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CYCLOHEXYLAMINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Cyclohexylamine is a weak indirect-acting sympathomimetic amine. It is a metabolite of cyclamate and is much more toxic than cyclamate. It is considered as a central nervous system toxin. It is also an industrial chemical used in the rubber, paint, nylon, and pesticide industries.

Specific Substances

    1) Aminocyclohexane
    2) Aminohexahydrobenzene
    3) Aniline, hexahydro-
    4) Benzenamine, hexahydro-
    5) CHA
    6) Cyclohexanamine
    7) Cyclohexylamine
    8) Hexahydroaniline
    9) Hexahydrobenzanamine
    10) CAS 108-91-8
    11) AMINO HEXAHYDROBENZENE
    12) CHA (CYCLOHEXYLAMINE)
    13) HEXAHYDROBENZENEAMINE
    1.2.1) MOLECULAR FORMULA
    1) C6-H13-N

Available Forms Sources

    A) SOURCES
    1) Cyclohexylamine is made from aniline by catalytic hydrogenation at high temperatures and pressures (Budavari, 1996).
    2) Cyclohexylamine is also a metabolite of the artificial sweetening agent cyclamate in humans, rats, and rabbits (Lee & Dixon, 1972).
    B) USES
    1) Cyclohexylamine is used as a rubber accelerator or inhibitor, as a corrosion inhibitor for water in boilers, as a dyeing aid, in paints and pigments, as a surfactant, as a processing agent in nylon fiber production, as an oxygen absorbing compound, and as an intermediate in organic chemical syntheses for the manufacture of insecticides, herbicides, plasticizers, corrosion inhibitors, rubber chemicals, dyestuffs, emulsifying agents, dry cleaning soaps, and absorbents for acid gases (Clayton & Flayton, 1994; Budavari, 1996) ACGIH, 1986; (ITI, 1995; EPA, 1985).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) In cases of reported human vapor exposure, workers developed nausea, lightheadedness, apprehension and anxiety, drowsiness, slurred speech, vomiting, and dilated pupils. Dermal irritation or moderately severe caustic burns may be seen. Skin sensitization may occur. Cyclohexylamine is a severe eye irritant.
    B) Ingestions have not been reported, but potentially serious injury to the esophagus and gastrointestinal tract might be predicted to occur based on the other irritative effects of cyclohexylamine.
    C) Additional effects in exposed EXPERIMENTAL ANIMALS have been methemoglobinemia, seizures with fatal exposure, degenerative changes in the brain, liver, and kidney following fatal doses and premortem shock, hyperactivity, anemia, and elevated metabolic rates and temperature. Teratogenic, mutagenic, and carcinogenic properties have been inconclusively demonstrated.
    0.2.4) HEENT
    A) Eye, nose, and throat irritation may occur. Mydriasis was observed in one worker with acute vapor exposure. Complete eye destruction occurred in a rabbit using the Standard Draize Test.
    0.2.6) RESPIRATORY
    A) Irritation of the respiratory tract may occur.
    0.2.7) NEUROLOGIC
    A) Drowsiness, dizziness, and lightheadedness have been reported. Exposed humans have developed anxiety and apprehension. In experimental animals, CNS stimulation, seizures and brain degenerative changes were observed.
    0.2.8) GASTROINTESTINAL
    A) Nausea and vomiting have been reported in exposed workers. Potentially severe esophageal and gastrointestinal tract irritation may occur after ingestion due to this agent's severe irritant properties.
    0.2.9) HEPATIC
    A) In animals, degenerative changes in the liver were observed. This effect has not been reported in exposed humans.
    0.2.10) GENITOURINARY
    A) Renal degenerative changes were observed in fatally poisoned experimental animals.
    B) Testicular toxicity was observed in animal studies.
    0.2.13) HEMATOLOGIC
    A) Cyclohexylamine is a weak methemoglobin forming agent. No human cases of methemoglobinemia from exposure to this agent have been reported.
    0.2.14) DERMATOLOGIC
    A) In humans, severe irritation and possible sensitization was reported.
    0.2.17) METABOLISM
    A) Elevated metabolic rates were reported in experimental animals administered cyclohexylamine. This effect has not been seen in exposed humans.
    0.2.20) REPRODUCTIVE
    A) The potential teratogenic effects of cyclohexylamine have been assessed as probably without significance in the setting of industrial exposure.
    B) Testicular atrophy was seen in some rats with chronic exposure. Based on a no-effect dose for the testes of rats, it was concluded that the acceptable daily intake in humans is 0 to 11 mg/kg/day.
    0.2.21) CARCINOGENICITY
    A) The potential mutagenic and carcinogenic effects of cyclohexylamine have been assessed as probably without significance in the setting of industrial exposure.

Laboratory Monitoring

    A) Monitor complete blood count and liver and renal function tests after significant exposure. Monitor chest x-ray and arterial blood gases in patients with respiratory tract irritation. Obtain methemoglobin levels in cyanotic 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) DILUTION: If no respiratory compromise is present, administer milk or water as soon as possible after ingestion. Dilution may only be helpful if performed in the first seconds to minutes after ingestion. The ideal amount is unknown; no more than 8 ounces (240 mL) in adults and 4 ounces (120 mL) in children is recommended to minimize the risk of vomiting.
    C) Consider aspiration of gastric contents using a small, flexible nasogastric tube if it can be performed within one hour in patients with large ingestions. The potential benefits of early gastric aspiration must be weighed against potential complications such as perforation or bleeding.
    D) Observe patients carefully for signs of esophageal or gastrointestinal tract irritation. Consider endoscopy within 24 hours in patients with evidence of significant GI irritation or burns after ingestion.
    E) Activated charcoal may obscure endoscopy results but may be useful in patients with large ingestions.
    1) 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.
    F) If central nervous system depression occurs, airway patency and oxygenation must be assured.
    G) 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.
    H) METHEMOGLOBINEMIA: Determine the methemoglobin concentration and evaluate the patient for clinical effects of methemoglobinemia (ie, dyspnea, headache, fatigue, CNS depression, tachycardia, metabolic acidosis). Treat patients with symptomatic methemoglobinemia with methylene blue (this usually occurs at methemoglobin concentrations above 20% to 30%, but may occur at lower methemoglobin concentrations in patients with anemia, or underlying pulmonary or cardiovascular disorders). Administer oxygen while preparing for methylene blue therapy.
    I) METHYLENE BLUE: INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules and 10 mg/1 mL (1% solution) vials. Additional doses may sometimes be required. Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection. NEONATES: DOSE: 0.3 to 1 mg/kg.
    J) Concomitant use of methylene blue with serotonergic drugs, including serotonin reuptake inhibitors (SRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), triptans, and ergot alkaloids may increase the risk of potentially fatal serotonin syndrome.
    0.4.3) INHALATION EXPOSURE
    A) INHALATION: Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm.
    0.4.4) EYE EXPOSURE
    A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Range Of Toxicity

    A) Workers exposed to 4 to 10 parts per million exhibited no symptoms.
    B) Experimental animals exposed by inhalation to 1,200 to 12,000 parts per million for 6 to 7 hours died.

Clinical Effects

Summary Of Exposure

    A) In cases of reported human vapor exposure, workers developed nausea, lightheadedness, apprehension and anxiety, drowsiness, slurred speech, vomiting, and dilated pupils. Dermal irritation or moderately severe caustic burns may be seen. Skin sensitization may occur. Cyclohexylamine is a severe eye irritant.
    B) Ingestions have not been reported, but potentially serious injury to the esophagus and gastrointestinal tract might be predicted to occur based on the other irritative effects of cyclohexylamine.
    C) Additional effects in exposed EXPERIMENTAL ANIMALS have been methemoglobinemia, seizures with fatal exposure, degenerative changes in the brain, liver, and kidney following fatal doses and premortem shock, hyperactivity, anemia, and elevated metabolic rates and temperature. Teratogenic, mutagenic, and carcinogenic properties have been inconclusively demonstrated.

Vital Signs

    3.3.3) TEMPERATURE
    A) Experimental animals administered cyclohexylamine intraperitoneally have developed elevated temperatures (Lee & Dixon, 1972). This effect has not occurred in exposed humans.

Heent

    3.4.1) SUMMARY
    A) Eye, nose, and throat irritation may occur. Mydriasis was observed in one worker with acute vapor exposure. Complete eye destruction occurred in a rabbit using the Standard Draize Test.
    3.4.3) EYES
    A) Severe eye irritation and corneal clouding may be seen following vapor exposure (Grant & Schuman, 1993). Cyclohexylamine induced severe eye irritation in the rabbit in the Standard Draize Test (RTECS , 1999).
    B) One drop of a 50% solution instilled into the conjunctival sac caused complete destruction of the eye in rabbits (ACGIH, 1986).
    C) CASE REPORT - Dilated pupils were described in one worker with acute vapor exposure and moderate symptoms (Clayton & Flayton, 1994).
    3.4.5) NOSE
    A) Exposure to vapors can produce nose and throat mucosal irritation (Plunkett, 1976).
    3.4.6) THROAT
    A) Exposure to vapors can produce nose and throat mucosal irritation (Plunkett, 1976).

Respiratory

    3.6.1) SUMMARY
    A) Irritation of the respiratory tract may occur.
    3.6.2) CLINICAL EFFECTS
    A) IRRITATION SYMPTOM
    1) Inhalation of vapors can cause irritation of the respiratory tract (ACGIH, 1986; (Plunkett, 1976; ITI, 1995). Severe respiratory tract irritation with possible bronchospasm or pulmonary edema could occur from exposure to oxides of nitrogen released from cyclohexylamine during fires involving this material (Student, 1981).

Neurologic

    3.7.1) SUMMARY
    A) Drowsiness, dizziness, and lightheadedness have been reported. Exposed humans have developed anxiety and apprehension. In experimental animals, CNS stimulation, seizures and brain degenerative changes were observed.
    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM DEFICIT
    1) Central nervous system depression, drowsiness, lightheadedness, and slurred speech have been reported in human exposures (Clayton & Flayton, 1994).
    B) ANXIETY
    1) Exposed humans have developed anxiety and apprehension (Clayton & Flayton, 1994).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) CNS STIMULATION
    a) Central nervous system stimulation similar to that seen following amphetamine administration has been observed in experimental animals (Lee & Dixon, 1972).
    2) SEIZURES
    a) Experimental animals have had seizures as a terminal event following administration of fatal doses (Clayton & Flayton, 1994). This effect has not been reported in exposed humans.
    3) ENCEPHALOPATHY
    a) Degenerative changes in the brain have been reported in fatally poisoned experimental animals (ACGIH, 1986). This effect has not been reported in exposed humans.

Gastrointestinal

    3.8.1) SUMMARY
    A) Nausea and vomiting have been reported in exposed workers. Potentially severe esophageal and gastrointestinal tract irritation may occur after ingestion due to this agent's severe irritant properties.
    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) Nausea and vomiting have been reported in exposed workers (Clayton & Flayton, 1994).
    B) GASTROENTERITIS
    1) No cases of ingestion have been reported, but potentially severe esophageal and gastrointestinal tract irritation may occur after ingestion due to this agent's severe irritant properties.

Hepatic

    3.9.1) SUMMARY
    A) In animals, degenerative changes in the liver were observed. This effect has not been reported in exposed humans.
    3.9.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HEPATOCELLULAR DAMAGE
    a) Degenerative changes in the liver have been reported in fatally poisoned experimental animals (ACGIH, 1986). This effect has not been reported in exposed humans.

Genitourinary

    3.10.1) SUMMARY
    A) Renal degenerative changes were observed in fatally poisoned experimental animals.
    B) Testicular toxicity was observed in animal studies.
    3.10.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) NEPHROPATHY TOXIC
    a) Degenerative changes in the kidneys have been reported in fatally poisoned experimental animals (ACGIH, 1986). This effect has not been reported in exposed humans.
    2) TESTIS DISORDER
    a) RATS - Testicular toxicity was observed in rats fed a 13 week diet of cyclohexylamine base 400 mg/kg/day. Testicular atrophy, demonstrated by decreased organ weight and histological changes, occurred in rats, but not in mice. Cyclohexylamine concentrations in blood and testes were lower in mice than in rats, suggesting species differences in pharmacokinetics (Roberts et al, 1989).
    1) The ratio of testis to plasma cyclohexylamine concentration in both mice and rats was measured as 4 following a single-dose study (Roberts & Renwick, 1989).

Hematologic

    3.13.1) SUMMARY
    A) Cyclohexylamine is a weak methemoglobin forming agent. No human cases of methemoglobinemia from exposure to this agent have been reported.
    3.13.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) ANEMIA
    a) A mild anemia has been produced with chronic administration to experimental animals (Clayton & Flayton, 1994). This effect has not been reported in exposed humans.
    2) METHEMOGLOBINEMIA
    a) Cyclohexylamine is a weak methemoglobin forming agent (ACGIH, 1986). No human cases of methemoglobinemia from exposure to this agent have been reported.

Dermatologic

    3.14.1) SUMMARY
    A) In humans, severe irritation and possible sensitization was reported.
    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) Patch testing with a 25% cyclohexylamine solution produced severe irritation in humans and possible sensitization, although guinea pig dermal sensitization testing was negative (Clayton & Flayton, 1994).
    3.14.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) DERMATITIS
    a) Cyclohexylamine induced severe skin irritation in humans and in rabbits in the Standard Draize Test (RTECS , 1999).

Reproductive

    3.20.1) SUMMARY
    A) The potential teratogenic effects of cyclohexylamine have been assessed as probably without significance in the setting of industrial exposure.
    B) Testicular atrophy was seen in some rats with chronic exposure. Based on a no-effect dose for the testes of rats, it was concluded that the acceptable daily intake in humans is 0 to 11 mg/kg/day.
    3.20.2) TERATOGENICITY
    A) FETOTOXICITY
    1) Reduction in litter sizes has been seen in some, but not all, experimental animal reproductive toxicity studies (Clayton & Flayton, 1994) ACGIH, 1986).
    2) Fetal death and fetotoxicity were observed in mouse studies (RTECS , 1999).
    B) EMBRYOTOXICITY
    1) Intraperitoneal injection of cyclohexylamine caused embryolethality in mice, but it was not considered to be a potent teratogen (ACGIH, 1986).
    C) LACK OF EFFECT
    1) Several teratogenicity studies in mouse, primate, rabbit, and rat found no evidence of teratogenicity associated with administration of cyclohexylamine (Torbin, 1976; Kennedy et al, 1969; Becker & Gibson, 1970; Wilson, 1972).
    2) The potential teratogenic effects of cyclohexylamine have been assessed as probably without significance in the setting of industrial exposure (ACGIH, 1986).
    3.20.3) EFFECTS IN PREGNANCY
    A) PERINATAL DISORDER
    1) Some animal studies have found no effects on reproductive abilities, while others have indicated decreases in pregnancy rates, number of live births, numbers of post-natal survivors, body weights in offspring, and number of male offspring (ACGIH, 1986; (Clayton & Flayton, 1994).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of cyclohexylamine exposure during lactation.
    3.20.5) FERTILITY
    A) FERTILITY DECREASED MALE
    1) Male and female reproductive effects affecting fertility have been reported in rats and dogs, but not mice; the increased sensitivity to mice may be due to pharmacokinetic differences. Male changes have included decreased testicular weight, testicular atrophy, changes in spermatogenesis, changes in epididymis and sperm duct, and pre-implantation and post-implantation mortality. Female changes included post-implantation mortality (Clayton & Flayton, 1994; Snyder, 1987) Roberts, 1989; (Roberts & Renwick, 1989a; RTECS , 1999).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS108-91-8 (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) The potential mutagenic and carcinogenic effects of cyclohexylamine have been assessed as probably without significance in the setting of industrial exposure.
    3.21.4) ANIMAL STUDIES
    A) BLADDER CARCINOMA
    1) RATS - Transitional cell cancer of the bladder, a rare tumor, was seen in one male rat chronically exposed to cyclohexylamine (Clayton & Clayton, 1982). Papillary tumors of the urinary bladder have been seen in rats exposed to both cyclamate and cyclohexylamine (Clayton & Clayton, 1982).
    B) LACK OF EFFECT
    1) Several animal studies have shown no evidence of carcinogenicity from cyclohexylamine exposure (Clayton & Clayton, 1982; (Schmahl, 1973).

Genotoxicity

    A) Mutations and chromosome aberrations induced by cyclohexylamine were detected in human cells and in the cells of some experimental animals.
    B) Humans exposed to cyclohexylamine have not had chromosome aberrations (Clayton & Clayton, 1982).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor complete blood count and liver and renal function tests after significant exposure. Monitor chest x-ray and arterial blood gases in patients with respiratory tract irritation. Obtain methemoglobin levels in cyanotic patients.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Monitor liver and renal function tests in patients with significant exposure.
    B) ACID/BASE
    1) Monitor arterial blood gases in patients with significant inhalation exposure or respiratory tract irritation.
    C) HEMATOLOGIC
    1) In cyanotic patients, obtain and monitor methemoglobin levels.
    2) Monitor complete blood count in patients with significant exposure.

Radiographic Studies

    A) CHEST RADIOGRAPH
    1) Monitor chest x-ray in patients with significant inhalation exposure or respiratory tract irritation.

Methods

    A) CHROMATOGRAPHY
    1) AIR - The concentration of cyclohexylamine can be determined by gas chromatography after adsorption on silica gel and elusion with acid (NIOSH, 1977). The range of measurement in air is 2400 mg/m(3) in a 10-liter of sample of air.
    2) Cyclohexylamine concentrations in rat urine have been determined by gas chromatography with flame thermoionic detection (Murayama, 1983).
    3) Cyclohexylamine concentrations in rat and mice urine has been determined by reverse-phase high performance liquid chromatography with fluorescence detection (Snyder, 1987).

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) As there is very limited clinical experience with cyclohexylamine poisoning in humans, all patients with significant exposure or symptoms should be admitted to the hospital and carefully observed until all symptomatology has resolved.
    6.3.3) DISPOSITION/INHALATION EXPOSURE
    6.3.3.1) ADMISSION CRITERIA/INHALATION
    A) As there is very limited clinical experience with cyclohexylamine poisoning in humans, all patients with significant exposure or symptoms should be admitted to the hospital and carefully observed until all symptomatology has resolved.
    B) If there has been potential inhalation of oxides of nitrogen released from cyclohexylamine during a fire (Student, 1981), late development of pulmonary edema up to 24 to 72 hours after exposure may occur. Such patients require prolonged observation in a controlled setting.

Monitoring

    A) Monitor complete blood count and liver and renal function tests after significant exposure. Monitor chest x-ray and arterial blood gases in patients with respiratory tract irritation. Obtain methemoglobin levels in cyanotic patients.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ORAL EXPOSURE
    1) Induction of emesis should be avoided.
    2) DILUTION
    a) DILUTION: If no respiratory compromise is present, administer milk or water as soon as possible after ingestion. Dilution may only be helpful if performed in the first seconds to minutes after ingestion. The ideal amount is unknown; no more than 8 ounces (240 mL) in adults and 4 ounces (120 mL) in children is recommended to minimize the risk of vomiting (Caravati, 2004).
    3) ACTIVATED CHARCOAL
    a) Activated charcoal may obscure endoscopy results but may be useful in patients with large ingestions.
    b) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    1) 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).
    a) 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.
    b) 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).
    c) CHARCOAL DOSE
    1) 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).
    a) 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).
    2) ADVERSE EFFECTS/CONTRAINDICATIONS
    a) 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.
    b) 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) Induced emesis should be avoided.
    B) GASTRIC ASPIRATION
    1) Consider aspiration of gastric contents using a small, flexible nasogastric tube if it can be performed within one hour in patients with large ingestions. The potential benefits of early gastric aspiration must be weighed against potential complications such as perforation or bleeding.
    C) DILUTION
    1) DILUTION: If no respiratory compromise is present, administer milk or water as soon as possible after ingestion. Dilution may only be helpful if performed in the first seconds to minutes after ingestion. The ideal amount is unknown; no more than 8 ounces (240 mL) in adults and 4 ounces (120 mL) in children is recommended to minimize the risk of vomiting (Caravati, 2004).
    D) ACTIVATED CHARCOAL
    1) Activated charcoal may obscure endoscopy results but may be useful in patients with large ingestions.
    2) 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.
    3) 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) DILUTION
    1) DILUTION: If no respiratory compromise is present, administer milk or water as soon as possible after ingestion. Dilution may only be helpful if performed in the first seconds to minutes after ingestion. The ideal amount is unknown; no more than 8 ounces (240 mL) in adults and 4 ounces (120 mL) in children is recommended to minimize the risk of vomiting (Caravati, 2004).
    B) OXYGEN
    1) If central nervous system depression occurs, airway patency and oxygenation should be assured.
    C) IRRITATION SYMPTOM
    1) Monitor patients with ingestion for potential serious esophageal and gastrointestinal irritation. Observe carefully for the development of perforation, bleeding, or abdominal pain.
    2) If signs of esophageal irritation are present, endoscopy should be considered within 24 hours of ingestion to determine the extent of injury.
    D) MONITORING OF PATIENT
    1) Monitor complete blood count and liver and renal function tests in patients with significant exposure.
    E) METHEMOGLOBINEMIA
    1) SUMMARY
    a) Determine the methemoglobin concentration and evaluate the patient for clinical effects of methemoglobinemia (ie, dyspnea, headache, fatigue, CNS depression, tachycardia, metabolic acidosis). Treat patients with symptomatic methemoglobinemia with methylene blue (this usually occurs at methemoglobin concentrations above 20% to 30%, but may occur at lower methemoglobin concentrations in patients with anemia, or underlying pulmonary or cardiovascular disorders). Administer oxygen while preparing for methylene blue therapy.
    2) METHYLENE BLUE
    a) INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules (Prod Info PROVAYBLUE(TM) intravenous injection, 2016) and 10 mg/1 mL (1% solution) vials (Prod Info methylene blue 1% intravenous injection, 2011). REPEAT DOSES: Additional doses may be required, especially for substances with prolonged absorption, slow elimination, or those that form metabolites that produce methemoglobin. NOTE: Large doses of methylene blue may cause methemoglobinemia or hemolysis (Howland, 2006). Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection (Prod Info methylene blue 1% intravenous injection, 2011; Herman et al, 1999). NEONATES: DOSE: 0.3 to 1 mg/kg (Hjelt et al, 1995).
    b) CONTRAINDICATIONS: G-6-PD deficiency (methylene blue may cause hemolysis), known hypersensitivity to methylene blue, methemoglobin reductase deficiency (Shepherd & Keyes, 2004)
    c) FAILURE: Failure of methylene blue therapy suggests: inadequate dose of methylene blue, inadequate decontamination, NADPH dependent methemoglobin reductase deficiency, hemoglobin M disease, sulfhemoglobinemia, or G-6-PD deficiency. Methylene blue is reduced by methemoglobin reductase and nicotinamide adenosine dinucleotide phosphate (NADPH) to leukomethylene blue. This in turn reduces methemoglobin. Red blood cells of patients with G-6-PD deficiency do not produce enough NADPH to convert methylene blue to leukomethylene blue (do Nascimento et al, 2008).
    d) DRUG INTERACTION: Concomitant use of methylene blue with serotonergic drugs, including serotonin reuptake inhibitors (SRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), triptans, and ergot alkaloids may increase the risk of potentially fatal serotonin syndrome (U.S. Food and Drug Administration, 2011; Stanford et al, 2010; Prod Info methylene blue 1% IV injection, 2011).
    3) TOLUIDINE BLUE OR TOLONIUM CHLORIDE (GERMANY)
    a) DOSE: 2 to 4 mg/kg intravenously over 5 minutes. Dose may be repeated in 30 minutes (Nemec, 2011; Lindenmann et al, 2006; Kiese et al, 1972).
    b) SIDE EFFECTS: Hypotension with rapid intravenous administration. Vomiting, diarrhea, excessive sweating, hypotension, dysrhythmias, hemolysis, agranulocytosis and acute renal insufficiency after overdose (Dunipace et al, 1992; Hix & Wilson, 1987; Winek et al, 1969; Teunis et al, 1970; Marquez & Todd, 1959).
    c) CONTRAINDICATIONS: G-6-PD deficiency; may cause hemolysis.
    F) SEIZURE
    1) Seizures have been reported in experimental animals only.
    2) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    3) 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 .
    4) 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).
    5) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2010; Chin et al, 2008).
    6) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    7) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    G) ENDOSCOPIC PROCEDURE
    1) There is little experience with the use of endoscopy, corticosteroids or surgical therapy after ingestion of concentrated cyclohexylamine. 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).
    H) 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).
    I) 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) OXYGEN
    1) Administer 100% supplemental oxygen with assisted ventilation as required. If central nervous system depression occurs, airway patency and oxygenation must be assured. Endotracheal intubation might be necessary.
    B) MONITORING OF PATIENT
    1) Monitor chest x-ray and arterial blood gases in patients with significant inhalation exposure or respiratory tract irritation.
    C) METHEMOGLOBINEMIA
    1) SUMMARY
    a) Determine the methemoglobin concentration and evaluate the patient for clinical effects of methemoglobinemia (ie, dyspnea, headache, fatigue, CNS depression, tachycardia, metabolic acidosis). Treat patients with symptomatic methemoglobinemia with methylene blue (this usually occurs at methemoglobin concentrations above 20% to 30%, but may occur at lower methemoglobin concentrations in patients with anemia, or underlying pulmonary or cardiovascular disorders). Administer oxygen while preparing for methylene blue therapy.
    2) METHYLENE BLUE
    a) INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules (Prod Info PROVAYBLUE(TM) intravenous injection, 2016) and 10 mg/1 mL (1% solution) vials (Prod Info methylene blue 1% intravenous injection, 2011). REPEAT DOSES: Additional doses may be required, especially for substances with prolonged absorption, slow elimination, or those that form metabolites that produce methemoglobin. NOTE: Large doses of methylene blue may cause methemoglobinemia or hemolysis (Howland, 2006). Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection (Prod Info methylene blue 1% intravenous injection, 2011; Herman et al, 1999). NEONATES: DOSE: 0.3 to 1 mg/kg (Hjelt et al, 1995).
    b) CONTRAINDICATIONS: G-6-PD deficiency (methylene blue may cause hemolysis), known hypersensitivity to methylene blue, methemoglobin reductase deficiency (Shepherd & Keyes, 2004)
    c) FAILURE: Failure of methylene blue therapy suggests: inadequate dose of methylene blue, inadequate decontamination, NADPH dependent methemoglobin reductase deficiency, hemoglobin M disease, sulfhemoglobinemia, or G-6-PD deficiency. Methylene blue is reduced by methemoglobin reductase and nicotinamide adenosine dinucleotide phosphate (NADPH) to leukomethylene blue. This in turn reduces methemoglobin. Red blood cells of patients with G-6-PD deficiency do not produce enough NADPH to convert methylene blue to leukomethylene blue (do Nascimento et al, 2008).
    d) DRUG INTERACTION: Concomitant use of methylene blue with serotonergic drugs, including serotonin reuptake inhibitors (SRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), triptans, and ergot alkaloids may increase the risk of potentially fatal serotonin syndrome (U.S. Food and Drug Administration, 2011; Stanford et al, 2010; Prod Info methylene blue 1% IV injection, 2011).
    3) TOLUIDINE BLUE OR TOLONIUM CHLORIDE (GERMANY)
    a) DOSE: 2 to 4 mg/kg intravenously over 5 minutes. Dose may be repeated in 30 minutes (Nemec, 2011; Lindenmann et al, 2006; Kiese et al, 1972).
    b) SIDE EFFECTS: Hypotension with rapid intravenous administration. Vomiting, diarrhea, excessive sweating, hypotension, dysrhythmias, hemolysis, agranulocytosis and acute renal insufficiency after overdose (Dunipace et al, 1992; Hix & Wilson, 1987; Winek et al, 1969; Teunis et al, 1970; Marquez & Todd, 1959).
    c) CONTRAINDICATIONS: G-6-PD deficiency; may cause hemolysis.
    D) BRONCHOSPASM
    1) If bronchospasm occurs, treatment with inhaled sympathomimetic agents may be necessary.
    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) 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).
    6.8.2) TREATMENT
    A) IRRITATION SYMPTOM
    1) Prolonged flushing may be required.
    B) REFERRAL TO OPHTHALMOLOGIST
    1) As severe eye damage may occur, early ophthalmic consultation should be obtained.
    C) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DERMAL DECONTAMINATION
    1) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
    6.9.2) TREATMENT
    A) IRRITATION SYMPTOM
    1) Treat dermal irritation with standard topical therapy.
    B) ACUTE ALLERGIC REACTION
    1) Dermal hypersensitivity reactions could require treatment with systemic corticosteroids or antihistamines.
    C) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Enhanced Elimination

    A) SUMMARY
    1) No studies have addressed the use of extracorporeal elimination techniques in cyclohexylamine poisoning.

Range Of Toxicity

Summary

    A) Workers exposed to 4 to 10 parts per million exhibited no symptoms.
    B) Experimental animals exposed by inhalation to 1,200 to 12,000 parts per million for 6 to 7 hours died.

Minimum Lethal Exposure

    A) ROUTE OF EXPOSURE
    1) Cyclohexylamine is classified as very toxic with a probable oral lethal dose of 50 to 500 mg/kg, or between 1 teaspoonful and 1 ounce, for a 70 kg (150 pound) person (EPA, 1985). It is considered a nerve poison (EPA, 1985).
    B) ANIMAL DATA
    1) RATS - Two of three rats exposed by inhalation to 12,000 parts per million for 6 hours died within the first 48 hours (ACGIH, 1986).
    2) ANIMALS - Rats, rabbits, and guinea pigs died following a 7 hour inhalation exposure to 1,200 parts per million (ACGIH, 1986).

Maximum Tolerated Exposure

    A) ROUTE OF EXPOSURE
    1) INHALATION - Workers acutely exposed to between 4 and 10 parts per million had no symptoms (ACGIH, 1986). Three workers exposed to unspecified higher concentrations developed transient nausea, vomiting, drowsiness, lightheadedness, anxiety, apprehension, slurred speech, and pupillary dilatation (ACGIH, 1986; (Clayton & Flayton, 1994).
    2) DERMAL - In human patch tests, a 25 percent solution produced severe skin irritation and possible skin sensitization (Clayton & Flayton, 1994).

Workplace Standards

    A) ACGIH TLV Values for CAS108-91-8 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Editor's Note: The listed values are recommendations or guidelines developed by ACGIH(R) to assist in the control of health hazards. They should only be used, interpreted and applied by individuals trained in industrial hygiene. Before applying these values, it is imperative to read the introduction to each section in the current TLVs(R) and BEI(R) Book and become familiar with the constraints and limitations to their use. Always consult the Documentation of the TLVs(R) and BEIs(R) before applying these recommendations and guidelines.
    a) Adopted Value
    1) Cyclohexylamine
    a) TLV:
    1) TLV-TWA: 10 ppm
    2) TLV-STEL:
    3) TLV-Ceiling:
    b) Notations and Endnotes:
    1) Carcinogenicity Category: A4
    2) Codes: Not Listed
    3) Definitions:
    a) A4: Not Classifiable as a Human Carcinogen: Agents which cause concern that they could be carcinogenic for humans but which cannot be assessed conclusively because of a lack of data. In vitro or animal studies do not provide indications of carcinogenicity which are sufficient to classify the agent into one of the other categories.
    c) TLV Basis - Critical Effect(s): URT and eye irr
    d) Molecular Weight: 99.17
    1) For gases and vapors, to convert the TLV from ppm to mg/m(3):
    a) [(TLV in ppm)(gram molecular weight of substance)]/24.45
    2) For gases and vapors, to convert the TLV from mg/m(3) to ppm:
    a) [(TLV in mg/m(3))(24.45)]/gram molecular weight of substance
    e) Additional information:

    B) NIOSH REL and IDLH Values for CAS108-91-8 (National Institute for Occupational Safety and Health, 2007):
    1) Listed as: Cyclohexylamine
    2) REL:
    a) TWA: 10 ppm (40 mg/m(3))
    b) STEL:
    c) Ceiling:
    d) Carcinogen Listing: (Not Listed) Not Listed
    e) Skin Designation: Not Listed
    f) Note(s):
    3) IDLH: Not Listed

    C) Carcinogenicity Ratings for CAS108-91-8 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): A4 ; Listed as: Cyclohexylamine
    a) A4 :Not Classifiable as a Human Carcinogen: Agents which cause concern that they could be carcinogenic for humans but which cannot be assessed conclusively because of a lack of data. In vitro or animal studies do not provide indications of carcinogenicity which are sufficient to classify the agent into one of the other categories.
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Assessed under the IRIS program. ; Listed as: Cyclohexylamine
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed ; Listed as: Cyclohexylamine
    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 CAS108-91-8 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) References: RTECS, 1999 Lewis, 1997 ITI, 1995
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 129 mg/kg
    2) LD50- (ORAL)MOUSE:
    a) 224 mg/kg
    3) LD50- (SUBCUTANEOUS)MOUSE:
    a) 1150 mg/kg
    4) LD50- (INHALATION)RAT:
    a) 8000 ppm for 4H
    5) LD50- (INTRAPERITONEAL)RAT:
    a) 300 mg/kg
    6) LD50- (ORAL)RAT:
    a) 11 mg/kg
    b) 156-710 mg/kg

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Cyclohexylamine possesses some weak sympathomimetic activity which is orders of magnitude less than other sympathomimetic amines (Clayton & Flayton, 1994). At levels found from metabolism of administered cyclamate in humans, no sympathomimetic effects occur (Clayton & Flayton, 1994).
    1) Cyclohexylamine, in large doses (up to 500 mg/kg in rats), may have pronounced sympathomimetic activity causing local alpha adrenergic-mediated vasoconstriction during absorption, decreasing blood flow and the rate of absorption from the gut (Roberts & Renwick, 1989).

Toxicologic Mechanism

    A) Cyclohexylamine is a direct irritant of skin, eyes, and mucous membranes (Clayton & Flayton, 1994) ACGIH, 1986).
    B) Cyclohexylamine may possess some questionable teratogenic, mutagenic, and carcinogenic properties which have not been conclusively demonstrated (Clayton & Flayton, 1994).
    C) Cyclohexylamine is a weak methemoglobin forming substance (Clayton & Flayton, 1994; EPA, 1985). No human cases of symptomatic methemoglobinemia due to cyclohexylamine have been reported.

Physicochemical

Physical Characteristics

    A) Cyclohexylamine is a colorless to yellow liquid with a strong fishy, ammonia, or amine odor (ACGIH, 1986; (Lewis, 1997; Student, 1981).

Ph

    A) 10.5 (0.01% aqueous solution) (Lewis, 1997)

Molecular Weight

    A) 99.17
    B) 99.20

Other

    A) ODOR THRESHOLD
    1) Currently not available (CHRIS , 2002).

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