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NITRIC OXIDE

See Occupational Exposure Standards

Human Health Effects:

Toxicity Summary:

IDENTIFICATION: Nitric oxide is a colorless, odorless gas that is only slightly soluble in water. The main sources of nitrogen oxides (including nitric oxide) emissions are combustion processes. Fossil fuel power stations, motor vehicles and domestic combustion appliances emit nitrogen oxides, mostly in the form of nitric oxide. Nitric oxide can be present at significant concentrations in ambient air and in indoor air. HUMAN EXPOSURE: Human exposure to nitrogen oxides varies from indoors to outdoors, from cities to the countryside, and with the time of day and season. Nitric oxide is readily oxidized to nitrogen dioxide and peroxidation then occurs. Because of the concurrent exposure to some nitrogen dioxide in nitric oxide exposures, it is difficult to discriminate nitric oxide effects from nitrogen dioxide. Nitric oxide functions as an intracellular second messenger modulating a wide variety of essential enzymes, and it inhibits its own production (e.g., negative feedback). Nitric oxide activates guanylate cyclase which in turn increases intracellular cGMP levels. Nitric oxide is acknowledged as an important endogenous second messenger within several organ systems. At certain levels, inhaled nitric oxide concentrations can cause vasodilation in the pulmonary circulation without affecting the systemic circulation. The lowest effective concentration is not established. Information on pulmonary function and lung host defenses consequent to nitric oxide exposure are too limited for any conclusions to be drawn. Relatively high concentrations have been used in clinical applications for brief periods without reported adverse effects. ANIMAL STUDIES: The toxicological database for nitric oxide is small, relative to nitrogen dioxide. It is often difficult to obtain pure nitric oxide in air without some contamination with nitrogen dioxide. Endogenous nitric oxide synthesis occurs by nitric oxide formation from physiological substrate in cells of many of the organ systems such as nerve tissue, blood vessels and the immune system. Nitric oxide may be more potent than nitrogen dioxide in introducing certain changes in lung morphology. In a study examining the effects of nitric oxide on bacterial defenses, there were no statistically significant effects for either sex at any of the time points studied. In vitro data indicate that nitric oxide stimulates guanylate cyclase and leads to smooth muscle relaxation and vasodilation and functional effects on the nervous system. These effects are probably responsible for vasodilation in the pulmonary circulation and an acute bronchodilator effect of inhaled nitric oxide. Nitric oxide has an affinity for haem-bound iron which is two times higher than that of carbon monoxide. This affinity leads to the formation of methaemoglobin and the stimulation of guanylate cyclase. Furthermore, nitric oxide reacts with thiol-associated iron in enzymes and eventually displaces the iron. This is a possible mechanism for the cytotoxic effects of nitric oxide. Nitric oxide can deaminate DNA, evoke DNA chain breaks, and inhibit DNA polymerase and ribonucleotide reductase. It might be antimitogenic and inhibit T cell proliferation in rat spleen cells.
[World Health Organization/International Programme on Chemical Safety. Environmental Health Criteria 188. Nitrogen oxides. pp. 1-18, 270-276, 331 (1997)]**PEER REVIEWED**

Human Toxicity Excerpts:

CHIEF TOXIC EFFECT ... ASCRIBED TO FORMATION OF METHEMOGLOBIN & SUBSEQUENT ACTION ON CNS.
[American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991.1090]**PEER REVIEWED**

SYMPTOMATOLOGY: 1. Usually no symptoms occur at the time of exposure, with the exception of a slight cough and perhaps fatigue and nausea. Exposure to low concn may result in impaired pulmonary defense mechanisms (macrophages, cilia) with complications. ... 2. Only very concn nitrous fumes produce prompt coughing, choking, headache, nausea, abdominal pain, and dyspnea (tightness and burning pain in the chest). 3. A symptom-free period follows exposure and lasts for 5-72 hr. 4. Fatigue, uneasiness, restlessness, cough, hyperpnea, and dyspnea appear insidiously, as the adult respiratory distress syndrome gradually develops. /Nitrogen oxides/
[Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. III-323]**PEER REVIEWED**

SYMPTOMATOLOGY: 5. Increasingly rapid and shallow respirations, cyanosis, mild or violent coughing with frothy expectoration and physical signs of pulmonary edema (for example rales and rhonchi). The vital capacity is rapidly reduced. A serous exudate may develop in the pleural cavity, but its volume is usually small. 6. Anxiety, mental confusion, lethary and finally loss of consciousness. 7. A weak, rapid pulse, dilated heart, venous congestion, intense cyanosis and severe hemoconcentration. Circulatory collapse is secondary to anoxia and hemoconcentration. 8. An asphyxial death due to blockade of gas exchange in the lungs. Death commonly occurs within a few hours after the first evidence of pulmonary edema. /Nitrogen oxides/
[Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. III-323]**PEER REVIEWED**

SYMPTOMATOLOGY: 9. Sometimes a second acute phase follows the initial pulmonary reaction after a quiescent period of several weeks. Cough, tachypnea, dyspnea, fever, tachycardia and cyanosis at this stage are usually due to bronchiolitis obliterans. The relapse may be abrupt and fulminating, leading either to death or a slow convalescence. 10. In nonfatal cases, convalescence may be complicated by infectious bronchitis, bronchiolitis obliterans, pneumonia and general asthenia. Rarely diffuse pulmonary fibrosis may develop. /Nitrogen oxides/
[Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. III-323]**PEER REVIEWED**

... SLOWLY EVOLVING BUT PROGRESSIVE INFLAMMATION OF LUNGS CAUSES PROFUSE EXUDATION INTO ALVEOLAR SPACE. FLUID LOSS FROM BLOOD PRODUCES MASSIVE PULMONARY EDEMA & SEVERE HEMOCONCENTRATION. ... IMPAIRED GAS EXCHANGE IN LUNG, BREATHING ... RAPID & CYANOSIS ... INTENSE. DEATH ... DUE TO ASPHYXIA ... /NITROGEN OXIDES/
[Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. III-320]**PEER REVIEWED**

CONTINUED INHALATION OF LOW CONCN CAUSES ... CORROSION OF TEETH ...
[U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Volume II. Washington, D.C.: U.S. Government Printing Office, 1984-5.]**PEER REVIEWED**

... INTOXICATION OF 2 PATIENTS ... FROM USE ... OF 75% NITROUS OXIDE IN OXYGEN THAT WAS CONTAMINATED WITH MORE THAN 1.5% NITRIC OXIDE ... /INCLUDED/ CYANOSIS & METHEMOGLOBINEMIA ... ONE DIED 18 HR AFTER ANESTHESIA ...
[American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991.1091]**PEER REVIEWED**

... SEVERE SYMPTOMS & DEATH OF UNKNOWN ETIOLOGY HAVE BEEN REPORTED IN FARMERS WHO WERE WORKING IN OR NEAR SILOS ... ("SILO-FILLERS' DISEASE") RESULTED FROM ACUTE EXPOSURE TO OXIDES OF NITROGEN. /NITROGEN OXIDES/
[Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. III-320]**PEER REVIEWED**

Moist skin facilitates the formation of nitric acid causing severe yellow-colored burns. /Nitrogen oxides, from table/
[Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 534]**PEER REVIEWED**

... exposed healthy subjects and smokers to 12,300 to 47, 970 ug/cu m (10 to 39 ppm) NO for 15 min. Total respiratory resistance increased significantly (10-12%) after exposure to greater than or equal to 24,600 ug/cu m (20 ppm) NO.
[WHO; Environ Health Criteria 188: Nitric oxide p.317 (1997)]**PEER REVIEWED**

Continued exposure to low concentration of the fumes, insufficient to cause pulmonary edema, is said to result in chronic irritation of the respiratory tract, with cough, headache, loss of appetite, dyspepsia, corrosion of the teeth, and gradual loss of strength.
[Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 2419]**PEER REVIEWED**

Skin, Eye and Respiratory Irritations:

Irritation of eyes, nose & throat.
[Sittig, M. Handbook of Toxic and Hazardous Chemicals and Carcinogens, 1985. 2nd ed. Park Ridge, NJ: Noyes Data Corporation, 1985. 649]**PEER REVIEWED**

/HAZARD WARNING:/ Only slightly irritating to upper respiratory tract and eyes ... dangerous amounts of fumes may ... be inhaled before any discomfort is noticed.
[Environment Canada; Tech Info for Problem Spills: Nitric Acid (Draft) p.98 (1985)]**PEER REVIEWED**

Higher concentrations (60-150 ppm) cause immediate irritation of the nose and throat, with coughing and burning in the throat and chest. These symptoms often clear upon breathing fresh air, and the worker may feel well for several hours. Some 6-24 hours after exposure, a sensation of tightness and burning in the chest develops, followed by shortness of breath, sleeplessness, and restlessness.
[Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 2419]**PEER REVIEWED**

Medical Surveillance:

Consider the points of attack, /respiratory system, lung/ in preplacement and periodic physical examination.
[Sittig, M. Handbook of Toxic and Hazardous Chemicals and Carcinogens, 1985. 2nd ed. Park Ridge, NJ: Noyes Data Corporation, 1985. 649]**PEER REVIEWED**

Probable Routes of Human Exposure:

INDUSTRIAL EXPOSURES CAN TAKE PLACE WHEREVER NITRIC ACID IS MADE OR USED & HAS OCCURRED MOST COMMONLY WHERE METALS ARE DIPPED IN ACID BATHS. ELECTRIC ARC WELDING, & TO LESSER EXTENT GAS WELDING, CAN GENERATE HAZARDOUS CONCN. FERMENTATION OF SILAGE PRODUCES HIGH CONCN, & POISONINGS OF FARMERS HAVE OCCURRED.
[Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. 4097]**PEER REVIEWED**

APPROX 1.5 MILLION USA WORKERS ARE EXPOSED DIRECTLY OR INDIRECTLY TO OXIDES OF NITROGEN (NITRIC OXIDE, NITROGEN DIOXIDE, NITRIC ACID) THROUGH OCCUPATIONS INVOLVING WELDING, SILO FILLING & EXPLOSIVE MANUFACTURE. /FROM TABLE/
[Doull, J., C.D. Klaassen, and M. D. Amdur (eds.). Casarett and Doull's Toxicology. 2nd ed. New York: Macmillan Publishing Co., 1980. 266]**PEER REVIEWED**

Emergency Medical Treatment:

Emergency Medical Treatment:

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The following Overview, *** NITRIC OXIDE ***, is relevant for this HSDB record chemical.

Life Support:
   o   This overview assumes that basic life support measures
       have been instituted.
Clinical Effects:
  0.2.1 SUMMARY OF EXPOSURE
   0.2.1.1 ACUTE EXPOSURE
     A)  WITH POISONING/EXPOSURE
      1)  Nitric oxide inhalation is approximately 1/5 as toxic
          as nitrogen dioxide. It is an inhalant toxin and is a
          compressed gas or vapor at normal temperatures. Human
          toxicity data is very limited.
      2)  Initial signs/symptoms may include coughing and
          burning in the throat and chest, nausea, fatigue and
          shortness of breath.
      3)  Severe exposures to nitric oxide may result in
          methemoglobinemia, hypoxemia, pulmonary edema, lung
          inflammation and decreased pulmonary vascular
          resistance, particularly in patients with heart
          disease or pulmonary hypertension.
       a)  The TLV for nitric oxide is based on its ability to
           form methemoglobin.
      4)  Nitric oxide is a skin, eye, and mucous membrane
          irritant.
      5)  Latent symptoms may include nervousness, rapid and
          shallow breathing, cyanosis, mental confusion, and
          finally loss of consciousness.
  0.2.3 VITAL SIGNS
   0.2.3.1 ACUTE EXPOSURE
     A)  WITH POISONING/EXPOSURE
      1)  Dyspnea may develop after a delay of several hours.
  0.2.4 HEENT
   0.2.4.1 ACUTE EXPOSURE
     A)  WITH POISONING/EXPOSURE
      1)  Conjunctivitis, not necessarily due to nitric oxide,
          is likely to occur under conditions where nitrogen
          dioxide would be formed.
  0.2.5 CARDIOVASCULAR
   0.2.5.1 ACUTE EXPOSURE
     A)  WITH POISONING/EXPOSURE
      1)  Toxicity may result in hypotension.
  0.2.6 RESPIRATORY
   0.2.6.1 ACUTE EXPOSURE
     A)  WITH POISONING/EXPOSURE
      1)  Nitric oxide has a markedly less toxic effect on human
          lung function than does nitrogen dioxide. Nitric oxide
          is oxidized in air to form nitrogen dioxide which may
          react with water in the respiratory tract at toxic
          concentrations to form nitric acid.
      2)  Cough, hyperpnea and dyspnea may be seen after some
          delay. Rapid and shallow respirations, coughing and
          physical signs of pulmonary edema may develop.
          Pulmonary edema may be delayed 4 to 24 hours. Gas
          exchange in the lungs is reduced, and asphyxia may
          develop.
   0.2.6.2 CHRONIC EXPOSURE
     A)  WITH POISONING/EXPOSURE
      1)  Impairment of pulmonary function may occur in the
          absence of acute symptoms.
     B)  ANIMAL STUDIES - Emphysematous lesions were produced in
         mice.
  0.2.7 NEUROLOGIC
   0.2.7.1 ACUTE EXPOSURE
     A)  WITH THERAPEUTIC USE
      1)  Paralysis and areflexia were noted in one case of
          therapeutic dosing with nitric oxide.
     B)  WITH POISONING/EXPOSURE
      1)  Fatigue, restlessness, anxiety, mental confusion,
          lethargy, and loss of consciousness may be noted.
  0.2.8 GASTROINTESTINAL
   0.2.8.1 ACUTE EXPOSURE
     A)  WITH POISONING/EXPOSURE
      1)  Nausea and abdominal pain may be occur.
  0.2.11 ACID-BASE
   0.2.11.1 ACUTE EXPOSURE
     A)  WITH THERAPEUTIC USE
      1)  Acidosis may occur secondary to anoxia.
     B)  WITH POISONING/EXPOSURE
      1)  Acidosis may occur secondary to anoxia.
  0.2.13 HEMATOLOGIC
   0.2.13.1 ACUTE EXPOSURE
     A)  WITH POISONING/EXPOSURE
      1)  Methemoglobinemia may occur following acute toxic
          exposures to nitric oxide.
  0.2.14 DERMATOLOGIC
   0.2.14.1 ACUTE EXPOSURE
     A)  WITH POISONING/EXPOSURE
      1)  Nitric oxide is a skin irritant.
  0.2.19 IMMUNOLOGIC
   0.2.19.2 CHRONIC EXPOSURE
     A)  WITH POISONING/EXPOSURE
      1)  Increased susceptibility to respiratory infection may
          occur following exposure to nitrogen dioxide.
  0.2.20 REPRODUCTIVE HAZARDS
    A)  Effects on newborns were seen in hamsters, mice, and
        rats. Methemoglobin inducers are considered harmful to
        the fetus.
  0.2.21 CARCINOGENICITY
   0.2.21.1 IARC CATEGORY
     A)  IARC Carcinogenicity Ratings for CAS10102-43-9 (IARC,
         2004):
      1)  Not Listed
     B)  IARC Carcinogenicity Ratings for CAS90880-94-7 (IARC,
         2004):
      1)  Not Listed
   0.2.21.2 HUMAN OVERVIEW
     A)  No carcinogenicity studies were found.
  0.2.22 GENOTOXICITY
    A)  Nitric oxide is genotoxic at the level of DNA
        inhibition, mutations in bacterial and mammalian cells,
        sister chromatid exchanges, and sex chromosome loss and
        nondisjunction in Drosophila.
  0.2.23 OTHER
   0.2.23.1 ACUTE EXPOSURE
     A)  WITH THERAPEUTIC USE
      1)  Abrupt withdrawal of therapeutic nitric oxide may
          result in hypoxemia, oxygen desaturation, and
          increased pulmonary hypertension.
     B)  WITH POISONING/EXPOSURE
      1)  Nitric oxide can be toxic by inhalation and absorption
          through the skin or eyes.
   0.2.23.2 CHRONIC EXPOSURE
     A)  WITH THERAPEUTIC USE
      1)  Nitrogen oxides are formed endogenously in the lung
          and respiratory tract and may play a role in airway
          and smooth muscle relaxation.
Laboratory:
   A)  Monitor pulmonary function in symptomatic patients.
   B)  Chest x-ray may be diagnostic and prognostic.
   C)  Monitor methemoglobin levels in symptomatic patients.
Treatment Overview:
  0.4.2 ORAL EXPOSURE
    A)  Because nitric oxide is a gas under ambient conditions,
        oral exposure normally does not occur.
  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 inhaled
        beta2 agonist and oral or parenteral corticosteroids.
    B)  Treatment of pulmonary edema caused by nitric oxide
        inhalation should be directed towards reversal of
        ventilatory failure by using oxygen in assisting
        ventilation. In patients with toxic bronchiolitis,
        steroids may be beneficial in decreasing the amount of
        inflammation.
    C)  ACUTE LUNG INJURY: Maintain ventilation and oxygenation
        and evaluate with frequent arterial blood gas or pulse
        oximetry monitoring. Early use of PEEP and mechanical
        ventilation may be needed.
    D)  METHEMOGLOBINEMIA: Administer 1 to 2 mg/kg of 1%
        methylene blue slowly IV in symptomatic patients.
        Additional doses may be required.
  0.4.4 EYE EXPOSURE
    A)  Significant eye exposure to nitric oxide is rare.
        However, this substance is a strong eye irritant due to
        the formation of nitric acid, which can permanently
        alter proteins. Because this reaction is relatively
        slow, permanent injury may possibly be prevented by
        IMMEDIATE DECONTAMINATION.
    B)  DECONTAMINATION: Irrigate exposed eyes with copious
        amounts of room temperature water for at least 15
        minutes. If irritation, pain, swelling, lacrimation, or
        photophobia persist, the patient should be seen in a
        health care facility.
  0.4.5 DERMAL EXPOSURE
    A)  OVERVIEW
     1)  Some chemicals can produce systemic poisoning by
         absorption through intact skin. Carefully observe
         patients with dermal exposure for the development of
         any systemic signs or symptoms and administer
         symptomatic treatment as necessary.
     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)  All patients with significant dermal exposure should be
         carefully observed for possible development of delayed
         clinical signs and symptoms. Follow treatment
         recommendations in the INHALATION EXPOSURE section
         where appropriate.
Range of Toxicity:
   A)  Nitric oxide inhalation is approximately 1/5 as toxic as
       nitrogen dioxide. Human toxicity data is very limited.
   B)  The TLV for nitric oxide is based on its ability to form
       methemoglobin.
   C)  Doses used in the treatment of pulmonary hypertension are
       usually in the range of 10 to 20 ppm; doses as high as 80
       ppm have been well tolerated.

[Rumack BH POISINDEX(R) Information System Micromedex, Inc., Englewood, CO, 2004; CCIS Volume 122, edition expires Nov, 2004. Hall AH & Rumack BH (Eds): TOMES(R) Information System Micromedex, Inc., Englewood, CO, 2004; CCIS Volume 122, edition expires Nov, 2004.]**PEER REVIEWED**

Antidote and Emergency Treatment:

Basic treatment: Establish a patent airway. Suction if necessary. Aggressive airway management may be needed. Encourage patient to take deep breaths. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuosly with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. ... /Nitrogen oxides (NOX) and related compounds/
[Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994.,p. 255-6]**PEER REVIEWED**

Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious or in respiratory arrest. Early intubation at the first signs of upper airway obstruction may be necessary. Positive-pressure ventilation techniques with a bag-valve-mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W TKO /SRP: "To keep open", minimal flow rate/. Consider drug therapy for pulmonary edema ... . Consider the use of vasopressors to treat hypotension without signs of hypovolemia ... . Administer 1% solution methylene blue if patient is symptomatic with severe hypoxia, cyanosis, and cardiac compromise not responding to oxygen. DIRECT PHYSICIAN ORDER ONLY ... . Use proparacaine hydrochloride to assist eye irrigation. /Nitrogen oxides (NOX) and related compounds/
[Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994. 256]**PEER REVIEWED**

Animal Toxicity Studies:

Toxicity Summary:

IDENTIFICATION: Nitric oxide is a colorless, odorless gas that is only slightly soluble in water. The main sources of nitrogen oxides (including nitric oxide) emissions are combustion processes. Fossil fuel power stations, motor vehicles and domestic combustion appliances emit nitrogen oxides, mostly in the form of nitric oxide. Nitric oxide can be present at significant concentrations in ambient air and in indoor air. HUMAN EXPOSURE: Human exposure to nitrogen oxides varies from indoors to outdoors, from cities to the countryside, and with the time of day and season. Nitric oxide is readily oxidized to nitrogen dioxide and peroxidation then occurs. Because of the concurrent exposure to some nitrogen dioxide in nitric oxide exposures, it is difficult to discriminate nitric oxide effects from nitrogen dioxide. Nitric oxide functions as an intracellular second messenger modulating a wide variety of essential enzymes, and it inhibits its own production (e.g., negative feedback). Nitric oxide activates guanylate cyclase which in turn increases intracellular cGMP levels. Nitric oxide is acknowledged as an important endogenous second messenger within several organ systems. At certain levels, inhaled nitric oxide concentrations can cause vasodilation in the pulmonary circulation without affecting the systemic circulation. The lowest effective concentration is not established. Information on pulmonary function and lung host defenses consequent to nitric oxide exposure are too limited for any conclusions to be drawn. Relatively high concentrations have been used in clinical applications for brief periods without reported adverse effects. ANIMAL STUDIES: The toxicological database for nitric oxide is small, relative to nitrogen dioxide. It is often difficult to obtain pure nitric oxide in air without some contamination with nitrogen dioxide. Endogenous nitric oxide synthesis occurs by nitric oxide formation from physiological substrate in cells of many of the organ systems such as nerve tissue, blood vessels and the immune system. Nitric oxide may be more potent than nitrogen dioxide in introducing certain changes in lung morphology. In a study examining the effects of nitric oxide on bacterial defenses, there were no statistically significant effects for either sex at any of the time points studied. In vitro data indicate that nitric oxide stimulates guanylate cyclase and leads to smooth muscle relaxation and vasodilation and functional effects on the nervous system. These effects are probably responsible for vasodilation in the pulmonary circulation and an acute bronchodilator effect of inhaled nitric oxide. Nitric oxide has an affinity for haem-bound iron which is two times higher than that of carbon monoxide. This affinity leads to the formation of methaemoglobin and the stimulation of guanylate cyclase. Furthermore, nitric oxide reacts with thiol-associated iron in enzymes and eventually displaces the iron. This is a possible mechanism for the cytotoxic effects of nitric oxide. Nitric oxide can deaminate DNA, evoke DNA chain breaks, and inhibit DNA polymerase and ribonucleotide reductase. It might be antimitogenic and inhibit T cell proliferation in rat spleen cells.
[World Health Organization/International Programme on Chemical Safety. Environmental Health Criteria 188. Nitrogen oxides. pp. 1-18, 270-276, 331 (1997)]**PEER REVIEWED**

Non-Human Toxicity Excerpts:

... /IT/ IS ABOUT 1/5 AN ACUTE TOXIC AS NITROGEN DIOXIDE, ASSUMING MINIMAL CONTAMINATION WITH NO2 & ... NO SYNERGISTIC ACTION.
[American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991.1090]**PEER REVIEWED**

ANIMAL STUDIES ... CITED IN WHICH 322 PPM ... PRODUCED 60% METHEMOGLOBINEMIA AFTER 6 HR.
[American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991.1090]**PEER REVIEWED**

... EMPHYSEMATOUS LESIONS IN MICE EXPOSED TO 10 PPM OF NITROGEN DIOXIDE FOR 2 HR/DAY, 5 DAYS/WK FOR VARIOUS PERIODS UP TO 30 WEEKS. ... MICE SIMILARLY EXPOSED TO 10 PPM OF NITRIC OXIDE SHOWED MUCH MORE PRONOUNCED EMPHYSEMATOUS CHANGES.
[Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. 4101]**PEER REVIEWED**

VERY HIGH LEVELS (UP TO 3500 PPB) OF NO(X) (MAINLY NITROGEN OXIDE) IN GREENHOUSES WERE INHIBITORY TO PLANT GROWTH. THE EFFECTS WERE NOT, HOWEVER, AS GREAT AS WOULD BE EXPECTED FROM SUCH HIGH CONCN.
[MANSFIELD TA ET AL; STUD ENVIRON SCI 21 (AIR POLLUT NITROGEN OXIDES): 595 (1982)]**PEER REVIEWED**

THE CYCLIC GUANOSINE MONOPHOSPHATE CONTENT OF RAT LUNG MINCE WAS INCR NEARLY 50 FOLD WITHIN 4 SEC FOLLOWING EXPOSURE TO NITRIC OXIDE. THIS RAPID INCR IN CYCLIC GUANOSINE MONOPHOSPHATE ACCUMULATION WAS PREVENTED BY 10 MMOLE, BUT NOT 1 MMOLE, DITHIOTHREITOL WHICH ITSELF CAUSED A SLOWER YET MASSIVE (100 FOLD) INCR IN THE CYCLIC GUANOSINE MONOPHOSPHATE CONTENT OF LUNG MINCE. APPARENTLY, SULFHYDRYL GROUP MODIFICATION IS A COMMON PATHWAY FOR THE ENHANCEMENT OF CYCLIC GUANOSINE MONOPHOSPHATE SYNTHESIS IN TISSUE BY A VARIETY OF STIMULI.
[BRAUGHLER JM; BIOCHEM PHARMACOL 31 (23): 3847 (1982)]**PEER REVIEWED**

Emphysema and bronchial inflammation was observed in rats exposed to the inhalation of 50 mg nitric oxide/cu m for 1 mo. The number of peripheral leukocytes and methemoglobin and diphosphoglycerated concn in blood incr, and the number of erythrocytes and hemoglobin concn in blood was above controls after 12 days and normalized after 30 days of the exposure.
[Yushkova LA et al; Gig Sanit 5: 91-92 (1988)]**PEER REVIEWED**

Nitric oxide produced a marked incr of erythrocyte count and of hemoglobin and methemoglobin concn and a decr in sulfhydryl components in the blood and in the level of oxygen consumption. Dystrophic disorders in different organs were also found.
[Borisova LB, Burhanov AI; Gig Sanit 4: 89-90 (1985)]**PEER REVIEWED**

Male Sprague-Dawley rats (number of animals not given) were placed in exposure chambers and subjected to atmospheres of 100 or 200 ppm nitric oxide (NO) for up to several hours. Nitrosylhemoglobin (Hb-NO) and methemoglobin (MetHb) content of blood were determined. The concentration of Hb-NO, expressed as percent of total Hb, reached a steady state after 30 min (100 ppm) and 60 min (200 ppm). MetHb reached a steady state at a later time in the 200 ppm treatment group and formed a higher percentage of the total Hb, indicating that the oxidation of Hb-NO to MetHb was faster than the reduction of MetHb to ferrous hemoglobin. As the concentration of NO in inspired air increased from 25 to 250 ppm, Hb-NO increased from 0.08 to 3% and MetHb increased from 0.6 to 20% after 60 min of exposure. The concentrations of these hemoglobins were similar in arterial and venous blood. When rats were placed in clean air following 60 min of exposure to 100 or 200 ppm NO, both Hb-NO and MetHb disappeared with a half-life of approximately 20 min. The effects of NO on erythrocytes in vivo were minimal; blood viscosity was similar, but a few undeformed cells were detected at high shear stress, and no change in the crosslinking of membrane proteins or alteration of acyl chain composition of membrane phospholipids was observed. Effects on erythrocytes had been reported in earlier in vitro studies by this group.
[Maeda N et al; Environ Health Perspect 73: 171-7 (1987)]**PEER REVIEWED**

Enlargement of air spaces and loss of interalveolar septa in proximal acinar regions were most severe in dogs that were exposed to oxides of nitrogen, oxides of sulfur, or oxides of sulfur with irradiated exhaust.
[Klaassen, C.D., M.O. Amdur, Doull J. (eds.). Casarett and Doull's Toxicology. The Basic Science of Poisons. 5th ed. New York, NY: McGraw-Hill, 1995. 873]**PEER REVIEWED**

/Researchers/ examined immunologic end points in mice exposed to 10 ppm nitric oxide for 2 hours per day, 5 days per week up to 30 weeks. Leukocytosis was evident by 5 weeks' exposure, while a decrease in mean hemoglobin content of red blood cells was found by 30 weeks. The ability of spleen cells to mount a graft-versus-host reaction was stimulated by 20 weeks' exposure but suppressed by 26 weeks. When the ability of mice to reject virus-induced tumors was assessed, fewer nitric oxide-exposed animals than controls survived tumor challenge; this suggests that nitric oxide at high levels may have affected the immune competence of the animals.
[Rom, W.N. (ed.). Environmental and Occupational Medicine. 2nd ed. Boston, MA: Little, Brown and Company, 1992. 511]**PEER REVIEWED**

BACKGROUND: The effect of inhaled nitric oxide (NO) treatment on pulmonary function in the setting of adult respiratory distress syndrome is controversial. We examined the effect of inhaled NO on pulmonary function in an isolated rabbit lung model of oleic acid (OA)-induced acute lung injury. We hypothesized that NO would decrease pulmonary artery pressure and improve oxygenation. METHODS: Rabbit heart-lung blocks were isolated, flushed in vivo, harvested, and immediately perfused with whole blood and ventilated with 50% oxygen (O2). Pulmonary artery pressure was determined every 15 seconds for 60 minutes of perfusion. Oxygenation was determined by blood gas analysis of pulmonary venous effluent at 0, 20, 40, and 60 minutes after initiation of OA infusion. Rabbits were randomized into four study groups: saline control; OA control, which received a 20-minute infusion of 50% OA/ethanol solution; NO treatment (20 ppm NO inhaled before OA infusion); and NO control, which underwent NO (20 ppm) pretreatment, followed by saline infusion. Pulmonary artery pressure, oxygenation (arteriovenous O2 difference), compliance, and wet/dry lung weight were determined. RESULTS: Pretreatment with NO caused significant increases in pulmonary artery pressure (NO treatment versus NO control and saline control; no significant difference between NO treatment group and OA control group), and did not improve oxygenation in our model. CONCLUSIONS: Contrary to our hypothesis, pretreatment with NO potentiates acute lung injury in our isolated lung model. There was significant exacerbation of pulmonary hypertension and no improvement in oxygenation. Further investigation of the possible deleterious effects of NO in acute lung injury are needed, especially in the early acute phases of this process.
[Rayhrer CS et al; Ann Thorac Surg 65 (4): 935-8 (1998)]**PEER REVIEWED**

Reactive oxygen species can initiate carcinogenesis by virtue of their capacity to react with DNA and cause mutations. Recently, it has been suggested that nitric oxide (NO) and its derivatives produced in inflamed tissues could contribute to the carcinogenesis process. Genotoxicity of NO follows its reaction with oxygen and superoxide. It can be due either to direct DNA damage or indirect DNA damage. Direct damage includes DNA base deamination, peroxynitrite-induced adducts formation and single strand breaks in the DNA. Indirect damage is due to the interaction of NO reactive species with other molecules such as amines, thiols and lipids. The efficiency of one pathway or another might depend on the cellular antioxidant status or the presence of free metals.
[Felley-Bosco E; Cancer Metastasis Rev 17 (1): 25-37 (1998)]**PEER REVIEWED**

The effect of nitric oxide (NO) inhalation on the ability of female Sprague-Dawley rats to reduce methemoglobin was investigated. Methemoglobin production was induced by injection of sodium nitrite. The levels of methemoglobin produced by sodium nitrite were significantly higher in rats previously exposed to NO than in controls, indicating that these rats were not as capable of reducing methemoglobin as the controls. Exposure to concn of NO as low as 15 ppm produced this effect. Exposure to NO evidently potentiates the oxidizing effects of nitrite ion and implies that NO exposure may do the same with other oxidative pollutants such as ozone and nitrogen dioxide.
[McFaul SJ, McGratu JJ; J Environ Sci Health Part A Environ Sci Eng 20 (3): 305-14 (1985)]**PEER REVIEWED**

The kinetics of functional impairment of erythrocytes by nitric oxide (NO) through formation of a complex with hemoglobin and formation of methemoglobin, and injury of erythrocytes due to acute NO exposure were studied in the rat. Specific pathogen free male Sprague-Dawley rats were exposed to between 25 and 250 ppm NO in a chamber, and blood was collected rapidly in an air tight syringe at various times during exposure. Determination of the hemoglobin complex with NO (hemoglobin/NO) and methemoglobin content in blood was carried out by electron paramagnetic resonance. The concn of hemoglobin/NO reached a steady state after 30 to 60 min followed by attainment of steady state levels of methemoglobin. The amount of methemoglobin was always greater than that of hemoglobin/NO, which ... demostrates that the oxidation process of hemoglobin/NO to methemoglobin is faster than the reduction process of methemoglobin to ferrous-hemoglobin. Injury to erythrocytes by NO exposure was manifested by an incr incidence of echinocytes in the blood and a low percentage of undeformed cells. When erythrocytes were exposed to pure NO, followed by nitrogen and then atmospheric oxygen, the polyacrylamide gel electrophoretic pattern of ghost membrane proteins showed a decr of monomeric spectrin as well as the appearance of new bands of higher molecular wt. The changes were reversed by addition of mercaptoethanol prior to electrophoresis. /It was concluded/ that the main rheological injury to NO exposed rat blood is due to the occurrence of oxidative crosslinking of erythrocyte membrane proteins, and injury that can be rapidly repaired by the antioxidative mechanism of the erythrocytes.
[Maeda N et al; Environ Health Perspect 73: 171-77 (1987)]**PEER REVIEWED**

Human red blood cells incubated under nitrogen with methylene blue and glucose at physiological temperature and pH can be used to test for the biotransformation of nitrogenous vasodilators to nitric oxide (NO). The NO generated was trapped as nitrosylated heme by reduced subunits on various hemoglobin valency species and quantified by electron paramagnetic resonance spectroscopy. It was possible to separate the various valency species of hemoglobin present in the mixture as (alpha 2 + beta 2)2, (alpha 2 + beta 3+)2, (alpha 3 + beta 2+)2, or (alpha 3 + beta 3+)2 by isoelectric focusing unless cyanide (from nitroprusside) or azide was present in the mixture. These anions bind tenaciously to oxidized subunits and prevent the separation of the various species by isoelectric. The fully oxidized tetramer, (alpha 3 + beta 3+)2, does not bind NO, but the other three species have reduced subunits units which can be nitrosylated. In the absence of cyanide or azide the valency species could be separated by isoelectric focusing, and it was possible to quantify the degree of nitrosylation on each individual species. The various agents tested (nitrite, glyceryl trinitrate, hydroxylamine, hydralazine, nitroprusside, and azide) produced different patterns of valency species and degrees of nitrosylation of reduced subunits. When oxidized subunits ligands were present or in cases of very low yields, it was still possible to quantify the total concentration of NO-reduced subunits in the mixture. Thus, the method could still be used to test for NO formation. All of the so-called NO vasodilators tested yielded detectable amounts of NO in the system.
[Kruszyna H et al; Toxicol Appl Pharmacol 91 (3): 429-38 (1987)]**PEER REVIEWED**

Metabolism/Pharmacokinetics:

Metabolism/Metabolites:

The biotransformation of nitric oxide (NO) and its intermed metabolites, nitrite and nitrate ions, was reviewed: absorption and conversion of NO in blood, metabolism and excretion of inhaled NO, and conversion of nitrite and nitrate in the digestive system. ... The major proportion of inhaled NO reaches the deeper portion of the lung and reacts with hemoglobin in erythrocytes to form nitrosylhemoglobin which is converted immediately to nitrite and nitrate. The nitrate and nitrite are then transferred to the serum, and the greater part of the nitrate is excreted into the urine through the kidney. ... Part of the nitrate in the blood is secreted into the oral cavity through saliva and is converted to nitrite by oral bacteria, part of the nitrite that reaches the stomach is converted to nitrogen gas with the proteins of the diet and disappears, the intestinal nitrate transferred from the blood and stomach is converted to ammonia or unknown compounds through nitrite by the intestinal bacteria, the thus produced ammonia is absorbed through the intestinal wall into the body, and this ammonia is metabolized to urea through the urea cycle and excreted into the urine.
[Yoshida K, Kasama K; Environ Health Perspect 73: 201-205 (1987)]**PEER REVIEWED**

Absorption, Distribution & Excretion:

ABSORPTION IS BY WAY OF LUNG.
[Thienes, C., and T.J. Haley. Clinical Toxicology. 5th ed. Philadelphia: Lea and Febiger, 1972. 189]**PEER REVIEWED**

ON INHALATION, CONSIDERABLE PORTION ... IS ABSORBED IN UPPER RESP TRACT.
[Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. 4099]**PEER REVIEWED**

Most of the inhaled nitric oxide is eventually eliminated from the body as nitrate.
[Rom, W.N. (ed.). Environmental and Occupational Medicine. 2nd ed. Boston, MA: Little, Brown and Company, 1992. 512]**PEER REVIEWED**

... it is efficiently (>80%) absorbed via inhalation ...
[Sullivan, J.B. Jr., G.R. Krieger (eds.). Hazardous Materials Toxicology-Clinical Principles of Environmental Health. Baltimore, MD: Williams and Wilkins, 1992. 965]**PEER REVIEWED**

When seven volunteers inhaled 0.33, 0.5, 1, or 5 ppm, 85% to 93% of the inspired nitric oxide was retained.
[American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991.1091]**PEER REVIEWED**

Mechanism of Action:

The effect of nitric oxide (NO) on blood hemoglobin was studied in vitro. Previously deoxygenated human blood was equilibrated with a continuous flow of 1,000 ppm NO, 5.6% carbon dioxide in nitrogen for 3 hours, and flushed for 30 min with 5.6% carbon dioxide in nitrogen. Nitrosylhemoglobin containing blood was equilibrated for various lengths of time with 21% oxygen and 5.6% carbon dioxide in nitrogen or 100% carbon monoxide for 1 hr. Methemoglobin was measured with an anaerobic method. Carboxyhemoglobin was measured. Anaerobic nitrosylhemoglobin blood/buffer solution was equilibratd with carbon monoxide and nitrogen. Acid/base blood changes in nitrosylhemoglobin and methemoglbin formation were determined after 1 hr of nitrogen equilibration, after 3 hr of NO equilibration, and after air exposure. The amount of methemoglobin formed was monitored by spectrophotometric changes of the anaerobic nitrosylhemoglobin solution after being exposed to air. Nitrosylhemoglobin exposure to oxygen incr the methemoglobin formation, with 59% and 78% of the total hemoglobin oxidized in the first 15 min and after 120 min of oxygen exposure, respectively. No significant methemoglobin was formed with nitrosylhemoglobin exposure to carbon dioxide. A total of 42% total hemoglobin in the nitrosylhemoglobin in the nitrosylhemoglobin blood/buffer solution was converted to methemoglobin after 30 min of air exposure and to 55% after 60 min of air exposure. NO exposure significantly decr the pH and base excess after 3 hr of exposure to NO. There were no significant changes after air exposure. ... /It was concluded/ that only under strict anaerobic conditions can NO combine with hemoglobin as nitrosylhemoglobin without any methemoglobin. NO is not a hemoglobin oxidant, it needs the presence of oxygen.
[Chiodi H, Mohler JG; Environ Res 37 (2): 355-63 (1985)]**PEER REVIEWED**

Interactions:

Nitric oxide (NO) is produced both by macrophages in vivo as a physiological response to infection and by a variety of cell types as an intercellular messenger. In addition, NO and nitrogen dioxide (NO2) are significant components of many combustion processes. The ubiquitous exposure of humans to nitrogen oxides (NOx), both endogenously and exogenously, may play a significant role in the carcinogenic process due to nitrosation of amines by NOx. We report here that exposure to low concentrations of NO, alone or in combination with NO2, results in significantly enhanced mutation in Salmonella typhimurium TA1535 using a modified Ames Salmonella reversion assay. The observed mutagenicity requires that the bacteria be actively dividing at the time of exposure to NO or NO2, suggesting that the nitrogen oxides, or their reaction products, function as direct-acting mutagens and that the induced lesion is easily repairable by non-dividing cells. Exposure to NO resulted in a time- and dose-dependent increase in the number of revertants approximately proportional to the square of the NO concentration from 0 to 20 ppm. NO was a more effective mutagen relative to NO2, however, the observed requirement for O2 suggests limited oxidation of NO (presumably to NO2) is necessary. Numerous lipid- and aqueous-phase inhibitors of nitrosation, as well as a number of other general antioxidants and free-radical trapping agents, were examined for their effectiveness in blocking the mutagenic effects of NO. The mutagenic activity of NO was most effectively inhibited by beta-carotene and tocopherols. BHT, dimethyl sulfoxide and mannitol also blocked the mutagenic effects of NOx but appeared less effective than beta-carotene or vitamin E, while ascorbate was ineffective as an inhibitor of mutation resulting from NO exposure.
[Arroyo PL et al; Mutat Res 281 (3): 193-202 (1992)]**PEER REVIEWED**

... THE MECHANISM OF NITRIC OXIDE INTOXICATION SUGGESTS THAT IN MIXTURES WITH CARBON MONOXIDE, AS WELL AS NITROGEN DIOXIDE, ADDITIVE EFFECTS SHOULD BE ASSUMED.
[American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values and Biological Exposure Indices. 5th ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists, 1986.429]**PEER REVIEWED**

The effects of nitric oxide (NO) and carbon monoxide on discrimination learning and brain activity were studied in rats. Male Long-Evans rats surgically instrumented with prefrontal and parietal electroencephalographic electrodes were exposed to 0, 100, or 500 ppm carbon monoxide or 10 or 50 ppm NO alone or in combination for 180 min. Effects on behavior (lever press task) and response to auditory stimulation were examined. Response to auditory stimulation was assessed by recording auditory evoked potentials. At the end of exposure, the rats were killed and blood carboxyhemoglobin and methemoglobin were determined. There was no significant difference between blood auditory evoked potential concn after exposure to 100 or 500 ppm carbon monoxide or 100 or 500 ppm carbon monoxide plus 10 or 50 ppm NO. Methemoglobin concn were significantly higher after exposure to 10 ppm NO plus 100 ppm carbon monoxide than after 10 ppm NO alone. Exposure to 50 ppm NO reduced the number of correct trials and the total number of lever presses significantly. Exposure to 500 ppm carbon monoxide decr the number of correct trials nonsignificantly and the total number of lever presses significantly. Combined carbon monoxide and NO exposure caused synergistic decr in number of correct trials and total number of trials. Carbon monoxide or NO caused increased amplitudes and prolonged latencies in early auditory evoked potential peaks. NO prolonged the latency of late auditory evoked potential peaks. Carbon monoxide incr the amplitude of the N150 peak, whereas NO decr its amplitude. The 10 ppm NO plus 100 ppm carbon monoxide exposure induced a combination effect that was less than additive. The 50 ppm NO plus 500 ppm carbon monoxide exposure induced an additive or synergistic effect on auditory evoked potential peak response. /It was concluded/ that NO plays a dominant role during intoxication with NO and carbon monoxide.
[Groll-Knapp E et al; Toxicol 49 (2-3): 441-47 (1988)]**PEER REVIEWED**

It as shown that preincubation of pancreatic islet cells with alpha-tocopherol significantly improves their resistance to toxic doses of nitric oxide. No protection was afforded by other antioxidants such as vitamin C or glutathione-monoethyl ester. The pathway of NO induced islet cell death involves DNA damage and excessive activation of poly(ADP-ribose)polymerase leading to irreversible depletion of intracellular NAD+. alpha-Tocopherol was found to interfere at early steps of this pathway, by preventing the occurrence of DNA strand breaks. This indicates that alpha-tocopherol directly interacts with nitric oxide or its reactive intermediates. Alpha-tocopherol is not only part of the cellular defence system against oxygen radicals but also protects eukaryotic cells from nitric oxide toxicity.
[Burkart V et al; FEBS Lett 364 (3): 259-63 (1995)]**PEER REVIEWED**

Pharmacology:

Therapeutic Uses:

Bronchodilator Agents; Free Radical Scavengers; Vasodilator Agents
[National Library of Medicine's Medical Subject Headings online file (MeSH, 1999)]**QC REVIEWED**

Although its use still is considered experimental, nitric oxide has been used successfully in some patients with persistent fetal circulation, pulmonary hypertension secondary to cardiac dysfunction or surgery, or with the adult respiratory distress syndrome.
[Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996. 356]**PEER REVIEWED**

Interactions:

Nitric oxide (NO) is produced both by macrophages in vivo as a physiological response to infection and by a variety of cell types as an intercellular messenger. In addition, NO and nitrogen dioxide (NO2) are significant components of many combustion processes. The ubiquitous exposure of humans to nitrogen oxides (NOx), both endogenously and exogenously, may play a significant role in the carcinogenic process due to nitrosation of amines by NOx. We report here that exposure to low concentrations of NO, alone or in combination with NO2, results in significantly enhanced mutation in Salmonella typhimurium TA1535 using a modified Ames Salmonella reversion assay. The observed mutagenicity requires that the bacteria be actively dividing at the time of exposure to NO or NO2, suggesting that the nitrogen oxides, or their reaction products, function as direct-acting mutagens and that the induced lesion is easily repairable by non-dividing cells. Exposure to NO resulted in a time- and dose-dependent increase in the number of revertants approximately proportional to the square of the NO concentration from 0 to 20 ppm. NO was a more effective mutagen relative to NO2, however, the observed requirement for O2 suggests limited oxidation of NO (presumably to NO2) is necessary. Numerous lipid- and aqueous-phase inhibitors of nitrosation, as well as a number of other general antioxidants and free-radical trapping agents, were examined for their effectiveness in blocking the mutagenic effects of NO. The mutagenic activity of NO was most effectively inhibited by beta-carotene and tocopherols. BHT, dimethyl sulfoxide and mannitol also blocked the mutagenic effects of NOx but appeared less effective than beta-carotene or vitamin E, while ascorbate was ineffective as an inhibitor of mutation resulting from NO exposure.
[Arroyo PL et al; Mutat Res 281 (3): 193-202 (1992)]**PEER REVIEWED**

... THE MECHANISM OF NITRIC OXIDE INTOXICATION SUGGESTS THAT IN MIXTURES WITH CARBON MONOXIDE, AS WELL AS NITROGEN DIOXIDE, ADDITIVE EFFECTS SHOULD BE ASSUMED.
[American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values and Biological Exposure Indices. 5th ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists, 1986.429]**PEER REVIEWED**

The effects of nitric oxide (NO) and carbon monoxide on discrimination learning and brain activity were studied in rats. Male Long-Evans rats surgically instrumented with prefrontal and parietal electroencephalographic electrodes were exposed to 0, 100, or 500 ppm carbon monoxide or 10 or 50 ppm NO alone or in combination for 180 min. Effects on behavior (lever press task) and response to auditory stimulation were examined. Response to auditory stimulation was assessed by recording auditory evoked potentials. At the end of exposure, the rats were killed and blood carboxyhemoglobin and methemoglobin were determined. There was no significant difference between blood auditory evoked potential concn after exposure to 100 or 500 ppm carbon monoxide or 100 or 500 ppm carbon monoxide plus 10 or 50 ppm NO. Methemoglobin concn were significantly higher after exposure to 10 ppm NO plus 100 ppm carbon monoxide than after 10 ppm NO alone. Exposure to 50 ppm NO reduced the number of correct trials and the total number of lever presses significantly. Exposure to 500 ppm carbon monoxide decr the number of correct trials nonsignificantly and the total number of lever presses significantly. Combined carbon monoxide and NO exposure caused synergistic decr in number of correct trials and total number of trials. Carbon monoxide or NO caused increased amplitudes and prolonged latencies in early auditory evoked potential peaks. NO prolonged the latency of late auditory evoked potential peaks. Carbon monoxide incr the amplitude of the N150 peak, whereas NO decr its amplitude. The 10 ppm NO plus 100 ppm carbon monoxide exposure induced a combination effect that was less than additive. The 50 ppm NO plus 500 ppm carbon monoxide exposure induced an additive or synergistic effect on auditory evoked potential peak response. /It was concluded/ that NO plays a dominant role during intoxication with NO and carbon monoxide.
[Groll-Knapp E et al; Toxicol 49 (2-3): 441-47 (1988)]**PEER REVIEWED**

It as shown that preincubation of pancreatic islet cells with alpha-tocopherol significantly improves their resistance to toxic doses of nitric oxide. No protection was afforded by other antioxidants such as vitamin C or glutathione-monoethyl ester. The pathway of NO induced islet cell death involves DNA damage and excessive activation of poly(ADP-ribose)polymerase leading to irreversible depletion of intracellular NAD+. alpha-Tocopherol was found to interfere at early steps of this pathway, by preventing the occurrence of DNA strand breaks. This indicates that alpha-tocopherol directly interacts with nitric oxide or its reactive intermediates. Alpha-tocopherol is not only part of the cellular defence system against oxygen radicals but also protects eukaryotic cells from nitric oxide toxicity.
[Burkart V et al; FEBS Lett 364 (3): 259-63 (1995)]**PEER REVIEWED**

Environmental Fate & Exposure:

Probable Routes of Human Exposure:

INDUSTRIAL EXPOSURES CAN TAKE PLACE WHEREVER NITRIC ACID IS MADE OR USED & HAS OCCURRED MOST COMMONLY WHERE METALS ARE DIPPED IN ACID BATHS. ELECTRIC ARC WELDING, & TO LESSER EXTENT GAS WELDING, CAN GENERATE HAZARDOUS CONCN. FERMENTATION OF SILAGE PRODUCES HIGH CONCN, & POISONINGS OF FARMERS HAVE OCCURRED.
[Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. 4097]**PEER REVIEWED**

APPROX 1.5 MILLION USA WORKERS ARE EXPOSED DIRECTLY OR INDIRECTLY TO OXIDES OF NITROGEN (NITRIC OXIDE, NITROGEN DIOXIDE, NITRIC ACID) THROUGH OCCUPATIONS INVOLVING WELDING, SILO FILLING & EXPLOSIVE MANUFACTURE. /FROM TABLE/
[Doull, J., C.D. Klaassen, and M. D. Amdur (eds.). Casarett and Doull's Toxicology. 2nd ed. New York: Macmillan Publishing Co., 1980. 266]**PEER REVIEWED**

Artificial Pollution Sources:

MAIN SOURCE OF URBAN NITRIC OXIDE ... IS COMBUSTION OF FOSSIL FUELS. ESCAPE OF ... GASES FROM INDUSTRIAL PROCESSES WHERE NITRIC OXIDE IS MADE OR USED, OR FROM FERTILIZER OR EXPLOSIVE FACTORIES, CAN BE IMPORTANT IN LOCAL AREA & IN PLANTS THEMSELVES. IN GENERAL, HIGHER COMBUSTION TEMP YIELD MORE NITROGEN OXIDES.
[Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. 4097]**PEER REVIEWED**

IN MOST URBAN AREAS THE CAR IS SINGLE LARGEST PRODUCER OF NITRIC OXIDE, WHICH MOVES SO RAPIDLY FROM ENGINE CYLINDER TO COOLER EXHAUST PIPES THAT IT IS PREVENTED FROM DECOMP ...
[Arena, J.M. Poisoning: Toxicology-Symptoms Treatments. Third Edition. Springfield, Illinois: Charles C. Thomas, 1974. 297]**PEER REVIEWED**

Volatile organics and nitrogen oxides are emitted by transportation and industrial sources. Oxides of nitrogen are emitted in the combustion of fossil fuels. /Nitrogen oxides/
[Sullivan TFP; Pollution Engineering p.24 (June 1987)]**PEER REVIEWED**

... RELEASED IN REACTION BETWEEN NITRIC ACID & ANY ORG MATERIAL; IN EXHAUST FROM METAL CLEANING ... FROM ELECTRIC ARC WELDING; IN ELECTROPLATING, ENGRAVING, & PHOTOGRAVURE OPERATIONS; IN DYNAMITE BLASTING ... IN DIESEL ENGINE EXHAUST; IN BURNING OF NITROCELLULOSE ... & IN COMBUSTION OF SOME SHOE POLISHES. /NITROGEN OXIDES/
[Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. III-320]**PEER REVIEWED**

Environmental Fate:

NITRIC OXIDE IS CONVERTED SPONTANEOUSLY IN AIR TO NITROGEN DIOXIDE, HENCE SOME OF LATTER GAS IS INVARIABLY PRESENT WHENEVER NITRIC OXIDE IS FOUND IN AIR. AT CONCN BELOW 50 PPM ... THIS REACTION IS SLOW ... & FREQUENTLY SUBSTANTIAL CONCN ... MAY OCCUR WITH NEGLIGIBLE QUANTITIES OF NITROGEN DIOXIDE ... .
[American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991.1090]**PEER REVIEWED**

PHOTOCHEMICAL AIR POLLUTION ARISES FROM A SERIES OF ATMOSPHERIC REACTIONS. THE MAIN COMPONENTS ARE OZONE, OXIDES OF NITROGEN, ALDEHYDES, PEROXYACETYL NITRATES, AND HYDROCARBONS. ... THEY ENTER INTO THE CHEMICAL REACTIONS THAT LEAD TO FORMATION OF PHOTOCHEMICAL SMOG. /OXIDES OF NITROGEN/
[Doull, J., C.D.Klassen, and M.D. Amdur (eds.). Casarett and Doull's Toxicology. 3rd ed., New York: Macmillan Co., Inc., 1986. 812]**PEER REVIEWED**

Atmospheric Concentrations:

IN TERMS OF AMT OF MATERIAL EMITTED ANNUALLY INTO AIR, FIVE MAJOR POLLUTANTS ACCOUNT FOR CLOSE TO 98% OF POLLUTION. ... NITROGEN OXIDES (6%). /NITROGEN OXIDES/
[Doull, J., C.D. Klaassen, and M. D. Amdur (eds.). Casarett and Doull's Toxicology. 2nd ed. New York: Macmillan Publishing Co., 1980. 608]**QC REVIEWED**

Environmental Standards & Regulations:

CERCLA Reportable Quantities:

Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 10 lb or 4.54 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b).
[40 CFR 302.4 (7/1/97)]**PEER REVIEWED**

Releases of CERCLA hazardous substances are subject to the release reporting requirement of CERCLA section 103, codified at 40 CFR part 302, in addition to the requirements of 40 CFR part 355. Nitric oxide is an extremely hazardous substance (EHS) subject to reporting requirements when stored in amounts in excess of its threshold planning quantity (TPQ) of 100 lbs.
[40 CFR 355 (7/1/97)]**PEER REVIEWED**

RCRA Requirements:

P076; As stipulated in 40 CFR 261.33, when nitric oxide, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to federal and/or state hazardous waste regulations. Also defined as a hazardous waste is any container or inner liner used to hold this waste or any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5(e)).
[40 CFR 261.33 (7/1/97)]**PEER REVIEWED**

State Drinking Water Guidelines:

(FL) FLORIDA 10,000 ug/l
[USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93)]**QC REVIEWED**

Chemical/Physical Properties:

Molecular Formula:

N-O
**PEER REVIEWED**

Molecular Weight:

30.006
[Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 76th ed. Boca Raton, FL: CRC Press Inc., 1995-1996.,p. 4-74]**PEER REVIEWED**

Color/Form:

COLORLESS GAS; BLUE LIQ
[Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 76th ed. Boca Raton, FL: CRC Press Inc., 1995-1996.,p. 4-74]**PEER REVIEWED**

BLUISH-WHITE SNOW WHEN SOLID
[Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 1131]**PEER REVIEWED**

Brown at high concn in air
[Sittig, M. Handbook of Toxic and Hazardous Chemicals and Carcinogens, 1985. 2nd ed. Park Ridge, NJ: Noyes Data Corporation, 1985. 648]**PEER REVIEWED**

Odor:

Sharp, sweet odor
[Sittig, M. Handbook of Toxic and Hazardous Chemicals and Carcinogens, 1985. 2nd ed. Park Ridge, NJ: Noyes Data Corporation, 1985. 648]**PEER REVIEWED**

Boiling Point:

-151.74 DEG C
[Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 76th ed. Boca Raton, FL: CRC Press Inc., 1995-1996.,p. 4-74]**PEER REVIEWED**

Melting Point:

-163.6 DEG C
[Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 76th ed. Boca Raton, FL: CRC Press Inc., 1995-1996.,p. 4-74]**PEER REVIEWED**

Critical Temperature & Pressure:

CRITICAL TEMP: -92.9 DEG C; CRITICAL PRESSURE: 64.6 ATM
[Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 1131]**PEER REVIEWED**

Density/Specific Gravity:

1.27 AT -150.2 DEG C, LIQ
[Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 1131]**PEER REVIEWED**

Heat of Vaporization:

3.293 KCAL/MOLE
[Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 1131]**PEER REVIEWED**

Solubilities:

7.38 ml/ 100 ml water at 0 deg C; 4.6 ml/ 100 ml water at 20 deg C; 2.37 ml/ 100 ml water at 60 deg C
[Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 1131]**PEER REVIEWED**

3.4 CC/100 CC SULFURIC ACID
[Weast, R.C. (ed.) Handbook of Chemistry and Physics. 69th ed. Boca Raton, FL: CRC Press Inc., 1988-1989.,p. B-111]**PEER REVIEWED**

26.6 CC/100 CC ALCOHOL
[Weast, R.C. (ed.) Handbook of Chemistry and Physics. 69th ed. Boca Raton, FL: CRC Press Inc., 1988-1989.,p. B-111]**PEER REVIEWED**

SOL IN CARBON DISULFIDE, IRON SULFATE
[Weast, R.C. (ed.) Handbook of Chemistry and Physics. 69th ed. Boca Raton, FL: CRC Press Inc., 1988-1989.,p. B-111]**PEER REVIEWED**

Spectral Properties:

Index of Refraction: 1.0002697 @ 25 deg C
[Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 1131]**PEER REVIEWED**

Vapor Density:

1.04 (AIR= 1)
[Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 1131]**PEER REVIEWED**

Vapor Pressure:

45600 MM HG AT -94.8 DEG C
[Weast, R.C. (ed.) Handbook of Chemistry and Physics. 69th ed. Boca Raton, FL: CRC Press Inc., 1988-1989.,p. D-196]**QC REVIEWED**

Viscosity:

0.0188 cP at 25 deg C @ 101.325 KPa (gas)
[Braker W, Mossman A; Matheson Gas Data Book 6th Ed p.514 (1980)]**PEER REVIEWED**

Other Chemical/Physical Properties:

TROUTON CONSTANT: 27.1; CONTAINS ODD NUMBERS OF ELECTRONS & IS PARAMAGNETIC
[Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 1131]**PEER REVIEWED**

CONVERSION FACTORS: 1 PPM IS EQUIVALENT TO 1.23 MG/CU M; 1 MG/CU M IS EQUIVALENT TO 0.813 PPM
[Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. 4098]**PEER REVIEWED**

HEAT OF FORMATION: -21.5 KCAL/MOLE AT 18 DEG C
[Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 1131]**PEER REVIEWED**

COMBINES WITH OXYGEN TO FORM NITROGEN DIOXIDE (BROWN GAS) & WITH CHLORINE & BROMINE TO FORM NITROSYL HALIDES, SUCH AS NITROSYL CHLORIDE.
[Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 1131]**PEER REVIEWED**

Ionization potential: 9.27 eV
[NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 94-116. Washington, D.C.: U.S. Government Printing Office, June 1994. 224]**PEER REVIEWED**

Chemical Safety & Handling:

DOT Emergency Guidelines:

Health: TOXIC; may be fatal if inhaled or absorbed through skin. Fire will produce irritating, corrosive and/or toxic gases. Contact with gas or liquefied gas may cause burns, severe injury and/or frostbite. Runoff from fire control may cause pollution. /Nitric oxide; Nitric oxide, compressed/
[U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-124]**QC REVIEWED**

Fire or explosion: Substance does not burn but will support combustion. Vapors from liquefied gas are initially heavier than air and spread along ground. These are strong oxidizers and will react vigorously or explosively with many materials including fuels. May ignite combustibles (wood, paper, oil, clothing, etc.). Some will react violently with air, moist air and/or water. Containers may explode when heated. Ruptured cylinders may rocket. /Nitric oxide; Nitric oxide, compressed/
[U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-124]**QC REVIEWED**

Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 100 to 200 meters (330 to 660 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Many gases are heavier than air and will spread along ground and collect in low or confined areas (sewers, basements, tanks). Keep out of low areas. Ventilate closed spaces before entering. /Nitric oxide; Nitric oxide, compressed/
[U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-124]**QC REVIEWED**

Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. /Nitric oxide; Nitric oxide, compressed/
[U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-124]**QC REVIEWED**

Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. /Nitric oxide; Nitric oxide, compressed/
[U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-124]**QC REVIEWED**

Fire: Small Fires: Water only; no dry chemical, CO2 or Halon. Contain fire and let burn. If fire must be fought, water spray or fog is recommended. Do not get water inside containers. Move containers from fire area if you can do it without risk. Damaged cylinders should be handled only by specialists. Fire involving Tanks: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Do not direct water at source of leak or safety devices; icing may occur. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible withdraw from area and let fire burn. /Nitric oxide; Nitric oxide, compressed/
[U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-124]**QC REVIEWED**

Spill or leak: Fully encapsulating, vapor protective clothing should be worn for spills and leaks with no fire. Do not touch or walk through spilled material. Keep combustibles (wood, paper, oil, etc.) away from spilled material. Stop leak if you can do it without risk. Use water spray to reduce vapors or divert vapor cloud drift. Avoid allowing water runoff to contact spilled material. Do not direct water at spill or source of leak. If possible, turn leaking containers so that gas escapes rather than liquid. Prevent entry into waterways, sewers, basements or confined areas. Isolate area until gas has dispersed. Ventilate the area. /Nitric oxide; Nitric oxide, compressed/
[U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-124]**QC REVIEWED**

First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Clothing frozen to the skin should be thawed before being removed. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Keep victim warm and quiet. Keep victim under observation. Effects of contact or inhalation may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. /Nitric oxide; Nitric oxide, compressed/
[U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-124]**QC REVIEWED**

Odor Threshold:

Low odor threshold 0.3600 mg/cu m; High odor threshold 1.2000 mg/cu m
[Ruth JH; Am Ind Hyg Assoc J 47: A-142-51 (1986)]**PEER REVIEWED**

Skin, Eye and Respiratory Irritations:

Irritation of eyes, nose & throat.
[Sittig, M. Handbook of Toxic and Hazardous Chemicals and Carcinogens, 1985. 2nd ed. Park Ridge, NJ: Noyes Data Corporation, 1985. 649]**PEER REVIEWED**

/HAZARD WARNING:/ Only slightly irritating to upper respiratory tract and eyes ... dangerous amounts of fumes may ... be inhaled before any discomfort is noticed.
[Environment Canada; Tech Info for Problem Spills: Nitric Acid (Draft) p.98 (1985)]**PEER REVIEWED**

Higher concentrations (60-150 ppm) cause immediate irritation of the nose and throat, with coughing and burning in the throat and chest. These symptoms often clear upon breathing fresh air, and the worker may feel well for several hours. Some 6-24 hours after exposure, a sensation of tightness and burning in the chest develops, followed by shortness of breath, sleeplessness, and restlessness.
[Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 2419]**PEER REVIEWED**

Fire Potential:

BURNS ONLY WHEN HEATED WITH HYDROGEN
[The Merck Index. 10th ed. Rahway, New Jersey: Merck Co., Inc., 1983. 944]**PEER REVIEWED**

Toxic Combustion Products:

WHEN HEATED TO DECOMP, IT EMITS HIGHLY TOXIC FUMES OF NO(X) ... .
[Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 2004]**QC REVIEWED**

Hazardous Reactivities & Incompatibilities:

WILL REACT WITH WATER OR STEAM TO PRODUCE HEAT & CORROSIVE FUMES
[Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 2419]**PEER REVIEWED**

CAN REACT VIGOROUSLY WITH REDUCING MATERIALS
[Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 2419]**PEER REVIEWED**

Fluorine, combustible materials, ozone, ammonia, chlorinated hydrocarbons, metals, carbon disulfide [Note: Reacts with water to form nitric acid. Rapidly converted in air to nitrogen dioxide].
[NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. 224]**QC REVIEWED**

NITRIC OXIDE & CARBON DISULFIDE REACT EXPLOSIVELY WITH EMISSION OF LIGHT; MIXTURE OF NITRIC OXIDE & CHLORINE MONOXIDE CAN BE EXPLOSIVE; NITROGEN TRICHLORIDE EXPLODES ON CONTACT WITH NITRIC OXIDE; MIXTURES OF NITRIC OXIDE & OZONE EXPLODE EVEN WHEN QUANTITY OF OZONE IS SMALL.
[Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997. ,p. 491-127]**QC REVIEWED**

IMMEDIATELY ON CONTACT WITH AIR, NITRIC OXIDE IS CONVERTED TO HIGHLY POISONOUS NITROGEN DIOXIDE, NITROGEN TETROXIDE, OR BOTH.
[The Merck Index. 10th ed. Rahway, New Jersey: Merck Co., Inc., 1983. 944]**PEER REVIEWED**

Amorphous (not crystalline) boron reacts with brilliant flashes at ambient temperature, and charcoal or phosphorus continue to burn more brilliantly than in air (which has a much lower oxygen content).
[Bretherick, L. Handbook of Reactive Chemical Hazards. 4th ed. Boston, MA: Butterworth-Heinemann Ltd., 1990 1343]**PEER REVIEWED**

A demonstration of combustion of carbon disulfide in nitrogen oxide (both endothermic compounds) exploded violently.
[Bretherick, L. Handbook of Reactive Chemical Hazards. 4th ed. Boston, MA: Butterworth-Heinemann Ltd., 1990 1342]**PEER REVIEWED**

Addition of oxygen to a mixture of phosphine and nitrogen oxide causes explosion.
[Bretherick, L. Handbook of Reactive Chemical Hazards. 4th ed. Boston, MA: Butterworth-Heinemann Ltd., 1990 1343]**PEER REVIEWED**

Can react violently with acetic anhydride, aluminum, BaO, BCl3, CsHC2, calcium, carbon + potassium hydrogen tartrate, charcoal, ClO, pyrophoric chromium, 1,2-dichloroethane, dichloroethylene, ethylene, fuels, hydrocarbons, hydrogen + oxygen, Na2O, uns-dimethyl hydrazine, CHCl3, iron, magnesium, manganese, CH2Cl2, olefins, phosphorus, PNH2, PH3, potassium, potassium sulfide, propylene, rubidium acetylide, sodium, sulfur, tungsten carbide, trichloroethylene, 1,1,1-trichloroethane, uns-tetrachloroethane, uranium, uranium dicarbide.
[Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 2419]**PEER REVIEWED**

The liquid is a sensitive explosive. Explosive reaction with carbon disulfide (when ignited), methanol (when ignited), pentacarbonyl iron (at 50 deg C), phosphine + oxygen, sodium diphenylketyl, dichlorine oxide, fluorine, nitrogen trichloride, ozone, perchloryl fluoride (at 100-300 deg C), vinyl chloride. Reacts to form explosive products with dienes (e.g., 1,3-butadiene, cyclopentadiene, propadiene).
[Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 2419]**PEER REVIEWED**

Hazardous Decomposition:

WHEN HEATED TO DECOMP, IT EMITS HIGHLY TOXIC FUMES OF /NITROGEN OXIDES/ ... .
[Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 2004]**QC REVIEWED**

Immediately Dangerous to Life or Health:

100 ppm
[NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. 224]**QC REVIEWED**

Protective Equipment & Clothing:

Vendor recommendations concerning the protective qualities of materials are as follows: Butyl and polyvinyl chloride received excellent or good ratings from less than three vendors, no fair or poor ratings, good or fair ratings with good ratings predominating, from several vendors.
[ACGIH; Guidelines Select of Chem Protect Clothing Volume #1 Field Guide p.64 (1983)]**PEER REVIEWED**

Recommendations for respirator selection. Max concn for use: 100 ppm. Respirator Class(es): Any supplied-air respirator operated in a continuous-flow mode. May require eye protection. Any chemical cartridge respirator with a full facepiece and cartridge(s) providing protection against the compound of concern. Only nonoxidizable solvents allowed (not charcoal). Any powered, air-purifying respirator with cartridge(s) providing protection against the compound of concern. Only nonoxidizable solvents allowed (not charcoal). May require eye protection. Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted canister providing protection against the compound of concern. Only nonoxidizable solvents allowed (not charcoal). Any supplied-air respirator. May require eye protection. Any self-contained breathing apparatus with a full facepiece.
[NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. 225]**QC REVIEWED**

Recommendations for respirator selection. Condition: Emergency or planned entry into unknown concn or IDLH conditions: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode.
[NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. 225]**QC REVIEWED**

Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted canister providing protection against the compound of concern. Only nonoxidizable sorbents allowed (not charcoal). Any appropriate escape-type, self-contained breathing apparatus.
[NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. 225]**QC REVIEWED**

Preventive Measures:

SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emmissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants.
**PEER REVIEWED**

SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place.
**PEER REVIEWED**

Shipment Methods and Regulations:

No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./
[49 CFR 171.2 (7/1/96)]**PEER REVIEWED**

The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials.
[IATA. Dangerous Goods Regulations. 39th Ed. Montreal, Canada and Geneva, Switzerland : International Air Transport Association, Dangerous Goods Regulations, 1998. 166]**PEER REVIEWED**

The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article.
[IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.2095 (1988)]**PEER REVIEWED**

Storage Conditions:

IN GENERAL, MATERIALS WHICH ARE TOXIC AS STORED OR WHICH CAN DECOMP INTO TOXIC COMPONENTS ... SHOULD BE STORED IN A COOL, WELL-VENTILATED PLACE, OUT OF DIRECT RAYS OF SUN, AWAY FROM AREAS OF HIGH FIRE HAZARD, & SHOULD BE PERIODICALLY INSPECTED ... INCOMPATIBLE MATERIALS SHOULD BE ISOLATED ... .
[Sax, N.I. Dangerous Properties of Industrial Materials. 4th ed. New York: Van Nostrand Reinhold, 1975. 962]**QC REVIEWED**

Cleanup Methods:

1) VENTILATE AREA OF LEAK OR RELEASE TO DISPERSE GAS. 2) STOP FLOW OF GAS. IF SOURCE ... IS CYLINDER & LEAK CANNOT BE STOPPED IN PLACE, REMOVE ... CYLINDER TO SAFE PLACE IN OPEN AIR, & REPAIR LEAK OR ALLOW ... TO EMPTY.
[Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. 1981.2]**PEER REVIEWED**

Disposal Methods:

Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number P076, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste.
[40 CFR 240-280, 300-306, 702-799 (7/1/97)]**PEER REVIEWED**

Nitric oxide is a poor candidate for incineration.
[USEPA; Engineering Handbook for Hazardous Waste Incineration p.3-9 (1981) EPA 68-03-3025]**PEER REVIEWED**

Occupational Exposure Standards:

OSHA Standards:

Permissible Exposure Limit: Table Z-1 8-hr Time Weighted Avg: 25 ppm (30 mg/cu m).
[29 CFR 1910.1000 (7/1/98)]**QC REVIEWED**

Threshold Limit Values:

8 hr Time Weighted Avg (TWA): 25 ppm.
[American Conference of Governmental Industrial Hygienists. TLVs & BEIs: Threshold limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. Cincinnati, OH. 2002.44]**QC REVIEWED**

Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded.
[American Conference of Governmental Industrial Hygienists. TLVs & BEIs: Threshold limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. Cincinnati, OH. 2002.6]**QC REVIEWED**

Biological Exposure Index (BEI): Determinant: methemoglobin in blood; Sampling Time: during or end of shift; BEI: 1.5% of hemoglobin. The determinant may be present in biological specimens collected from subjects who have not been occupationally exposed, at a concentration which could affect interpretation of the result. Such background concentrations are incorporated in the BEI value. The determinant is nonspecific, since it is also observed after exposure to other chemicals. The biological determinant is an indicator of exposure to the chemical, but the quantitative interpretation of the measurement is ambiguous. These determinants should be used as a screening test if a quantitative test is not practical or as a confirmatory test if the quantitative test is not specific and the origin of the determinant is in question. /Methemoglobin inducers/
[American Conference of Governmental Industrial Hygienists. TLVs & BEIs: Threshold limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. Cincinnati, OH. 2002.91]**QC REVIEWED**

NIOSH Recommendations:

Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 25 ppm (30 mg/cu m).
[NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. 224]**QC REVIEWED**

Immediately Dangerous to Life or Health:

100 ppm
[NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. 224]**QC REVIEWED**

Manufacturing/Use Information:

Major Uses:

MANUFACTURE OF NITRIC ACID; IN BLEACHING OF RAYON; STABILIZER FOR PROPYLENE, METHYL ETHER
[Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 1131]**PEER REVIEWED**

TO PREPARE NITROSYL CARBONYLS
[Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 823]**PEER REVIEWED**

MEDICATION
**PEER REVIEWED**

Manufacturers:

Matheson Gas Products, Inc, Hq, 30 Seaview Dr, Secaucus, NJ 07094, (201) 867-4100; Production site: Twinsburg Township, OH 44087
[SRI. 1997 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International 1997.. 769]**PEER REVIEWED**

Methods of Manufacturing:

PREPARED INDUSTRIALLY BY PASSING AIR THROUGH ELECTRIC ARC (BASIS OF ATMOSPHERIC NITROGEN FIXATION) OR BY OXIDATION OF AMMONIA OVER PLATINUM GAUZE.
[Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 1131]**PEER REVIEWED**

Oxidation of ammonia above 500 deg C; decomposition of nitrous oxide solution
[Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 823]**PEER REVIEWED**

General Manufacturing Information:

NITRIC OXIDE ... IS FORMED WHEN COMBUSTION TAKES PLACE AT HIGH ENOUGH TEMP TO CAUSE REACTION BETWEEN AIR'S NITROGEN & OXYGEN.
[Arena, J.M. Poisoning: Toxicology-Symptoms Treatments. Third Edition. Springfield, Illinois: Charles C. Thomas, 1974. 297]**PEER REVIEWED**

Formulations/Preparations:

Grade: Pure, 99%
[Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 823]**PEER REVIEWED**

Laboratory Methods:

Analytic Laboratory Methods:

NITRITE ION (NO2-) DETECTED IN AIR BY SPECTROPHOTOMETRIC ANALYSIS AT 540 NM AFTER OXIDATION TO NITROGEN DIOXIDE, COLLECTION ON TRIETHANOLAMINE-COATED MOLECULAR SIEVE & DESORPTION WITH TRIETHANOLAMINE. RANGE 11.1 TO 48 PPM IN 1.5 L AIR SAMPLE.
[U.S. Department of Health, Education Welfare, Public Health Service. Center for Disease Control, National Institute for Occupational Safety Health. NIOSH Manual of Analytical Methods. 2nd ed. Volumes 1-7. Washington, DC: U.S. Government Printing Office, 1977-present.p. V4 S321]**PEER REVIEWED**

CHEMILUMINESCENT METHOD DEPENDS ON REACTION BETWEEN NITRIC OXIDE & OZONE, WHICH EMITS LIGHT THAT CAN BE MEASURED. ... COMMERCIAL INSTRUMENTS ... DEVELOPED THAT ARE STABLE, SENSITIVE & DURABLE. ... GAS-PHASE TITRATION IS USED TO ATTAIN SATISFACTORY PRECISION: JONES W & RIDGIK T, AM IND HYG ASSOC J 41: 433 (1980).
[Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. 4114]**PEER REVIEWED**

Sampling Procedures:

... COLLECTION ON TRIETHANOLAMINE-COATED MOLECULAR SIEVE & DESORPTION WITH TRIETHANOLAMINE. ...
[U.S. Department of Health, Education Welfare, Public Health Service. Center for Disease Control, National Institute for Occupational Safety Health. NIOSH Manual of Analytical Methods. 2nd ed. Volumes 1-7. Washington, DC: U.S. Government Printing Office, 1977-present.p. V4 S321]**PEER REVIEWED**

Special References:

Special Reports:

Environment Canada; Tech Info for Problem Spills: Nitric Acid (Draft) (1985).

USEPA; Draft Criteria Document: Oxides of Nitrogen (1983).

Synonyms and Identifiers:

Synonyms:

Amidogen, oxo-
**PEER REVIEWED**

BIOXYDE D'AZOTE (FRENCH)
**PEER REVIEWED**

MONONITROGEN MONOXIDE
**PEER REVIEWED**

NITROGEN MONOXIDE
**PEER REVIEWED**

NITROGEN OXIDE (NO)
**PEER REVIEWED**

OXYDE NITRIQUE (FRENCH)
**PEER REVIEWED**

STICKMONOXYD (GERMAN)
**PEER REVIEWED**

Formulations/Preparations:

Grade: Pure, 99%
[Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 823]**PEER REVIEWED**

Shipping Name/ Number DOT/UN/NA/IMO:

UN 1660; Nitric oxide

IMO 2.0; Nitric oxide; Nitric oxide and nitrogen tetroxide mixtures

UN 1975; Nitric oxide and nitrogen tetroxide mixtures

Standard Transportation Number:

49 203 30; Nitric oxide

EPA Hazardous Waste Number:

P076; An acute hazardous waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate.

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