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NICKEL CARBONYL

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Nickel carbonyl is an intermediate in nickel refining. It is produced by passing carbon monoxide over finely divided nickel.

Specific Substances

    1) Nickel carbonyl
    2) Nickel tetracarbonyl
    3) CAS 13463-39-3
    4) NICKEL TETRACARBONILE
    1.2.1) MOLECULAR FORMULA
    1) C4-Ni-O4 Ni(CO)4

Available Forms Sources

    A) FORMS
    1) Nickel carbonyl is a colorless, volatile liquid which oxidizes in air; exposure often occurs to the vapor or gas (Budavari, 1996; Lewis, 1996).
    B) SOURCES
    1) It is formed by passing carbon monoxide over fine, divided nickel (Budavari, 1996).
    C) USES
    1) It is used as a catalyst or reagent in organic synthesis and chemical manufacture, used in glass plating, a chemical intermediate for the manufacture and refining of high purity nickel (Mond process), and used for vapor plating in other metallurgical and electronic industries. It is also used in continuous nickel coatings on steel and other metals (Budavari, 1996; HSDB , 2000).

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: Nickel carbonyl is a nickel compound used as a chemical reagent that is toxic by inhalation. It is an intermediate in nickel refining. Exposure often occurs to vapor or gas. It is used as a catalyst or reagent in organic synthesis and chemical manufacture, used in glass plating, a chemical intermediate for the manufacture and refining of high purity nickel (Mond process), and used for vapor plating in other metallurgical and electronic industries. It is also used in continuous nickel coatings on steel and other metals.
    B) TOXICOLOGY: Nickel carbonyl is an extremely toxic gas which can produce significant but delayed effects. Most poisonings involve inhalation with or without dermal exposure. Animal studies have found that the pulmonary parenchyma is the target tissue for nickel carbonyl toxicity regardless of route of exposure. Type I alveolar cells are principally affected, but type II alveolar cells are also damaged as a direct effect of nickel carbonyl. The cause of most deaths has been attributed chiefly to impaired gas exchange in the lungs secondary to the parenchymal tissue damage. Nickel carbonyl inhibits numerous enzyme activities and disrupts other pathways involved in RNA synthesis.
    C) EPIDEMIOLOGY: Exposure are rare, but fatalities have been reported following inadvertent exposures.
    D) WITH POISONING/EXPOSURE
    1) MILD EXPOSURE: INHALATION: Chronic low dose inhalational exposure can result in asthma. Diffuse pulmonary infiltrates or fibrosis can be seen on chest radiograph. DERMAL: Contact of the liquid with the skin may produce adverse effects. There is little information concerning dermal exposure in the absence of inhalational exposure; it is unknown if systemic effects might develop. OCULAR: Severe irritation or damage to the eyes can occur from vapor exposure. INGESTION: Although ingestion reportedly may result in toxicity, no cases of ingestion have been found and ingestion is highly unlikely.
    2) SEVERE EXPOSURE: INHALATION: Nickel carbonyl is a severe pulmonary irritant which is rapidly absorbed following inhalation. Immediate effects include nausea, vomiting, abdominal pain, headache, dizziness, blurred vision, weakness, paresthesias, chest tightness, cough and chest pain. These effects usually subside once the victim is in fresh air, although more severe effects may develop over the next few days. Delayed effects generally occur 12 to 36 hours postexposure in patients with severe poisoning, but may be delayed longer to as long as 5 or more days after exposure and can include weakness, myalgias, fatigue, cough, dyspnea, sore throat, fever, tachypnea, hoarseness, cyanosis, hypoxemia, gastrointestinal disturbances and pneumonitis. In severe cases, delirium, CNS depression, seizures, transaminitis, acute lung injury and seizures may develop. Toxic myocarditis and dysrhythmias occasionally occur. EEG abnormalities have been reported in nickel carbonyl workers. Late changes involve pulmonary edema and interstitial fibrosis. Severe irritation or damage to the eyes can occur from exposure. In fatal exposures, death has occurred within 3 to 13 days of exposure. Recovery from acute exposure may require several months.
    0.2.3) VITAL SIGNS
    A) WITH POISONING/EXPOSURE
    1) Tachypnea is a delayed effect. Fever and tachycardia have been reported.
    0.2.4) HEENT
    A) WITH POISONING/EXPOSURE
    1) Severe irritation or damage to the eyes can occur from exposure to the gas or liquid. Anophthalmia and microphthalmia were seen in offspring of rats after nickel carbonyl was inhaled early in pregnancy. Sore throat and hoarseness may develop following inhalation.
    0.2.20) REPRODUCTIVE
    A) In humans, no adverse reproductive effects or birth defects following exposure have been described. No data were available evaluating the effects of exposure from breastfeeding. Nickel carbonyl decomposes to carbon monoxide and nickel. Carbon monoxide is a known reproductive hazard.
    B) In animals, eye and ear abnormalities have been described in offspring following gestational exposure. Other defects observed following exposure during pregnancy include cleft palate, exencephaly and cystic lungs. Other animal studies describe fetal death, fetotoxicity, decreased litter size and decreased neonatal growth. Following exposure of dams prior to mating resulted in decreased fertility in the male offspring.
    0.2.21) CARCINOGENICITY
    A) Nickel carbonyl, has been listed as a probable human carcinogen based on inadequate human data but sufficient animal data. Potential cancer: lung and nasal.

Laboratory Monitoring

    A) Monitor serum electrolytes, renal function and CBC. Institute continuous cardiac monitoring and obtain an ECG.
    B) Monitor urinary nickel concentrations after suspected exposure and during chelation. Blood nickel carbonyl concentrations are not clinically useful since nickel carbonyl is rapidly metabolized and eliminated. Nickel carbonyl is not typically measurable in the blood of exposed individuals. Urinary nickel concentrations are the best indicator of the severity of poisoning, and urinary nickel concentrations correlate well with clinical symptoms in acute exposures.
    C) Some authors suggest monitoring carboxyhemoglobin concentrations as carbon monoxide is a result of nickel carbonyl decomposition. Monitor symptomatic patients as indicated. Inhalation of inhaled nickel carbonyl rapidly decomposes to nickel and carbon monoxide.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treat significant vomiting and/or dehydration with IV fluids and antiemetics in cases of severe vomiting. Administer supplemental oxygen for hypoxia and use bronchodilators and corticosteroids as needed for bronchospasm.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) ACUTE LUNG INJURY: Maintain ventilation and oxygenation and evaluate with frequent arterial blood gases or pulse oximetry monitoring. Early use of PEEP and mechanical ventilation may be needed. SEIZURES: Administer benzodiazepines as needed. Consider phenobarbital or propofol if seizures recur after large doses of benzodiazepines. Administer diethyldithiocarbonate or disulfiram.
    C) DECONTAMINATION
    1) INGESTION: Ingestion of nickel carbonyl is UNLIKELY, because exposure are usually due to gas. Ingestion would most likely occur in persons having direct access to cylinders of condensed nickel carbonyl.
    2) OCULAR: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature water for at least 15 minutes.
    3) INHALATION: Move patient to fresh air. The first phase of nickel carbonyl inhalation is deceptive in its lack of severe symptoms. Monitor for respiratory distress.
    4) DERMAL: Remove contaminated clothing and wash exposed area thoroughly with soap and water. Treat dermal irritation or burns with standard topical therapy. Patients developing dermal hypersensitivity reactions may require treatment with systemic or topical corticosteroids or antihistamines. The degree to which nickel carbonyl is dermally absorbed is not known.
    D) CHELATION
    1) Diethyldithiocarbamate (DDC) is the preferred chelating agent. Collect an 8 hour urine sample immediately after exposure. Results can be interpreted as follows: Less than 10 mcg/dL: delayed symptoms are not expected; DDC is unnecessary. If symptoms develop, treat as listed for urinary nickel levels of 10 to 50 mcg/dL. 10 to 50 mcg/dL: DDC should be administered orally (50 mg/kg/day on day 1, then 400 mg every 8 hours until the patient is symptom free and urine nickel is under 10 mcg/dL). Greater than 50 mcg/dL: the dose of DDC parenterally is 25 mg/kg. Additional DDC is based on clinical presentation and urinary nickel. Severe cases may use 100 mg/kg for the first 24 hours.
    2) If there is a doubt as to the severity of the exposure, give a course of 2 g of DDC orally until a urine nickel level can be obtained. Therapy should be not be delayed while awaiting for diagnostic data. If significant exposure is suspected or uncertain, parenteral DDC should be administered, urinary nickel concentrations levels monitored and the patient carefully evaluated for the development of delayed symptoms which may occur as much as a week after exposure.
    3) If DDC is not available, disulfiram may prove of some use. Although the optimal dose has not been established, one molecule disulfiram is metabolized to 2 molecules of DDC.. Avoid ethanol with disulfiram or DDC use given the risk of a disulfiram reaction.
    4) All patients with significant exposure should be admitted to a hospital and carefully observed and treated for possible delayed effects. Individuals with an 8-hour urinary nickel concentration of 10 mcg or greater/100 mL should be carefully followed for at least a week, even if they have received DDC.
    E) ENHANCED ELIMINATION
    1) Hemodialysis and hemoperfusion are not known to be of benefit. High volume hemofiltration in conjunction with disulfiram therapy was used in one patient with severe pulmonary injury from nickel carbonyl.
    F) PATIENT DISPOSITION
    1) HOME CRITERIA: All patients with exposure to nickel carbonyl should be monitored in a healthcare facility as it is an extremely toxic gas. Patients should not be managed at home if inhalation is suspected, the patient needs to be evaluated by monitoring either urine or plasma nickel levels.
    2) OBSERVATION CRITERIA: All patients with significant exposure should be admitted to a hospital and carefully observed and treated for possible delayed effects.
    3) ADMISSION CRITERIA: All patients with significant exposure irregardless of whether they are immediately symptomatic or not should be admitted for observation as clinical effects can be delayed.
    4) CONSULT CRITERIA: Consult a medical toxicologist for assistance with medical management.
    G) TOXICOKINETICS
    1) ABSORPTION: Nickel carbonyl is readily absorbed via inhalation, dermal absorption is unknown. METABOLISM: The nickel is released from nickel carbonyl intracellular oxidation to Ni (II), then it is released into the blood and is bound to albumin and other substances. The carbon monoxide becomes bound to hemoglobin and is transported to the lungs. EXCRETION: Inhaled nickel carbonyl is excreted in the urine as nickel.
    H) DIFFERENTIAL DIAGNOSIS
    1) Flu-like illness or infectious bronchopneumonia. Inhalation of other irritant or toxic gases (ie, acids, alkalia, phosgene).
    0.4.3) INHALATION EXPOSURE
    A) INHALATION: Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm.
    B) ACUTE LUNG INJURY: Maintain ventilation and oxygenation and evaluate with frequent arterial blood gases and/or pulse oximetry monitoring. Early use of PEEP and mechanical ventilation may be needed.
    C) CHELATION
    1) DIETHYLDITHIOCARBAMATE
    a) Diethyldithiocarbamate (DDC) is the preferred chelating agent.
    b) Collect an 8 hour urine sample immediately after exposure.
    1) Urinary nickel levels of:
    1) Less than 10 mcg/dL: Delayed, serious symptoms are not expected. DDC is usually unnecessary. If symptoms develop, treat as listed for urinary nickel levels of 10 to 50 mcg/dL.
    2) 10 to 50 mcg/dL: Administered DDC orally in divided doses for a total of 35 to 45 mg/kg on day 1, then 400 mg every 8 hours until the patient is symptom free and urine nickel is under 10 mcg/dL.
    3) Greater than 50 mcg/dL: Initial DDC dose parenterally is 25 mg/kg. Additional DDC based on clinical presentation and urinary nickel. Severe cases may need 100 mg/kg for the first 24 hours.
    c) If there is doubt as to the severity of the exposure, give 2 g of DDC orally in divided doses. Base additional treatment on clinical presentation and urinary nickel levels.
    2) DISULFIRAM
    a) DISULFIRAM (ANTABUSE(R)): It is metabolized to 2 molecules of DDC. If DDC is not available, disulfiram may prove of some use. Optimal dose has not been established. Doses of 500 mg every 12 hours and 750 mg every 8 hours orally or via NG tube have been used in adults.
    D) DIURESIS
    1) Diuresis may be helpful to reduce the elimination half-life of serum nickel.
    E) 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.
    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.
    B) Treat ocular irritation or burns with standard topical therapy.
    C) Observe patients with eye exposure carefully for development of systemic signs and symptoms, and follow treatment recommendations in the INHALATIONAL EXPOSURE section where appropriate.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
    2) Treat dermal irritation or burns with standard topical therapy. Patients developing dermal hypersensitivity reactions may require treatment with systemic or topical corticosteroids or antihistamines.
    3) Follow treatment recommendations listed under inhalational exposure.

Range Of Toxicity

    A) TOXICITY: The estimated lethal dose (inhalation) in humans has ranged from 3 to 30 ppm for a 30 minute exposure. 2 ppm is considered immediately dangerous to life and health. Maximum tolerated dose: The threshold limit value for an 8 hour work day (TLV TWA) is 0.05 ppm as nickel. It has been recommended that a plasma level of 10 mcg/L be set as a biomonitoring limit for nickel refinery workers. Serum nickel in an unexposed person is 2 to 10 mcg/L.

Clinical Effects

Summary Of Exposure

    A) USES: Nickel carbonyl is a nickel compound used as a chemical reagent that is toxic by inhalation. It is an intermediate in nickel refining. Exposure often occurs to vapor or gas. It is used as a catalyst or reagent in organic synthesis and chemical manufacture, used in glass plating, a chemical intermediate for the manufacture and refining of high purity nickel (Mond process), and used for vapor plating in other metallurgical and electronic industries. It is also used in continuous nickel coatings on steel and other metals.
    B) TOXICOLOGY: Nickel carbonyl is an extremely toxic gas which can produce significant but delayed effects. Most poisonings involve inhalation with or without dermal exposure. Animal studies have found that the pulmonary parenchyma is the target tissue for nickel carbonyl toxicity regardless of route of exposure. Type I alveolar cells are principally affected, but type II alveolar cells are also damaged as a direct effect of nickel carbonyl. The cause of most deaths has been attributed chiefly to impaired gas exchange in the lungs secondary to the parenchymal tissue damage. Nickel carbonyl inhibits numerous enzyme activities and disrupts other pathways involved in RNA synthesis.
    C) EPIDEMIOLOGY: Exposure are rare, but fatalities have been reported following inadvertent exposures.
    D) WITH POISONING/EXPOSURE
    1) MILD EXPOSURE: INHALATION: Chronic low dose inhalational exposure can result in asthma. Diffuse pulmonary infiltrates or fibrosis can be seen on chest radiograph. DERMAL: Contact of the liquid with the skin may produce adverse effects. There is little information concerning dermal exposure in the absence of inhalational exposure; it is unknown if systemic effects might develop. OCULAR: Severe irritation or damage to the eyes can occur from vapor exposure. INGESTION: Although ingestion reportedly may result in toxicity, no cases of ingestion have been found and ingestion is highly unlikely.
    2) SEVERE EXPOSURE: INHALATION: Nickel carbonyl is a severe pulmonary irritant which is rapidly absorbed following inhalation. Immediate effects include nausea, vomiting, abdominal pain, headache, dizziness, blurred vision, weakness, paresthesias, chest tightness, cough and chest pain. These effects usually subside once the victim is in fresh air, although more severe effects may develop over the next few days. Delayed effects generally occur 12 to 36 hours postexposure in patients with severe poisoning, but may be delayed longer to as long as 5 or more days after exposure and can include weakness, myalgias, fatigue, cough, dyspnea, sore throat, fever, tachypnea, hoarseness, cyanosis, hypoxemia, gastrointestinal disturbances and pneumonitis. In severe cases, delirium, CNS depression, seizures, transaminitis, acute lung injury and seizures may develop. Toxic myocarditis and dysrhythmias occasionally occur. EEG abnormalities have been reported in nickel carbonyl workers. Late changes involve pulmonary edema and interstitial fibrosis. Severe irritation or damage to the eyes can occur from exposure. In fatal exposures, death has occurred within 3 to 13 days of exposure. Recovery from acute exposure may require several months.

Vital Signs

    3.3.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Tachypnea is a delayed effect. Fever and tachycardia have been reported.
    3.3.2) RESPIRATIONS
    A) WITH POISONING/EXPOSURE
    1) TACHYPNEA can occur and is usually delayed hours or days after exposure (Jones, 1973; National Research Council, 1975; Sunderman, 1979; Kurta et al, 1993; Seet et al, 2005).
    3.3.3) TEMPERATURE
    A) WITH POISONING/EXPOSURE
    1) FEVER occurs occasionally, but usually does not exceed 101 degrees Fahrenheit; onset may be delayed (Seet et al, 2005; Sunderman & Kincaid, 1954; Jones, 1973; Sunderman, 1979; Zhicheng, 1986; Kurta et al, 1993).
    2) HYPOTHERMIA and impaired thermoregulation with cold intolerance may occur (Zhicheng, 1986; Sunderman et al, 1988).
    3) Chills and sweats may be seen in phase 1 of nickel carbonyl inhalations (Jones, 1973). Hypothermia and impaired thermoregulation may occur (Sunderman et al, 1988).
    4) Acute intoxication of nickel carbonyl has 2 stages: immediate and delayed. An exposed individual may develop a delayed fever, but it will seldom rise above 101 degrees (Clayton & Clayton, 1994).

Heent

    3.4.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Severe irritation or damage to the eyes can occur from exposure to the gas or liquid. Anophthalmia and microphthalmia were seen in offspring of rats after nickel carbonyl was inhaled early in pregnancy. Sore throat and hoarseness may develop following inhalation.
    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) IRRITATION: Severe irritation or damage to the eyes can occur from exposure to the gas or liquid (CHRIS , 2000).
    2) Anophthalmia and microphthalmia were seen in offspring of rats after nickel carbonyl was inhaled early in pregnancy (Grant & Schuman, 1993).
    3.4.6) THROAT
    A) WITH POISONING/EXPOSURE
    1) IRRITATION: Sore throat and hoarseness may develop following inhalation (Sunderman & Kincaid, 1954; Jones, 1973; Sunderman et al, 1988).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) MYOCARDITIS
    1) WITH POISONING/EXPOSURE
    a) Toxic myocarditis was present in 3 out of 179 cases of acute nickel carbonyl poisoning in China (Zhicheng, 1986).
    B) ELECTROCARDIOGRAM ABNORMAL
    1) WITH POISONING/EXPOSURE
    a) Zhi-cheng (1986) reported ECG irregularities in 20 of 179 cases of nickel carbonyl poisoning, including sinus tachycardia, sinus bradycardia, sinus irregularity with or without heart block, PVCs, and toxic myocarditis with changes in S-T and T-waves, and Q-T prolongation (Zhi-Cheng, 1986).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) ACUTE LUNG INJURY
    1) WITH POISONING/EXPOSURE
    a) The onset of potentially fatal congestion and pulmonary edema can be delayed hours (eg, 12 to 36 hours) to as long as 5 or more days after exposure (Jones, 1973; Sunderman, 1977; Zhicheng, 1986; Sunderman, 1990).
    b) Initial symptoms may be mild, transient, and can resemble a flu-like illness or bronchopneumonia, with sore throat, nausea, malaise, fever, chills, cough, dyspnea and chest pain upon inspiration. The initial symptoms worsen and may be accompanied by cyanosis, hypoxemia and abnormal chest x-rays (Jones, 1973; Kurta et al, 1993).
    c) Chest x-rays have shown irregular linear shadows, diffuse irregular mottling, patchy shadows and increased hilar density (Jones, 1973; Zhicheng, 1986; Kurta et al, 1993).
    B) TOXIC INHALATION INJURY
    1) WITH POISONING/EXPOSURE
    a) INHALATION exposure injuries (nickel carbonyl) occurs in 2 phases:
    1) COUGH AS THE EARLY PHASE EFFECT
    a) ACUTE INHALATION EXPOSURE injury occurs in two phases. Immediate effects often include nonproductive cough, headache, vertigo, weakness, and chest pain, followed by delayed effects, including tachypnea, dyspnea, and ARDS (Kurta et al, 1993a; Kurta et al, 1991; Zhicheng, 1986).
    2) PULMONARY EDEMA AS THE LATE EFFECT
    a) Reported late changes include pulmonary edema and interstitial fibrosis. Alveolar walls are replaced with connective tissue which resolves slowly (ACGIH, 1991a; Ashford, 1951).
    b) X-ray may show irregular linear shadows, diffuse irregular nodular mottling, pulmonary fibrous and edema, and pleural effusions (Clayton & Clayton, 1994; Zhi-Cheng et al, 1986).
    c) Autopsy shows hemorrhage, atelectasis, necrosis, and infiltration of connective tissue.
    d) PULMONARY EOSINOPHILIA: Chronic exposure to nickel dust may cause Loefflar's syndrome (pulmonary eosinophilia) (Clayton & Clayton, 1994; Sunderman, 1981).
    b) INGESTION may result in COUGH and DYSPNEA:
    1) Workers who accidentally drank water contaminated with 1.63 g of nickel salts per liter developed cough and shortness of breath (Sunderman et al, 1988).
    c) DERMAL EXPOSURE may result in bronchospasm.
    1) ASTHMA has been reported from dermal exposure to nickel sulfide (Clayton & Clayton, 1994; McConnell et al, 1973a).
    C) PNEUMONITIS
    1) WITH POISONING/EXPOSURE
    a) Severe pulmonary irritation and pneumonitis can occur and has been associated with a fatal outcome. Symptoms may be immediate or may develop within 12 hours to 5 days of exposure (Sunderman, 1977; Hathaway et al, 1996; Harbison, 1998; Seet et al, 2005).
    b) The signs and symptoms are similar to those occurring with pneumonitis, bronchopneumonia, viral or influenzal pneumonia and can progress to severe pulmonary edema (Jones, 1973; Kurta et al, 1993; Hathaway et al, 1996).
    c) Chest x-ray evidence of interstitial pneumonitis lasted three to four weeks in some cases (Vuopala et al, 1970).
    D) DYSPNEA
    1) WITH POISONING/EXPOSURE
    a) Dyspnea is very common. Retrosternal pain, pleuritic chest pain, cough and dyspnea may be immediate or can develop within 12 hours to 5 days. Severe, delayed symptom onset began with paroxysms of coughing in a study of 100 exposed workers (Vuopala et al, 1970; Jones, 1973; Sunderman, 1977; Sunderman & Kincaid, 1954; Seet et al, 2005).
    E) SMELL OF BREATH - FINDING
    1) WITH POISONING/EXPOSURE
    a) The exhaled breath may have a strong odor of soot which is strongest within the first or second day after exposure (Vuopala et al, 1970).
    F) BRONCHOSPASM
    1) WITH POISONING/EXPOSURE
    a) ASTHMA/LOFFLER'S SYNDROME: Chronic, low dose inhalational exposure to nickel carbonyl resulted in asthma and Loffler's syndrome (transient pulmonary infiltrates and eosinophilia) in one case. Dermatitis and sensitivity reactions to a coin (25% nickel) and nickel foil were present (Sunderman & Sunderman, 1961).
    b) Other forms of nickel (eg, nickel salts) have produced asthma (McConnell et al, 1973).
    G) RESPIRATORY FINDING
    1) WITH POISONING/EXPOSURE
    a) Pulmonary function tests were initially consistent with acute interstitial disease (eg, decreased VC and FEV1%), but pulmonary function appeared normal by 3 months after exposure in a study of 25 cases (Vuopala et al, 1970).
    H) FIBROSIS OF LUNG
    1) WITH POISONING/EXPOSURE
    a) LUNG FINDING
    1) Diffuse pulmonary infiltrates or bilateral basal pulmonary infiltrates were seen on chest x-rays of 7 patients exposed to nickel carbonyl (Seet et al, 2005).
    2) Chest x-rays showed interstitial fibrosis in cases one year after acute poisoning (National Research Council, 1975).
    3.6.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) Animals exposed to nickel carbonyl by inhalation for 5 days, 12 hours/day had signs of dyspnea, fever, vomiting, diarrhea, apathy, anorexia, tachypnea, cyanosis and occasionally hind-limb paralysis with generalized convulsions followed by death (Clayton & Clayton, 1994).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) TOXIC ENCEPHALOPATHY
    1) WITH POISONING/EXPOSURE
    a) Symptoms of encephalopathy (details not provided) developed in 4 out of 156 exposed workers, but disappeared within 3 to 5 weeks without apparent sequelae (Sunderman, 1989).
    B) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) Seizures may occur prior to death (Sunderman & Kincaid, 1954; Hathaway et al, 1996).
    C) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH POISONING/EXPOSURE
    a) ACUTE TOXICITY
    1) INHALATION exposures (nickel carbonyl) may result in early and later phase symptoms.
    a) Early effects after inhalation are dizziness, giddiness, weakness, dysphoria, blurred vision, and numbness (Sunderman & Kincaid, 1954; Zhi-Cheng et al, 1986). Frontal throbbing headache and dizziness were common initial symptoms in several studies of exposed workers (Vuopala et al, 1970; Zhicheng, 1986; Kurta et al, 1993; Sunderman, 1989)
    b) Second phase signs and symptoms may include cold and clammy skin, cerebral edema (Jones, 1973), and sleeplessness (Sunderman, 1971). Weakness and somnolence can persist 3 to 6 months after exposure (Zhi-Cheng et al, 1986).
    c) INCIDENCE: In a review of 179 cases of acute inhalation exposure to nickel carbonyl, 98 (66.2%) patients with mild toxicity developed dizziness compared to 129 (72.1%) with severe exposure. Headache was more likely to occur following severe poisoning. Other less likely symptoms were sleeplessness and somnolence (Zhicheng, 1986).
    b) CHRONIC TOXICITY
    1) CASE SERIES: In a study of workers (n=76) chronically exposed to low levels of nickel carbonyl, workers were more likely to have the following signs and symptoms: neurosis syndrome, excitement, sleeplessness, dreams, headache, dizziness, weakness, hypomnesis, chest tightness, polyhydrosis and hair loss (Zhi-cheng et al, 1986).
    D) PARESTHESIA
    1) WITH POISONING/EXPOSURE
    a) Paresthesias, numbness and weakness have been reported (Zhicheng, 1986; Kurta et al, 1993).
    E) DISTURBANCE IN THINKING
    1) WITH POISONING/EXPOSURE
    a) Some individuals became irrational after inhalation of nickel carbonyl (Sunderman & Kincaid, 1954).
    F) FATIGUE
    1) WITH POISONING/EXPOSURE
    a) NEURASTHENIC SYNDROME: The recovery from an acute exposure may require several months and is characterized by excessive fatigue and weakness (Zhicheng, 1986).
    G) ELECTROENCEPHALOGRAM ABNORMAL
    1) WITH POISONING/EXPOSURE
    a) A significant decrease in serum monoaminoxidase (SMAO) and EEG abnormalities were reported among nickel carbonyl workers. The decrease of SMAO level parallels the abnormality rate of EEG. It is considered that SMAO and EEG can be used as objective indices for dynamic observation of chronic influence of nickel carbonyl upon workers (Zhi-Cheng et al, 1986).
    H) CEREBRAL HEMORRHAGE
    1) WITH POISONING/EXPOSURE
    a) Cerebral hemorrhage and edema have been found at autopsy (Jones, 1973; National Research Council, 1975).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH POISONING/EXPOSURE
    a) Nausea and vomiting occur shortly after nickel carbonyl exposure or can be delayed (Sunderman & Kincaid, 1954; Jones, 1973; Zhicheng, 1986).
    b) INCIDENCE: In a review of 179 cases of acute inhalation exposure to nickel carbonyl, 84 (56.8%) patients with mild exposure developed nausea compared to 115 (64.2%) with severe exposure. Vomiting was more likely to occur following severe poisoning (Zhicheng, 1986).
    B) DIARRHEA
    1) WITH POISONING/EXPOSURE
    a) Diarrhea developed in several cases 2 to 3 days after exposure (Sunderman & Kincaid, 1954).
    C) ABDOMINAL PAIN
    1) WITH POISONING/EXPOSURE
    a) Epigastric, abdominal or sternal pain are common early symptoms (Jones, 1973; Zhicheng, 1986; Sunderman, 1989).
    b) INCIDENCE: In a review of 179 cases of acute nickel carbonyl poisoning, only 1 patient reported abdominal pain following mild exposure and 3 patients reported abdominal pain with severe exposure (Zhicheng, 1986).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH POISONING/EXPOSURE
    a) SGPT levels were slightly increased in 6 out of 179 cases (3.4%) and returned to normal within 3 weeks in one study (Zhicheng, 1986).
    b) In another report, 8 out of 25 patients had slightly elevated SGOT and SGPT the first few days after exposure, peaking at day 7 and returning to normal within one month (Vuopala et al, 1970).
    c) Abnormal liver function tests were found in 62 of 96 workers within 2 months of exposure (Sunderman, 1989).
    d) Mildly increased bilirubin, LDH and alkaline phosphatase levels were reported in one case (Kurta et al, 1993).
    B) JAUNDICE
    1) WITH POISONING/EXPOSURE
    a) Hepatic tenderness and mild jaundice was present in severe exposures, and persisted in several cases 2 months after exposure (Sunderman & Kincaid, 1954; Sunderman, 1989).
    C) LIVER DAMAGE
    1) WITH POISONING/EXPOSURE
    a) Mild to moderate parenchymal degenerative changes and hepatic edema have been found upon autopsy of 3 cases; hepatic effects have not been reported upon autopsy of other fatal cases (National Research Council, 1975).
    3.9.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HEPATIC NECROSIS
    a) Animal studies have shown necrosis of liver cells, human cases report only liver congestion (Sunderman, 1971).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) TOXIC VACUOLIZATION
    1) WITH POISONING/EXPOSURE
    a) Pathological changes found in the kidney in a fatal case showed vacuolization of the proximal convoluted tubules, but no tubular necrosis (Jones, 1973).
    B) ALBUMINURIA
    1) WITH POISONING/EXPOSURE
    a) Twenty-six out of 92 individuals had greater than a trace of protein in the urine up to 2 months after exposure during an industrial accident (Sunderman, 1989).
    C) LACK OF EFFECT
    1) WITH POISONING/EXPOSURE
    a) Among 156 exposed workers, renal function tests were normal in those individuals tested (Sunderman, 1989).
    3.10.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) ALBUMINURIA
    a) Proteinuria, aminoaciduria and increased urinary ammonia occurred in rats after inhalation of a LD50 dose of nickel carbonyl and were considered an indicator of nephrotoxicity since plasma amino acid concentrations were unaffected by nickel carbonyl exposure (Horak & Sunderman, 1980).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) LEUKOCYTOSIS
    1) WITH POISONING/EXPOSURE
    a) Leukocytosis is a delayed response to acute exposure.
    b) CASE SERIES: Fever with leukocytosis was present in 25 of 179 cases of acute nickel carbonyl poisoning resulting from leaks, spills or vapor releases. Fifty nine cases (32.9%) had exposure lasting less than 30 minutes; 51 (28.5%) one hour; 48 (26.8%) one to two hours and 21 (11.7%) more than two hours. Leucocytosis correlated positively with the severity of exposure and ranged from 12 to 23000 mm(3) (note: the onset of leucocytosis was not described in the report) (Zhicheng, 1986).
    c) CASE SERIES: Moderate leukocytosis (10,000 to 15,000 leukocytes/mm(3)) was present in critically ill cases (Sunderman & Kincaid, 1954).
    B) EOSINOPHIL COUNT RAISED
    1) WITH POISONING/EXPOSURE
    a) Severe eosinophilia has been reported in one case, but was not a feature of other cases of nickel carbonyl poisoning (Sunderman & Sunderman, 1961; Zhicheng, 1986).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) CHEMICAL BURN
    1) WITH POISONING/EXPOSURE
    a) Second or third degree burns may result from brief exposure to the liquid (CHRIS , 2000).
    B) SKIN IRRITATION
    1) WITH POISONING/EXPOSURE
    a) Severe irritation may occur from exposure to the liquid (CHRIS , 2000).
    C) CYANOSIS
    1) WITH POISONING/EXPOSURE
    a) Cyanosis can occur as a delayed effect and has been observed in several cases 2 months after exposure (Sunderman, 1989; Vuopala et al, 1970; Jones, 1973).
    b) The pink or cherry-red skin color associated with carbon monoxide poisoning is not present (Vuopala et al, 1970).
    D) EXCESSIVE SWEATING
    1) WITH POISONING/EXPOSURE
    a) Chills and diaphoresis can occur shortly after exposure or as delayed effects (Jones, 1973; Vuopala et al, 1970).
    E) CONTACT DERMATITIS
    1) WITH POISONING/EXPOSURE
    a) Allergic responses to nickel foil and a coin containing 25% nickel were documented in a worker chronically exposed to low concentrations of nickel carbonyl gas. Dermatitis, asthma, and Loffler's syndrome were also present (Sunderman & Sunderman, 1961).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCLE WEAKNESS
    1) WITH POISONING/EXPOSURE
    a) Profound weakness and fatigue is common in significant exposures and may be delayed in onset (Sunderman & Kincaid, 1954; National Research Council, 1975; Hathaway et al, 1996).
    b) CASE SERIES: Ninety-eight out of 179 cases of carbonyl poisoning experienced weakness. After hospital discharge about one-third of the 179 patients developed neurasthenic syndrome and weakness, which in some cases persisted for 3 to 6 months (Zhicheng, 1986).
    B) MUSCLE PAIN
    1) WITH POISONING/EXPOSURE
    a) Delayed muscle cramps or pain which persisted for more than 3 weeks have been reported (Vuopala et al, 1970; National Research Council, 1975).

Reproductive

    3.20.1) SUMMARY
    A) In humans, no adverse reproductive effects or birth defects following exposure have been described. No data were available evaluating the effects of exposure from breastfeeding. Nickel carbonyl decomposes to carbon monoxide and nickel. Carbon monoxide is a known reproductive hazard.
    B) In animals, eye and ear abnormalities have been described in offspring following gestational exposure. Other defects observed following exposure during pregnancy include cleft palate, exencephaly and cystic lungs. Other animal studies describe fetal death, fetotoxicity, decreased litter size and decreased neonatal growth. Following exposure of dams prior to mating resulted in decreased fertility in the male offspring.
    3.20.2) TERATOGENICITY
    A) HUMANS
    1) No adverse reproductive effects or birth defects were reported among 150 to 200 women employed in a nickel carbonyl refinery in Wales during World War I and II (Warner, 1979).
    2) Nickel carbonyl decomposes to pure nickel and carbon monoxide when heated to 200 degrees Centigrade, as can occur during the Mond process (Goyer, 1991).
    3) Nickel carbonyl is easily absorbed from the lung. It rapidly decomposes to nickel and carbon monoxide (HSDB, 2002). The specific reproductive effects of carbon monoxide exposure as a consequence of nickel carbonyl heating or decomposition in humans are not known (HSDB , 2000; Sunderman, 1977).
    4) No birth defects or other adverse reproductive findings were reported in a cohort of women working in a nickel carbonyl refinery in Wales (Schardein, 1993).
    B) EMBRYOTOXICITY
    1) CARBON MONOXIDE crosses the placenta and is harmful to the human fetus and is both embryotoxic and fetotoxic in animals, depending on amount, duration and time of exposure during gestation (Barlow & Sullivan, 1982).
    C) ANIMAL STUDIES
    1) OCULAR ANOMALIES: Anophthalmia and/or microphthalmia were present in offspring of rats which inhaled nickel carbonyl (0.06 to 0.12 mg/L of air/15 min) during gestational days 7 or 8 (Sunderman et al, 1978) and in only 1 fetus in another study in which pregnant hamsters were exposed to nickel carbonyl (0.06 mg/L of air per 15 min) during gestational days 4 through 8 (Sunderman et al, 1980).
    2) EAR ABNORMALITIES: Abnormal development of the ear has been reported in animals (RTECS , 2000).
    3) CLEFT PALATE and other anomalies were present in offspring of hamsters exposed during pregnancy to nickel carbonyl, 0.006 mg/L/15 minutes on gestational days 4 through 8 (Sunderman et al, 1980).
    4) CNS ABNORMALITIES: Exencephaly was present in 7 out of 171 hamster fetuses of dams exposed to nickel carbonyl (0.06 mg/L/15 min) during pregnancy; the rate of exencephaly in controls was 0 of 97 fetuses (Sunderman et al, 1980).
    5) RESPIRATORY SYSTEM ABNORMALITIES: Cystic lungs and other anomalies were present in offspring of hamsters exposed during pregnancy to nickel carbonyl, 0.06 mg/L/15 min on gestational days 4 or 5 (Sunderman et al, 1980).
    3.20.3) EFFECTS IN PREGNANCY
    A) HUMANS
    1) No adverse reproductive effects or birth defects were reported among 150 to 200 women employed in a nickel carbonyl refinery in Wales during World War I and II (Warner, 1979).
    B) ANIMAL STUDIES
    1) FETOTOXICITY/GROWTH RETARDATION: Fetal death, fetotoxicity, decreased litter size, decreased neonatal growth and abnormal eye and ear formation were reported in rats (Sunderman et al, 1979).
    2) Fetal death, changes in the viability index and developmental abnormalities have been reported in hamsters (Sunderman et al, 1980).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) No studies were found on the effects of nickel carbonyl during lactation.
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) DECREASED FERTILITY: Changes in the male fertility index in rats were reported when female rats were administered nickel carbonyl prior to mating (RTECS , 2000).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS13463-39-3 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) IARC Classification
    a) Listed as: Nickel carbonyl
    b) Carcinogen Rating: 1
    1) The agent (mixture) is carcinogenic to humans. The exposure circumstance entails exposures that are carcinogenic to humans. This category is used when there is sufficient evidence of carcinogenicity in humans. Exceptionally, an agent (mixture) may be placed in this category when evidence of carcinogenicity in humans is less than sufficient but there is sufficient evidence of carcinogenicity in experimental animals and strong evidence in exposed humans that the agent (mixture) acts through a relevant mechanism of carcinogenicity.
    3.21.2) SUMMARY/HUMAN
    A) Nickel carbonyl, has been listed as a probable human carcinogen based on inadequate human data but sufficient animal data. Potential cancer: lung and nasal.
    3.21.3) HUMAN STUDIES
    A) CARCINOMA
    1) Nickel and certain nickel compounds are labeled as carcinogens or as substances which may reasonably be anticipated to be carcinogens (IARC, 1987; IARC, 1990; US DHHS, 1994; ACGIH, 1991; NIOSH , 2000; HSDB , 2000).
    2) NICKEL CARBONYL, CAS 13463-39-3 - probable human carcinogen based on inadequate human data but sufficient animal data. Potential cancer: lung and nasal ((IRIS, 2000); NIOSH , 2000).
    3) Occupational studies have previously linked working with nickel refining by the Mond process, in which nickel carbonyl is used, with cancers of the nasal sinuses and lung. Similar cancers were also seen in other nickel refining processes which did not use nickel carbonyl. Exposure to furnace fumes has more recently been proposed as the explanation for the cancers (ACGIH, 1991).
    a) Other possible carcinogenic agents, including arsenic, have also been present in the nickel refining process (Tatarskaya, 1965).
    3.21.4) ANIMAL STUDIES
    A) CARCINOMA
    1) There is sufficient evidence of carcinogenicity of nickel carbonyl in laboratory animals according to the IRIS system. Lung cancer following inhalation and multiple site malignant tumors following injection have been reported in rats ((IRIS, 2000)).
    2) The IARC considers the evidence for carcinogenicity in animals as limited (IARC, 1990).
    3) In rat studies, nickel carbonyl was found to be an equivocal tumorigenic agent and carcinogenic by RTECS criteria (RTECS , 2000).
    4) Rats exposed to 0.03 and 0.06 mg/L nickel carbonyl for 30 minutes, three times per week for 12 months, showed inflammation of the lung in all, extensive squamous metaplasia in several, and lung tumors in 4 out of 9 rats which survived 2 yrs. A single exposure to 0.25 mg/L was sufficient to induce squamous-cell carcinoma of the lung in one rat and papillary bronchial adenomas in another (HSDB , 2000).
    5) Tumors at various sites, including the liver, kidney, mammary, leukemia and lymphomas, developed in rats given nickel carbonyl at 9 mg Ni/kg in the tail vein in six doses given every two to four weeks (Lau et al, 1972).
    6) Rats inhaling nickel carbonyl at airborne concentrations of 0.0017 and 0.0005 mg/L for only 2 weeks developed tumors of the uterus, ovaries, and breast (Sanina, 1963).

Genotoxicity

    A) No significant increases of chromosome aberrations or sister-chromatid exchange rates were found in peripheral lymphocytes of 65 persons occupationally exposed to nickel carbonyl, compared with smoking and non-smoking controls.
    B) ANIMAL STUDIES
    1) Nickel carbonyl did not induce dominant lethal mutations in male rats exposed by inhalation at 0.05 mg Ni/L for 15 minutes, but it was positive when injected intravenously at 22 mg Ni/kg.
    2) Nickel carbonyl injected IV significantly reduced radiolabeled thymidine incorporation into liver and kidney DNA of rats, as compared to controls, but did not cause DNA damage. Radiolabeled nickel binding to DNA of liver and kidney tissues was present in rats injected IV with radiolabeled nickel carbonyl.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor serum electrolytes, renal function and CBC. Institute continuous cardiac monitoring and obtain an ECG.
    B) Monitor urinary nickel concentrations after suspected exposure and during chelation. Blood nickel carbonyl concentrations are not clinically useful since nickel carbonyl is rapidly metabolized and eliminated. Nickel carbonyl is not typically measurable in the blood of exposed individuals. Urinary nickel concentrations are the best indicator of the severity of poisoning, and urinary nickel concentrations correlate well with clinical symptoms in acute exposures.
    C) Some authors suggest monitoring carboxyhemoglobin concentrations as carbon monoxide is a result of nickel carbonyl decomposition. Monitor symptomatic patients as indicated. Inhalation of inhaled nickel carbonyl rapidly decomposes to nickel and carbon monoxide.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Blood nickel carbonyl concentrations are not clinically useful since nickel carbonyl is rapidly metabolized and eliminated. Nickel carbonyl is not typically measurable in the blood of exposed individuals (Baselt & Cravey, 1995).
    2) Serum concentrations of the nickel carbonyl metabolite, ionic nickel, can be used as an indicator of exposure if measured within minutes or hours of exposure, but vary considerably (Sunderman, 1977; National Research Council, 1975).
    3) SERUM NICKEL IN UNEXPOSED PERSONS: 1.1 to 4.6 mcg/L (National Research Council, 1975; Baselt & Cravey, 1995).
    4) For urine obtained within 18 hours of exposure 60 to 100 mcg/L indicates mild intoxication; 100 to 500 mcg/L indicated moderate intoxication and more than 500 mcg/L indicates severe intoxication (Sunderman & Sunderman, 1958).
    B) HEMATOLOGIC
    1) CARBOXYHEMOGLOBIN LEVELS: Since animal studies have reported carbon monoxide production as a result of nickel carbonyl decomposition in vivo, and some processes which produce nickel carbonyl may produce carbon monoxide, some authors recommend monitoring carboxyhemoglobin concentrations (Vuopala et al, 1970; Sax & Lewis, 1984; Budavari, 1989).
    4.1.3) URINE
    A) URINARY CONCENTRATION
    1) Obtain an 8-hour urine sample for nickel analysis (Sunderman, 1990).
    2) Urinary nickel concentrations are the best indicator of the severity of poisoning; urinary nickel concentrations correlate well with clinical symptoms in acute exposures (Sunderman, 1977; Sunderman, 1990).
    3) URINARY NICKEL IN UNEXPOSED PERSONS: 2 to 10 mcg/L (Baselt & Cravey, 1995).
    4.1.4) OTHER
    A) OTHER
    1) EEG
    a) In one study of workers chronically exposed to low concentrations of nickel carbonyl, EEG studies were able to detect the chronic influence of exposure (Zhi-cheng et al, 1986).

Radiographic Studies

    A) CHEST RADIOGRAPH
    1) Monitor chest x-ray and arterial blood gases.

Methods

    A) SPECTROSCOPY/SPECTROMETRY
    1) Gas chromatographic technique, the same method of determining the concentration of nickel carbonyl in the air, has been used to determine concentrations on the breath and in the blood (Clayton & Clayton, 1994).
    B) CHROMATOGRAPHY
    1) A gas chromatographic method for detecting nickel carbonyl in blood is described (Sunderman et al, 1968). Nickel carbonyl concentrations in blood are not commonly measured in poisoning cases due to rapid metabolism and elimination (Baselt & Cravey, 1995).
    C) ATOMIC ABSORPTION
    1) Flameless atomic absorption spectroscopy has been used to determine nickel content in urine and hair after nickel carbonyl exposure (Hagedorn-Gotz et al, 1977).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.3) DISPOSITION/INHALATION EXPOSURE
    6.3.3.1) ADMISSION CRITERIA/INHALATION
    A) All patients with significant exposure irregardless of whether they are immediately symptomatic or not should be admitted for observation as clinical effects can be delayed.
    B) Hospitalization, treatment with diethyldithiocarbamate (DDC) and observation has been recommended by Sunderman (1971) for the following (Sunderman, 1971):
    1) Urinary nickel less than 10 mcg/dL with severe, delayed symptoms
    2) Urinary nickel greater than 10 mcg/dL
    6.3.3.2) HOME CRITERIA/INHALATION
    A) All patients with exposure to nickel carbonyl should be monitored in a healthcare facility as it is an extremely toxic gas. Patients should not be managed at home if inhalation is suspected, the patient needs to be evaluated by monitoring either urine or plasma nickel levels.
    6.3.3.3) CONSULT CRITERIA/INHALATION
    A) Consult a medical toxicologist for assistance with medical management.
    6.3.3.5) OBSERVATION CRITERIA/INHALATION
    A) MONITORING
    1) The first phase of nickel carbonyl intoxication is deceptive in its lack of severe symptoms. Nickel carbonyl is an extremely toxic gas which can produce significant but delayed effects.
    2) If significant exposure is suspected or uncertain, diethyldithiocarbamate (DDC) should be administered, urinary nickel levels monitored and the patient carefully evaluated for the development of delayed symptoms which may occur as much as a week after exposure (Sunderman, 1971).
    3) All patients with significant exposure should be admitted to a hospital and carefully observed and treated for possible delayed effects.
    4) Individuals with an 8-hour urinary nickel concentration of 10 mcg or greater/100 mL should be carefully followed for at least a week, even if they have received diethyldithiocarbamate (DDC) (Sunderman, 1971).
    6.3.4) DISPOSITION/EYE EXPOSURE
    6.3.4.5) OBSERVATION CRITERIA/EYE
    A) Nickel carbonyl can be absorbed through the eye (Finkel, 1983). Persons exposed to nickel carbonyl should be carefully observed for at least one week for the possible development of delayed symptoms (Proctor et al, 1988).
    B) Observe patients with eye exposure carefully for development of systemic signs and symptoms, and follow treatment recommendations in the INHALATIONAL EXPOSURE section where appropriate.

Monitoring

    A) Monitor serum electrolytes, renal function and CBC. Institute continuous cardiac monitoring and obtain an ECG.
    B) Monitor urinary nickel concentrations after suspected exposure and during chelation. Blood nickel carbonyl concentrations are not clinically useful since nickel carbonyl is rapidly metabolized and eliminated. Nickel carbonyl is not typically measurable in the blood of exposed individuals. Urinary nickel concentrations are the best indicator of the severity of poisoning, and urinary nickel concentrations correlate well with clinical symptoms in acute exposures.
    C) Some authors suggest monitoring carboxyhemoglobin concentrations as carbon monoxide is a result of nickel carbonyl decomposition. Monitor symptomatic patients as indicated. Inhalation of inhaled nickel carbonyl rapidly decomposes to nickel and carbon monoxide.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) Ingestion of nickel carbonyl is UNLIKELY, because exposures are usually to the gas. Ingestion would most likely occur in persons having direct access to cylinders of condensed nickel carbonyl.
    B) DILUTION
    1) If no respiratory compromise is present, administer milk or water as soon as possible after ingestion. The exact ideal amount is unknown; no more than 8 ounces (240 mL) in adults and 4 ounces (120 mL) in children is recommended to minimize the risk of vomiting (Caravati, 2004).
    2) USE OF DILUENTS IS CONTROVERSIAL: While experimental models have suggested that immediate dilution may lessen caustic injury (Homan et al, 1993; Homan et al, 1994; Homan et al, 1995), this has not been adequately studied in humans.
    3) DILUENT TYPE: Use any readily available nontoxic, cool liquid. Both milk and water have been shown to be effective in experimental studies of caustic ingestion (Maull et al, 1985; Rumack & Burrington, 1977; Homan et al, 1995; Homan et al, 1994; Homan et al, 1993).
    4) ADVERSE EFFECTS: Potential adverse effects include vomiting and airway compromise (Caravati, 2004).
    5) CONTRAINDICATIONS: Do NOT attempt dilution in patients with respiratory distress, altered mental status, severe abdominal pain, nausea or vomiting, or patients who are unable to swallow or protect their airway. Diluents should not be force fed to any patient who refuses to swallow (Rao & Hoffman, 2002).
    C) INHALATION
    1) 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.
    2) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    3) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.
    D) DERMAL
    1) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) Ingestion of nickel carbonyl is UNLIKELY, because exposures are usually to the gas. Ingestion would most likely occur in persons having direct access to cylinders of condensed nickel carbonyl.
    B) DILUTION
    1) If no respiratory compromise is present, administer milk or water as soon as possible after ingestion. The exact ideal amount is unknown; no more than 8 ounces (240 mL) in adults and 4 ounces (120 mL) in children is recommended to minimize the risk of vomiting (Caravati, 2004).
    2) USE OF DILUENTS IS CONTROVERSIAL: While experimental models have suggested that immediate dilution may lessen caustic injury (Homan et al, 1993; Homan et al, 1994; Homan et al, 1995), this has not been adequately studied in humans.
    3) DILUENT TYPE: Use any readily available nontoxic, cool liquid. Both milk and water have been shown to be effective in experimental studies of caustic ingestion (Maull et al, 1985; Rumack & Burrington, 1977; Homan et al, 1995; Homan et al, 1994; Homan et al, 1993).
    4) ADVERSE EFFECTS: Potential adverse effects include vomiting and airway compromise (Caravati, 2004).
    5) CONTRAINDICATIONS: Do NOT attempt dilution in patients with respiratory distress, altered mental status, severe abdominal pain, nausea or vomiting, or patients who are unable to swallow or protect their airway. Diluents should not be force fed to any patient who refuses to swallow (Rao & Hoffman, 2002).
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treat significant vomiting and/or dehydration with IV fluids and antiemetics in cases of severe vomiting. Administer supplemental oxygen for hypoxia and use bronchodilators and corticosteroids as needed for bronchospasm.

Inhalation Exposure

    6.7.1) DECONTAMINATION
    A) DECONTAMINATION
    1) 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.
    2) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    3) 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.
    4) Remove contaminated clothing and wash exposed skin to prevent further exposure.
    6.7.2) TREATMENT
    A) OXYGEN
    1) Administer 100% humidified oxygen as necessary.
    2) Carbon monoxide exposure may also be present. Refer to the CARBON MONOXIDE management for more information.
    B) MONITORING OF PATIENT
    1) The first phase of nickel carbonyl intoxication is deceptive in its lack of severe symptoms. Nickel carbonyl is an extremely toxic gas. If inhalational exposure is suspected, the patient needs to be evaluated by monitoring urinary nickel levels, with treatment instituted as described below under DIETHYLDITHIOCARBAMATE.
    2) Monitor serum electrolytes, renal function and CBC. Institute continuous cardiac monitoring and obtain an ECG.
    3) Monitor urinary nickel concentrations after suspected exposure and during chelation. Blood nickel carbonyl levels are not clinically useful since nickel carbonyl is rapidly metabolized and eliminated. Nickel carbonyl is not typically measurable in the blood of exposed individuals. Urinary nickel concentrations levels are the best indicator of the severity of poisoning, and urinary nickel concentrations correlate well with clinical symptoms in acute exposures.
    4) Some authors suggest monitoring carboxyhemoglobin levels as carbon monoxide is a result of nickel carbonyl decomposition. Monitor symptomatic patients as indicated. Inhalation of inhaled nickel carbonyl rapidly decomposes to nickel and carbon monoxide.
    C) 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).
    D) CHELATION THERAPY
    1) DIETHYLDITHIOCARBAMATE - AVAILABILITY
    a) Case reports suggest that diethyldithiocarbamate (DDC) may be efficacious in treatment of human nickel carbonyl poisoning (Sunderman, 1979; Sunderman, 1990); however it is NOT pharmaceutically available in the United States (Curtis & Haggerty, 2011).
    b) Pharmaceutical-grade DDC may be available through a compounding pharmacy; contact a regional poison center to assist with treatment (Curtis & Haggerty, 2011).
    c) DDC seems to be effective in animal studies, primarily when administered rapidly after exposure. Effects are seen with administration 8 hours post exposure, but the agent appears ineffective at 24 hours (Bradberry & Vale, 1999).
    2) INDICATIONS
    a) Collect an 8 hour urine sample immediately after exposure. Recommended treatment, as presented by Sunderman is as follows (Sunderman, 1971; Sunderman, 1990):
    1) Urinary nickel levels of -
    a) Less than 10 mcg/dL = Mild exposure: Delayed, severe symptoms are not expected. Diethyldithiocarbamate (DDC) is usually unnecessary. If severe symptoms develop, admit the patient and give DDC as outlined for Moderate exposure.
    b) 10 to 50 mcg/dL = Moderate exposure: Delayed symptoms possible. Day one: DDC should be administered orally 35 to 45 mg/kg total dose on day 1; give as divided doses to decrease nausea.
    1) Suggested divided dosage schedule for a 72.7 kg adult:
    1) 1.0 gram total (give 5 - 0.2 g capsules) within the first hour
    2) 0.8 gram total (give 4 - 0.2 g capsules) from hour 1 to hour 4
    3) 0.6 gram total (give 3 - 0.2 g capsules) from hour 4 to hour 8
    4) 0.4 gram total (give 2 - 0.2 g capsules) between hour 8 to hour 16
    2) After day 1, give 400 mg every 8 hours until the patient is symptom free and the urinary nickel is less than 10 mcg/dL.
    c) Greater than 50 micrograms/deciliter = severe exposure - Serious illness possible. Initial dose of DDC parenterally is 25 milligrams/kilogram. Preparation of diethyldithiocarbamate (DDC) for parenteral injection: Add 10 mL of sterile solution of phosphate buffer (0.5 g NaH(2)PO(4) per 100 mL) to 1 g of powdered, sterile diethyldithiocarbamate (DDC).
    1) Additional dosing should be based on clinical presentation. Severe cases may require 100 mg/kg for the first 24 hours.
    b) TREATMENT IF EXPOSURE LEVEL UNCERTAIN
    1) If there is doubt as to the severity of the exposure, give 2 g of DDC orally in divided doses. Additional treatment should be based on symptoms and urinary nickel levels (Sunderman, 1971; Sunderman, 1990). Based upon animal studies, it appears that the antidote is most effective when given shortly after exposure (Bradberry & Vale, 1999). Therapy should probably not be delayed while awaiting diagnostic data.
    c) PREVENTION OF NAUSEA
    1) Nausea usually develops if 2 g of diethyldithiocarbamate (DDC) are given together, thus divided doses are necessary. Sunderman (1990) has recommended oral administration of 0.2 g DDC with water every 2 min for 5 doses along with 0.2 g sodium bicarbonate in order to reduce nausea. Additional treatment with DDC should be based on the patients symptoms and urinary nickel levels.
    d) AVOID ETHANOL
    1) Patients who receive diethyldithiocarbamate (DDC) should avoid ingestion of ethanol for one week after treatment or they may experience symptoms similar to those occurring after treatment with Antabuse (Sunderman, 1971).
    E) DISULFIRAM
    1) Disulfiram (Antabuse) is metabolized to 2 molecules of diethyldithiocarbamate (DDC) (Sunderman, 1981). If DDC is not available, disulfiram may prove of some use (Sunderman, 1981). However, there are no controlled clinical trails evaluating its efficacy (Bradberry & Vale, 1999).
    2) DOSE: In one study, the disulfiram regimen was 750 mg orally ever 8 hours for 24 hours followed by 250 mg every 8 hours (Curtis & Haggerty, 2011).
    3) CASE REPORT: Disulfiram administered for 2 days, followed by several days of diethyldithiocarbamate (DDC), were used to treat a case of significant nickel carbonyl toxicity. The urinary nickel level was 1,720 mcg/L and serum nickel level 146 mcg/L. Disulfiram was initially administered since diethyldithiocarbamate (DDC) was not available. The patient improved. The contribution of disulfiram to the clinical outcome cannot be determined (Dean & Krenzelok, 1991).
    4) ANIMAL DATA: Preliminary studies with rats indicate that oral disulfiram reduced mortality from nickel carbonyl toxicity in rats at a dose of 1000 milligrams/kilogram but not at 500 mg/kg (Baselt & Hanson, 1982). However, in some animal studies, disulfiram increased nickel concentration in brain tissue (Curtis & Haggerty, 2011).
    a) In the same study diethyldithiocarbamate (DDC) and d-penicillamine reduced mortality at oral doses of 1000, 500, 250 and 125 milligrams/kilogram (Baselt & Hanson, 1982).
    F) CHELATING AGENT
    1) Other chelating agents do not appear to be effective
    2) DIMERCAPROL
    a) Dimercaprol (BAL) increased the toxicity of nickel carbonyl by a factor of 2 in rats (Sunderman, 1971).
    3) PENICILLAMINE
    a) Although penicillamine has an effect, diethyldithiocarbamate (DDC) is the preferred chelating agent (Goyer, 1996a).
    b) Some studies found PENICILLAMINE had questionable effects as compared to diethyldithiocarbamate and had greater side effects when tested in animals (Sunderman, 1981). Another study reported d-penicillamine was superior to sodium diethyldithiocarbamate when given 6 hours after nickel carbonyl inhalation by rats (Baselt et al, 1977).
    4) EDTA
    a) EDTA: It had no antidotal effect in animal studies (West & Sunderman, 1958) (Sunderman, 1971).
    G) SEIZURE
    1) Seizures occur with severe exposures to nickel carbonyl. Onset may be delayed by several days (Finkel, 1983).
    2) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    3) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    4) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    5) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2010; Chin et al, 2008).
    6) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    7) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    H) 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) DERMAL DECONTAMINATION
    1) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
    6.9.2) TREATMENT
    A) BURN
    1) APPLICATION
    a) These recommendations apply to patients with MINOR chemical burns (FIRST DEGREE; SECOND DEGREE: less than 15% body surface area in adults; less than 10% body surface area in children; THIRD DEGREE: less than 2% body surface area). Consultation with a clinician experienced in burn therapy or a burn unit should be obtained if larger area or more severe burns are present. Neutralizing agents should NOT be used.
    2) DEBRIDEMENT
    a) After initial flushing with large volumes of water to remove any residual chemical material, clean wounds with a mild disinfectant soap and water.
    b) DEVITALIZED SKIN: Loose, nonviable tissue should be removed by gentle cleansing with surgical soap or formal skin debridement (Moylan, 1980; Haynes, 1981). Intravenous analgesia may be required (Roberts, 1988).
    c) BLISTERS: Removal and debridement of closed blisters is controversial. Current consensus is that intact blisters prevent pain and dehydration, promote healing, and allow motion; therefore, blisters should be left intact until they rupture spontaneously or healing is well underway, unless they are extremely large or inhibit motion (Roberts, 1988; Carvajal & Stewart, 1987).
    3) TREATMENT
    a) TOPICAL ANTIBIOTICS: Prophylactic topical antibiotic therapy with silver sulfadiazine is recommended for all burns except superficial partial thickness (first-degree) burns (Roberts, 1988). For first-degree burns bacitracin may be used, but effectiveness is not documented (Roberts, 1988).
    b) SYSTEMIC ANTIBIOTICS: Systemic antibiotics are generally not indicated unless infection is present or the burn involves the hands, feet, or perineum.
    c) WOUND DRESSING:
    1) Depending on the site and area, the burn may be treated open (face, ears, or perineum) or covered with sterile nonstick porous gauze. The gauze dressing should be fluffy and thick enough to absorb all drainage.
    2) Alternatively, a petrolatum fine-mesh gauze dressing may be used alone on partial-thickness burns.
    d) DRESSING CHANGES:
    1) Daily dressing changes are indicated if a burn cream is used; changes every 3 to 4 days are adequate with a dry dressing.
    2) If dressing changes are to be done at home, the patient or caregiver should be instructed in proper techniques and given sufficient dressings and other necessary supplies.
    e) Analgesics such as acetaminophen with codeine may be used for pain relief if needed.
    4) TETANUS PROPHYLAXIS
    a) The patient's tetanus immunization status should be determined. Tetanus toxoid 0.5 milliliter intramuscularly or other indicated tetanus prophylaxis should be administered if required.
    B) ACUTE ALLERGIC REACTION
    1) NICKEL DERMATITIS: DISULFIRAM (Antabuse(R)) which is metabolized to 2 molecules of diethyldithiocarbamate (DDC), has been shown effective in clearing cases of nickel dermatitis. 50 to 100 mg/day were used in the treatment . Disulfiram does not facilitate the oral absorption of nickel as does DDC (Menne & Kaaber, 1978; Christensen & Kristensen, 1982).
    2) DIETHYLDITHIOCARBAMATE: Spruit et al (1978) tried to treat contact dermatitis with diethyldithiocarbamate (DDC). Although the amount of nickel excreted increased greatly, it did not prevent hypersensitive eczematous skin reactions, even when an excess of the chelating agent was present.
    3) CYCLOSPORINE: Thomson et al (1986) demonstrated an inhibition of skin patch test responses to nickel in the presence of topical cyclosporine (5% w/v) in 4 of 18 patients with proven nickel contact dermatitis.
    4) TRIENTINE: Burrows et al (1986) treated 23 nickel-sensitive patients with hand eczema with trientine (triethylenetetramine) 300 mg daily and a placebo in a double-blind, crossover trial. There was significant improvement in the hand eczema and no detectable increase in urinary nickel excretion.
    C) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Abstracts

Case Reports

    A) ROUTE OF EXPOSURE
    1) INHALATION
    a) ADULT: A 46-year-old man inhaled nickel carbonyl from contaminated clothing for several hours. Initial symptoms of headache, shortness of breath, chest pain, and weakness progressed and he presented after 24 hours. He was tachypneic and had chest tightness and paresthesias. The chest x-ray showed ARDS. He was treated with disulfiram 750 mg every 8 hours for 24 hours, then 250 mg every 8 hours. On the second day, dithiocarb was started. He required aggressive therapy with methylprednisolone, aminophylline, albuterol, antibiotics, oxygen (70 to 80%), and CPAP. He gradually improved and was discharged on the 18th day. Pulmonary function tests showed moderate restrictive impairment, which resolved by 3-month follow-up (Kurta et al, 1993a).

Range Of Toxicity

Summary

    A) TOXICITY: The estimated lethal dose (inhalation) in humans has ranged from 3 to 30 ppm for a 30 minute exposure. 2 ppm is considered immediately dangerous to life and health. Maximum tolerated dose: The threshold limit value for an 8 hour work day (TLV TWA) is 0.05 ppm as nickel. It has been recommended that a plasma level of 10 mcg/L be set as a biomonitoring limit for nickel refinery workers. Serum nickel in an unexposed person is 2 to 10 mcg/L.

Minimum Lethal Exposure

    A) ROUTE OF EXPOSURE
    1) INHALATION: It has been estimated that inhalation of 30 ppm may be lethal to humans exposed for 30 minutes (AIHA, 1968; Vuopala et al, 1970; Hathaway et al, 1996; Harbison, 1998).

Workplace Standards

    A) ACGIH TLV Values for CAS13463-39-3 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Editor's Note: The listed values are recommendations or guidelines developed by ACGIH(R) to assist in the control of health hazards. They should only be used, interpreted and applied by individuals trained in industrial hygiene. Before applying these values, it is imperative to read the introduction to each section in the current TLVs(R) and BEI(R) Book and become familiar with the constraints and limitations to their use. Always consult the Documentation of the TLVs(R) and BEIs(R) before applying these recommendations and guidelines.
    a) Under Study
    1) Nickel carbonyl
    a) TLV:
    1) TLV-TWA:
    2) TLV-STEL:
    3) TLV-Ceiling:
    b) Notations and Endnotes:
    1) Carcinogenicity Category: Not Listed
    2) Codes: Not Listed
    3) Definitions: Not Listed
    c) TLV Basis - Critical Effect(s):
    d) Molecular Weight:
    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) Adopted Value
    1) Nickel carbonyl, as Ni
    a) TLV:
    1) TLV-TWA: 0.05 ppm
    2) TLV-STEL:
    3) TLV-Ceiling:
    b) Notations and Endnotes:
    1) Carcinogenicity Category: Not Listed
    2) Codes: Not Listed
    3) Definitions: Not Listed
    c) TLV Basis - Critical Effect(s): Lung and nasal cancer
    d) Molecular Weight: 170.73
    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 CAS13463-39-3 (National Institute for Occupational Safety and Health, 2007):
    1) Listed as: Nickel carbonyl
    2) REL:
    a) TWA: 0.001 ppm (0.007 mg/m(3))
    b) STEL:
    c) Ceiling:
    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: 2 ppm
    b) Note(s): Ca
    1) Ca: NIOSH considers this substance to be a potential occupational carcinogen (See Appendix A).

    C) Carcinogenicity Ratings for CAS13463-39-3 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed ; Listed as: Nickel carbonyl
    2) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed ; Listed as: Nickel carbonyl, as Ni
    3) EPA (U.S. Environmental Protection Agency, 2011): B2 ; Listed as: Nickel carbonyl
    a) B2 : Probable human carcinogen - based on sufficient evidence of carcinogenicity in animals.
    4) 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): 1 ; Listed as: Nickel carbonyl
    a) 1 : The agent (mixture) is carcinogenic to humans. The exposure circumstance entails exposures that are carcinogenic to humans. This category is used when there is sufficient evidence of carcinogenicity in humans. Exceptionally, an agent (mixture) may be placed in this category when evidence of carcinogenicity in humans is less than sufficient but there is sufficient evidence of carcinogenicity in experimental animals and strong evidence in exposed humans that the agent (mixture) acts through a relevant mechanism of carcinogenicity.
    5) NIOSH (National Institute for Occupational Safety and Health, 2007): Ca ; Listed as: Nickel carbonyl
    a) Ca : NIOSH considers this substance to be a potential occupational carcinogen (See Appendix A in the NIOSH Pocket Guide to Chemical Hazards).
    6) MAK (DFG, 2002): Not Listed
    7) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS13463-39-3 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Listed as: Nickel carbonyl (as Ni)
    2) Table Z-1 for Nickel carbonyl (as Ni):
    a) 8-hour TWA:
    1) ppm: 0.001
    a) Parts of vapor or gas per million parts of contaminated air by volume at 25 degrees C and 760 torr.
    2) mg/m3: 0.007
    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

Pharmacology Toxicology

Toxicologic Mechanism

    A) PULMONARY DAMAGE -
    1) Animal studies have found that the pulmonary parenchyma is the target tissue for nickel carbonyl toxicity regardless of route of exposure (National Academy of Sciences, 1975).
    2) Type I alveolar cells are principally affected, but type II alveolar cells are also damaged as a direct effect of nickel carbonyl (Sunderman, 1977; Vuopala et al, 1970).
    3) The cause of death has been attributed chiefly to impaired gas exchange in the lungs secondary to the parenchymal tissue damage (Sunderman & Kincaid, 1954).
    B) ROLE OF CARBON MONOXIDE -
    1) The mechanisms of toxicity following inhalation have been considered to be due in part to carbon monoxide (Sax & Lewis, 1984), an idea refuted by others (Vuopala et al, 1970).
    2) Animal studies have reported carbon monoxide production as a result of nickel carbonyl decomposition in vivo, with carboxyhemoglobinemia reported after IV injection of nickel carbonyl in rats (National Academy of Sciences, 1975).
    3) Another study in dogs, cats and rabbits reported that carbon monoxide poisoning was not a major factor in toxicity (National Academy of Sciences, 1975).
    4) Human cases of exposure have reported an absence of carboxyhemoglobinemia or signs of carbon monoxide poisoning (Sunderman & Kincaid, 1954; Vuopala et al, 1970).
    C) BIOCHEMICAL MECHANISMS - Animal studies have shown that nickel carbonyl inhibits numerous enzyme activities and disrupts other pathways involved in RNA synthesis (National Academy of Sciences, 1975).

Physicochemical

Physical Characteristics

    A) Nickel carbonyl is a volatile, colorless to yellow liquid or gas with a characteristic odor described as musty or sooty (ACGIH, 1991; Budavari, 1996) AAR, 1998; (HSDB , 2000).
    B) Nickel carbonyl can be found as colorless needles (HSDB , 2000).

Ph

    1) No information found at the time of this review.

Molecular Weight

    A) 170.75

Other

    A) ODOR THRESHOLD
    1) 1-3 ppm (CHRIS , 2000; ACGIH, 1991)

References

General Bibliography

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