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NITROGEN TRIFLUORIDE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Nitrogen trifluoride is used as a fluoride source in the electronics industry, an oxidizer for high energy fuels and in chemical synthesis. This chemical substance is defined as the gaseous form of Nitrogen Trifluoride also known as nitrogen fluoride. Information regarding tetrafluorohydrazine will not be discussed.

Specific Substances

    A) No Synonyms were found in group or single elements
    1.2.1) MOLECULAR FORMULA
    1) F3-N NF3

Available Forms Sources

    A) FORMS
    1) Nitrogen trifluoride is available as an etchant grade (99.5%) and a technical grade (98%) (HSDB, 2002).
    B) SOURCES
    1) The electrolysis of molten ammonium bifluoride in the presence of an electrical discharge will produce nitrogen trifluoride (HSDB, 2002).
    2) Nitrogen trifluoride is prepared by electrolysis from melted ammonium acid fluoride (Budavari, 2000; Lewis, 1997a).
    C) USES
    1) Nitrogen trifluoride's principal use is as a fluorine source in the electronics industry and for high-energy chemical lasers. It is also used in the production of perfluoroammonium salts, as an oxidizing agent in rocketry and high energy fuels, in plasma etching of semiconductor materials, organic synthesis, and a gas filler to increase the life and brightness of lamps (CGA, 1999; HSDB, 2002; ITI, 1995; 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) Nitrogen trifluoride may be irritating to the eyes, skin, and mucous membranes. The primary toxic effect of nitrogen trifluoride is methemoglobinemia. Signs and symptoms of exposure may include weakness, dizziness, headache, and cyanosis.
    B) Liver and kidney injury, incoordination, collapse, and seizures have occurred in experimental animals.
    C) No human clinical experience with nitrogen trifluoride was located at the time of this review.
    0.2.4) HEENT
    A) Dogs exposed to 9600 ppm for 60 minutes developed slight eye irritation (Hathaway et al, 1996).
    0.2.5) CARDIOVASCULAR
    A) Hypotension may occur secondary to anoxia.
    0.2.6) RESPIRATORY
    A) Cyanosis, most likely due to methemoglobinemia, was reported in animal studies.
    B) Tachypnea and dyspnea are other possible effects.
    0.2.7) NEUROLOGIC
    A) Seizures and CNS depression were reported in animals most likely secondary to anoxia from methemoglobinemia.
    0.2.9) HEPATIC
    A) Slight hepatic histologic changes were noted in animals exposed to toxic doses via chronic inhalation.
    0.2.10) GENITOURINARY
    A) Slight histologic changes were noted in rats given toxic doses via chronic inhalation.
    0.2.13) HEMATOLOGIC
    A) Methemoglobinemia has been reported in several animal species after inhalation.

Laboratory Monitoring

    A) Monitor blood for methemoglobinemia. If the patient is cyanotic, obtain CBC, electrolytes, and arterial blood gases with measured oxygen saturation and methemoglobin levels.

Treatment Overview

    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) METHEMOGLOBINEMIA
    1) Oxygen should be administered to all cyanotic patients. Cyanosis secondary to methemoglobinemia will not respond to oxygen therapy.
    2) 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.
    3) 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.
    4) 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.
    C) 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.
    D) HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid. If hypotension persists, administer dopamine (5 to 20 mcg/kg/min) or norepinephrine (ADULT: begin infusion at 0.5 to 1 mcg/min; CHILD: begin infusion at 0.1 mcg/kg/min); titrate to desired response.
    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.

Range Of Toxicity

    A) No toxic level has been established in man. The TLV is 10 ppm.
    B) Animals given a single injection of 8 to 15 mg/kg of the gas became cyanotic and developed enlarged spleens.

Clinical Effects

Summary Of Exposure

    A) Nitrogen trifluoride may be irritating to the eyes, skin, and mucous membranes. The primary toxic effect of nitrogen trifluoride is methemoglobinemia. Signs and symptoms of exposure may include weakness, dizziness, headache, and cyanosis.
    B) Liver and kidney injury, incoordination, collapse, and seizures have occurred in experimental animals.
    C) No human clinical experience with nitrogen trifluoride was located at the time of this review.

Heent

    3.4.1) SUMMARY
    A) Dogs exposed to 9600 ppm for 60 minutes developed slight eye irritation (Hathaway et al, 1996).
    3.4.3) EYES
    A) IRRITATION - Dogs exposed to 9600 ppm for 60 minutes did develop some slight eye irritation (Hathaway et al, 1996).

Cardiovascular

    3.5.1) SUMMARY
    A) Hypotension may occur secondary to anoxia.
    3.5.2) CLINICAL EFFECTS
    A) HEART FAILURE
    1) Mild myocardial degeneration was noted in rats given 9 IP injections of the gas (Torkelson et al, 1962).
    B) HYPOTENSIVE EPISODE
    1) Hypotension may occur secondary to anoxia.

Respiratory

    3.6.1) SUMMARY
    A) Cyanosis, most likely due to methemoglobinemia, was reported in animal studies.
    B) Tachypnea and dyspnea are other possible effects.
    3.6.2) CLINICAL EFFECTS
    A) CYANOSIS
    1) Cyanosis was reported in animal studies, most likely due to methemoglobinemia (ACGIH, 1991). Tachypnea and dyspnea are other likely reactions.

Neurologic

    3.7.1) SUMMARY
    A) Seizures and CNS depression were reported in animals most likely secondary to anoxia from methemoglobinemia.
    3.7.2) CLINICAL EFFECTS
    A) SEIZURE
    1) Seizures were reported in animals, most likely secondary to anoxia from methemoglobinemia (Proctor et al, 1988).
    B) CENTRAL NERVOUS SYSTEM DEFICIT
    1) CNS depression symptoms ranging from headaches and dizziness to lethargy, disorientation and syncope may occur secondary to methemoglobinemia.

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) SPLENOMEGALY
    1) Enlarged spleens were seen in animal studies (Torkelson et al, 1962) possibly due to the methemoglobinemia.

Hepatic

    3.9.1) SUMMARY
    A) Slight hepatic histologic changes were noted in animals exposed to toxic doses via chronic inhalation.
    3.9.2) CLINICAL EFFECTS
    A) LIVER DAMAGE
    1) Slight histological changes were noted in rats given toxic doses via inhalation (Torkelson et al, 1962). Repeated doses of 100 ppm for 7 hours/day, 5 days/week for 19 weeks showed hepatic damage somewhat characteristic of fluoride (ACGIH, 1991).

Genitourinary

    3.10.1) SUMMARY
    A) Slight histologic changes were noted in rats given toxic doses via chronic inhalation.
    3.10.2) CLINICAL EFFECTS
    A) ABNORMAL RENAL FUNCTION
    1) Slight histological changes were noted in rats given toxic doses by way of inhalation (Torkelson et al, 1962). Repeated doses of 100 ppm for 7 hours/day, 5 days/week for 19 weeks showed renal damage somewhat characteristic of fluorides (ACGIH, 1991).

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) ACIDOSIS
    1) Metabolic acidosis may occur if methemoglobin concentration exceeds 50%.

Hematologic

    3.13.1) SUMMARY
    A) Methemoglobinemia has been reported in several animal species after inhalation.
    3.13.2) CLINICAL EFFECTS
    A) METHEMOGLOBINEMIA
    1) Methemoglobinemia has been reported in several species of animals after inhalation (Torkelson et al, 1962). Rats exposed to 10,000 ppm for 60 to 70 minutes developed 60 to 70% methemoglobinemia (Hathaway et al, 1996).
    2) Rats inhaling 1000 ppm for 4 hours demonstrated a substantial increase in circulating methemoglobin, but this was not seen with inhalation of 3000 ppm for 10 minutes (ACGIH, 1991).
    3) Blood may become chocolate brown with concentrations greater than 15%.

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) FLUOROSIS
    1) Inhaled nitrogen trifluoride may cause fluorosis. Although one study in rats showed no significant increases of tooth and bone fluoride (ACGIH, 1991), most references still indicate that fluorosis may occur with prolonged or repeated exposures.

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS7783-54-2 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor blood for methemoglobinemia. If the patient is cyanotic, obtain CBC, electrolytes, and arterial blood gases with measured oxygen saturation and methemoglobin levels.
    4.1.2) SERUM/BLOOD
    A) HEMATOLOGIC
    1) Monitor blood for methemoglobinemia. If the patient is cyanotic, obtain CBC. Methemoglobin levels may be reduced if the blood is not analyzed rapidly (within a few hours) because of endogenous methemoglobin reductase.
    B) BLOOD/SERUM CHEMISTRY
    1) If patient is cyanotic, obtain electrolytes.
    2) Consider monitoring of blood or urinary fluoride concentrations in individuals with chronic and/or large exposures.
    C) ACID/BASE
    1) If patient is cyanotic, obtain blood gases with measured oxygen saturation and methemoglobin levels.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Monitor blood for methemoglobinemia. If the patient is cyanotic, obtain CBC, electrolytes, and arterial blood gases with measured oxygen saturation and methemoglobin levels.

Oral Exposure

    6.5.3) TREATMENT
    A) SUPPORT
    1) Ingestion is unlikely. Oral exposure to escaping gas might cause frostbite injury to the upper gastrointestinal and respiratory tracts. Administer oxygen and maintain airway as clinically indicated.

Inhalation Exposure

    6.7.1) DECONTAMINATION
    A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
    B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.
    6.7.2) TREATMENT
    A) OXYGEN
    1) Oxygen should be administered to all cyanotic patients. Cyanosis secondary to methemoglobinemia will not respond to oxygen therapy.
    2) CYANOSIS: Profound cyanosis may occur in individuals with methemoglobinemia who appear to be in no respiratory distress. The blood should be examined and compared to normal blood to identify chocolate-brown color, signifying a methemoglobin level of at least 15%.
    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.
    C) HYPERBARIC OXYGEN THERAPY
    1) If the patient is not responsive to methylene blue, hyperbaric oxygen may be considered while preparations are made to perform exchange transfusion.
    D) 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).
    E) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    F) MONITORING OF PATIENT
    1) Monitor all patients for potential liver and kidney damage.
    G) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Eye Exposure

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

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DERMAL DECONTAMINATION
    1) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Enhanced Elimination

    A) EXCHANGE TRANSFUSION
    1) Should be done immediately in children if the methemoglobinemia is not responsive to methylene blue and is progressing in a symptomatic individual. The mortality rate from methemoglobin levels greater than 70% is high and exchange transfusion should be considered if levels approach this figure and cannot be controlled by the use of methylene blue.

Range Of Toxicity

Summary

    A) No toxic level has been established in man. The TLV is 10 ppm.
    B) Animals given a single injection of 8 to 15 mg/kg of the gas became cyanotic and developed enlarged spleens.

Minimum Lethal Exposure

    A) ADULT
    1) Fatality may occur when methemoglobin levels are about 85-90% (Hathaway et al, 1996).
    B) ANIMAL DATA
    1) 87% of the rats died after an exposure to nitrogen trifluoride at 10,000 ppm for 60-70 minutes (ACGIH, 1991; Hathaway et al, 1996; HSDB , 2002).
    2) Rats died after a single exposure of nitrogen trifluoride for 4 hours at 2500 ppm (ACGIH, 1991; HSDB , 2002).
    3) 80% of the total hemoglobin was found as methemoglobin in lethal exposures (HSDB , 2002).
    4) Animals given 8 to 15 mg/kg became cyanotic and developed enlarged spleens (Torkelson et al, 1962).

Maximum Tolerated Exposure

    A) ADULT
    1) No reports of nitrogen trifluoride intoxication are available (Hathaway et al, 1996).
    2) Methemoglobin levels of 70% may cause coma in humans (Hathaway et al, 1996).
    B) ANIMAL DATA
    1) Dogs survived after an exposure to nitrogen trifluoride at 9600 ppm for 60 minutes, but had decreased hematocrit, decreased hemoglobin levels, reduced red blood cell count, Heinz body anemia, and clinical signs consistent with anoxia due to methemoglobin formation (ACGIH, 1991; Hathaway et al, 1996).
    2) Inhalation of 3000 ppm of nitrogen trifluoride for 10 minutes had no effect on rats, but at 2500 pm for 4 hours fatalities were commonplace (ACGIH, 1991; HSDB , 2002).
    3) Daily repeated seven-hour exposures of rats at 100 ppm for 19 weeks resulted in mild to moderate pathologic changes in the liver and kidneys. Significant effect on the spleen, as in acute exposure, was not reported. Possible evidence of fluorosis was seen in the kidneys only and not in the teeth or bones (ACGIH, 1991; Hathaway et al, 1996).

Workplace Standards

    A) ACGIH TLV Values for CAS7783-54-2 (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) Nitrogen trifluoride
    a) TLV:
    1) TLV-TWA: 10 ppm
    2) TLV-STEL:
    3) TLV-Ceiling:
    b) Notations and Endnotes:
    1) Carcinogenicity Category: Not Listed
    2) Codes: BEI(M)
    3) Definitions:
    a) BEI(M): 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. Substances identified as Methemoglobin Inducers (for which methemoglobin is the principal cause of toxicity) are part of this notation.
    c) TLV Basis - Critical Effect(s): MeHB-emia; liver and kidney dam
    d) Molecular Weight: 71
    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 CAS7783-54-2 (National Institute for Occupational Safety and Health, 2007):
    1) Listed as: Nitrogen trifluoride
    2) REL:
    a) TWA: 10 ppm (29 mg/m(3))
    b) STEL:
    c) Ceiling:
    d) Carcinogen Listing: (Not Listed) Not Listed
    e) Skin Designation: Not Listed
    f) Note(s):
    3) IDLH:
    a) IDLH: 1000 ppm
    b) Note(s): Not Listed

    C) Carcinogenicity Ratings for CAS7783-54-2 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed ; Listed as: Nitrogen trifluoride
    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): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed ; Listed as: Nitrogen trifluoride
    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 CAS7783-54-2 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Listed as: Nitrogen trifluoride
    2) Table Z-1 for Nitrogen trifluoride:
    a) 8-hour TWA:
    1) ppm: 10
    a) Parts of vapor or gas per million parts of contaminated air by volume at 25 degrees C and 760 torr.
    2) mg/m3: 29
    a) Milligrams of substances per cubic meter of air. When entry is in this column only, the value is exact; when listed with a ppm entry, it is approximate.
    3) Ceiling Value:
    4) Skin Designation: No
    5) Notation(s): Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) References: RTECS, 2002
    1) LD50- (INTRAPERITONEAL)RAT:
    a) 26 mg/kg -- methomoglobinemia; carboxyhemoglobin
    2) TCLo- (INHALATION)RAT:
    a) 100 ppm for 6H/2W-intermittent -- normocytic anemia

Pharmacology Toxicology

Toxicologic Mechanism

    A) Nitrogen trifluoride is a potent oxidizer. In the body it oxidizes hemoglobin to methemoglobin.

Physicochemical

Physical Characteristics

    A) Nitrogen trifluoride is a colorless gas. Pure samples have little odor, but traces of active fluorides can render a pungent, moldy odor. The chemical solidifies at -206.8 degrees C (HSDB , 2002; Lewis, 2000; NIOSH , 2002).
    B) At 250 degrees C (482 degrees F) its reactivity is similar to oxygen (CGA, 1999).
    C) "At higher temperatures, its reactivity is similar to fluorine owing to appreciable dissociation into NF2 and F-." The peak temperature ranges from 1100-1500 (CGA, 1999).

Molecular Weight

    A) 71.00

Other

    A) ODOR THRESHOLD
    1) 500 ppm (ACGIH, 1991)

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