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NITROBENZENE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Nitrobenzene is a CNS depressant.

Specific Substances

    1) Nitrobenzol
    2) Essence of mirbane
    3) Essence of myrbane
    4) Oil of myrbane
    5) Oil of mirbane
    6) CAS 98-95-3 (nitrobenzene)
    7) CAS 82-68-8 (pentachloronitrobenzene)
    8) BENZENE, NITRO-
    9) MYRBANE OIL
    1.2.1) MOLECULAR FORMULA
    1) C6-H5-N-O2

Available Forms Sources

    A) FORMS
    1) Nitrobenzene is an oily liquid, clear or pale yellow to dark brown in color. It has an almond odor (AAR, 1998; Budavari, 1996a).
    B) SOURCES
    1) Nitrobenzene is produced by nitrating benzene with a mixture of nitric acid and sulfuric acid (Budavari, 1996a; Lewis, 1997a).
    C) USES
    1) Nitrobenzene is used in the manufacture of aniline, soaps, shoe polishes, floor polishes, and metal polishes. It is used as a preservative in spray paints and as an artificial flavor and scent in food and perfumes (HSDB, 2000; Lewis, 1998).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) Nitrobenzene may be toxic by all routes of exposure, depending on dose; usual routes are inhalation of vapor and skin contact with vapor or liquid. The mean adult lethal oral dose is estimated to be about 1 to 5 g. Alcohol ingestion may worsen the effects.
    B) Signs and symptoms may include eye and skin irritation and methemoglobinemia, associated with headache, cyanosis, weakness, dizziness, confusion, rapid heart rate, labored breathing, chest pain, nausea and vomiting, and coma. These are usually delayed in onset for up to 1 to 4 hours. Chronic exposure may produce liver toxicity.
    C) A bitter almond odor may be present in urine or vomitus, which suggests cyanide poisoning, but cyanide produces symptoms much more rapidly than nitrobenzene.
    0.2.3) VITAL SIGNS
    A) Tachycardia, tachypnea, hypotension, and respiratory depression may occur.
    0.2.4) HEENT
    A) Brown discoloration of the vessels of the fundus and conjunctiva may occur. Changes in visual acuity, decreased visual fields, irritation and central scotoma may occur.
    0.2.5) CARDIOVASCULAR
    A) Tachycardia, hypotension, and cardiac dysrhythmias may occur secondary to methemoglobinemia.
    0.2.6) RESPIRATORY
    A) Respiratory failure may occur.
    0.2.7) NEUROLOGIC
    A) Headache, dizziness, lethargy, and coma are possible.
    0.2.8) GASTROINTESTINAL
    A) Nausea and vomiting may occur. Urine and vomitus may have the odor of bitter almonds.
    0.2.10) GENITOURINARY
    A) Urine may have the odor of oil of bitter almonds.
    0.2.13) HEMATOLOGIC
    A) Methemoglobinemia may occur.
    0.2.14) DERMATOLOGIC
    A) Persistent cyanosis in spite of oxygen therapy usually occurs when the methemoglobin level is greater than 15 percent.
    0.2.20) REPRODUCTIVE
    A) Nitrobenzene is a possible animal teratogen.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, no studies were found on the possible carcinogenic activity of nitrobenzene in humans.

Laboratory Monitoring

    A) Plasma nitrobenzene levels are not clinically useful.
    B) Determine methemoglobin levels in all cyanotic patients. Cyanosis generally occurs when the plasma methemoglobin levels exceed 15%.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) EMESIS: Ipecac-induced emesis is not recommended because of the potential for CNS depression and seizures.
    B) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
    C) GASTRIC LAVAGE: Consider after ingestion of a potentially life-threatening amount of poison if it can be performed soon after ingestion (generally within 1 hour). Protect airway by placement in the head down left lateral decubitus position or by endotracheal intubation. Control any seizures first.
    1) CONTRAINDICATIONS: Loss of airway protective reflexes or decreased level of consciousness in unintubated patients; following ingestion of corrosives; hydrocarbons (high aspiration potential); patients at risk of hemorrhage or gastrointestinal perforation; and trivial or non-toxic ingestion.
    D) 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.
    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.
    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) Persistent cyanosis in spite of oxygen treatment is consistent with methemoglobinemia.
    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) If patient is cyanotic and symptomatic, methemoglobinemia is likely and methylene blue therapy should be initiated.

Range Of Toxicity

    A) Insufficient data to assess the minimal toxic dose.
    B) The estimated mean lethal adult dose is about 1 to 5 grams. Neonates, infants and young children may be more susceptible.

Clinical Effects

Summary Of Exposure

    A) Nitrobenzene may be toxic by all routes of exposure, depending on dose; usual routes are inhalation of vapor and skin contact with vapor or liquid. The mean adult lethal oral dose is estimated to be about 1 to 5 g. Alcohol ingestion may worsen the effects.
    B) Signs and symptoms may include eye and skin irritation and methemoglobinemia, associated with headache, cyanosis, weakness, dizziness, confusion, rapid heart rate, labored breathing, chest pain, nausea and vomiting, and coma. These are usually delayed in onset for up to 1 to 4 hours. Chronic exposure may produce liver toxicity.
    C) A bitter almond odor may be present in urine or vomitus, which suggests cyanide poisoning, but cyanide produces symptoms much more rapidly than nitrobenzene.

Vital Signs

    3.3.1) SUMMARY
    A) Tachycardia, tachypnea, hypotension, and respiratory depression may occur.
    3.3.2) RESPIRATIONS
    A) Nitrobenzene may cause respiratory failure.
    3.3.5) PULSE
    A) Tachycardia may be present.

Heent

    3.4.1) SUMMARY
    A) Brown discoloration of the vessels of the fundus and conjunctiva may occur. Changes in visual acuity, decreased visual fields, irritation and central scotoma may occur.
    3.4.3) EYES
    A) Brown discoloration of the vessels of the fundus and conjunctiva may occur secondary to methemoglobinemia. Changes in visual acuity, decreased visual fields, and central scotoma have been associated with nitrobenzene poisoning but are not well documented (Grant, 1986).
    B) Nitrobenzene induced mild eye irritation in the rabbit in the Standard Draize Test (RTECS , 1991).

Cardiovascular

    3.5.1) SUMMARY
    A) Tachycardia, hypotension, and cardiac dysrhythmias may occur secondary to methemoglobinemia.
    3.5.2) CLINICAL EFFECTS
    A) CARDIAC FINDING
    1) Tachycardia, hypotension, and cardiac dysrhythmias may occur secondary to methemoglobinemia. Symptoms may be delayed in onset for 1 to 4 hours in exposures by ingestion or percutaneous absorption. Acute nitrobenzene intoxication characteristically results in the early appearance of cyanosis due to methemoglobin formation.

Respiratory

    3.6.1) SUMMARY
    A) Respiratory failure may occur.
    3.6.2) CLINICAL EFFECTS
    A) ACUTE RESPIRATORY FAILURE
    1) WITH POISONING/EXPOSURE
    a) Death from respiratory failure has been reported (Proctor et al, 1988).
    b) CASE REPORT: A 17-year-old girl presented to the emergency department in a comatose condition approximately 6 hours after intentionally ingesting an unknown quantity of nitrobenzene. Upon presentation her heart rate was 130 beats/min and her blood pressure was 110/70 mmHg. She was intubated and placed on mechanical ventilation. Over a 2-day period she became increasingly cyanotic. She did not regain consciousness and her condition deteriorated as cyanosis persisted and oxygen saturation dropped to 66%. She died 4 days after admission (Gupta et al, 2012).

Neurologic

    3.7.1) SUMMARY
    A) Headache, dizziness, lethargy, and coma are possible.
    3.7.2) CLINICAL EFFECTS
    A) COMA
    1) WITH POISONING/EXPOSURE
    a) SIGNS OF INTOXICATION: Inhalation can result in almost immediate onset of clinical signs resembling ethanol intoxication with headache, nausea, vertigo, depressed respirations, visual disturbances, disorientation, coma, and death from respiratory failure.
    b) CASE REPORT: A 17-year-old girl presented to the emergency department with a Glasgow Coma Scale score of 3 approximately 6 hours after intentionally ingesting an unknown amount of nitrobenzene. Upon presentation her heart rate was 130 beats/min and her blood pressure was 110/70 mmHg. She was intubated and placed on mechanical ventilation. Over a 2-day period she became increasingly cyanotic. She did not regain consciousness and her condition deteriorated as cyanosis persisted. She died 4 days after admission. Autopsy findings included bilateral cerebral petechial hemorrhages (Gupta et al, 2012).
    B) CENTRAL NERVOUS SYSTEM DEFICIT
    1) WITH POISONING/EXPOSURE
    a) CNS depression may be preceded by a period of stimulation.

Gastrointestinal

    3.8.1) SUMMARY
    A) Nausea and vomiting may occur. Urine and vomitus may have the odor of bitter almonds.
    3.8.2) CLINICAL EFFECTS
    A) VOMITING
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Prior to presenting to the emergency department (ED), a 17-year-old girl experienced 4 episodes of vomiting after intentionally ingesting an unknown quantity of nitrobenzene. She was comatose when she presented to the ED 6 hours after ingestion. After initially being intubated and placed on mechanical ventilation, she developed metabolic acidosis, methemoglobinemia, and severe leukocytosis. She died 4 days after admission despite treatment with IV ascorbic acid and oral methylene blue (Gupta et al, 2012).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) HEPATOCELLULAR LIVER DAMAGE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 17-year-old girl presented to the emergency department in a comatose condition 6 hours after she intentionally ingested an unknown amount of nitrobenzene. Upon presentation, all liver enzymes were within normal limits. She was intubated, placed on mechanical ventilation, and treated with oral methylene blue and IV ascorbic acid. Over the following 2 days her liver enzyme levels tripled and cyanosis persisted. She died 4 days after admission despite continued treatment. Autopsy findings included hepatic centrilobular necrosis and hepatic congestion (Gupta et al, 2012).
    3.9.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HEPATOCELLULAR DAMAGE
    a) MICE: The liver and spleen were the primary target organs for nitrobenzene in mice given doses up to 300 mg/kg by gavage (Burns et al, 1994).

Genitourinary

    3.10.1) SUMMARY
    A) Urine may have the odor of oil of bitter almonds.
    3.10.2) CLINICAL EFFECTS
    A) ABNORMAL URINE
    1) WITH POISONING/EXPOSURE
    a) Urine may have the odor of oil of bitter almonds.

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) ACIDOSIS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Metabolic acidosis, methemoglobinemia, and severe leukocytosis developed in a 17-year-old girl after she intentionally ingested an unknown quantity of nitrobenzene. She presented to the emergency department in a comatose condition 6 hours after ingestion with arterial blood gas (ABG) analysis showing a pH of 7.26, PaO2 of 29.9 mmHg, PaCO2 of 41.8 mmHg, and HCO3 of 18.3 meq/L. She was intubated and placed on mechanical ventilation. Repeat ABG analysis 24 hours after presentation showed pH 7.42, PaO2 75 mmHg, PaCO2 34.2 mmHg, HCO3 19.4 meq/L. Her condition deteriorated over the next 2 days as cyanosis persisted and her oxygen saturation dropped to 66%. She died 4 days after admission despite treatment with IV ascorbic acid and oral methylene blue (Gupta et al, 2012).

Hematologic

    3.13.1) SUMMARY
    A) Methemoglobinemia may occur.
    3.13.2) CLINICAL EFFECTS
    A) METHEMOGLOBINEMIA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 17-year-old girl developed a fatal case of methemoglobinemia after intentionally ingesting an unknown amount of nitrobenzene. She presented to the emergency department 6 hours after ingestion with a Glasgow Coma Scale score of 3, heart rate of 130 beats/min, and blood pressure of 110/70 mmHg. Cyanosis was noted to her fingers and tongue. She was intubated and placed on mechanical ventilation. Arterial blood gas results showed acute metabolic acidosis and laboratory analysis revealed a methemoglobin level of 63.3% (normal; 1%). Renal and liver enzymes, serum electrolytes, urinalysis, chest x-ray and ECG were all normal. Initial treatment included 100 mg (2 mg/kg) of oral methylene blue and ascorbic acid 500 mg IV every 12 hours. After 1 hour of treatment, her methemoglobin level decreased to 36.6%; however it rebounded to 47.7% within 24 hours and continued rising to 76.5% despite ongoing treatment. Over a 2-day period she became increasingly cyanotic. She did not regain consciousness and her condition deteriorated as cyanosis persisted and oxygen saturation dropped to 66%. Splenomegaly developed along with severe leukocytosis. She died 4 days after admission. Autopsy examination showed bilateral cerebral petechial hemorrhages, hepatic and splenetic congestion, renal tubular necrosis and hepatic centrilobular necrosis (Gupta et al, 2012).
    b) CASE REPORT: An 82-year-old man developed severe methemoglobinemia after ingesting approximately 250 mL of a nitrobenzene containing solvent. On presentation to the hospital he was comatose (GCS 6) and hypotensive, with a methemoglobin level of 70% and anuric renal failure. CT of the brain revealed hypoxic ischemic encephalopathy. Methemoglobinemia persisted (30%) despite treatment with methylene blue (dose not specified) so he was treated with exchange transfusion with a reduction to 18% methemoglobin. He developed hypotension refractory to vasopressors and died 3 days after admission (Martinez et al, 2003).
    B) LEUKOCYTOSIS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 17-year-old girl developed severe leukocytosis (56,600/mm(3)), splenomegaly, and methemoglobinemia after intentionally ingesting an unknown amount of nitrobenzene. She presented to the emergency department 6 hours after ingestion in a comatose condition with a leukocyte count of 8000/mm(3). She was intubated, placed on mechanical ventilation, and treated with oral methylene blue and IV ascorbic acid. She died 4 days after admission despite continued treatment (Gupta et al, 2012).
    C) SPLENOMEGALY
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 17-year-old girl developed splenomegaly palpable to 4 cm after intentionally ingesting an unknown quantity of nitrobenzene. She presented to the emergency department 6 hours after ingestion in a comatose condition, was intubated, and placed on mechanical ventilation. She also developed metabolic acidosis, methemoglobinemia, and severe leukocytosis. She died 4 days after admission despite treatment with IV ascorbic acid and oral methylene blue. Autopsy findings included splenic and hepatic congestion (Gupta et al, 2012).

Dermatologic

    3.14.1) SUMMARY
    A) Persistent cyanosis in spite of oxygen therapy usually occurs when the methemoglobin level is greater than 15 percent.
    3.14.2) CLINICAL EFFECTS
    A) CYANOSIS
    1) WITH POISONING/EXPOSURE
    a) Persistent cyanosis in spite of oxygen therapy usually occurs when the methemoglobin level is greater than 15%.
    b) CASE REPORT: A 17-year-old girl developed a fatal case of methemoglobinemia after intentionally ingesting an unknown amount of nitrobenzene. She presented with cyanotic fingers and tongue. Her methemoglobin level at presentation was 63.3% (normal; 1%) and peaked at 76.5%. Despite ventilation and treatment with IV ascorbic acid and oral methylene blue, cyanosis persisted and she died 4 days after admission (Gupta et al, 2012).
    B) DERMATITIS
    1) WITH POISONING/EXPOSURE
    a) Nitrobenzene induced mild skin irritation in the rabbit in the Standard Draize Test (RTECS , 1991).

Reproductive

    3.20.1) SUMMARY
    A) Nitrobenzene is a possible animal teratogen.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) In rat studies, fetal death and developmental abnormalities were observed (RTECS , 1991).
    2) Nitrobenzene was reported to cause birth defects and alterations in the placenta when rats were given a dose of 125 mg/kg/day (HSDB , 2000).
    3.20.3) EFFECTS IN PREGNANCY
    A) SUMMARY
    1) Nitrobenzene has been mentioned in review articles as being particularly toxic during pregnancy (Josephson, 1980; Kuntz, 1976; Anon, 1976), possibly because of its ability to induce methemoglobinemia.
    2) At the time of this review, no original studies were found on the possible reproductive effects of nitrobenzene in humans. There was one report of fibrotic changes in the placenta and chorionic tissues, but mixed exposure with other chemicals was involved (Ferster, 1970).
    3) Nitrobenzene was previously used to induce abortions, but the practice was discontinued because it seemed to be equally toxic to the mother as to the fetus (Van Oettingen WF, 1941).
    B) METHEMOGLOBINEMIA
    1) Infants (and presumably the fetus) are extremely susceptible to developing methemoglobinemia following nitrobenzene exposure. There are several reports of poisoning of infants following dermal absorption of nitrobenzene-containing laundry marking ink from diapers (Zeligs, 1929).
    2) In twin infants, methemoglobinemia was produced by inhaling vapors of a disinfectant containing nitrobenzene; exposed adults did not develop cyanosis (Stevens, 1928).
    3) Fetal hemoglobin is more readily oxidized to methemoglobin than the adult form, and is more slowly reduced back to normal hemoglobin (Mansouri, 1985). Also, the fetus may be more susceptible to reductions in oxygen transport than the adult.
    C) PLACENTAL BARRIER
    1) Whether nitrobenzene can cross the placenta is unknown, however it is highly lipid-soluble and placental penetration may be expected to occur.
    D) ANIMAL STUDIES
    1) Pre-implantation mortality was an observed toxic effect on fertility in female rats (RTECS , 1991).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS98-95-3 (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: Nitrobenzene
    b) Carcinogen Rating: 2B
    1) The agent (mixture) is possibly carcinogenic to humans. The exposure circumstance entails exposures that are possibly carcinogenic to humans. This category is used for agents, mixtures and exposure circumstances for which there is limited evidence of carcinogenicity in humans and less than sufficient evidence of carcinogenicity in experimental animals. It may also be used when there is inadequate evidence of carcinogenicity in humans but there is sufficient evidence of carcinogenicity in experimental animals. In some instances, an agent, mixture or exposure circumstance for which there is inadequate evidence of carcinogenicity in humans but limited evidence of carcinogenicity in experimental animals together with supporting evidence from other relevant data may be placed in this group.
    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, no studies were found on the possible carcinogenic activity of nitrobenzene in humans.
    3.21.4) ANIMAL STUDIES
    A) NEOPLASM
    1) Pulmonary and thyroid tumors were seen in mice and rats, and liver tumors in female mice in chronic inhalation studies (Cattley et al, 1994).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Plasma nitrobenzene levels are not clinically useful.
    B) Determine methemoglobin levels in all cyanotic patients. Cyanosis generally occurs when the plasma methemoglobin levels exceed 15%.
    4.1.2) SERUM/BLOOD
    A) HEMATOLOGY
    1) Monitor methemoglobin level in patients who are cyanotic and/or symptomatic.
    2) Monitor arterial blood gases in patients with methemoglobinemia or respiratory distress. Pulse oximetry may be unreliable in patients with methemoglobinemia, particularly if methylene blue has been administered.
    B) SERUM CHEMISTRY
    1) Monitor serum electrolytes in patients with severe symptoms or methemoglobinemia.

Methods

    A) OTHER
    1) The urine is dark in color and the blood may be a chocolate color from the present of methemoglobin. Urine and vomitus may have the odor of oil of bitter almonds.
    2) Analysis of plasma for methemoglobin concentration should be available at all hospitals; results may be expressed as grams of methemoglobin or as a percentage (percent of total hemoglobin that has been converted to methemoglobin).
    a) To calculate percent methemoglobin, determine the ratio of methemoglobin (metHb)/hemoglobin (Hb) in grams - eg, if metHb = 3 g/dL of blood and Hb = 12 g/dL of blood, then 3/12 X 100 = 25 percent methemoglobinemia. Patients with greater than 30 percent are usually symptomatic.
    3) METHEMOGLOBIN LEVELS WILL BE REDUCED - by endogenous methemoglobin reductase if blood is not analyzed rapidly (few hours).
    4) INITIAL BEDSIDE DETERMINATION - can be made by placing a drop of blood on filter paper with a control drop of blood nearby. If the methemoglobinemia is greater than 15 percent the blood will have a chocolate brown color in comparison with the control blood.
    B) MULTIPLE ANALYTICAL METHODS
    1) Confirmation of exposure to nitrobenzene can be made by gas chromatographic analysis of expired air collected in a saran bag.
    2) Nitrobenzene itself may be measured by infrared spectrophotometry, ultraviolet spectrophotometry, gas chromatography, or high pressure liquid chromatography (Snyder, 1990).
    3) Nitrobenzene concentration in blood was determined by gas chromatography with flame ionization detection and confirmed by GC-MS in one fatal case(Martinez et al, 2003).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Plasma nitrobenzene levels are not clinically useful.
    B) Determine methemoglobin levels in all cyanotic patients. Cyanosis generally occurs when the plasma methemoglobin levels exceed 15%.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) EMESIS/NOT RECOMMENDED
    1) EMESIS: Ipecac-induced emesis is not recommended because of the potential for CNS depression and seizures.
    B) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) EMESIS/NOT RECOMMENDED
    1) EMESIS: Ipecac-induced emesis is not recommended because of the potential for CNS depression and seizures.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    C) GASTRIC LAVAGE
    1) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).
    a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.
    2) PRECAUTIONS:
    a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
    b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.
    3) LAVAGE FLUID:
    a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
    b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
    c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.
    4) COMPLICATIONS:
    a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
    b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).
    5) CONTRAINDICATIONS:
    a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.
    6.5.3) TREATMENT
    A) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    B) 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.

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.
    D) Persistent cyanosis in spite of oxygen treatment is consistent with methemoglobinemia.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DERMAL DECONTAMINATION
    1) Remove contaminated clothing immediately.
    2) 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).

Enhanced Elimination

    A) EXCHANGE TRANSFUSION
    1) Exchange transfusion may be considered in patients with significant symptoms and high levels of methemoglobin not responsive to methylene blue administration.

Abstracts

Case Reports

    A) ADULT
    1) A 19-year-old chemistry student presented with unconsciousness and severe cyanosis after ingesting 5 to 20 mL of a brown liquid. Serum methemoglobin was found to be 65 percent. Lavage, intravenous bicarbonate, ascorbic acid, and methylene blue therapy were instituted with limited success.
    a) Exchange transfusion was performed for six hours for rapid reduction of methemoglobin levels. This resulted in a reduction of serum methemoglobin to 25 percent. The patient made a gradual, uneventful recovery over the next 19 days.
    b) Analysis of gastric aspirate revealed the presence of aniline and nitrobenzene (Harrison, 1977).

Range Of Toxicity

Summary

    A) Insufficient data to assess the minimal toxic dose.
    B) The estimated mean lethal adult dose is about 1 to 5 grams. Neonates, infants and young children may be more susceptible.

Minimum Lethal Exposure

    A) GENERAL/SUMMARY
    1) The mean lethal oral dose in humans is not known, but has been estimated as 1 to 5 grams (Gosselin et al, 1984). Children may be more susceptible.

Maximum Tolerated Exposure

    A) ADULT
    1) Exposure of 6 ppm has caused symptoms of methemoglobinemia (ACGIH, 1991).
    2) An air concentration of 1 ppm generally is considered a no-observed-adverse-effect level (ACGIH, 1991).
    B) ROUTE OF EXPOSURE
    1) Inhalation of 200 ppm for one hour was reported to be the maximum concentration to not result in serious toxicity (ACGIH, 1986).
    2) Acute ingestion of 50 mL resulted in a methemoglobin level of 82% with cyanosis and coma (Myslak et al, 1971).
    C) ACUTE
    1) TDLo (ORAL) WOMAN - 200 mg/kg
    2) LDLo (Unreported) MAN - 35 mg/kg
    3)
    a) References RTECS, 1991

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) OCCUPATIONAL
    a) Workers exposed daily for 8 hours at average air concentrations of 19 mg/m(3) developed blood methemoglobin levels averaging 4.3% (Pacseri et al, 1958).
    b) OVERDOSE
    1) CASE REPORT - An 82-year-old man who died after ingesting approximately 250 mL of a nitrobenzene solvent over 24 hours, had a blood nitrobenzene concentration of 3.2 micrograms/mL 48 hours after ingestion. He developed severe methemoglobinemia (70% methemoglobin), anuric renal failure, hypoxic ischemic encephalopathy, and refractory shock and died 3 days after presentation (Martinez et al, 2003).

Workplace Standards

    A) ACGIH TLV Values for CAS98-95-3 (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) Nitrobenzene
    a) TLV:
    1) TLV-TWA: 1 ppm
    2) TLV-STEL:
    3) TLV-Ceiling:
    b) Notations and Endnotes:
    1) Carcinogenicity Category: A3
    2) Codes: BEI, Skin
    3) Definitions:
    a) A3: Confirmed Animal Carcinogen with Unknown Relevance to Humans: The agent is carcinogenic in experimental animals at a relatively high dose, by route(s) of administration, at site(s), of histologic type(s), or by mechanism(s) that may not be relevant to worker exposure. Available epidemiologic studies do not confirm an increased risk of cancer in exposed humans. Available evidence does not suggest that the agent is likely to cause cancer in humans except under uncommon or unlikely routes or levels of exposure.
    b) BEI: The BEI notation is listed when a BEI is also recommended for the substance listed. Biological monitoring should be instituted for such substances to evaluate the total exposure from all sources, including dermal, ingestion, or non-occupational.
    c) Skin: This refers to the potential significant contribution to the overall exposure by the cutaneous route, including mucous membranes and the eyes, either by contact with vapors or, of likely greater significance, by direct skin contact with the substance. It should be noted that although some materials are capable of causing irritation, dermatitis, and sensitization in workers, these properties are not considered relevant when assigning a skin notation. Rather, data from acute dermal studies and repeated dose dermal studies in animals or humans, along with the ability of the chemical to be absorbed, are integrated in the decision-making toward assignment of the skin designation. Use of the skin designation provides an alert that air sampling would not be sufficient by itself in quantifying exposure from the substance and that measures to prevent significant cutaneous absorption may be warranted. Please see "Definitions and Notations" (in TLV booklet) for full definition.
    c) TLV Basis - Critical Effect(s): MeHb-emia
    d) Molecular Weight: 123.11
    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 CAS98-95-3 (National Institute for Occupational Safety and Health, 2007):
    1) Listed as: Nitrobenzene
    2) REL:
    a) TWA: 1 ppm (5 mg/m(3))
    b) STEL:
    c) Ceiling:
    d) Carcinogen Listing: (Not Listed) Not Listed
    e) Skin Designation: [skin]
    1) Indicates the potential for dermal absorption; skin exposure should be prevented as necessary through the use of good work practices and gloves, coveralls, goggles, and other appropriate equipment.
    f) Note(s):
    3) IDLH:
    a) IDLH: 200 ppm
    b) Note(s): Not Listed

    C) Carcinogenicity Ratings for CAS98-95-3 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): A3 ; Listed as: Nitrobenzene
    a) A3 :Confirmed Animal Carcinogen with Unknown Relevance to Humans: The agent is carcinogenic in experimental animals at a relatively high dose, by route(s) of administration, at site(s), of histologic type(s), or by mechanism(s) that may not be relevant to worker exposure. Available epidemiologic studies do not confirm an increased risk of cancer in exposed humans. Available evidence does not suggest that the agent is likely to cause cancer in humans except under uncommon or unlikely routes or levels of exposure.
    2) EPA (U.S. Environmental Protection Agency, 2011): Likely to be carcinogenic to humans (Combined route) ; Listed as: Nitrobenzene
    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): 2B ; Listed as: Nitrobenzene
    a) 2B : The agent (mixture) is possibly carcinogenic to humans. The exposure circumstance entails exposures that are possibly carcinogenic to humans. This category is used for agents, mixtures and exposure circumstances for which there is limited evidence of carcinogenicity in humans and less than sufficient evidence of carcinogenicity in experimental animals. It may also be used when there is inadequate evidence of carcinogenicity in humans but there is sufficient evidence of carcinogenicity in experimental animals. In some instances, an agent, mixture or exposure circumstance for which there is inadequate evidence of carcinogenicity in humans but limited evidence of carcinogenicity in experimental animals together with supporting evidence from other relevant data may be placed in this group.
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed ; Listed as: Nitrobenzene
    5) MAK (DFG, 2002): Category 3B ; Listed as: Nitrobenzene
    a) Category 3B : Substances for which in vitro or animal studies have yielded evidence of carcinogenic effects that is not sufficient for classification of the substance in one of the other categories. Further studies are required before a final decision can be made. A MAK value can be established provided no genotoxic effects have been detected. (Footnote: In the past, when a substance was classified as Category 3 it was given a MAK value provided that it had no detectable genotoxic effects. When all such substances have been examined for whether or not they may be classified in Category 4, this sentence may be omitted.)
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): R ; Listed as: Nitrobenzene
    a) R : RAHC = Reasonably anticipated to be a human carcinogen

    D) OSHA PEL Values for CAS98-95-3 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Listed as: Nitrobenzene
    2) Table Z-1 for Nitrobenzene:
    a) 8-hour TWA:
    1) ppm: 1
    a) Parts of vapor or gas per million parts of contaminated air by volume at 25 degrees C and 760 torr.
    2) mg/m3: 5
    a) Milligrams of substances per cubic meter of air. When entry is in this column only, the value is exact; when listed with a ppm entry, it is approximate.
    3) Ceiling Value:
    4) Skin Designation: Yes
    5) Notation(s): Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) References: RTECS, 2000 OHM/TADS, 2000
    1) LD50- (ORAL)MOUSE:
    a) 590 mg/kg
    2) LD50- (INTRAPERITONEAL)RAT:
    a) 640 mg/kg -- Behavioral, Liver, Kidney, Ureter, Bladder
    3) LD50- (ORAL)RAT:
    a) 640 mg/kg (OHM/TADS, 2000)
    4) LD50- (SKIN)RAT:
    a) 2100 mg/kg

Pharmacology Toxicology

Toxicologic Mechanism

    A) METHEMOGLOBINEMIA -
    1) Nitrobenzene causes methemoglobin formation and is a central nervous system depressant (Harbison, 1998). Although the formation of methemoglobinemia by nitrobenzene occurs more slowly than with aniline, dinitrobenzene, or nitroaniline, cyanosis is more persistent. Toxicity may also include sulfhemoglobin formation.
    2) The basic mechanism in methemoglobin formation is the oxidation (loss of electrons) of ferrous (Fe+2) hemoglobin to form its ferric (Fe+3) derivative, methemoglobin (Finkel, 1983).
    3) While oxygen binds to methemoglobin, it is so firmly attached that it is not available to tissues. Consequently, it is unable to transport oxygen, and hypoxia results (Finkel, 1983).
    4) However, methemoglobin also causes a "left shift" of the oxyhemoglobin dissociation curve so that it interferes with the release of oxygen from normal hemoglobin (Braunwald et al, 1987). Consequently, hypoxia may be more severe than methemoglobin levels might suggest (Finkel, 1983).

Physicochemical

Physical Characteristics

    A) Nitrobenzene is an oily liquid, clear or pale yellow to dark brown in color. It has an almond odor (AAR, 1998; (Budavari, 1996).

Molecular Weight

    A) 123.11 (Budavari, 1996)

References

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