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AMINOMESITYLENE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Aminomesitylene is a primary amine aniline derivative (Considine, 1974).

Specific Substances

    A) No Synonyms were found in group or single elements
    1.2.1) MOLECULAR FORMULA
    1) C9-H13-N

Available Forms Sources

    A) FORMS
    1) Aminomesitylene is a liquid (HSDB, 2003).
    B) SOURCES
    1) It is produced by reduction of 1,3,5-trimethyl-2-nitrobenzene, which is obtained by nitration of mesitylene under special conditions (HSDB, 2003).
    C) USES
    1) It is used in dyes (HSDB, 2003).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) Aminomesitylene exposure causes eye and skin irritation. Chronic workplace exposure has been associated with various vision changes. Dermal sensitization may occur. Methemoglobinemia has not been reported in exposed humans, but exposure to other aniline compounds has caused this effect.
    0.2.4) HEENT
    A) Eye, ear, nose, and throat irritation may occur.
    0.2.6) RESPIRATORY
    A) Respiratory tract irritation may develop.
    0.2.8) GASTROINTESTINAL
    A) Gastrointestinal tract irritation may develop following ingestion.
    0.2.9) HEPATIC
    A) Cirrhosis of the liver was produced in rats in chronic dietary studies.
    0.2.13) HEMATOLOGIC
    A) Methemoglobinemia with central "chocolate brown" cyanosis unresponsive to inhalation of 100% supplemental oxygen could occur (by analogy with other aniline compounds).
    0.2.14) DERMATOLOGIC
    A) Dermal irritation may occur.
    0.2.20) REPRODUCTIVE
    A) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.
    B) At the time of this review, no data were available to assess the teratogenic potential of this agent.
    0.2.21) CARCINOGENICITY
    A) No studies were found on the possible carcinogenicity of aminomesitylene in humans.

Laboratory Monitoring

    A) If cyanosis is present, obtain and monitor arterial blood gases and methemoglobin levels.
    B) A number of chemicals produce abnormalities of the hematopoietic system, liver, and kidneys. Monitoring complete blood count, urinalysis, and liver and kidney function tests is suggested for patients with significant exposure.
    C) If respiratory tract irritation or respiratory depression is evident, monitor arterial blood gases, chest x-ray, and pulmonary function tests.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) Induced emesis should be AVOIDED.
    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) Significant esophageal or gastrointestinal tract irritation or burns may occur following ingestion. The possible benefit of early removal of some ingested material by cautious gastric lavage must be weighed against potential complications of bleeding or perforation.
    D) 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.
    E) 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.
    F) 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.
    G) 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.
    H) Observe patients with ingestion carefully for the possible development of esophageal or gastrointestinal tract irritation or burns. If signs or symptoms of esophageal irritation or burns are present, consider endoscopy to determine the extent of injury.
    0.4.3) INHALATION EXPOSURE
    A) INHALATION: Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm.
    B) 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.
    C) If bronchospasm and wheezing occur, consider treatment with inhaled sympathomimetic agents.
    0.4.4) EYE EXPOSURE
    A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
    2) Treat dermal irritation or burns with standard topical therapy. Patients developing dermal hypersensitivity reactions may require treatment with systemic or topical corticosteroids or antihistamines.

Range Of Toxicity

    A) Minimum lethal human exposure is unknown.

Clinical Effects

Summary Of Exposure

    A) Aminomesitylene exposure causes eye and skin irritation. Chronic workplace exposure has been associated with various vision changes. Dermal sensitization may occur. Methemoglobinemia has not been reported in exposed humans, but exposure to other aniline compounds has caused this effect.

Heent

    3.4.1) SUMMARY
    A) Eye, ear, nose, and throat irritation may occur.
    3.4.3) EYES
    A) CONJUNCTIVITIS - Eye irritation may occur (Grant, 1986; EPA, 1985).
    B) IRRITATION - Aminomesitylene induced moderate eye irritation in the rabbit in the Standard Draize Test (RTECS , 1996).
    C) VISION EFFECTS - Workers who were exposed to both aminomesitylene and aniline for between 11 and 20 years during manufacturing of these agents were reported to develop various vision effects, including narrowed peripheral visual fields, increased size of the blind spot, and decreased "photosensitivity" (Grant, 1986).
    D) RETINAL CHANGES - Changes in the morphology of the retina have been seen with aminomesitylene exposure in rats and rabbits (Grant, 1986).
    3.4.5) NOSE
    A) MUCOSAL IRRITATION - Although nose and throat irritation have not been reported in exposed humans, such effects may be predicted based on this agent's other irritant properties.
    3.4.6) THROAT
    A) MUCOSAL IRRITATION - Although nose and throat irritation have not been reported in exposed humans, such effects may be predicted based on this agent's other irritant properties.

Respiratory

    3.6.1) SUMMARY
    A) Respiratory tract irritation may develop.
    3.6.2) CLINICAL EFFECTS
    A) IRRITATION SYMPTOM
    1) Although respiratory tract irritation has not been reported in exposed humans, such effects may be predicted based on this agent's other irritant properties.
    2) Respiratory tract irritation, if severe, can progress to pulmonary edema which may be delayed in onset up to 24 to 72 hours after exposure in some cases.

Gastrointestinal

    3.8.1) SUMMARY
    A) Gastrointestinal tract irritation may develop following ingestion.
    3.8.2) CLINICAL EFFECTS
    A) GASTRITIS
    1) Although gastrointestinal tract irritation has NOT been reported in human ingestions, such effects may be predicted based on this agent's other irritant properties.

Hepatic

    3.9.1) SUMMARY
    A) Cirrhosis of the liver was produced in rats in chronic dietary studies.
    3.9.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    a) Cirrhosis of the liver occurred in male rats exposed to aminomesitylene in chronic dietary studies (Weisburger et al, 1978).

Hematologic

    3.13.1) SUMMARY
    A) Methemoglobinemia with central "chocolate brown" cyanosis unresponsive to inhalation of 100% supplemental oxygen could occur (by analogy with other aniline compounds).
    3.13.2) CLINICAL EFFECTS
    A) METHEMOGLOBINEMIA
    1) Methemoglobinemia has not been reported in exposed humans, but as exposure to many aniline compounds has caused this effect, it should be suspected in patients with significant exposure (EPA, 1985; Hall et al, 1986).
    2) Aminomesitylene is an aniline derivative, and as such could produce methemoglobinemia with central "chocolate-brown" cyanosis that does not improve with inhalation of 100% supplemental oxygen (EPA, 1985; Hall et al, 1986).

Dermatologic

    3.14.1) SUMMARY
    A) Dermal irritation may occur.
    3.14.2) CLINICAL EFFECTS
    A) SKIN IRRITATION
    1) Aminomesitylene exposure can cause skin irritation (EPA, 1985; Lewis, 1992).
    3.14.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    a) Aminomesitylene induced moderate skin irritation in the rabbit in the Standard Draize Test (RTECS , 1996).

Reproductive

    3.20.1) SUMMARY
    A) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.
    B) At the time of this review, no data were available to assess the teratogenic potential of this agent.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the teratogenic potential of this agent.
    3.20.3) EFFECTS IN PREGNANCY
    A) HUMANS
    1) METHEMOGLOBINEMIA
    a) METHEMOGLOBIN INDUCERS - There is a concern for the unborn with prenatal exposure to methemoglobin inducers. Infants may be particularly susceptible to methemoglobin inducers because fetal hemoglobin is more easily oxidized to methemoglobin than the adult form, and because fetal methemoglobin is more slowly reduced back to normal fetal hemoglobin than is the adult form (Harris et al, 1979; Filer et al, 1970; Mansouri, 1985; Hall et al, 1986).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS88-05-1 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) IARC Classification
    a) Listed as: 2,4,6-Trimethylaniline
    b) Carcinogen Rating: 3
    1) The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.
    3.21.2) SUMMARY/HUMAN
    A) No studies were found on the possible carcinogenicity of aminomesitylene in humans.
    3.21.4) ANIMAL STUDIES
    A) ANIMAL STUDIES
    1) CARCINOMA
    a) Aminomesitylene was carcinogenic in dietary studies in male rats and male and female mice (Weisburger et al, 1978).
    b) A pituitary tumor occurred in a female rat exposed to aminomesitylene at 1.1 mmole/kg in the diet for 18 months (Kovi & Morris, 1976).

Genotoxicity

    A) Aminomesitylene has induced DNA damage, DNA repair, and mutations.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) If cyanosis is present, obtain and monitor arterial blood gases and methemoglobin levels.
    B) A number of chemicals produce abnormalities of the hematopoietic system, liver, and kidneys. Monitoring complete blood count, urinalysis, and liver and kidney function tests is suggested for patients with significant exposure.
    C) If respiratory tract irritation or respiratory depression is evident, monitor arterial blood gases, chest x-ray, and pulmonary function tests.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) If cyanosis is present, arterial blood gases and methemoglobin levels should be obtained and monitored.
    2) A number of chemicals produce abnormalities of the hematopoietic system, liver, and kidneys. Monitoring complete blood count and liver and kidney function tests is suggested for patients with significant exposure.
    B) MONITORING
    1) If respiratory tract irritation is present, monitor arterial blood gases and chest x-ray.
    4.1.3) URINE
    A) URINALYSIS
    1) A number of chemicals produce abnormalities of the hematopoietic system, liver, and kidneys. Monitoring urinalysis is suggested for patients with significant exposure.
    4.1.4) OTHER
    A) OTHER
    1) PULMONARY FUNCTION TESTS
    a) If respiratory tract irritation is present, it may be useful to monitor pulmonary function tests.

Radiographic Studies

    A) CHEST RADIOGRAPH
    1) If respiratory tract irritation is present, monitor chest x-ray.

Methods

    A) OTHER
    1) A bedside screening test for the presence of methemoglobin can be done by placing a drop of the patient's blood alongside a normal control on filter paper. Blood from a patient with 15% or greater methemoglobinemia will dry a deep, "chocolate brown" color in comparison to the normal control (Hall et al, 1986).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients symptomatic following exposure should be observed in a controlled setting until all signs and symptoms have fully resolved.

Monitoring

    A) If cyanosis is present, obtain and monitor arterial blood gases and methemoglobin levels.
    B) A number of chemicals produce abnormalities of the hematopoietic system, liver, and kidneys. Monitoring complete blood count, urinalysis, and liver and kidney function tests is suggested for patients with significant exposure.
    C) If respiratory tract irritation or respiratory depression is evident, monitor arterial blood gases, chest x-ray, and pulmonary function tests.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) GENERAL -
    1) Exposed individuals should have a careful, thorough medical history and physical examination performed, looking for any abnormalities. Exposure to chemicals with a strong odor often results in such nonspecific symptoms as headache, dizziness, weakness, and nausea.
    B) ORAL EXPOSURE -
    1) Emesis should not be induced.
    2) 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.
    3) 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.
    a) 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.
    4) Observe patients with ingestion carefully for the possible development of esophageal or gastrointestinal tract irritation or burns. If signs or symptoms of esophageal irritation or burns are present, consider endoscopy to determine the extent of injury.
    C) INHALATION EXPOSURE -
    1) 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.
    2) If bronchospasm and wheezing occur, consider treatment with inhaled sympathomimetic agents.
    3) 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.
    D) DERMAL EXPOSURE -
    1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
    2) Some chemicals can produce systemic poisoning by absorption through intact skin. Carefully observe patients with dermal exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    3) Treat dermal irritation or burns with standard topical therapy. Patients developing dermal hypersensitivity reactions may require treatment with systemic or topical corticosteroids or antihistamines.
    E) EYE EXPOSURE -
    1) 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.
    2) Patients with any visual or ocular complaints following chronic exposure should have a thorough ophthalmologic evaluation.
    6.5.2) PREVENTION OF ABSORPTION
    A) EMESIS/NOT RECOMMENDED
    1) As esophageal irritation may occur, EMESIS SHOULD NOT BE INDUCED.
    B) GASTRIC LAVAGE
    1) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).
    a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.
    2) PRECAUTIONS:
    a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
    b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.
    3) LAVAGE FLUID:
    a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
    b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
    c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.
    4) COMPLICATIONS:
    a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
    b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).
    5) CONTRAINDICATIONS:
    a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.
    6.5.3) TREATMENT
    A) 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) BURN
    1) Observe patients with ingestion carefully for the possible development of esophageal or gastrointestinal tract irritation or burns. If signs or symptoms of esophageal irritation or burns are present, consider endoscopy to determine the extent of injury.
    C) METHEMOGLOBINEMIA
    1) If cyanosis is present, administer 100% supplemental oxygen and obtain and monitor arterial blood gases and methemoglobin levels.
    2) SUMMARY
    a) Determine the methemoglobin concentration and evaluate the patient for clinical effects of methemoglobinemia (ie, dyspnea, headache, fatigue, CNS depression, tachycardia, metabolic acidosis). Treat patients with symptomatic methemoglobinemia with methylene blue (this usually occurs at methemoglobin concentrations above 20% to 30%, but may occur at lower methemoglobin concentrations in patients with anemia, or underlying pulmonary or cardiovascular disorders). Administer oxygen while preparing for methylene blue therapy.
    3) METHYLENE BLUE
    a) INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules (Prod Info PROVAYBLUE(TM) intravenous injection, 2016) and 10 mg/1 mL (1% solution) vials (Prod Info methylene blue 1% intravenous injection, 2011). REPEAT DOSES: Additional doses may be required, especially for substances with prolonged absorption, slow elimination, or those that form metabolites that produce methemoglobin. NOTE: Large doses of methylene blue may cause methemoglobinemia or hemolysis (Howland, 2006). Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection (Prod Info methylene blue 1% intravenous injection, 2011; Herman et al, 1999). NEONATES: DOSE: 0.3 to 1 mg/kg (Hjelt et al, 1995).
    b) CONTRAINDICATIONS: G-6-PD deficiency (methylene blue may cause hemolysis), known hypersensitivity to methylene blue, methemoglobin reductase deficiency (Shepherd & Keyes, 2004)
    c) FAILURE: Failure of methylene blue therapy suggests: inadequate dose of methylene blue, inadequate decontamination, NADPH dependent methemoglobin reductase deficiency, hemoglobin M disease, sulfhemoglobinemia, or G-6-PD deficiency. Methylene blue is reduced by methemoglobin reductase and nicotinamide adenosine dinucleotide phosphate (NADPH) to leukomethylene blue. This in turn reduces methemoglobin. Red blood cells of patients with G-6-PD deficiency do not produce enough NADPH to convert methylene blue to leukomethylene blue (do Nascimento et al, 2008).
    d) DRUG INTERACTION: Concomitant use of methylene blue with serotonergic drugs, including serotonin reuptake inhibitors (SRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), triptans, and ergot alkaloids may increase the risk of potentially fatal serotonin syndrome (U.S. Food and Drug Administration, 2011; Stanford et al, 2010; Prod Info methylene blue 1% IV injection, 2011).
    4) TOLUIDINE BLUE OR TOLONIUM CHLORIDE (GERMANY)
    a) DOSE: 2 to 4 mg/kg intravenously over 5 minutes. Dose may be repeated in 30 minutes (Nemec, 2011; Lindenmann et al, 2006; Kiese et al, 1972).
    b) SIDE EFFECTS: Hypotension with rapid intravenous administration. Vomiting, diarrhea, excessive sweating, hypotension, dysrhythmias, hemolysis, agranulocytosis and acute renal insufficiency after overdose (Dunipace et al, 1992; Hix & Wilson, 1987; Winek et al, 1969; Teunis et al, 1970; Marquez & Todd, 1959).
    c) CONTRAINDICATIONS: G-6-PD deficiency; may cause hemolysis.
    D) HOSPITAL ADMISSION
    1) Patients symptomatic following exposure should be observed in a controlled setting until all signs and symptoms have fully resolved.

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) SUPPORT
    1) Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    B) BRONCHOSPASM
    1) If bronchospasm and wheezing occur, consider treatment with inhaled sympathomimetic agents.
    C) IRRITATION SYMPTOM
    1) Respiratory tract irritation, if severe, can progress to noncardiogenic pulmonary edema which may be delayed in onset up to 24 to 72 hours after exposure in some cases.
    2) There are no controlled studies indicating that early administration of corticosteroids can prevent the development of noncardiogenic pulmonary edema in patients with inhalation exposure to respiratory irritant substances, and long-term use may cause adverse effects (Boysen & Modell, 1989).
    a) However, based on anecdotal experience, some clinicians do recommend early administration of corticosteroids (such as methylprednisolone 1 gram intravenously as a single dose) in an attempt to prevent the later development of pulmonary edema.
    1) Anecdotal experience with dimethyl sulfate inhalation showed possible benefit of methylprednisolone in the TREATMENT of noncardiogenic pulmonary edema (Ip et al, 1989).
    3) Anecdotal experience also indicated that systemic corticosteroids may have possible efficacy in the TREATMENT of drug-induced noncardiogenic pulmonary edema (Zitnik & Cooper, 1990; Stentoft, 1990; Chudnofsky & Otten, 1989) or noncardiogenic pulmonary edema developing after cardiopulmonary bypass (Maggart & Stewart, 1987).
    4) It is not clear from the published literature that administration of systemic corticosteroids early following inhalation exposure to respiratory irritant substances can PREVENT the development of noncardiogenic pulmonary edema. The decision to administer or withhold corticosteroids in this setting must currently be made on clinical grounds.
    D) 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).
    E) 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) GENERAL TREATMENT
    1) OPHTHALMOLOGIC EXAMINATION - Patients with a history of prolonged exposure and eye complaints should have a thorough ophthalmologic examination.
    B) 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) SKIN ABSORPTION
    1) Some chemicals can produce systemic poisoning by absorption through intact skin. Carefully observe patients with dermal exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    B) IRRITATION SYMPTOM
    1) Treat dermal irritation or burns with standard topical therapy. Patients developing dermal hypersensitivity reactions may require treatment with systemic or topical corticosteroids or antihistamines.
    C) GENERAL TREATMENT
    1) Patients who develop dermal sensitization and skin hypersensitivity reactions may need to be precluded from further exposure.
    D) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Enhanced Elimination

    A) EFFICACY
    1) No studies have addressed the utilization of extracorporeal elimination techniques in poisoning with this agent.

Range Of Toxicity

Summary

    A) Minimum lethal human exposure is unknown.

Minimum Lethal Exposure

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

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) The maximum tolerated human exposure to this agent has not been delineated.
    B) ANIMAL DATA
    1) Rabbit skin was moderately irritated when 500 milligrams of aminomesitylene were applied for 24 hours (RTECS , 1996). Rabbit eyes were severely irritated when 20 milligrams of aminomesitylene were applied for 24 hours (RTECS , 1996).

Workplace Standards

    A) ACGIH TLV Values for CAS88-05-1 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS88-05-1 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS88-05-1 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): 3 ; Listed as: 2,4,6-Trimethylaniline
    a) 3 : The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS88-05-1 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) References: RTECS, 1996
    1) LD50- (ORAL)MOUSE:
    a) 590 mg/kg
    2) LD50- (ORAL)RAT:
    a) 743 mg/kg

Pharmacology Toxicology

Toxicologic Mechanism

    A) Aminomesitylene is a direct irritant of the eyes and skin (EPA, 1985; RTECS , 1996). It may cause dermal sensitization with chronic exposure (EPA, 1985).
    B) Aminomesitylene is an aniline derivative and as such could induce methemoglobinemia (EPA, 1985).
    1) The basic mechanism in methemoglobin formation is the oxidation (loss of electrons) of ferrous hemoglobin to ferric methemoglobin by an oxidant drug or chemical: 
                             Oxidation
          Hgb Fe+2 -----------------> Met Hgb Fe+3

Physicochemical

Physical Characteristics

    A) Aminomesitylene is a liquid (EPA, 1985).

Molecular Weight

    A) 135.23 (Lewis, 1992)

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