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HYDRAZINES

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Hydrazine is an inorganic nitrogen compound. Hydrazines have a variety of industrial applications including polymer chemistry, rocket fuels, and power plant regulation.

Specific Substances

    A) Hydrazine
    1) CAS 302-01-2
    1,1-dimethylhydrazine
    1) UDMH
    2) 1,1-unsymmetrical di-methyl hydrazine
    Monomethyl hydrazine
    1) MMH
    1,2-dimethylhydrazine
    1) SDMH
    GENERAL TERMS
    1) HYDRAZINE
    2) DIAMIDE
    3) DIAMINE
    4) HYDRAZINE, ANHYDROUS
    5) HYDRAZINE, AQUEOUS SOLUTIONS
    6) HYDRAZINE, AQUEOUS SOLUTIONS with more than 64% hydrazine, by weight
    7) HYDRAZINE BASE
    8) HYDRAZYNA (Polish)
    9) NITROGEN HYDRIDE
    10) LEVOXINE
    11) OXYTREAT 35
    12) MONOMETHYL HYDRAZINE
    13) HYDRAZOMETHANE (CAS 60-34-4)
    14) DMH (DIMETHYLHYDRAZINE)
    15) HYDRAZINECABOTHIOAMIDE

    1.2.1) MOLECULAR FORMULA
    1) H4-N2

Available Forms Sources

    A) USES
    1) Hydrazine is used as a high-energy rocket propellant, in jet fuel, and in fuel cells. It is also used as a reducing agent for many elements; as a corrosion inhibitor in boiler water and reactor cooling water; in wastewater treatment and nuclear fuel reprocessing; and in electroplating (ITI, 1988; Lewis, 1993). Hydrazines are also used in the manufacture of certain drugs, dyes, photographic supplies, textile treatments, and in silvering of mirrors and plastics (Zelnick et al, 2003; Kauppinen et al, 1989).
    2) Hydrazine sulfate, which may influence carbohydrate metabolism, has been evaluated in clinical drug trials for its effects on anorexia and cachexia of advanced cancers, with disappointing results (Watanabe & Bruera, 1996).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Hydrazines have a variety of industrial applications including polymer chemistry, rocket fuels, and power plant regulation.
    B) TOXICOLOGY: Hydrazines inhibit pyridoxine kinase and to a lesser extent, glutamic acid decarboxylase resulting in decreased production of the GABA neurotransmitter. Hydrazine exposure can cause refractory seizures, hepatotoxicity, hemolysis, and skin/mucosal irritation.
    C) EPIDEMIOLOGY: Hydrazine exposure is rare and usually occurs in an industrial or laboratory setting. Death is rare in hydrazine exposure although prolonged hepatic injury has been reported.
    D) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Acute small volume/low concentration exposures have resulted in nausea, vomiting, anorexia, abdominal pain, local irritation, and CNS depression. Acute exposure to hydrazine can cause trembling, twitching, clonic movements, hyperactive reflexes, restlessness, ataxia, hypesthesia of the hands, paresthesias of the arms and legs, confusion, and lethargy. Hydrazine vapors are very irritating to mucous membranes. Hypersensitivity reactions have also been reported with dermal exposures. Chronic inhalational exposure in workers has resulted in a variety of gastrointestinal, skin, eyes, and pulmonary complaints. No evidence of increased morbidity or mortality in a series of 427 hydrazine plant workers followed for 47 years.
    2) SEVERE TOXICITY: Acute exposures can result in seizures metabolic acidosis, methemoglobinemia, hypotension, gastrointestinal hemorrhage, coma, and death. Hydrazine is hepatotoxic. Chronic exposure can result in hepatic encephalopathy. Pulmonary edema can occur after inhalational exposure. Dermal exposures to concentrated solutions can result in severe burns. Ocular exposures can result in corneal injury and temporary blindness.
    0.2.3) VITAL SIGNS
    A) WITH THERAPEUTIC USE
    1) Fever has been reported.
    0.2.20) REPRODUCTIVE
    A) Hydrazine has been embryotoxic and fetotoxic in rats and mice, but at doses which were also toxic to the mothers. There is no evidence that hydrazine is a human reproductive hazard, but data are lacking.
    0.2.21) CARCINOGENICITY
    A) Hydrazine has been carcinogenic in rats, mice, and hamsters and is a suspected human carcinogen. Limited epidemiological evidence suggests that occupational exposure does not increase the risk of cancer, however.

Laboratory Monitoring

    A) Monitor vital signs and mental status.
    B) Monitor serum electrolytes, CBC, pH, lactate concentration, renal function, and liver enzymes.
    C) A chest x-ray should be obtained in patients with pulmonary symptoms.
    D) Hydrazines can induce methemoglobinemia, which may not be apparent for several days. Monitor methemoglobin levels.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Remove from exposure. Remove contaminated clothing and decontaminate skin with irrigation if dermal exposure occurs. No data to suggest gastrointestinal decontamination in ingestion. Irrigate eyes with water or normal saline following ocular exposure. Topical hypersensitivity reactions should be treated with antihistamines and corticosteroids.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Administer pyridoxine 25 mg/kg IM or IV plus a benzodiazepine for seizures. Repeat as necessary, up to 5 g of pyridoxine has been given. For inhalational exposures with symptoms, provide 100% oxygen with assisted ventilation as needed. Bronchospasm should be treated with inhaled beta2-agonist and a corticosteroid.
    C) DECONTAMINATION
    1) PREHOSPITAL: Remove from exposure. Remove contaminated clothing and flush skin with water. Irrigate exposed eyes with water or saline.
    2) HOSPITAL: Remove contaminated clothing and flush skin with water. Irrigate exposed eyes with water or saline. It is unknown if activated charcoal is effective, but it can be considered for patients with a protected airway presenting soon after exposure.
    D) AIRWAY MANAGEMENT
    1) Airway management may be required for patients in status epilepticus or patients with severe pulmonary symptoms. Intubate the patient prophylactically to facilitate GI decontamination in the asymptomatic or mildly symptomatic patients.
    E) ANTIDOTE
    1) Pyridoxine 25 mg/kg IM or IV given in conjunction with a benzodiazepine has been shown to successfully treat seizures, CNS depression, and lactic acidosis associated with hydrazine exposure. Repeat as necessary, up to 5 g of pyridoxine has been given. Adverse effects in acute dosing are rare. CNS depression may occur if greater than 5 g of pyridoxine is given using 1 mL vials due to the presence of the diluent chlorobutanol. Chronic pyridoxine use can result in peripheral neuropathy.
    F) METHEMOGLOBINEMIA
    1) Initiate oxygen therapy. Treat with methylene blue if patient is symptomatic (usually at methemoglobin concentrations greater than 20% to 30% or at lower concentrations in patients with anemia, underlying pulmonary or cardiovascular disease). 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) ENHANCED ELIMINATION
    1) Hemodialysis may be effective, but little human data exists. Most patients recover with pyridoxine and symptomatic and supportive care.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: Dermal exposures without burns can be watched at home if they are rapidly and adequately decontaminated.
    2) OBSERVATION CRITERIA: Patients with gastrointestinal or pulmonary symptoms should be observed until asymptomatic. Any patient with hydrazine ingestion should be referred to a healthcare facility for evaluation.
    3) ADMISSION CRITERIA: Patients with CNS symptoms or persistent pulmonary or gastrointestinal symptoms should be admitted. Patients who are seizure free for 12 hours are safe to discharge.
    4) CONSULT CRITERIA: Consult a toxicologist for patients with CNS symptoms, acidosis, or severe pulmonary symptoms.
    I) PITFALLS
    1) Failure to consider hydrazine exposure in a patient with refractory seizure.
    J) PHARMACOKINETICS
    1) Absorption is rapid. Dermal exposure is unlikely to result in systemic symptoms, but severe local injury can occur. Inhalational exposure can cause both pulmonary and systemic symptoms, including hepatic injury. Seizure is unlikely in acute or chronic pulmonary exposure.
    K) DIFFERENTIAL DIAGNOSIS
    1) Dermal, pulmonary, and nonspecific systemic complaints are common with many occupational exposures. Refractory seizure can result from Gyromitra spp. exposure, cyanide toxicity, and alcohol or benzodiazepine withdrawal. Hepatoxicity with refractory seizure is also consistent with isoniazid toxicity.
    0.4.3) INHALATION EXPOSURE
    A) INHALATION: Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm.
    0.4.4) EYE EXPOSURE
    A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) Hydrazine can SPONTANEOUSLY IGNITE upon contact with cloth; clothing should be removed immediately.
    2) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Range Of Toxicity

    A) TOXICITY: A mouthful caused confusion and hepatotoxicity. TLV-TWA is 0.01 ppm, 50 ppm is considered immediately dangerous to life and health. ATSDR an intermediate inhalation Minimal Risk Level (MRL) of 0.004 ppm (0.005 mg/m(3)).
    B) A man developed fatal hepatic encephalopathy, renal failure, profound coagulopathy and severe gastrointestinal hemorrhage within 3 to 4 months of taking hydrazine sulfate (180 mg/day).

Clinical Effects

Summary Of Exposure

    A) USES: Hydrazines have a variety of industrial applications including polymer chemistry, rocket fuels, and power plant regulation.
    B) TOXICOLOGY: Hydrazines inhibit pyridoxine kinase and to a lesser extent, glutamic acid decarboxylase resulting in decreased production of the GABA neurotransmitter. Hydrazine exposure can cause refractory seizures, hepatotoxicity, hemolysis, and skin/mucosal irritation.
    C) EPIDEMIOLOGY: Hydrazine exposure is rare and usually occurs in an industrial or laboratory setting. Death is rare in hydrazine exposure although prolonged hepatic injury has been reported.
    D) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Acute small volume/low concentration exposures have resulted in nausea, vomiting, anorexia, abdominal pain, local irritation, and CNS depression. Acute exposure to hydrazine can cause trembling, twitching, clonic movements, hyperactive reflexes, restlessness, ataxia, hypesthesia of the hands, paresthesias of the arms and legs, confusion, and lethargy. Hydrazine vapors are very irritating to mucous membranes. Hypersensitivity reactions have also been reported with dermal exposures. Chronic inhalational exposure in workers has resulted in a variety of gastrointestinal, skin, eyes, and pulmonary complaints. No evidence of increased morbidity or mortality in a series of 427 hydrazine plant workers followed for 47 years.
    2) SEVERE TOXICITY: Acute exposures can result in seizures metabolic acidosis, methemoglobinemia, hypotension, gastrointestinal hemorrhage, coma, and death. Hydrazine is hepatotoxic. Chronic exposure can result in hepatic encephalopathy. Pulmonary edema can occur after inhalational exposure. Dermal exposures to concentrated solutions can result in severe burns. Ocular exposures can result in corneal injury and temporary blindness.

Vital Signs

    3.3.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Fever has been reported.
    3.3.3) TEMPERATURE
    A) WITH POISONING/EXPOSURE
    1) Acute exposure to hydrazine can cause fever (Makarovsky et al, 2008).

Heent

    3.4.2) HEAD
    A) WITH POISONING/EXPOSURE
    1) EDEMA: Facial edema may occur (Durant & Harris, 1980).
    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) Acute exposure to hydrazine can cause eye irritation, conjunctivitis, miosis followed by mydriasis, cornea injury, and temporary blindness. Chronic exposure can result in lateral nystagmus (Makarovsky et al, 2008).
    2) CONJUNCTIVITIS: Liquids may cause severe eye damage (Comstock et al, 1954). Severe facial edema (Durant & Harris, 1980) conjunctivitis (Sotaniemi et al, 1971) have been reported.
    3) MIOSIS: Alternating with reactive mydriasis was reported in a dermal exposure to 1,1 dimethylhydrazine (Dhennin et al, 1988).
    3.4.5) NOSE
    A) WITH POISONING/EXPOSURE
    1) RHINITIS: Vapors may cause rhinitis (Makarovsky et al, 2008; ACGIH, 1986).
    3.4.6) THROAT
    A) WITH POISONING/EXPOSURE
    1) SALIVATION may occur in both humans and animals.
    2) SORE THROAT and cough may be seen (Richter et al, 1992).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) CARDIOVASCULAR FINDING
    1) WITH POISONING/EXPOSURE
    a) Acute exposure to hydrazine can cause hypotension and possibly heart failure. Chronic exposure can result in atrial fibrillation, enlargement of the heart, degeneration of heart muscle fibers (Makarovsky et al, 2008).
    B) HYPOTENSIVE EPISODE
    1) Acute exposure to hydrazine can cause hypotension (Makarovsky et al, 2008).
    2) The hypotension is believed to be caused by both direct and indirect effects on smooth muscle (Murtha & Wills, 1953).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) RESPIRATORY FINDING
    1) WITH POISONING/EXPOSURE
    a) Acute exposure to hydrazine can cause nose and throat irritation, rhinorrhea, increased salivation, laryngitis, tachypnea, cough, wheezing, dyspnea, chemical pneumonitis, cyanosis, and acute lung injury. Chronic exposure can result in tracheitis, destruction of bronchial mucosa, and bronchitis (Makarovsky et al, 2008).
    b) Pulmonary irritation is present when workers are exposed to spills. Dyspnea and choking can occur hundreds of yards from spills of dimethylhydrazine (Shook & Cowart, 1957).
    c) CASE SERIES: After an F-16 aircraft pilot accidentally activated the emergency power units (EPU) containing a mixture of 70% hydrazines and 30% water, 11 ground crew members of an Air National Guard unit developed respiratory symptoms (cough, dyspnea, chest discomfort) and mucous membrane irritation. The crew members were exposed to the exhaust products (ammonia, hydrogen, and nitrogen gases, and small amounts of unburned hydrazine, water, aniline, and carbon dioxide) generated by catalytic decomposition of hydrazine and water. Five patients were evaluated; four of these were asymptomatic by the time they presented to hospital. All five had normal oxygen saturation and peak flow measurements. The only patient who was symptomatic on presentation was admitted overnight for observation and was asymptomatic the following day. (Erdman et al, 2002).
    B) ACUTE LUNG INJURY
    1) WITH POISONING/EXPOSURE
    a) Acute exposure to hydrazine can cause acute lung injury (Makarovsky et al, 2008).
    b) Acute exposure to low concentrations of hydrazines may cause delayed death (days) and produce bronchial mucous destruction and pulmonary edema (Hall, 1959).
    c) Pulmonary edema has occurred in several cases of inhalation of hydrazine vapors by humans. Pulmonary edema was successfully treated with pyridoxine (ACGIH, 1986).
    d) CASE REPORT: Pulmonary edema was one of the causes of death in a case of 6 months' occupational exposure to hydrazine hydrate (Sotaniemi et al, 1971).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH POISONING/EXPOSURE
    a) Acute exposure to hydrazine can cause trembling, twitching, clonic movements, hyperactive reflexes, restlessness, violent behavior, ataxia, hypesthesia of the hands, paresthesias of the arms and legs, confusion, lethargy, neurogenic atrophy, seizures, and coma. Chronic exposure can result in difficulties in concentration, comprehension, memory, and task performance, mood changes, insomnia, paresthesias, sensorimotor abnormalities, loss of the ability to sense vibrations, and polyneuritis (Makarovsky et al, 2008).
    B) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) Hydrazines are central nervous system stimulants, which often lead to seizures (Jenny & Pfeiffer, 1958). This may occur after absorption by any route. A large number of hydrazines are convulsants.
    b) METHYLHYDRAZINE is the strongest convulsant and most toxic of the methyl derivatives (Clayton & Clayton, 1981).
    c) The MONOACYL HYDRAZINES (eg, acetylhydrazine) have greater convulsant activity and toxicity than the simple 1, 2-diacylhydrazines (eg, 1,2-diacetylhydrazine) (Clayton & Clayton, 1981).
    d) Inhalation of vapors has also caused dizziness (Comstock et al, 1954).
    C) COMA
    1) WITH POISONING/EXPOSURE
    a) Coma was reported 14 hours after exposure in a patient with a thermal burn secondary to a hydrazine explosion. Coma persisted for 60 hours, until 4 hours after initiation of pyridoxine therapy (Kirklin et al, 1976).
    D) IMPAIRED COGNITION
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Deficits in concentration, comprehension, memory, task performance, and mood status were reported in a water technician with respiratory and dermal exposures (Richter et al, 1992).
    E) TOXIC ENCEPHALOPATHY
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 76-year-old man with esophageal squamous cell carcinoma developed severe encephalopathy after taking hydrazine sulfate 180 mg/day for 2 weeks followed by 360 mg/day for 5 weeks. Following symptomatic therapy and high-dose pyridoxine (5 grams IV), his encephalopathy resolved. He died 9 months later from progressive esophageal carcinoma (Nagappan & Riddell, 2000).
    F) CENTRAL NERVOUS SYSTEM DEFICIT
    1) WITH POISONING/EXPOSURE
    a) Prolonged CNS depression has been reported following hydrazine ingestion and may be associated with elevation of gamma-amino-butyric acid levels (Zelnick et al, 2003).
    G) CENTRAL STIMULANT ADVERSE REACTION
    1) WITH POISONING/EXPOSURE
    a) Tremors and excitability, and other signs of CNS stimulation may occur (CHRIS , 1991; EPA, 1985).
    H) DISTURBANCE OF CONSCIOUSNESS
    1) WITH POISONING/EXPOSURE
    a) Lethargy and incoherence were seen in one fatal case of 6 months' exposure to hydrazine hydrate (Sotaniemi et al, 1971). Restlessness, lethargy, and confusion were seen in another patient (Harati & Niakan, 1986).
    I) SEQUELA
    1) WITH POISONING/EXPOSURE
    a) Persistent ataxia and inability to write were evident in a patient who had ingested hydrazine (Reid, 1965).
    b) Paresthesias and limb weakness, diagnosed as sensory polyneuropathy with axonal degeneration, were noted in a patient who had ingested hydrazine. The condition resolved spontaneously over the next 6 months. The polyneuropathy was attributed primarily to the pyridoxine therapy (Harati & Niakan, 1986).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) GASTROENTERITIS
    1) WITH POISONING/EXPOSURE
    a) Acute exposure to hydrazine can cause nausea, vomiting, anorexia, diarrhea, abdominal pain, and gastrointestinal hemorrhage (Makarovsky et al, 2008; Sittig, 1985; Clayton & Clayton, 1981a; McGrath et al, 1952; Reid, 1965).
    b) CHRONIC: Vomiting, diarrhea, abdominal pains, and black stools were seen in one fatal case of chronic occupational exposure to hydrazine hydrate (Sotaniemi et al, 1971).
    B) LOSS OF APPETITE
    1) WITH POISONING/EXPOSURE
    a) Anorexia is common (Makarovsky et al, 2008; Clayton & Clayton, 1981; McGrath et al, 1952).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER DAMAGE
    1) WITH POISONING/EXPOSURE
    a) Hydrazine is a hepatotoxin, working in both the cell mitochondria and nucleus (Doull et al, 1980; Doull et al, 1986). Damage is especially prominent after chronic exposure. It produces fatty degeneration (ACGIH, 1986). The liver damage may be more severe than renal toxicity (EPA, 1985).
    b) Acute exposure to hydrazine can cause focal hepatic necrosis and cell degeneration, and fatty liver. Chronic exposure can result in hepatic encephalopathy (Makarovsky et al, 2008).
    c) Elevations in AST, LDH, and total bilirubin were noted 3 days after ingestion of hydrazine in an adult (Harati & Niakan, 1986).
    d) Agents known to cause hepatic damage include: diisopropylhydrazine, benzhydrazine, phenacethydrazide, acetylhydrazine, phenylhydrazine, acetylphenylhydrazine, hydrazine sulfate, isoniazid and iproniazide.
    e) Damage has not been reported with single exposures to methyl derivatives, or even chronic use of 1, 1-dimethylhydrazine.
    f) Liver damage in humans has been suggested with 1,1-dimethylhydrazine even though it has not been demonstrated in animals (Clayton & Clayton, 1981; Peterson et al, 1970).
    g) One retrospective survey of 140 persons handling missile fuels found no evidence of abnormal hematocrits or urinalyses. SGPT and thymol turbidity tests, both indications of liver function, were borderline abnormal for some of the employees, however (King et al, 1969).
    B) HEPATIC ENCEPHALOPATHY
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 55-year-old man with squamous-cell carcinoma of the left maxillary sinus developed fatal hepatic encephalopathy, renal failure, profound coagulopathy and severe gastrointestinal hemorrhage within 3 to 4 months of taking hydrazine sulfate (180 mg/day). Autopsy showed kidney autolysis and submassive bridging necrosis of the liver involving the centrilobular and midzonal regions (Hainer et al, 2000).
    C) TOXIC LIVER DISEASE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 31-year-old aircraft technician developed mild hepatotoxicity (peak enzyme levels: ALT 237 Units/L on day 6; AST 110 Units/L on day 4) after inhaling hydrazine vapor for approximately 10 minutes due to a leaking fuel cell (a mixture of 70% hydrazine and 30% water by weight). His hepatic enzymes normalized by day 28 (Kao et al, 2007).
    D) HYPERBILIRUBINEMIA
    1) WITH POISONING/EXPOSURE
    a) Chronic exposure can result in hyperbilirubinemia (Makarovsky et al, 2008).
    E) HYPOALBUMINEMIA
    1) WITH POISONING/EXPOSURE
    a) Chronic exposure can result in hypoalbuminemia (Makarovsky et al, 2008).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) ABNORMAL RENAL FUNCTION
    1) WITH POISONING/EXPOSURE
    a) Acute exposure to hydrazine can cause nephritis. Chronic exposure can result in renal tubular necrosis, and renal insufficiency (Makarovsky et al, 2008).
    b) Hydrazines may cause kidney damage directly, or indirectly due to red blood cell hemolysis (Clayton & Clayton, 1981). Severe tubular necrosis and nephritis have been reported (Sotaniemi et al, 1971).
    B) RENAL FAILURE SYNDROME
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 55-year-old man with squamous-cell carcinoma of the left maxillary sinus developed fatal hepatic encephalopathy, renal failure (serum urea nitrogen 15.7 mmol/L (44 mg/dL); serum creatinine 450.8 mcmol/L (5.1 mg/dL)), profound coagulopathy and severe gastrointestinal hemorrhage within 3 to 4 months of taking hydrazine sulfate (180 mg/day). Autopsy showed kidney autolysis and submassive bridging necrosis of the liver involving the centrilobular and midzonal regions (Hainer et al, 2000).
    b) Oliguria and eventual death from kidney failure were seen in one case of 6 months' exposure to hydrazine hydrate (Sotaniemi et al, 1971).

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) METABOLIC ACIDOSIS
    1) WITH POISONING/EXPOSURE
    a) Acute exposure to hydrazine can cause metabolic acidosis (Makarovsky et al, 2008).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) HEMOLYSIS
    1) WITH POISONING/EXPOSURE
    a) Hydrazine is a hemolytic agent. It hydrolyzes red blood cells when injected or placed directly into the stomach. This effect is less prominent by inhalation, occurring mainly after chronic and severe intoxication (ACGIH, 1986).
    b) Hydrazine is less potent than methyl hydrazine for hemolytic effects (Clark et al, 1968).
    B) HEMOLYTIC ANEMIA
    1) WITH POISONING/EXPOSURE
    a) Hydrazine can induce hemolytic anemia (Makarovsky et al, 2008; ACGIH, 1986).
    b) Phenylhydrazine has the most potent and consistent hemolytic effect regardless of route of administration. It has also caused anemia. Diphenylhydrazine and diisopropylhydrazine are potent hemolysins. Of all the methyl derivatives, monomethylhydrazine is the most potent hemolysin, having greater activity than hydrazine or the dimethylhydrazines. Intravascular hemolysis has been reported after a single 4-hour exposure to monomethylhydrazine (Bodansky, 1924).
    1) 1, 1-dimethylhydrazine may cause hemolysis after chronic inhalation (Clayton & Clayton, 1981).
    C) METHEMOGLOBINEMIA
    1) WITH POISONING/EXPOSURE
    a) Acute exposure to hydrazine can cause methemoglobinemia (Makarovsky et al, 2008).
    D) THROMBOCYTOPENIC DISORDER
    1) WITH POISONING/EXPOSURE
    a) Chronic exposure can result in thrombocytopenia and leukocytosis (Makarovsky et al, 2008).
    b) CASE REPORT: Thrombocytopenia has been reported in a water technician exposed to hydrazine-containing mixtures (Richter et al, 1992).
    E) BLOOD COAGULATION DISORDER
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 55-year-old man with squamous-cell carcinoma of the left maxillary sinus developed fatal hepatic encephalopathy, renal failure, profound coagulopathy (prothrombin time 19.5 seconds; platelets 111 x 10(9) cells/L) and severe gastrointestinal hemorrhage within 3 to 4 months of taking hydrazine sulfate (180 mg/day). Autopsy showed kidney autolysis and submassive bridging necrosis of the liver involving the centrilobular and midzonal regions (Hainer et al, 2000).
    F) LEUKOCYTOSIS
    1) WITH POISONING/EXPOSURE
    a) Chronic exposure can result in leukocytosis (Makarovsky et al, 2008).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) SKIN IRRITATION
    1) WITH POISONING/EXPOSURE
    a) Acute exposure to hydrazine can cause skin irritation, contact dermatitis, edema, papules, urticaria, facial edema, and in severe cases caustic-like burns (Makarovsky et al, 2008).
    b) Hydrazine has been known to cause strong skin and mucous membrane irritation (Clayton & Clayton, 1981).
    c) Hydrazine is corrosive to tissue (AAR, 1987). It can cause second or third degree burns from short contact (CHRIS , 1991).
    d) Hydrazines, in descending order of skin irritancy are: phenylhydrazine, hydrazine, methyl hydrazine, dimethylhydrazines (Clayton & Clayton, 1981a).
    e) 1, 1-dimethylhydrazine is less irritating and less absorbed dermally (Clayton & Clayton, 1981).
    f) CASE REPORT: Systemic toxicity was reported in a patient with extensive burns incurred during an explosion of 1,1-dimethylhydrazine. Symptoms included confusion, lethargy, hypoventilation, and agitation. Pyridoxine 25 mg/kg IV/IM resulted in improvement of mental status. Liver enzymes were elevated persistently 108 days after the incident. At this time polyneuritis was also noted (Dhennin et al, 1988).
    B) CONTACT DERMATITIS
    1) WITH POISONING/EXPOSURE
    a) Acute exposure to hydrazine can cause contact dermatitis (Makarovsky et al, 2008).
    b) Skin sensitization of various hydrazines has been less completely studied. Hydrazine, and especially phenylhydrazine, are skin irritants and sensitizers (Wheeler et al, 1965; Evans, 1959).
    1) Hydrazines, in descending order of skin irritant potency, are: phenylhydrazine, hydrazine, monomethylhydrazine, dimethylhydrazines (Clayton & Clayton, 1981).
    c) CASE SERIES: Allergic contact dermatitis, consisting of hand and periorbital eczema, was reported in 2 patients working in the gold-plating industry (Wrangsio & Martensson, 1986).
    d) CASE SERIES: Severe contact dermatitis with generalized erythema, edema, papules, vesicles, and urticaria, was reported in 5 of 6 chemistry students exposed to N-(a-chlorobenzylidene) phenylhydrazine. This compound was shown to be a strong allergic sensitizer, producing reactions to concentrations of 0.01% within 1 day of exposure (Rothe, 1988).
    e) Twelve out of 34 female workers using a soldering flux containing hydrazine hydrochloride developed eczematous contact dermatitis. There was some cross reactivity with phenylhydrazine, Apresoline, and Isoniazid (Frost & Hjorth, 1959).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) JOINT PAIN
    1) WITH POISONING/EXPOSURE
    a) Acute exposure to hydrazine can cause arthralgias (Makarovsky et al, 2008; Durant & Harris, 1980).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPOGLYCEMIA
    1) WITH POISONING/EXPOSURE
    a) Acute exposure to hydrazine can cause hyperglycemia followed by hypoglycemia (Makarovsky et al, 2008).
    b) Abnormalities in blood sugar measurements have been reported with hydrazine. These measurements may vary by the amount of glycogen in the liver. If glycogen stores are greater than 5 mg/g, then hyperglycemia (1 to 3 days after ingestion) will proceed to hypoglycemia. If glycogen stores are depleted, only hypoglycemia may be seen (Clark et al, 1968).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) DRUG-INDUCED LUPUS ERYTHEMATOSUS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A lupus-like syndrome has been reported in a laboratory worker exposed to hydrazine sulfate, including photosensitivity, malar rash, antinuclear antibody, and a DNA antibody. The patient was shown to be a slow acetylator and had a genetic predisposition as demonstrated by HLA phenotype (Reidenberg et al, 1983).

Reproductive

    3.20.1) SUMMARY
    A) Hydrazine has been embryotoxic and fetotoxic in rats and mice, but at doses which were also toxic to the mothers. There is no evidence that hydrazine is a human reproductive hazard, but data are lacking.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) In rat and mouse studies, fetotoxicity and specific developmental abnormalities of the musculoskeletal system, urogenital system and central nervous system were observed. In the rat studies fetal death and a change in the viability index were also observed (RTECS , 1991).
    2) Hydrazine was not teratogenic in the rat (Schardein, 1985).
    3) Hydrazine was embryotoxic in rats at doses which were toxic to the mother, up to 10 mg/kg IP on days 6 to 15 (HSDB , 1991).
    4) From animal studies, it would appear that the fetus is not sensitive to hydrazine at doses which are not toxic to the mother (ACGIH, 1986).
    5) Hydrazine was teratogenic when injected in mice at doses of 4 to 40 mg/kg and produced soft tissue and skeletal effects (Lyng RD et al, 1980). When given orally to hamsters at a dose of 260 mg/kg, it inhibited the development of intestinal enzymes (Schiller, 1979).
    6) Hydrazine has induced malformations in toads (Greenhouse, 1976) and chicks (Stoll, 1967), but the implications of these latter studies for occupational exposure are unknown.
    3.20.3) EFFECTS IN PREGNANCY
    A) ANIMAL STUDIES
    1) In rat studies, postimplantation mortality was observed. Observed maternal toxic effects in rats include changes in the ovaries and the fallopian tubes (RTECS , 1991).
    2) In rats, hydrazine increased pre- and post-implantation deaths but was not teratogenic when given orally, with a no-effect level at 0.002 mg/L (Dymin, 1984). In the same study, inhalation exposure to an airborne concentration of 0.85 mg/m(3) was embryotoxic (Dymin, 1984). It was embryotoxic, but not teratogenic, when injected in rats at doses up to 10 mg/kg (Gaworski CL, 1982) (Keller et al, 1983).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) No studies were found on transfer of hydrazine in breast milk at the time of this review.

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS302-01-2 (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) IARC Classification
    a) Listed as: Hydrazine
    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) Hydrazine has been carcinogenic in rats, mice, and hamsters and is a suspected human carcinogen. Limited epidemiological evidence suggests that occupational exposure does not increase the risk of cancer, however.
    3.21.3) HUMAN STUDIES
    A) ANIMAL STUDIES
    1) Hydrazine causes animal tumors, as do many of its derivatives, such as mono and dimethylhydrazine and azoxymethane (Doull et al, 1980). Benign nasal tumors were predominant in rats exposed to hydrazine in concentrations as low as 0.05 ppm for 1 year.
    a) Higher exposure levels (5 ppm) produced malignant nasal tumors (Vernot et al, 1985).
    B) MELANOMA MALIGNANT
    1) CASE REPORT: One case of fatal choroidal melanoma was reported in a worker exposed to hydrazines for 6 years (Albert & Puliafito, 1977).
    C) LEUKEMIA
    1) Two patients developed chronic myeloid leukemia after receiving hydrazine (Freund et al, 1985).
    D) EPITHELIOID SARCOMA
    1) CASE REPORT: A 22-year-old woman, with the United States Air Force, developed an epithelioid sarcoma on her left thumb following occupational cutaneous exposure to hydrazine fuels. Histopathologic examination of the tumor, following excision, showed a distinct nodular arrangement of tumor cells, epithelioid in shape, with a propensity for central degeneration and necrosis. Lymph node examination did not indicate any enlarged epitrochlear or axillary nodes and CT scan of the chest showed no evidence of pulmonary metastasis. It is believed that development of the epithelioid sarcoma was a direct consequence of cutaneous exposure to hydrazine fuels (Helmers et al, 2004).
    E) LUNG/COLORECTAL CANCER
    1) In a study of 6044 aerospace workers exposed to hydrazine between 1950 and 2001, the cause of death was reported as cancer in 600 workers (28%); lung cancer was the most common cause of death (194 cases; 32% of all cancer deaths). Exposure to high levels of hydrazine was associated with both an increased incidence and mortality from lung cancer; dose-response trends were suggested when exposures were lagged by 20 years. From 1988 through 2000, 691 incident cancers were identified among 5049 workers at risk. Moderate and high exposure levels increased the incidence rate of colorectal cancers; however, little or no association was found for colorectal cancer mortality (Ritz et al, 2006).
    F) LACK OF EFFECT
    1) CASE SERIES: An epidemiologic study of workers exposed to hydrazine vapor showed no increase in the incidence of cancer (Ward & Doll, 1983).
    2) Preliminary results in another study have not shown elevated deaths from cancer in persons exposed to hydrazine (Roe, 1978).
    3) No increased deaths from any cancer were seen in a cohort of 427 men who had been occupationally exposed to hydrazine for at least 6 months between 1945 and 1971, but due to the small number of cases, a 3.5-fold increase in lung cancer could not be excluded (Morris et al, 1995).
    4) In an early study, there were no indications of increased risk for incidence of mortality from any types of cancer in employees with hydrazine exposure for up to 35 years in 9 hydrazine factories (Roe FJ, 1977). The author did point out several limitations of this study, including small sample sizes, lack of complete chemical exposure history, mixed exposures, no information on possible contribution of smoking, incomplete follow-up, and possibility of a long latent period for development of cancer.
    5) A more recent occupational study of 427 workers found no excess cancers (Wald, 1984).
    3.21.4) ANIMAL STUDIES
    A) ANIMAL STUDIES
    1) In the rat, hydrazine was found to be an equivocal tumorigenic agent and carcinogenic by RTECS criteria with thyroid tumors and sense organs and special senses tumors. In the mouse, hydrazine was found to be an equivocal tumorigenic agent, neoplastic and carcinogenic by RTECS criteria with lung, thorax, or respiration tumors, lymphomas (including Hodgkin's disease) and leukemia. In the hamster, hydrazine was found to be an equivocal tumorigenic agent by RTECS criteria with colon tumors and sense organs and special senses tumors (RTECS , 1991).
    2) Benign nasal tumors were predominant in rats exposed to hydrazine in concentrations as low as 0.05 ppm for 1 year. Higher exposure levels (5 ppm) produced malignant nasal tumors (Vernot, 1985).
    3) In the NTP Fifth Annual Report On Carcinogens, 1989, hydrazine was anticipated to be a carcinogen (RTECS , 1991).
    4) A recent drinking water study in rats found that hydrazine was weakly carcinogenic at the highest dose employed (50 mg/L), but other overt toxicity was seen. No carcinogenicity was seen in mice in preliminary findings (Steinhoff & Mohr, 1988).
    5) Neoplasia and hyperplasia were seen in the transitional epithelium in the anterior nose of rats and hamsters more than 24 months after exposure to 750 ppm hydrazine, and were similar to results seen in a chronic study of 5 ppm for 6 hours per day, 5 days per week for 1 year.
    a) Duration of exposure appears to be more critical than concentration for induction of neoplastic lesions (Latendresse et al, 1995).
    6) Hydrazine has caused cancer in several species of laboratory animals. It was carcinogenic in mice and rats when given orally and by inhalation (ACGIH, 1992; (Clayton & Clayton, 1994). Types of tumors produced in mice included lung adenomas and carcinomas, hepatocarcinomas, myeloid leukemia, reticulum cell sarcoma of the mediastinum, and lymphomas (Clayton & Clayton, 1994). Rats developed malignant and benign nasal tumors after inhalation of airborne levels up to 5 ppm (Clayton & Clayton, 1994). There have also been 2 chronic oral exposure studies in mice with negative outcomes (Toth, 1969; Steinhoff & Mohr, 1988).
    7) Oral administration to rats produced liver tumors and lung adenomas and carcinomas (Clayton & Clayton, 1994).
    8) Hydrazine was not carcinogenic in hamsters exposed by the oral route, and in dogs after inhalation of airborne levels up to 5 ppm for 1 year (Clayton & Clayton, 1994) ACGIH, 1992).
    9) It produced mostly benign nasal tumors in rats and hamsters after intermittent inhalation exposure to concentrations as high as 5 ppm for 1 year (Vernot, 1985).
    10) Hydrazine is in IARC Group 2B (possibly carcinogenic to humans) and is a NIOSH carcinogen (ACGIH, 1992). It is currently classified as A3 (animal carcinogen) by the ACGIH (ACGIH, 1996).

Genotoxicity

    A) Several hydrazines caused oxyhemoglobin-dependent strand breakage of DNA in vitro (Runge-Morris et al, 1994).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and mental status.
    B) Monitor serum electrolytes, CBC, pH, lactate concentration, renal function, and liver enzymes.
    C) A chest x-ray should be obtained in patients with pulmonary symptoms.
    D) Hydrazines can induce methemoglobinemia, which may not be apparent for several days. Monitor methemoglobin levels.

Methods

    A) MULTIPLE ANALYTICAL METHODS
    1) Analytical methods exist for analyzing these compounds, but are not commonly available. These methods include colorimetric, chromatographic (with flame ionization detention) procedures (Clayton & Clayton, 1981).
    2) Air sampling of dimethylhydrazine may be done by continuous colorimetric titration (Buck & Eldridge, 1965).
    3) Other: An aqueous solution of hydrazine reacts with a 1.5% alcoholic solution of picryl chloride in neutral or mildly alkaline solution to form a violet pink color. The test is said to be qualitative for concentrations greater than 1:400,000.
    a) A modification of this test (soaking filter paper with the 1.5% picryl chloride, touching the exposed body part to the paper, then holding the paper over ammonia vapor) was used to detect the presence of hydrazine in patients suspected of hydrazine dermatitis (Evans, 1959).

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 with CNS symptoms or persistent pulmonary or gastrointestinal symptoms should be admitted. Patients who are seizure free for 12 hours are safe to discharge.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Dermal exposures without burns can be watched at home if they are rapidly and adequately decontaminated.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a toxicologist for patients with CNS symptoms, acidosis, or severe pulmonary symptoms.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with gastrointestinal or pulmonary symptoms should be observed until asymptomatic. Any patient with hydrazine ingestion should be referred to a healthcare facility for evaluation.

Monitoring

    A) Monitor vital signs and mental status.
    B) Monitor serum electrolytes, CBC, pH, lactate concentration, renal function, and liver enzymes.
    C) A chest x-ray should be obtained in patients with pulmonary symptoms.
    D) Hydrazines can induce methemoglobinemia, which may not be apparent for several days. Monitor methemoglobin levels.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) PREHOSPITAL: Remove from exposure. Remove contaminated clothing, flush skin with water.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY: It is unknown if activated charcoal is effective, but it can be considered for patients with a protected airway presenting soon after exposure.
    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).
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Monitor vital signs and mental status.
    2) Monitor serum electrolytes, CBC, pH, lactate concentration, renal function, and liver enzymes.
    3) A chest x-ray should be obtained in patients with pulmonary symptoms.
    4) Hydrazines can induce methemoglobinemia, which may not be apparent for several days. Monitor methemoglobin levels.
    B) PYRIDOXINE
    1) Pyridoxine may be antidotal for coma and seizures (Kirklin et al, 1976), as well as for the milder effects of hydrazine poisoning (Frierson, 1965).
    2) DOSE: Pyridoxine 25 mg/kg IM or IV given in conjunction with a benzodiazepine has been shown to successfully treat seizure, CNS depression, lactic acidosis, and pulmonary edema associated with hydrazine exposure. Repeat as necessary, up to 5 g of pyridoxine has been given. Adverse effects in acute dosing are rare. CNS depression may occur if greater than 5 g of pyridoxine is given using 1 mL vials due to the presence of the diluent chlorobutanol. Chronic pyridoxine use can result in peripheral neuropathy.
    3) Doses suggested in case reports include: pyridoxine 25 mg/kg parenterally. In one case, this produced rapid reversal of coma in 4 hours for a patient who had been comatose for over 60 hours (Kirklin et al, 1976).
    4) Inhalation of a mixture of hydrazine and unsymmetrical dimethylhydrazine produced one case of mild symptoms (twitching, nausea, headache and dyspnea). These symptoms, but not pulmonary edema, were eliminated by 200 milligrams of pyridoxine intravenously and 400 milligrams intramuscularly (Frierson, 1965a).
    5) Early animal studies indicated pyridoxine to be effective against unsymmetrical dimethylhydrazine, but not hydrazine. When used to treat animal exposed to hydrazine-unsymmetrical dimethylhydrazine mixtures, pyridoxine has been less effective (Azar et al, 1970).
    a) Predictions of its usefulness vary by species (Clark et al, 1968).
    6) CAUTION: Pyridoxine doses of 0.2 to 5 grams per day for 2 to 40 months have caused ataxia and severe sensory nervous system dysfunction (Schaumburg et al, 1983; Parry & Bredesen, 1985; Berger & Schaumberg, 1984; Dalton, 1985). The maximum nontoxic pyridoxine dose is unknown.
    a) Case reports have described only the use of single parenteral doses in treatment of hydrazine toxicity. One study reports the use of 10 grams of pyridoxine intravenously in a 24 year old man who ingested "a mouthful" of hydrazine. One week later the patient developed paresthesias of his hands and feet and mild distal limb weakness. Three weeks post injection he had diminished pinprick, vibration, touch and position senses in his distal arms to the wrists and distal legs to the ankles. The neuropathy spontaneously cleared over the next 6 months. Although the neuropathy may have been due to the hydrazine, the symptoms are similar to those of pyridoxine toxicity (Harati & Niakan, 1986).
    C) 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).
    D) HYPERGLYCEMIA
    1) Monitor blood sugar. Elevated blood sugar early may be evidence of glycogenolysis and could be followed by sudden, severe hypoglycemia requiring immediate treatment. Severe hypoglycemia may appear without the preceding hyperglycemia.
    E) ACUTE LUNG INJURY
    1) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
    2) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).
    a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)
    3) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
    4) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
    5) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
    6) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
    7) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).
    F) 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.
    6.7.2) TREATMENT
    A) AIRWAY MANAGEMENT
    1) Hydrazines are pulmonary irritants, so respiratory support may be necessary early if the concentrations are high.
    2) Airway management may be required for patients in status epilepticus or patients with severe pulmonary symptoms. Intubate the patient prophylactically to facilitate GI decontamination in the asymptomatic or mildly symptomatic patients.
    3) Most hydrazines are absorbed through the lungs, so treatment will be similar to that of oral exposure, with more attention given to respiratory support.
    B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Eye Exposure

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

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
    6.9.2) TREATMENT
    A) IRRITATION SYMPTOM
    1) Hydrazines are skin irritants and sensitizers.
    B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Enhanced Elimination

    A) SUMMARY
    1) Hemodialysis may be effective, but little human data exists. Most patients recover with pyridoxine and symptomatic and supportive care.
    B) DIURESIS
    1) Rising free hemoglobin, and methemoglobin may require forced diuresis to prevent deposition in the kidneys and may require hemodialysis.
    C) URINE ACIDIFICATION/NOT RECOMMENDED
    1) Increased urine flow with saline or mannitol to a level of 10 to 15 milliliters/minute with acidification may aid in hydrazine elimination (Clark et al, 1968). The usefulness of this treatment may be limited by hydrazines' nephrotoxicity.
    D) HEMODIALYSIS
    1) Hemodialysis and peritoneal dialysis should be effective, but there are no human data (Clark et al, 1968).

Abstracts

Case Reports

    A) ROUTE OF EXPOSURE
    1) ORAL
    a) In a case of acute oral ingestion of hydrazine, vomiting and loss of consciousness occurred after ingestion of from 1 mouthful to a cupful. While in the hospital, the patient appeared flushed, afebrile, unconscious, mydriatic, and was vomiting. Twelve hours post-ingestion, the vomiting had decreased, the pupils were reduced, but the patient was sporadically violent. The patient was treated with pyridoxine. Later in the hospitalization, memory and voluntary movements were normal, but the patient was ataxic and unable to write (Reid, 1965a).
    b) A 24-year-old man became restless, lethargic, and confused after ingestion of a mouthful of hydrazine. Three days after ingestion liver function tests became elevated. The following day these were increased (AST 1920 mU/mL, LDH 1263 mU/mL, total bilirubin 5 mg/dL). He was given pyridoxine 10 grams intravenously, which resulted in improved mental status and liver function. One week later he noted paresthesias and limb weakness. A sensory polyneuropathy with axonal degeneration was diagnosed, which resolved spontaneously over the next 6 months. The polyneuropathy was attributed primarily to the pyridoxine therapy (Harati & Niakan, 1986).
    2) DERMAL
    a) Systemic toxicity was reported in a 31-year-old man with extensive burns incurred during an explosion of 1,1-dimethylhydrazine. Symptoms included confusion, lethargy, hypoventilation, and agitation. Hypotension occurred for the first 4 hours after the burn. Pupils alternated between miosis and reactive mydriasis. Pyridoxine 25 mg/kg (25% IV/75%IM) resulted in improvement of mental status. Three additional doses were given 1 hour, 24 hours, and 48 hours later. The EEG showed irregular scattered theta and delta activity, which persisted for 55 days after the burn. Liver enzymes were elevated initially and persistently 108 days after the incident. At this time sensory polyneuritis was also noted (Dhennin et al, 1988).
    B) CHRONIC EFFECTS
    1) Hydrazine hydrate was handled by a worker once a week for 6 months. He developed symptoms of lethargy, fever, vomiting, diarrhea, abdominal pains, black stools, and incoherence. He eventually became oliguric, had electrolyte imbalances and died 20 days after his last exposure due to pulmonary edema and kidney damage (Sotaniemi et al, 1971).

Range Of Toxicity

Summary

    A) TOXICITY: A mouthful caused confusion and hepatotoxicity. TLV-TWA is 0.01 ppm, 50 ppm is considered immediately dangerous to life and health. ATSDR an intermediate inhalation Minimal Risk Level (MRL) of 0.004 ppm (0.005 mg/m(3)).
    B) A man developed fatal hepatic encephalopathy, renal failure, profound coagulopathy and severe gastrointestinal hemorrhage within 3 to 4 months of taking hydrazine sulfate (180 mg/day).

Minimum Lethal Exposure

    A) CASE REPORT: A 55-year-old man with squamous-cell carcinoma of the left maxillary sinus developed fatal hepatic encephalopathy, renal failure, profound coagulopathy and severe gastrointestinal hemorrhage within 3 to 4 months of taking hydrazine sulfate (180 mg/day). Autopsy showed kidney autolysis and submassive bridging necrosis of the liver involving the centrilobular and midzonal regions (Hainer et al, 2000).

Maximum Tolerated Exposure

    A) TLV-TWA is 0.01 ppm (National Toxicology Program, 2011; American Conference of Governmental Industrial Hygienists, 2010), 50 ppm is considered immediately dangerous to life and health (National Toxicology Program, 2011; National Institute for Occupational Safety and Health, 2007). ATSDR an intermediate inhalation Minimal Risk Level (MRL) of 0.004 ppm (0.005 mg/m(3)) (Makarovsky et al, 2008).
    B) No evidence of increased morbidity or mortality in a series of 427 hydrazine plant workers followed for 47 years (Morris et al, 1995).
    C) CASE REPORTS
    1) A 24-year-old man who ingested a mouthful of hydrazine developed mental status changes and hepatotoxicity (Harati & Niakan, 1986).
    2) Vomiting, weakness, and irregular breathing with recovery in 5 days occurred following ingestion of 20 to 30 mL of a 6% aqueous solution (ACGIH, 1991).
    D) ANIMAL DATA
    1) In a developmental toxicity study, rats were given oral doses of 0, 2.5, 5, or 10 mg hydrazine (free base)/kg from days 6 to 15 of gestation. Maternal toxicity and fetal toxicity occurred at the 5 and 10 mg dose levels with 2.5 mg/kg being an apparent no-observed-effect level (ACGIH, 1991).

Workplace Standards

    A) ACGIH TLV Values for CAS302-01-2 (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) Hydrazine
    a) TLV:
    1) TLV-TWA: 0.01 ppm
    2) TLV-STEL:
    3) TLV-Ceiling:
    b) Notations and Endnotes:
    1) Carcinogenicity Category: A3
    2) Codes: 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) 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): URT cancer
    d) Molecular Weight: 32.05
    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 CAS302-01-2 (National Institute for Occupational Safety and Health, 2007):
    1) Listed as: Hydrazine
    2) REL:
    a) TWA:
    b) STEL:
    c) Ceiling: 0.03 ppm (0.04 mg/m(3)) [2-hour]
    d) Carcinogen Listing: (Ca) NIOSH considers this substance to be a potential occupational carcinogen (See Appendix A in the NIOSH Pocket Guide to Chemical Hazards).
    e) Skin Designation: Not Listed
    f) Note(s): See Appendix A
    3) IDLH:
    a) IDLH: 50 ppm
    b) Note(s): Ca
    1) Ca: NIOSH considers this substance to be a potential occupational carcinogen (See Appendix A).

    C) Carcinogenicity Ratings for CAS302-01-2 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): A3 ; Listed as: Hydrazine
    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): B2 ; Listed as: Hydrazine/Hydrazine sulfate
    a) B2 : Probable human carcinogen - based on sufficient evidence of carcinogenicity in animals.
    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: Hydrazine
    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): Ca ; Listed as: Hydrazine
    a) Ca : NIOSH considers this substance to be a potential occupational carcinogen (See Appendix A in the NIOSH Pocket Guide to Chemical Hazards).
    5) MAK (DFG, 2002): Category 2 ; Listed as: Hydrazine
    a) Category 2 : Substances that are considered to be carcinogenic for man because sufficient data from long-term animal studies or limited evidence from animal studies substantiated by evidence from epidemiological studies indicate that they can make a significant contribution to cancer risk. Limited data from animal studies can be supported by evidence that the substance causes cancer by a mode of action that is relevant to man and by results of in vitro tests and short-term animal studies.
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): R ; Listed as: Hydrazine
    a) R : RAHC = Reasonably anticipated to be a human carcinogen

    D) OSHA PEL Values for CAS302-01-2 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Listed as: Hydrazine
    2) Table Z-1 for Hydrazine:
    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: 1.3
    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) 1,1-DMH
    1) LD50- (INHALATION)RAT:
    a) 252 ppm
    2) LD50- (ORAL)RAT:
    a) 122 mg
    B) 1,2-DMH
    1) LD50- (INHALATION)RAT:
    a) 280-400 ppm
    2) LD50- (ORAL)RAT:
    a) 160 mg
    C) Hydrazine
    1) LD50- (INHALATION)RAT:
    a) 570 ppm
    2) LD50- (ORAL)RAT:
    a) 60 mg
    D) MH
    1) LD50- (INHALATION)RAT:
    a) 74 ppm
    2) LD50- (ORAL)RAT:
    a) 32.5 mg

Pharmacology Toxicology

Toxicologic Mechanism

    A) The toxicity of hydrazines (including hepatotoxicity) may depend somewhat on the competing rates of conversion to hydrazine and monoacylhydrazine (liver and CNS toxins) versus diacylhydrazines (not liver toxins).
    B) Hydrazine sulfate causes liver damage by nuclear and nucleolar enlargement, mitochondrial swelling, filling of the Golgi cisternae, and increased antibodies (Ganote & Rosenthal, 1968).
    C) Hydrazines produce a functional pyridoxine deficiency by means of inhibition of coenzymes synthesis or inactivation of the coenzyme (Clark et al, 1968).
    D) Hydrazines cause a dose-dependent depletion of hepatic ATP when tested in animal models (Preece et al, 1990).
    E) Animal data indicates the CNS toxicity is primarily due to action on the brain stem, but there is some spinal cord involvement (Fine et al, 1950).
    F) The gastrointestinal effects are due to local irritation if ingested, or via the vagus nerve (established via animal studies) by other routes (Fine et al, 1950).

Physicochemical

Physical Characteristics

    A) CHARACTERISTIC ODOR: Odors of the various compounds may be ammonia-like or "fishy" (Clayton & Clayton, 1981). These substances are detectable at 1 to 10 ppm.
    B) Hydrazine is a colorless, fuming, oily liquid with an ammonia odor.
    C) N-(a-chlorobenzylidene) phenylhydrazine is a brownish-white crystalline odorless substance.
    D) Hydrazine (H4-N2) is a colorless, oily liquid that fumes in air. It has a penetrating odor resembling that of ammonia. It burns with a violet flame (Budavari, 1989).
    E) Hydrazine dihydrochloride (Cl2-H6-N2) is a white crystalline powder (Budavari, 1989).
    F) Hydrazine contracts on freezing (Budavari, 1989).
    G) One gallon of the commercial product weighs 8.38 pounds (Budavari, 1989).
    H) Hydrazine forms salts with inorganic acids (Budavari, 1989).
    I) Hydrazine forms an azeotropic mixture with water, with a boiling point of 120.3 degrees C at 760 mm Hg (Budavari, 1989).
    J) Hydrazine is a hygroscopic liquid (NFPA, 1991).

Molecular Weight

    A) 32.05 (Budavari, 1989)

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