Barceloux, 1988).
    b) CASE REPORT: A 6-year-old developed tachycardia (163 beats/min) following exposure to dinitrophenol along with tachypnea and a decreased level of consciousness (Macnab & Fielden, 1998). The child recovered with supportive care.
    c) CASE REPORT: A 17-year-old girl, who had been taking 2,4-dinitrophenol as a weight loss supplement, developed hypotension, respiratory failure that necessitated mechanical ventilation, and a cardiac dysrhythmia that deteriorated into asystole. She died approximately 3 hours after hospital admission. Her blood 2,4-dinitrophenol concentration at admission was 36.1 mg/L (Miranda et al, 2006).
    d) CASE REPORT: A 25-year-old woman presented with fever and muscle pain. Vital signs showed tachycardia (114 beats/minute), tachypnea (20 breaths/minute) and hyperthermia (39.7 degrees C). History of the patient revealed that she had been taking a body slimming pill for a month prior to presentation. Laboratory data revealed peak serum creatine kinase and lactate dehydrogenase concentrations of 915 units/L (reference interval 42 to 190 units/L) and 768 units/L (reference interval 211 to 370 units/L), respectively. With supportive therapy, the patient recovered and was discharged 4 days later. The patient was asymptomatic a follow-up 1 month later. Analysis of the body slimming pill revealed that it contained 2,4-dinitrophenol (Lee et al, 2014).
    B) ELECTROCARDIOGRAM ABNORMAL
    1) WITH POISONING/EXPOSURE
    a) Abnormal electrocardiographic findings included diphasic T wave, T wave reversal, elevation or depression of the S-T segment, and reduction of amplitude of the R wave (Kaiser, 1964). At dosages of 25 mg/kg or more, the tracings were bizarre with no characteristic waves.
    C) CARDIAC ARREST
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 20-year-old man became increasingly agitated after taking 600 mg DNP for 4 days for apparent weight loss. The patient was febrile (102 F degrees orally) and diaphoretic on admission; other vital signs were stable. Shortly after admission to the emergency department, the patient's status deteriorated; he became bradycardic, developed asystole, and died despite resuscitation efforts (McFee et al, 2004).
    b) CASE REPORT: A 27-year-old woman presented with nausea, fatigue, and excessive sweating after doubling the dose of the DNP-containing diet preparation she had bought over the internet. She was diaphoretic, tachycardic (140 beats/min), and hyperventilating (RR 60). One hour after admission, the patient desaturated to <90%; however, intubation was not possible due to widespread sustained muscle rigidity. She developed asystole and died despite resuscitation efforts (Tewari et al, 2009).
    c) CASE REPORT: A 49-year-old woman and a 41-year-old man experienced 2,4 dinitrophenol toxicity secondary to inhalation and dermal exposure after collecting nylon bags used as 2,4 DNP packaging. The patients were collecting the bags on a warm weather day, with little skin protection on arms and legs, and only minimal protection on the face. Upon admission to the hospital, both patients were noted to have yellow stained skin and black stained feet and hands from handling the tainted packaging. The woman presented with a 10 hour history of diaphoresis, dizziness, and gasping for breath. The man presented with an 8 hour history of the same symptoms. Physical exam revealed hypertension, hyperthermia, and tachycardia for both patients. Despite treatment of symptoms, both patients developed asystole and died (Jiang Jiukun et al, 2011).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) HYPERVENTILATION
    1) WITH POISONING/EXPOSURE
    a) Respiratory rate is usually markedly increased (Lee et al, 2014; Miranda et al, 2006; Macnab & Fielden, 1998; Gosselin et al, 1984) .
    b) CASE REPORT: A 27-year-old woman presented with nausea, fatigue, and excessive sweating after doubling the dose of the DNP-containing diet preparation she had bought over the internet. She was diaphoretic, tachycardic (140 beats/min), and hyperventilating (RR 60). One hour after admission, the patient desaturated to <90%; however, intubation was not possible due to widespread sustained muscle rigidity. She developed asystole and died despite resuscitation efforts (Tewari et al, 2009).
    B) ACUTE LUNG INJURY
    1) WITH POISONING/EXPOSURE
    a) Pulmonary edema may develop (Gosselin et al, 1984).
    b) CASE REPORT: Severe pulmonary edema was noted at autopsy of a 28-year-old man who died after taking 2,4-dinitrophenol as a bodybuilding supplement (Miranda et al, 2006).
    C) RESPIRATORY FAILURE
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 17-year-old girl, who had been taking 2,4-dinitrophenol as a weight loss supplement, developed hypotension, respiratory failure that necessitated mechanical ventilation, and a cardiac dysrhythmia that deteriorated into asystole. She died approximately 3 hours after hospital admission (Miranda et al, 2006). Her blood 2,4-dinitrophenol concentration at admission was 36.1 mg/L.
    D) MASSETER SPASM
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 27-year-old woman presented with nausea, fatigue, and excessive sweating after doubling the dose of the DNP-containing diet preparation she had bought over the internet. She was diaphoretic, tachycardic (140 beats/min), and hyperventilating (RR 60). One hour after admission, the patient desaturated to <90% and became asystolic. Despite receiving suxamethonium and vecuronium, she could not be intubated or ventilated because of widespread sustained muscle rigidity. She died despite resuscitation efforts (Tewari et al, 2009).
    3.6.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HYPERVENTILATION
    a) ANIMAL DATA: Oxygen consumption, ventilation, and respiratory frequency increased with increasing doses of intravenous dinitrophenol given to anesthetized dogs (Cardus & Hoff, 1963).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) Restlessness, hyperactivity, seizures, and coma are common findings (Grundlingh et al, 2011; Bidstrup & Payne, 1951).
    b) CASE REPORT: A 20-year-old man became increasingly agitated after taking 600 mg DNP for 4 days for apparent weight loss. The patient was febrile (102 F degrees orally) and diaphoretic on admission; other vital signs were stable. Shortly after admission to the ED, the patient's status deteriorated; he became bradycardic, developed asystole, and died despite resuscitation efforts (McFee et al, 2004).
    B) CENTRAL NERVOUS SYSTEM DEFICIT
    1) WITH POISONING/EXPOSURE
    a) Dinitrophenols exerts direct action on the cerebrum and lower brain centers causing stimulation followed by depression (Simon, 1953).
    C) NEURITIS
    1) WITH POISONING/EXPOSURE
    a) PERIPHERAL NEURITIS may be among the occasional hypersensitivity reactions observed with repeat exposure (Gosselin et al, 1984).
    D) CEREBRAL EDEMA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORTS : Cerebral edema was found on autopsy in 2 agricultural workers exposed to dinitro-ortho-cresol spray for 1 month (Bidstrup & Payne, 1951).
    b) CASE REPORT: Severe cerebral edema with uncal herniation was noted at autopsy of a 28-year-old man who died after taking 2,4-dinitrophenol as a bodybuilding supplement (Miranda et al, 2006).
    E) COMA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 6-year-old was found unresponsive following exposure to dinitrophenol (Macnab & Fielden, 1998). Neurological improvement was observed within 48 hours of supportive care.
    F) CRANIAL NERVE DISORDER
    1) WITH POISONING/EXPOSURE
    a) Ophthalmoplegia developed (left sixth cranial nerve) in a 6-year-old boy poisoned with dinitrophenol (Macnab & Fielden, 1998).
    G) DISORDER OF THE PERIPHERAL NERVOUS SYSTEM
    1) WITH THERAPEUTIC USE
    a) CASE REPORT/CHRONIC USE: A 19-year-old woman presented with a 1-year history of progressive dysesthesias that began in her feet and ascending to her pelvis and hands. Other than decreased pinprick sensation from her feet to thighs and hands to elbows, her physical examination was normal. Laboratory data was also within normal limits. Nerve conduction studies indicated decreased distal peroneal motor amplitude and absent bilateral sural and plantar sensory responses, all of which were consistent with a diagnosis of axonal sensorimotor polyneuropathy. Interview of the patient revealed that she had been taking dinitrophenol for weight loss, up to 1 gram daily for 6 months prior to symptom onset and for a year after symptom onset. The patient's symptoms showed moderate improvement at follow-up 2 years following discontinuation of the dinitrophenol (Phillips & Singer, 2013).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) GASTRIC ULCER
    1) WITH POISONING/EXPOSURE
    a) BURNS: Ingestion of concentrated solutions has produced corrosion of the oropharyngeal, esophageal, and gastric mucous membranes (Swamy, 1953).
    B) NAUSEA AND VOMITING
    1) WITH POISONING/EXPOSURE
    a) Nausea and vomiting are common symptoms (Miranda et al, 2006).
    b) CASE REPORT: A 27-year-old woman presented with nausea, fatigue and excessive sweating after doubling the dose of the DNP-containing diet preparation she had bought over the internet. She was diaphoretic, tachycardic (140 beats/min), and hyperventilating (RR 60). One hour after admission, the patient's status deteriorated, she developed asystole and died despite resuscitation efforts (Tewari et al, 2009).
    C) DIARRHEA
    1) WITH POISONING/EXPOSURE
    a) Stools may be a bright yellow color (Smith, 1981; Macnab & Fielden, 1998).
    b) Stools may be watery and loose.

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) HEPATIC NECROSIS
    1) WITH POISONING/EXPOSURE
    a) Hepatic necrosis and jaundice may occur following ingestion (Miranda et al, 2006; Haddad et al, 1998).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) CRUSH SYNDROME
    1) WITH POISONING/EXPOSURE
    a) Dinitrophenols may produce a necrotizing tubular injury of the kidneys characterized by oliguria, albuminuria, cylindruria, and sometimes, hematuria (Cann & Verhulst, 1960).
    B) ACUTE RENAL FAILURE SYNDROME
    1) WITH POISONING/EXPOSURE
    a) Renal failure may occur 12 to 72 hours after the exposure (Grundlingh et al, 2011; McFee et al, 2004; Macnab & Fielden, 1998; Wood et al, 1983) .
    C) ABNORMAL URINE
    1) WITH POISONING/EXPOSURE
    a) Urine may be colored bright yellow or orange (ITI, 1988; Macnab & Fielden, 1998).

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) ACIDOSIS
    1) WITH POISONING/EXPOSURE
    a) Metabolic acidosis has developed following dinitrophenol exposure (Gosselin et al, 1984; Macnab & Fielden, 1998).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) METHEMOGLOBINEMIA
    1) WITH POISONING/EXPOSURE
    a) Methemoglobinemia may occur in some cases (Haddad et al, 1998; Hayes, 1982).
    b) Methemoglobinemia is produced by 2,4-dinitrophenol but not by the 2,3-, 2,5-, 2,6-, and 3,4-isomers (Magne et al, 1932b).
    B) LEUKOPENIA
    1) WITH POISONING/EXPOSURE
    a) NEUTROPENIA can occur after chronic exposure (Kurt, 1986).
    C) HEMOLYTIC ANEMIA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Hemolytic anemia was reported in a worker who impregnated wooden poles with dinitrophenol, arsenic, and sodium fluoride (Saita, 1949). It is unclear as to the causative agent. Arsine gas can cause profound hemolytic anemia, occurring when arsenic reacts with hydrogen or reducing agents in aqueous solutions.

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) DISCOLORATION OF SKIN
    1) WITH POISONING/EXPOSURE
    a) PIGMENTATION: Yellow staining of the skin and hair frequently occurs following contact with nitrophenolic chemicals (Grundlingh et al, 2011; Leftwich et al, 1982; Smith, 1981).
    b) A 49-year-old woman and a 41-year-old man experienced fatal 2,4 dinitrophenol toxicity secondary to inhalation and dermal exposure after collecting nylon bags used as 2,4 DNP packaging. The patients were collecting the bags on a warm weather day, with little skin protection on arms and legs, and only minimal protection on the face. Upon admission to the hospital, both patients were noted to have yellow stained skin and black stained feet and hands from handling the tainted packaging. Despite treatment, both died as a result of cardiovascular collapse secondary to exposure (Jiang Jiukun et al, 2011).
    B) EXCESSIVE SWEATING
    1) WITH POISONING/EXPOSURE
    a) DIAPHORESIS is a common finding (Lee et al, 2014; Grundlingh et al, 2011; Tewari et al, 2009; Miranda et al, 2006; Barker et al, 2006; McFee et al, 2004; Macnab & Fielden, 1998; Wood et al, 1983) .
    C) ERUPTION
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 30-year-old man, with a recent history of ingesting a bodybuilding pill for 10 days, presented with a maculopapular rash on his forehead and shortness of breath. The rash generalized to his trunk, limbs, neck, and oral mucosa with sloughing of skin. Other than an increased respiratory rate (18 breaths/minute), all other vital signs were normal. The patient was discharged on hospital day 2 and was not available for follow-up. Analysis of the pill detected the presence of 2,4-dinitrophenol (2,4-DNP). Further analysis via high-performance liquid chromatography-diode array detector estimated the amount of 2,4-DNP contained within each pill was 72 mg (Lee et al, 2014).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) INCREASED MUSCLE TONE
    1) WITH POISONING/EXPOSURE
    a) MUSCLE RIGOR may occur because of heat and/or lactic acid (Gosselin et al, 1984).
    b) Muscle rigidity and myalgias were reported following the use of 2,4-dinitrophenol as a weight loss/bodybuilding supplement (Miranda et al, 2006).
    c) CASE REPORT: A 27-year-old woman presented with nausea, fatigue, and excessive sweating after doubling the dose of the DNP-containing diet preparation she had bought over the internet. She was diaphoretic, tachycardic (140 beats/min), and hyperventilating (RR 60). One hour after admission, the patient desaturated to <90%; however, intubation was not possible due to widespread sustained muscle rigidity. She developed asystole and died despite resuscitation efforts (Tewari et al, 2009).
    B) MUSCLE PAIN
    1) WITH POISONING/EXPOSURE
    a) Muscle rigidity and myalgias were reported following the use of 2,4-dinitrophenol as a weight loss/bodybuilding supplement (Miranda et al, 2006).
    b) CASE REPORT: A 25-year-old woman presented with fever and muscle pain. Vital signs showed tachycardia (114 beats/minute), tachypnea (20 breaths/minute) and hyperthermia (39.7 degrees C). History of the patient revealed that she had been taking a body slimming pill for a month prior to presentation. Laboratory data revealed peak serum creatine kinase and lactate dehydrogenase concentrations of 915 units/L (reference interval 42 to 190 units/L) and 768 units/L (reference interval 211 to 370 units/L), respectively. With supportive therapy, the patient recovered and was discharged 4 days later. The patient was asymptomatic a follow-up 1 month later. Analysis of the body slimming pill revealed that it contained 2,4-dinitrophenol (Lee et al, 2014).

Endocrine

    3.16.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) THYROID DISORDER
    a) Animal studies show varying effects of dinitrophenol.
    1) Thyroid hypofunction occurs on repeated administration to animals (Lagerspety & Tarkkonen, 1961). In vitro, dinitrophenol appears to block further iodination of monoiodotyrosine (Gosselin et al, 1984).
    2) Increased thyroxine secretion was reported following administration of dinitrophenol in rats (England et al, 1973).

Immunologic

    3.19.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) IMMUNE SYSTEM DISORDER
    a) Studies in laboratory animals indicate that dinoseb has the potential to cause damage to the immune system (EPA, 1985).

Reproductive

    3.20.1) SUMMARY
    A) Animal studies show developmental malformations involving the neurologic, ophthalmic, urologic, and skeletal systems of offsprings.
    3.20.2) TERATOGENICITY
    A) CONGENITAL ANOMALY
    1) DEVELOPMENTAL TOXICITY - Neurological and skeletal malformations were observed in laboratory animals exposed to dinoseb (Matsumoto et al, 2008; EPA, 1985).
    a) Intraperitoneal administration of 7.5 mg/kg/day of dinitrophenol to pregnant mice resulted in an increased incidence of fetal resorption, low birth weight offspring, retardation, kinky tail, hydrocephalus, hydronephrosis, and delayed bone ossification in the fetuses (Preache & Gibson, 1975).
    B) STILLBIRTH
    1) EMBRYOTOXICITY - Pregnant rats given dinoseb 200 ppm in their feed showed reductions in embryonic survival rates; surviving fetuses had lower birth weights than normal (Spencer & Tat Sing, 1982).
    C) UROGENITAL MALFORMATION
    1) Initial morphologic abnormalities of the kidney have been described in the offspring of female rats given intraperitoneal dinoseb; however, renal function and morphology subsequently returned to normal (McCormack et al, 1980).
    2) Dinoseb administered intraperitoneally to pregnant rats on gestation days 10 to 12 at a dose of 10.5 mg/kg/day caused weight reduction in the neonates which persisted beyond weaning. This was attributed to the temporary delay in the maturation of urine concentrating ability (Daston et al, 1988).
    D) CNS CONGENITAL ANOMALY
    1) OCULAR MALFORMATIONS - 2,4-Dinitrophenol caused cataracts in rabbit kits from treatment through pregnancy or late gestation (Vassilev et al, 1959).
    2) OCULAR MALFORMATIONS - Maternal toxicity and malformations of the eye were observed among the offsprings of pregnant rats fed 200 ppm of dinoseb (Giavini et al, 1986).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS88-85-7 (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) Limited evidence of carcinogenicity is available among animals.
    3.21.3) HUMAN STUDIES
    A) CARCINOMA
    1) The EPA (1985) classified dinoseb as a carcinogen with limited evidence of carcinogenicity in animals. Several formulations were also found to be contaminated with nitrosamines, which are cancer-causing substances.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Nitrophenolic plasma levels can be obtained by an adaptation of the dinitro-o-cresol method, but acute availability of testing may be limited.
    B) Monitor fluids and electrolytes carefully. Monitor blood glucose, arterial blood gases, and liver and renal function tests in symptomatic patients.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Levels of 10 mcg/mL or greater are usually seen when toxicity is present (NIOSH, 1978).
    2) One patient who survived with supportive treatment after poisoning with dinitro-ortho-cresol had a blood level of 60 mcg/g (ppm) (Pollard & Filbee, 1951).
    3) Blood levels of dinitro-ortho-cresol have not correlated with urine levels (Harvey, 1952).
    4) Blood chemistries should be monitored to evaluate fluid and electrolyte status, assess hepatic and/or renal involvement, and to rule out glucose intolerance which has been described after exposure to dinitrophenol (MacBryde & Taussig, 1935).
    5) Obtain baseline arterial blood gases (ABGs) and repeat as indicated following significant exposure.
    4.1.3) URINE
    A) URINALYSIS
    1) Examine urine for the following: albumin, casts, bile pigments, and sometimes blood. Also observe for rapid darkening on contact with the air.
    B) SPECIFIC AGENT
    1) Dinitrophenol and 2-amino-4-nitrophenol can be detected using Derrien's test (ILO, 1983).

Methods

    A) MULTIPLE ANALYTICAL METHODS
    1) Unmetabolized nitrophenols and nitrocresols can be identified spectrophotometrically, or by gas-liquid chromatography, in the serum and urine (Morgan, 1989).
    B) OTHER
    1) Parent drug can usually be detected in plasma and urine, but these values are of little use in the acute management of the poisoned patient (Baselt, 1980).

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) Aggressive supportive measures should be provided immediately.
    1) Fulminant poisoning produces severe symptoms and sudden death within 24 to 48 hours, with death ensuing from respiratory or circulatory collapse.
    2) Liver and kidney damage may ensue within 12 to 72 hours postexposure.
    3) If the condition does not continue to deteriorate rapidly after the institution of absolute rest, cooling, and oxygen, recovery is likely to be rapid and complete within 12 to 24 hours (ILO, 1983).
    B) Because the excretion of the dinitrophenols is very slow, persons who have shown symptoms of intoxication should be shielded against risks of further absorption for at least 6 weeks (Finkel, 1983).

Monitoring

    A) Nitrophenolic plasma levels can be obtained by an adaptation of the dinitro-o-cresol method, but acute availability of testing may be limited.
    B) Monitor fluids and electrolytes carefully. Monitor blood glucose, arterial blood gases, and liver and renal function tests in symptomatic patients.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) EMESIS/NOT RECOMMENDED
    1) EMESIS: Ipecac-induced emesis is not recommended because of the potential for CNS depression and seizures.
    B) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    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).
    6.5.2) 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) 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.
    C) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Monitor hepatic enzymes, serum electrolytes, CK and renal function carefully.
    B) FLUID/ELECTROLYTE BALANCE REGULATION
    1) Fluids, electrolytes, and acid-base data should be monitored and intravenous replacement of losses provided.
    2) All intravenous solutions should contain adequate amounts of glucose to supply the requirements of the increased metabolism.
    3) Unless there are manifestations of cerebral or pulmonary edema or of inadequate renal function, administer intravenous fluids to restore hydration and support physiologic mechanisms for heat loss and toxicant disposition.
    C) BODY TEMPERATURE ABOVE REFERENCE RANGE
    1) Control agitation with parenteral benzodiazepines; minimize physical activity.
    2) Remove patient's clothing, bathe or spray with tepid water and direct fans at patient to enhance evaporative cooling.
    3) A rectal electrode thermometer should be used to continuously monitor temperature.
    4) If tepid bathing is not sufficient, use hypothermic blanket or immersion in ice water.
    5) Dantrolene administration has been reported to be effective in reducing the body temperature in a patient with dinitrophenol-induced hyperthermia; however, they did not report if other measures including benzodiazepines or external cooling were performed (Barker et al, 2006).
    6) Administration of SALICYLATES to reduce hyperpyrexia is CONTRAINDICATED. This drug is also an oxidative phosphorylation uncoupler and may aggravate hyperpyrexia.
    D) AIRWAY MANAGEMENT
    1) If intubation or any procedure that reduces respiratory drive (eg, sedation) is performed, monitor arterial blood gases carefully to avoid uncompensated metabolic acidosis and severe acidemia (Barker et al, 2006).
    2) SURGICAL AIRWAY MAY BE NECESSARY - Inability to intubate or ventilate due to widespread muscle rigidity (despite suxamethonium and vecuronium administration) has been reported after 2,4-dinitrophenol poisoning (Tewari et al, 2009). Be prepared to perform a surgical airway if necessary.
    E) DELIRIUM
    1) Control agitation and involuntary motor activity to reduce body heat production (Morgan, 1989).
    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) Because barbiturates may exacerbate the biochemical disturbances produced by dinitrophenol, Magos & Manson (1988) do not recommend their use for restlessness due to DNP poisoning.
    F) ACUTE LUNG INJURY
    1) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
    2) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).
    a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)
    3) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
    4) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
    5) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
    6) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
    7) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).
    G) CEREBRAL EDEMA
    1) CLINICAL IMPLICATIONS
    a) Cerebral edema and elevated intracranial pressure (ICP) may occur. Emergent management includes head elevation and administration of mannitol; hyperventilation should be performed if there is evidence of impending herniation.
    2) MONITORING
    a) Patients will usually require endotracheal intubation and mechanical ventilation. Monitor intracranial pressure, cerebral perfusion pressure and cerebral blood flow.
    3) TREATMENT
    a) Most information on the treatment of cerebral edema is derived from studies of traumatic brain injury.
    4) MANNITOL
    a) ADULT/PEDIATRIC DOSE: 0.25 to 1 gram/kilogram intravenously over 10 to 15 minutes (None Listed, 2000).
    b) AVAILABLE FORMS: Mannitol injection (5%, 10%, 15%, 20%, 25%).
    c) MAJOR ADVERSE REACTIONS: Congestive heart failure, hypernatremia, hyponatremia, hyperkalemia, renal failure, pulmonary edema, and allergic reactions.
    d) PRECAUTIONS: Contraindicated in well-established anuria or impaired renal function not responding to a test dose, pulmonary edema, CHF, severe dehydration; caution in progressive oliguria and azotemia. Do not add to whole blood for transfusions; enhanced neuromuscular blockade has occurred with tubocurarine. Keep serum osmolarity below 320 mOsm.
    e) MONITORING PARAMETERS: Renal function, urine output, fluid balance, serum potassium levels, serum osmolarity, and CVP.
    5) HYPERTONIC SALINE
    a) Preliminary studies suggest that hypertonic saline (7.5% saline/6% dextran) 100 ml reduced ICP more effectively than 200 mL of 20% mannitol in adults with elevated ICP after traumatic brain injury(Battison et al, 2005).
    6) ELEVATION
    a) Elevation of the head of the bed to approximately 30 degrees decreases ICP and improves cerebral perfusion pressure (Meixensberger et al, 1997; Schneider et al, 1993; Feldman et al, 1992).
    7) MECHANICAL DECOMPRESSION
    a) Early surgical decompression, ventriculostomy with CSF drainage, or craniectomy may be useful in patients with persistent elevation of ICP (Sahuquillo & Arikan, 2006; Sakai et al, 1998; Polin et al, 1997; Taylor et al, 2001). Most experience with these modalities has been in patients with traumatic brain injury.
    8) HYPERVENTILATION
    a) SUMMARY: Hyperventilation has been associated with adverse outcomes and should not be performed routinely (Muizelaar et al, 1991). It is indicated in patients who have clinical evidence of herniation or if there is intracranial hypertension refractory to sedation, paralysis, CSF drainage and osmotic diuretics (None Listed, 2000a).
    b) RECOMMENDATION:
    1) The PCO2 must be controlled in the range of 25 torr; further lowering of PCO2 may create undesirable effects secondary to local tissue hypoxia.
    2) End-tidal CO2 tension, correlated with an initial ABG measurement, provides a noninvasive means of monitoring PCO2 (Mackersie & Karagianes, 1990).
    3) Most authorities advise that hyperventilation should be considered a temporizing measure only; SUSTAINED hyperventilation should be avoided (Am Acad Neurol, 1997; Bullock et al, 1996; Kirkpatrick, 1997).
    H) CONTRAINDICATED TREATMENT
    1) ATROPINE IS ABSOLUTELY CONTRAINDICATED - and it is essential not to confuse the evidence for dinitrophenol poisoning with manifestations of cholinesterase inhibition (Hayes, 1982; Finkel, 1983).
    I) ENDOSCOPIC PROCEDURE
    1) There is little experience with the use of endoscopy, corticosteroids, or surgical therapy after ingestion of concentrated dinitrophenol. The following information is derived from ingestion of other caustic substances.
    2) SUMMARY: Obtain consultation concerning endoscopy as soon as possible, and perform endoscopy within the first 24 hours when indicated.
    3) INDICATIONS: Endoscopy should be performed in adults with a history of deliberate ingestion, adults with any signs or symptoms attributable to inadvertent ingestion, and in children with stridor, vomiting, or drooling after unintentional ingestion (Crain et al, 1984). Endoscopy should also be performed in children with dysphagia or refusal to swallow, significant oral burns, or abdominal pain after unintentional ingestion (Gaudreault et al, 1983; Nuutinen et al, 1994). Children and adults who are asymptomatic after accidental ingestion do not require endoscopy (Gupta et al, 2001; Lamireau et al, 2001; Gorman et al, 1992).
    4) RISKS: Numerous large case series attest to the relative safety and utility of early endoscopy in the management of caustic ingestion.
    a) REFERENCES: (Dogan et al, 2006; Symbas et al, 1983; Crain et al, 1984a; Gaudreault et al, 1983a; Schild, 1985; Moazam et al, 1987; Sugawa & Lucas, 1989; Previtera et al, 1990; Zargar et al, 1991; Vergauwen et al, 1991; Gorman et al, 1992)
    5) The risk of perforation during endoscopy is minimized by (Zargar et al, 1991):
    a) Advancing across the cricopharynx under direct vision
    b) Gently advancing with minimal air insufflation
    c) Never retroverting or retroflexing the endoscope
    d) Using a pediatric flexible endoscope
    e) Using extreme caution in advancing beyond burn lesion areas
    f) Most authors recommend endoscopy within the first 24 hours of injury, not advancing the endoscope beyond areas of severe esophageal burns, and avoiding endoscopy during the subacute phase of healing when tissue slough increases the risk of perforation (5 to 15 days after ingestion) (Zargar et al, 1991).
    6) GRADING
    a) Several scales for grading caustic injury exist. The likelihood of complications such as strictures, obstruction, bleeding, and perforation is related to the severity of the initial burn (Zargar et al, 1991):
    b) Grade 0 - Normal examination
    c) Grade 1 - Edema and hyperemia of the mucosa; strictures unlikely.
    d) Grade 2A - Friability, hemorrhages, erosions, blisters, whitish membranes, exudates and superficial ulcerations; strictures unlikely.
    e) Grade 2B - Grade 2A plus deep discreet or circumferential ulceration; strictures may develop.
    f) Grade 3A - Multiple ulcerations and small scattered areas of necrosis; strictures are common, complications such as perforation, fistula formation or gastrointestinal bleeding may occur.
    g) Grade 3B - Extensive necrosis through visceral wall; strictures are common, complications such as perforation, fistula formation, or gastrointestinal bleeding are more likely than with 3A.
    7) FOLLOW UP - If burns are found, follow 10 to 20 days later with barium swallow or esophagram.
    8) SCINTIGRAPHY - Scans utilizing radioisotope labelled sucralfate (technetium 99m) were performed in 22 patients with caustic ingestion and compared with endoscopy for the detection of esophageal burns. Two patients had minimal residual isotope activity on scanning but normal endoscopy and two patients had normal activity on scan but very mild erythema on endoscopy. Overall the radiolabeled sucralfate scan had a sensitivity of 100%, specificity of 81%, positive predictive value of 84% and negative predictive value of 100% for detecting clinically significant burns in this population (Millar et al, 2001). This may represent an alternative to endoscopy, particularly in young children, as no sedation is required for this procedure. Further study is required.
    9) MINIPROBE ULTRASONOGRAPHY - was performed in 11 patients with corrosive ingestion . Findings were categorized as grade 0 (distinct muscular layers without thickening, grade I (distinct muscular layers with thickening), grade II (obscured muscular layers with indistinct margins) and grade III (muscular layers that could not be differentiated). Findings were further categorized as to whether the worst appearing image involved part of the circumference (type a) or the whole circumference (type b). Strictures did not develop in patients with grade 0 (5 patients) or grade I (4 patients) lesions. Transient stricture formation developed in the only patient with grade IIa lesions, and stricture requiring repeated dilatation developed in the only patient with grade IIIb lesions (Kamijo et al, 2004).
    J) CORTICOSTEROID
    1) CORROSIVE INGESTION/SUMMARY: The use of corticosteroids for the treatment of caustic ingestion is controversial. Most animal studies have involved alkali-induced injury (Haller & Bachman, 1964; Saedi et al, 1973). Most human studies have been retrospective and generally involve more alkali than acid-induced injury and small numbers of patients with documented second or third degree mucosal injury.
    2) FIRST DEGREE BURNS: These burns generally heal well and rarely result in stricture formation (Zargar et al, 1989; Howell et al, 1992). Corticosteroids are generally not beneficial in these patients (Howell et al, 1992).
    3) SECOND DEGREE BURNS: Some authors recommend corticosteroid treatment to prevent stricture formation in patients with a second degree, deep-partial thickness burn (Howell et al, 1992). However, no well controlled human study has documented efficacy. Corticosteroids are generally not beneficial in patients with a second degree, superficial-partial thickness burn (Caravati, 2004; Howell et al, 1992).
    4) THIRD DEGREE BURNS: Some authors have recommended steroids in this group as well (Howell et al, 1992). A high percentage of patients with third degree burns go on to develop strictures with or without corticosteroid therapy and the risk of infection and perforation may be increased by corticosteroid use. Most authors feel that the risk outweighs any potential benefit and routine use is not recommended (Boukthir et al, 2004; Oakes et al, 1982; Pelclova & Navratil, 2005).
    5) CONTRAINDICATIONS: Include active gastrointestinal bleeding and evidence of gastric or esophageal perforation. Corticosteroids are thought to be ineffective if initiated more than 48 hours after a burn (Howell, 1987).
    6) DOSE: Administer daily oral doses of 0.1 milligram/kilogram of dexamethasone or 1 to 2 milligrams/kilogram of prednisone. Continue therapy for a total of 3 weeks and then taper (Haller et al, 1971; Marshall, 1979). An alternative regimen in children is intravenous prednisolone 2 milligrams/kilogram/day followed by 2.5 milligrams/kilogram/day of oral prednisone for a total of 3 weeks then tapered (Anderson et al, 1990).
    7) ANTIBIOTICS: Animal studies suggest that the addition of antibiotics can prevent the infectious complications associated with corticosteroid use in the setting of caustic burns. Antibiotics are recommended if corticosteroids are used or if perforation or infection is suspected. Agents that cover anaerobes and oral flora such as penicillin, ampicillin, or clindamycin are appropriate (Rosenberg et al, 1953).
    8) STUDIES
    a) ANIMAL
    1) Some animal studies have suggested that corticosteroid therapy may reduce the incidence of stricture formation after severe alkaline corrosive injury (Haller & Bachman, 1964; Saedi et al, 1973a).
    2) Animals treated with steroids and antibiotics appear to do better than animals treated with steroids alone (Haller & Bachman, 1964).
    3) Other studies have shown no evidence of reduced stricture formation in steroid treated animals (Reyes et al, 1974). An increased rate of esophageal perforation related to steroid treatment has been found in animal studies (Knox et al, 1967).
    b) HUMAN
    1) Most human studies have been retrospective and/or uncontrolled and generally involve small numbers of patients with documented second or third degree mucosal injury. No study has proven a reduced incidence of stricture formation from steroid use in human caustic ingestions (Haller et al, 1971; Hawkins et al, 1980; Yarington & Heatly, 1963; Adam & Brick, 1982).
    2) META ANALYSIS
    a) Howell et al (1992), analyzed reports concerning 361 patients with corrosive esophageal injury published in the English language literature since 1956 (10 retrospective and 3 prospective studies). No patients with first degree burns developed strictures. Of 228 patients with second or third degree burns treated with corticosteroids and antibiotics, 54 (24%) developed strictures. Of 25 patients with similar burn severity treated without steroids or antibiotics, 13 (52%) developed strictures (Howell et al, 1992).
    b) Another meta-analysis of 10 studies found that in patients with second degree esophageal burns from caustics, the overall rate of stricture formation was 14.8% in patients who received corticosteroids compared with 36% in patients who did not receive corticosteroids (LoVecchio et al, 1996).
    c) Another study combined results of 10 papers evaluating therapy for corrosive esophageal injury in humans published between January 1991 and June 2004. There were a total of 572 patients, all patients received corticosteroids in 6 studies, in 2 studies no patients received steroids, and in 2 studies, treatment with and without corticosteroids was compared. Of 109 patients with grade 2 esophageal burns who were treated with corticosteroids, 15 (13.8%) developed strictures, compared with 2 of 32 (6.3%) patients with second degree burns who did not receive steroids (Pelclova & Navratil, 2005).
    3) Smaller studies have questioned the value of steroids (Ferguson et al, 1989; Anderson et al, 1990), thus they should be used with caution.
    4) Ferguson et al (1989) retrospectively compared 10 patients who did not receive antibiotics or steroids with 31 patients who received both antibiotics and steroids in a study of caustic ingestion and found no difference in the incidence of esophageal stricture between the two groups (Ferguson et al, 1989).
    5) A randomized, controlled, prospective clinical trial involving 60 children with lye or acid induced esophageal injury did not find an effect of corticosteroids on the incidence of stricture formation (Anderson et al, 1990).
    a) These 60 children were among 131 patients who were managed and followed-up for ingestion of caustic material from 1971 through 1988; 88% of them were between 1 and 3 years old (Anderson et al, 1990).
    b) All patients underwent rigid esophagoscopy after being randomized to receive either no steroids or a course consisting initially of intravenous prednisolone (2 milligrams/kilogram per day) followed by 2.5 milligrams/kilogram/day of oral prednisone for a total of 3 weeks prior to tapering and discontinuation (Anderson et al, 1990).
    c) Six (19%), 15 (48%), and 10 (32%) of those in the treatment group had first, second and third degree esophageal burns, respectively. In contrast, 13 (45%), 5 (17%), and 11 (38%) of the control group had the same levels of injury (Anderson et al, 1990).
    d) Ten (32%) of those receiving steroids and 11 (38%) of the control group developed strictures. Four (13%) of those receiving steroids and 7 (24%) of the control group required esophageal replacement. All but 1 of the 21 children who developed strictures had severe circumferential burns on initial esophagoscopy (Anderson et al, 1990).
    e) Because of the small numbers of patients in this study, it lacked the power to reliably detect meaningful differences in outcome between the treatment groups (Anderson et al, 1990).
    6) ADVERSE EFFECTS
    a) The use of corticosteroids in the treatment of caustic ingestion in humans has been associated with gastric perforation (Cleveland et al, 1963) and fatal pulmonary embolism (Aceto et al, 1970).
    K) SURGICAL PROCEDURE
    1) SUMMARY: Initially if severe esophageal burns are found a string may be placed in the stomach to facilitate later dilation. Insertion of a specialized nasogastric tube after confirmation of a circumferential burn may prevent strictures. Dilation is indicated after 2 to 4 weeks if strictures are confirmed. If dilation is unsuccessful colonic intraposition or gastric tube placement may be needed. Early laparotomy should be considered in patients with evidence of severe esophageal or gastric burns on endoscopy.
    2) STRING - If a second degree or circumferential burn of the esophagus is found a string may be placed in the stomach to avoid false channel and to provide a guide for later dilation procedures (Gandhi et al, 1989).
    3) STENT - The insertion of a specialized nasogastric tube or stent immediately after endoscopically proven deep circumferential burns is preferred by some surgeons to prevent stricture formation (Mills et al, 1978; (Wijburg et al, 1985; Coln & Chang, 1986).
    a) STUDY - In a study of 11 children with deep circumferential esophageal burns after caustic ingestion, insertion of a silicone rubber nasogastric tube for 5 to 6 weeks without steroids or antibiotics was associated with stricture formation in only one case (Wijburg et al, 1989).
    4) DILATION - Dilation should be performed at 1 to 4 week intervals when stricture is present(Gundogdu et al, 1992). Repeated dilation may be required over many months to years in some patients. Successful dilation of gastric antral strictures has also been reported (Hogan & Polter, 1986; Treem et al, 1987).
    5) COLONIC REPLACEMENT - Intraposition of colon may be necessary if dilation fails to provide an adequate sized esophagus (Chiene et al, 1974; Little et al, 1988; Huy & Celerier, 1988).
    6) LAPAROTOMY/LAPAROSCOPY - Several authors advocate laparotomy or laparoscopy in patients with endoscopic evidence of severe esophageal or gastric burns to evaluate for the presence of transmural gastric or esophageal necrosis (Cattan et al, 2000; Estrera et al, 1986; Meredith et al, 1988; Wu & Lai, 1993).
    a) STUDY - In a retrospective study of patients with extensive transmural esophageal necrosis after caustic ingestion, all 4 patients treated in the conventional manner (esophagoscopy, steroids, antibiotics, and repeated evaluation for the occurrence of esophagogastric necrosis and perforation) died while all 3 patients treated with early laparotomy and immediate esophagogastric resection survived (Estrera et al, 1986).

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) MONITORING OF PATIENT
    1) Monitor hepatic enzymes and renal function carefully.
    B) FLUID/ELECTROLYTE BALANCE REGULATION
    1) Fluids, electrolytes, and acid-base data should be monitored and intravenous replacement of losses provided.
    2) All intravenous solutions should contain adequate amounts of glucose to supply the requirements of the increased metabolism.
    3) Unless there are manifestations of cerebral or pulmonary edema or of inadequate renal function, administer intravenous fluids to restore hydration and support physiologic mechanisms for heat loss and toxicant disposition.
    C) BODY TEMPERATURE ABOVE REFERENCE RANGE
    1) Control agitation with parenteral benzodiazepines; minimize physical activity.
    2) Remove patient's clothing, bathe or spray with tepid water and direct fans at patient to enhance evaporative cooling.
    3) A rectal electrode thermometer should be used to continuously monitor temperature.
    4) If tepid bathing is not sufficient, use hypothermic blanket or immersion in ice water.
    5) Dantrolene administration has been reported to be effective in reducing the body temperature in a patient with dinitrophenol-induced hyperthermia; however, they did not report if other measures including benzodiazepines or external cooling were performed (Barker et al, 2006).
    6) Administration of SALICYLATES to reduce hyperpyrexia is CONTRAINDICATED. This drug is also an oxidative phosphorylation uncoupler and may aggravate hyperpyrexia.
    D) DELIRIUM
    1) Control agitation and involuntary motor activity to reduce body heat production (Morgan, 1989).
    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) Because barbiturates may exacerbate the biochemical disturbances produced by dinitrophenol, Magos & Manson (1988) do not recommend their use for restlessness due to DNP poisoning.
    E) ACUTE LUNG INJURY
    1) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
    2) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).
    a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)
    3) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
    4) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
    5) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
    6) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
    7) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).
    F) CEREBRAL EDEMA
    1) CLINICAL IMPLICATIONS
    a) Cerebral edema and elevated intracranial pressure (ICP) may occur. Emergent management includes head elevation and administration of mannitol; hyperventilation should be performed if there is evidence of impending herniation.
    2) MONITORING
    a) Patients will usually require endotracheal intubation and mechanical ventilation. Monitor intracranial pressure, cerebral perfusion pressure and cerebral blood flow.
    3) TREATMENT
    a) Most information on the treatment of cerebral edema is derived from studies of traumatic brain injury.
    4) MANNITOL
    a) ADULT/PEDIATRIC DOSE: 0.25 to 1 gram/kilogram intravenously over 10 to 15 minutes (None Listed, 2000).
    b) AVAILABLE FORMS: Mannitol injection (5%, 10%, 15%, 20%, 25%).
    c) MAJOR ADVERSE REACTIONS: Congestive heart failure, hypernatremia, hyponatremia, hyperkalemia, renal failure, pulmonary edema, and allergic reactions.
    d) PRECAUTIONS: Contraindicated in well-established anuria or impaired renal function not responding to a test dose, pulmonary edema, CHF, severe dehydration; caution in progressive oliguria and azotemia. Do not add to whole blood for transfusions; enhanced neuromuscular blockade has occurred with tubocurarine. Keep serum osmolarity below 320 mOsm.
    e) MONITORING PARAMETERS: Renal function, urine output, fluid balance, serum potassium levels, serum osmolarity, and CVP.
    5) HYPERTONIC SALINE
    a) Preliminary studies suggest that hypertonic saline (7.5% saline/6% dextran) 100 ml reduced ICP more effectively than 200 mL of 20% mannitol in adults with elevated ICP after traumatic brain injury(Battison et al, 2005).
    6) ELEVATION
    a) Elevation of the head of the bed to approximately 30 degrees decreases ICP and improves cerebral perfusion pressure (Meixensberger et al, 1997; Schneider et al, 1993; Feldman et al, 1992).
    7) MECHANICAL DECOMPRESSION
    a) Early surgical decompression, ventriculostomy with CSF drainage, or craniectomy may be useful in patients with persistent elevation of ICP (Sahuquillo & Arikan, 2006; Sakai et al, 1998; Polin et al, 1997; Taylor et al, 2001). Most experience with these modalities has been in patients with traumatic brain injury.
    8) HYPERVENTILATION
    a) SUMMARY: Hyperventilation has been associated with adverse outcomes and should not be performed routinely (Muizelaar et al, 1991). It is indicated in patients who have clinical evidence of herniation or if there is intracranial hypertension refractory to sedation, paralysis, CSF drainage and osmotic diuretics (None Listed, 2000a).
    b) RECOMMENDATION:
    1) The PCO2 must be controlled in the range of 25 torr; further lowering of PCO2 may create undesirable effects secondary to local tissue hypoxia.
    2) End-tidal CO2 tension, correlated with an initial ABG measurement, provides a noninvasive means of monitoring PCO2 (Mackersie & Karagianes, 1990).
    3) Most authorities advise that hyperventilation should be considered a temporizing measure only; SUSTAINED hyperventilation should be avoided (Am Acad Neurol, 1997; Bullock et al, 1996; Kirkpatrick, 1997).
    G) CONTRAINDICATED TREATMENT
    1) ATROPINE IS ABSOLUTELY CONTRAINDICATED - and it is essential not to confuse the evidence for dinitrophenol poisoning with manifestations of cholinesterase inhibition (Hayes, 1982; Finkel, 1983).
    H) 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 jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. Rescue personnel and bystanders should avoid direct contact with contaminated skin, clothing, or other objects (Burgess et al, 1999). Since contaminated leather items cannot be decontaminated, they should be discarded (Simpson & Schuman, 2002).
    B) OTHER
    1) SKIN DISCOLORATION - Cutaneous exposure is usually accompanied by a yellowish discoloration which does not have to be removed entirely to prevent absorption.
    C) DERMAL ABSORPTION
    1) Severe systemic dinitrophenol poisoning can occur from dermal exposure; hence aggressive and immediate skin decontamination must be undertaken and a physician consulted as soon as possible.
    6.9.2) TREATMENT
    A) GENERAL TREATMENT
    1) Treatment should include recommendations listed in the INHALATION EXPOSURE section when appropriate.
    B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Is expected to be of no value because of the high degree of binding to plasma proteins (Edson, 1955; Morgan, 1989).

Abstracts

Case Reports

    A) ADULT
    1) ACUTE EFFECTS
    a) A 61-year-old white man died within 24 hours of accidental ingestion of a fluid containing derivatives of 2,4-dinitrophenol (Cann & Verhulst, 1960). The patient mistook the fluid for grape juice, which actually contained a small quantity of weed killer containing alkanolamine salts of dinitro-o-sec-butylphenol (derivatives of 2,4-dinitrophenol). Autopsy showed yellow staining of the right palm, yellow discoloration of gastric rugae, parenchymatous degeneration of renal tubular epithelium, and coronary arteriosclerosis without occlusion.
    b) DERMAL
    1) A 49-year-old woman and a 41-year-old man experienced 2,4 dinitrophenol (DNP) toxicity secondary to inhalation and dermal exposure from 2,4 DNP powder from nylon bags they were collecting. The bags had previously been used as 2,4 DNP packaging. The patients were collecting the bags on a warm weather day, with little skin protection from the powder on arms and legs, and only minimal protection on the face, which were contributing factors to dermal absorption. Upon admission to the hospital, both patients were noted to have yellow stained skin, with black stained hands and feet from handling the tainted packaging. Despite treatment, both died as a result of cardiovascular collapse secondary to 2,4 DNP exposure (Jiang Jiukun et al, 2011).
    2) When the hose of a weed sprayer ruptured, a worker sprayed dinitrophenol into his eyes and developed conjunctivitis. The patient was treated with Neosporin(R) ophthalmic ointment and an eye patch and his vision remained impaired for one month (ACF 59-433:4-6).
    3) A tractor driver was opening a can of dinitrophenol and splattered it into his face and eyes. His face peeled following contact (ACF 59-433:4-6).
    2) CHRONIC EFFECTS
    a) Saita (1949) reported a single case of hemolytic anemia in a worker who impregnated wooden poles with dinitrophenol, arsenic, and sodium fluoride for 15 days. The lowest red cell count was 3,400,000 and the illness, with no note of specific hemolytic episode and with incomplete basis for hemolysis, had no signs and symptoms attributable to arsenic or fluoride (Saita, 1949).

Range Of Toxicity

Summary

    A) The fatal dose in adults is about 1 to 3 grams by mouth, 3 grams has proven fatal even in divided doses over a period of 5 days. A 20-year-old obese male died after ingesting a total of 2.4 grams DNP over 4 days (600 mg daily).
    B) Inhalation or dermal exposure may result in toxicity.

Minimum Lethal Exposure

    A) ACUTE
    1) Correlation of ingested doses in fatal outcomes has been poor due to the lack of adequate history.
    2) The fatal dose in adults is about 1 to 3 grams by mouth and 3 grams has proved fatal even in divided doses over a period of 5 days (MacBryde & Taussig, 1935).
    3) The acute fatal dose of dinitrophenol is approximately 1 gram (Dreisbach, 1983).
    4) CASE REPORTS - A 20-year-old obese male took 600 mg DNP for 4 days (total 2.4 grams), and developed increasing agitation. Upon admission, the patient was febrile and diaphoretic and was becoming increasingly agitated. Over the next hour, the patient's condition deteriorated and severe bradycardia was observed followed by asystole. Resuscitation efforts were unsuccessful (McFee et al, 2004).
    B) SPECIFIC SUBSTANCE
    1) DINITROPHENOL COMPOUNDS -
    a) The survival doses and lethal doses from application of 3% solutions of various dinitrophenol compounds to guinea pigs is shown below (Spencer et al, 1963) -
    COMPOUNDSURVIVAL DOSE G/KGLETHAL DOSE G/KG
    2-sec-Butyl-4,6-dinitrophenol0.10.5
    4,6-Dinitro-o-cresol0.20.5
    2,4-Dinitrophenol0.20.7
    2-Cyclohexyl-4,6-dinitrophenol1.0 or more>1.0
    2-Cyclohexyl-4,6-dinitrophenol compound with dicyclohexylamine1.0 or more>1.0

Maximum Tolerated Exposure

    A) ACUTE
    1) Onset of symptoms is rapid. If a patient has not demonstrated symptoms within a few hours following ingestion, it is unlikely that he or she will ever do so. The fatal dose in adults is about 1 to 3 grams by mouth, 3 grams has proven fatal even in divided doses over a period of 5 days (HSDB , 1998).
    2) Inhalation or dermal exposure may result in toxicity. A 49-year-old woman and a 41-year-old man experienced 2,4 dinitrophenol toxicity secondary to inhalation and dermal exposure after collecting nylon bags used as 2,4 DNP packaging. The patients were collecting the bags on a warm weather day, with little skin protection on arms and legs, and only minimal protection on the face. Upon admission to the hospital, both patients were noted to have yellow stained skin and black stained feet and hands from handling the tainted packaging. The woman presented with a 10 hour history of diaphoresis, dizziness, and gasping for breath. The man presented with an 8 hour history of the same symptoms. Physical exam revealed hypertension, hyperthermia, and tachycardia for both patients. Despite treatment of symptoms, both patients developed asystole and died (Jiang Jiukun et al, 2011).
    B) CHRONIC
    1) CHRONIC excessive exposure may lead to liver or hematologic dysfunction as well as delayed onset of lenticular cataracts.
    2) INHALATION is a source of marked toxicity and is usually encountered when the material has been sprayed as a wood preservative in enclosed areas.
    a) Disophenol may produce signs and symptoms of toxicity following as little as 10 milligrams/kilogram administered subcutaneously. However, toxicity is most likely following 30 and 40 milligrams/kilogram (Liao & Oehme, 1980).
    3) The EPA (1985) has set the NOEL of dinoseb for developmental toxicity at 3 mg/kg/day.
    4) Although EPA has suspended the registration of dinoseb because of its potential developmental toxicity, it is believed that there is no hazard to persons consuming food that has been treated with dinoseb (EPA, 1985).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) GENERAL
    a) Serum levels of 10 mcg/mL or greater are usually seen when toxicity is present (NIOSH , 1996).
    b) Blood dinitro-o-cresol values that exceed 20 ppm (20 mcg/mL) indicate serious intoxication (Finkel, 1983).
    2) CASE REPORTS
    a) A patient who survived with supportive treatment after poisoning with di-nitro-ortho-cresol had a blood level of 60 micrograms/gram (parts per million) (Polland et al, 1951).
    b) Two patients, who had been taking 2,4-dinitrophenol as a weight loss/bodybuilding supplement, developed hyperthermia, rapid pulse and respiration, myalgia, and muscle rigidity (Miranda et al, 2006).
    1) The first patient also developed respiratory failure and cardiac dysrhythmias that deteriorated into asystole. She died approximately 3 hours after hospital admission. Autopsy revealed the presence of a yellowish, serous fluid in the pleural, peritoneal, and pericardial cavities. Her blood 2,4-dinitrophenol concentration, obtained at admission, was 36.1 mg/L.
    2) The second patient's clinical condition deteriorated rapidly and he died approximately 50 minutes after hospital admission. At autopsy, he was jaundiced with left ventricular hypertrophy. He had cerebral edema, severe pulmonary edema, centrilobular hepatocyte necrosis, and evidence of hemorrhagic gastritis. His blood 2,4-dinitrophenol concentration, obtained at admission, was 28 mg/L. Post-mortem concentrations of gastric contents, urine, and vitreous were 850 mg, 53 mg/L, and 3.4 mg/L, respectively.

Workplace Standards

    A) ACGIH TLV Values for CAS88-85-7 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS88-85-7 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS88-85-7 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): D ; Listed as: Dinoseb
    a) D : Not classifiable as to human carcinogenicity.
    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 CAS88-85-7 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (INTRAPERITONEAL)MOUSE:
    1) 52 mg/kg (Kaiser, 1964)
    2) 14-20 mg/kg (Preache & Gibson, 1975)
    3) 26 mg/kg (ITI, 1988)
    B) LD50- (ORAL)MOUSE:
    1) 72 mg/kg (Kaiser, 1964)
    2) 20-40 mg/kg (Bough et al, 1965)
    C) LD50- (SUBCUTANEOUS)MOUSE:
    1) 58 mg/kg (Kaiser, 1964)
    D) LD50- (INTRAPERITONEAL)RAT:
    1) 60 mg/kg (Kaiser, 1964)
    2) 20 mg/kg (ITI, 1988)
    E) LD50- (ORAL)RAT:
    1) 50 mg/kg (reviewed in Budavari, 1996)
    F) LD50- (SUBCUTANEOUS)RAT:
    1) 44 mg/kg (Kaiser, 1964)

Pharmacology Toxicology

Toxicologic Mechanism

    A) These chemicals act as uncouplers of oxidative phosphorylation and cause a hyper-metabolic state. When metabolism in all body cells is stimulated, energy is released in the mitochondria as heat. This results in an increase in body temperature and other systemic responses (increased oxygen consumption, breathing rate and heart rate). With toxic doses there can be renal, hepatic and neurologic sequelae; death with prompt rigor mortis has been reported (Tewari et al, 2009).
    B) Dinitrophenol appears to act by interfering with the intracellular synthesis of high energy phosphate esters and not by hydrolyzing or otherwise inactivating them (Eisenhardt & Rosenthal, 1964; Pinchot, 1967). The energy made available by oxidation is not converted to active phosphate but is expended in raising the body temperature. Fatal hyperpyrexia have been reported (Bidstrup & Payne, 1951).
    C) Anoxia and acidosis develop because circulation and respiration do not accelerate in proportion to the metabolic demand (Hayes, 1982), lactate oxidation is inhibited (Hayes, 1982), and mitochondrial permeability to hydrogen ions is increased with the disruption of the conversion of ADP to ATP (EPA, 1985).
    D) Weight loss occurs with dinitrophenol toxicity because lipogenesis from pyruvate and lactate is inhibited (Rognstad & Katz, 1969), and body fat serves as the major fuel for the extra metabolism (Tainter et al, 1935; Shils & Goldwater, 1953).

Physicochemical

Physical Characteristics

    A) Dinitrophenol forms explosive yellow orthorhombic crystals (Hayes, 1982; ITI, 1988).
    B) Dinoseb, chemically known as 2-(sec-butyl)-4,6-dinitrophenol, is a dark-brown or reddish brown solid or viscous liquid with a pungent odor (EPA, 1985).

Molecular Weight

    A) 184.11 (Hayes, 1982; ITI, 1988; Budavari, 1996)

Animal Toxicology

Clinical Effects

    11.1.3) CANINE/DOG
    A) Tremor, tonic seizures, and early rigor mortis were demonstrated in poisoned dogs (Kaiser, 1964).
    B) Two male English Setters developed rapid breathing, hyperexcitability, and incoordination after roaming a rural area for 2 hours. The fur of both dogs was stained with a brilliant yellow liquid. The yellow liquid was analyzed after both dogs died and identified by gas chromatography-mass spectroscopy to be dinoseb (Fikes et al, 1989).
    1) Before dying, one dog appeared disoriented, was atactic and weak, and had tachypnea and mildly responsive miotic pupils. Toxicity occurred mainly through dermal absorption (Fikes et al, 1989).

Treatment

    11.2.2) LIFE SUPPORT
    A) GENERAL
    1) MAINTAIN VITAL FUNCTIONS: Secure airway, supply oxygen, and begin supportive fluid therapy if necessary.
    11.2.4) DECONTAMINATION
    A) GASTRIC DECONTAMINATION
    1) GENERAL TREATMENT
    a) EMESIS/GASTRIC LAVAGE -
    1) DO NOT induce emesis unless within 15 to 30 minutes of ingestion. Vomitng may trigger CNS signs. Massive ingestion may necessitate gastric lavage to remove significant amounts of the ingested agent (Fikes et al, 1989).
    2) LAVAGE: In the absence of a gag reflex or if vomiting cannot be induced, place a cuffed endotracheal tube and begin gastric lavage.
    a) Pass large bore stomach tube and instill 5 to 10 milliliters/kilogram water or lavage solution, then aspirate. Repeat 10 times.
    b) DERMAL DECONTAMINATION -
    1) Wash exposed animals with soap and water. If possible, shave or clip long hair to facilitate thorough cleaning. All handlers should wear gloves and protect themselves from exposure.
    2) Some chemicals can produce systemic toxicosis via absorption through the intact skin. Carefully observe patients with dermal exposure for the development of any systemic signs and treat as necessary.
    c) OCULAR DECONTAMINATION -
    1) Rinse eyes with copious amounts of tepid water for 15 minutes. If irritation, pain, or photophobia persist, see your veterinarian.
    11.2.5) TREATMENT
    A) GENERAL TREATMENT
    1) VITAL FUNCTIONS -
    a) OXYGENATION - Assure adequate oxygenation by administration of oxygen if necessary (Fikes et al, 1989).
    2) HYPERTHERMIA -
    a) Control excessive body temperature with ice water or alcohol baths and cold water enemas (Fikes et al, 1989). Stressing the animals should be avoided.
    3) SEIZURES -
    a) SEIZURES/LARGE ANIMALS: May be controlled with diazepam.
    1) HORSES/DIAZEPAM: Neonates: 0.05 to 0.4 milligrams/kilogram; Adults: 25 to 50 milligrams. Give slowly intravenously to effect; repeat in 30 minutes if necessary.
    2) CATTLE, SHEEP AND SWINE/DIAZEPAM: 0.5 to 1.5 milligrams/kilogram intravenously to effect.
    b) SEIZURES/DOGS & CATS:
    1) DIAZEPAM: 0.5 to 2 milligrams/kilogram intravenous bolus; may repeat dose every ten minutes for four total doses. Give slowly over 1 to 2 minutes to effect.
    2) PHENOBARBITAL: 5 to 30 milligrams/kilogram over 5 to 10 minutes intravenously to effect.
    3) REFRACTORY SEIZURES: Consider anaesthesia or heavy sedation. Administer pentobarbital to DOGS & CATS at a dose of 3 to 15 milligrams/kilogram intravenously slowly to effect. May need to repeat in 4 to 8 hours. Be sure to protect the airway.
    4) ATROPINE -
    a) Signs and symptoms resemble organophosphate or carbamate poisoning, however, atropine sulfate is CONTRAINDICATED in nitrophenol poisonings (Fikes et al, 1989).
    5) FLUID/ELECTROLYTE BALANCE -
    a) Correct electrolyte balance and administer fluids as necessary to prevent shock (Fikes et al, 1989). Positive energy balance should be maintained with intravenous administration of dextrose and/or oral alimentation as necessary.
    6) MONITORING -
    a) Symptomatic patients must be monitored continuously. Refer to an emergency hospital or critical care clinic for 24 hour monitoring.
    7) FOLLOW-UP -
    a) Instruct the owner to return for a follow up appointment at which physical examination and appropriate laboratory tests will be repeated.

Range Of Toxicity

    11.3.2) MINIMAL TOXIC DOSE
    A) GENERAL
    1) These compounds are highly toxic on an acute basis. Sufficient absorption may occur from dermal exposure to produce life-threatening effects (Fikes et al, 1989).

Continuing Care

    11.4.2) DECONTAMINATION
    11.4.2.2) GASTRIC DECONTAMINATION
    A) GASTRIC DECONTAMINATION
    1) GENERAL TREATMENT
    a) EMESIS/GASTRIC LAVAGE -
    1) DO NOT induce emesis unless within 15 to 30 minutes of ingestion. Vomitng may trigger CNS signs. Massive ingestion may necessitate gastric lavage to remove significant amounts of the ingested agent (Fikes et al, 1989).
    2) LAVAGE: In the absence of a gag reflex or if vomiting cannot be induced, place a cuffed endotracheal tube and begin gastric lavage.
    a) Pass large bore stomach tube and instill 5 to 10 milliliters/kilogram water or lavage solution, then aspirate. Repeat 10 times.
    b) DERMAL DECONTAMINATION -
    1) Wash exposed animals with soap and water. If possible, shave or clip long hair to facilitate thorough cleaning. All handlers should wear gloves and protect themselves from exposure.
    2) Some chemicals can produce systemic toxicosis via absorption through the intact skin. Carefully observe patients with dermal exposure for the development of any systemic signs and treat as necessary.
    c) OCULAR DECONTAMINATION -
    1) Rinse eyes with copious amounts of tepid water for 15 minutes. If irritation, pain, or photophobia persist, see your veterinarian.

Kinetics

    11.5.1) ABSORPTION
    A) SPECIFIC TOXIN
    1) Dinitro phenol compounds can be well absorbed through intact skin (Fikes et al, 1989).

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