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Nitrogen pentoxide

1. NAME
   1.1 Substance
   1.2 Group
   1.3 Synonyms
   1.4 Identification numbers
      1.4.1 CAS number
      1.4.2 Other numbers
   1.5 Brand names, Trade names
   1.6 Manufacturers, Importers
2. SUMMARY
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First-aid measures and management principles
3. PHYSICO-CHEMICAL PROPERTIES
   3.1 Origin of the substance
   3.2 Chemical structure
   3.3 Physical properties
      3.3.1 Colour
      3.3.2 State/form
      3.3.3 Description
   3.4 Hazardous characteristics
4. USES/CIRCUMSTANCES OF POISONING
   4.1 Uses
      4.1.1 Uses
      4.1.2 Description
   4.2 High risk circumstance of poisoning
   4.3 Occupationally exposed populations
5. ROUTES OF ENTRY
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Others
6. KINETICS
   6.1 Absorption by route of exposure
   6.2 Distribution by route of exposure
   6.3 Biological half-life by route of exposure
   6.4 Metabolism
   6.5 Elimination by route of exposure
7. TOXICOLOGY
   7.1 Mode of Action
   7.2 Toxicity
      7.2.1 Human data
         7.2.1.1 Adults
         7.2.1.2 Children
      7.2.2 Relevant animal data
      7.2.3 Relevant in vitro data
      7.2.4 Workplace standards
      7.2.5 Acceptable daily intake (ADI) and other guideline levels
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
   8.1 Material sampling plan
      8.1.1 Sampling and specimen collection
         8.1.1.1 Toxicological analyses
         8.1.1.2 Biomedical analyses
         8.1.1.3 Arterial blood gas analysis
         8.1.1.4 Haematological analyses
         8.1.1.5 Other (unspecified) analyses
      8.1.2 Storage of laboratory samples and specimens
         8.1.2.1 Toxicological analyses
         8.1.2.2 Biomedical analyses
         8.1.2.3 Arterial blood gas analysis
         8.1.2.4 Haematological analyses
         8.1.2.5 Other (unspecified) analyses
      8.1.3 Transport of laboratory samples and specimens
         8.1.3.1 Toxicological analyses
         8.1.3.2 Biomedical analyses
         8.1.3.3 Arterial blood gas analysis
         8.1.3.4 Haematological analyses
         8.1.3.5 Other (unspecified) analyses
   8.2 Toxicological Analyses and Their Interpretation
      8.2.1 Tests on toxic ingredient(s) of material
         8.2.1.1 Simple Qualitative Test(s)
         8.2.1.2 Advanced Qualitative Confirmation Test(s)
         8.2.1.3 Simple Quantitative Method(s)
         8.2.1.4 Advanced Quantitative Method(s)
      8.2.2 Tests for biological specimens
         8.2.2.1 Simple Qualitative Test(s)
         8.2.2.2 Advanced Qualitative Confirmation Test(s)
         8.2.2.3 Simple Quantitative Method(s)
         8.2.2.4 Advanced Quantitative Method(s)
         8.2.2.5 Other Dedicated Method(s)
      8.2.3 Interpretation of toxicological analyses
   8.3 Biomedical investigations and their interpretation
      8.3.1 Biochemical analysis
         8.3.1.1 Blood, plasma or serum
         8.3.1.2 Urine
         8.3.1.3 Other fluids
      8.3.2 Arterial blood gas analyses
      8.3.3 Haematological analyses
      8.3.4 Interpretation of biomedical investigations
   8.4 Other biomedical (diagnostic) investigations and their interpretation
   8.5 Overall Interpretation of all toxicological analyses and toxicological investigations
   8.6 References
9. CLINICAL EFFECTS
   9.1 Acute poisoning
      9.1.1 Ingestion
      9.1.2 Inhalation
      9.1.3 Skin exposure
      9.1.4 Eye contact
      9.1.5 Parenteral exposure
      9.1.6 Other
   9.2 Chronic poisoning
      9.2.1 Ingestion
      9.2.2 Inhalation
      9.2.3 Skin exposure
      9.2.4 Eye contact
      9.2.5 Parenteral exposure
      9.2.6 Other
   9.3 Course, prognosis, cause of death
   9.4 Systematic description of clinical effects
      9.4.1 Cardiovascular
      9.4.2 Respiratory
      9.4.3 Neurological
         9.4.3.1 Central Nervous System (CNS)
         9.4.3.2 Peripheral nervous system
         9.4.3.3 Autonomic nervous system
         9.4.3.4 Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary
         9.4.6.1 Renal
         9.4.6.2 Others
      9.4.7 Endocrine and reproductive systems
      9.4.8 Dermatological
      9.4.9 Eye, ears, nose, throat: local effects
      9.4.10 Haematological
      9.4.11 Immunological
      9.4.12 Metabolic
         9.4.12.1 Acid-base disturbances
         9.4.12.2 Fluid and electrolyte disturbances
         9.4.12.3 Others
      9.4.13 Allergic reactions
      9.4.14 Other clinical effects
      9.4.15 Special risks
   9.5 Others
   9.6 Summary
10. MANAGEMENT
   10.1 General principles
   10.2 Life supportive procedures and symptomatic treatment
   10.3 Decontamination
   10.4 Enhanced elimination
   10.5 Antidote treatment
      10.5.1 Adults
      10.5.2 Children
   10.6 Management discussion
11. ILLUSTRATIVE CASES
   11.1 Case reports from literature
12. ADDITIONAL INFORMATION
   12.1 Specific preventive measures
   12.2 Other
13. REFERENCES
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESSES
    NITROGEN OXIDES

    International Programme on Chemical Safety
    Poisons Information Monograph (Group Monograph) G017
    Chemical

    1.  NAME

        1.1  Substance

             Nitrogen oxides

        1.2  Group

             Nitric oxide
             Nitrous oxide
             Nitrogen dioxide
             Nitrogen pentoxide

        1.3  Synonyms

             Nitiric oxide: mononitrogen monoxide;
             nitrogen monoxide

             Nitrous oxide: dinitrogen monoxide: 
             laughing gas; factitious air;
             hyponitrous acid anhydride; 
             mononitrogen monoxide; nitric oxide;
             nitrogen oxide;

             Nitrogen pentoxide: dinitrogen pentoxide;
             nitric anhydride;

             Nitrogen dioxide: nitrogen tetroxide

        1.4  Identification numbers

             1.4.1  CAS number

                    Nitric oxide            10102-43-9
                    Nitrous oxide           10024-97-2
                    Nitrogen dioxide        10102-44-0

             1.4.2  Other numbers

        1.5  Brand names, Trade names

        1.6  Manufacturers, Importers

    2.  SUMMARY

        2.1  Main risks and target organs

             Inhalation of any oxides of nitrogen causes toxic
             effects. The main target organ is the lung.

        2.2  Summary of clinical effects

             There may be three stages of toxicity. Initially there
             may be  mild irritation of the upper respiratory tract,
             cough, sore  throat, conjunctivitis, dyspnoea, headache,
             vertigo, and tightness of the chest.
    
             After a latent period of 3 to 30 hours, inflammation of the 
             lungs, pulmonary oedema, dyspnoea, wheezing and cyanosis 
             resulting in severe respiratory failure.
    
             Approximately half the patients who survive pulmonary oedema 
             develop bronchiolitis obliterans within a few weeks.

        2.3  Diagnosis

             Diagnosis depends on a history of exposure and the
             presence of  symptoms and signs related to the respiratory
             system.
    
             Arterial blood gas studies may show hypoxia, hypercapnia and
             acidosis.
    
             Pulmonary function tests may show obstructive, restrictive
             and diffusion defects.

        2.4  First-aid measures and management principles

             First-aid measures:
    
             Remove the patient to from the source of exposure and admit
             to hospital as soon as possible.
    
             Management principles:
    
             Establish an adequate airway and maintain respiration.
             Give oxygen and assisted ventilation if necessary. Treat
             bronchospasm with bronchodilators.
             Remove secretions.
             Give corticosteroids if moderate respiratory symptoms or
             pulmonary oedema are present.
             Keep under observation.

    3.  PHYSICO-CHEMICAL PROPERTIES

        3.1  Origin of the substance

             Oxides of nitrogen are synthesized or occur as
             by-products of chemical processes or fires.
    
             On a global scale, quantities of nitric oxide and nitrogen 
             dioxide produced naturally by bacterial and volcanic action 
             and by lightning by far outweigh those generated by man's 
             activities (WHO, 1977).The major source of man-made emission 
             of oxides of nitrogen is the combustion of fossil fuels in 
             stationary sources (heating, power generation) and in motor 
             vehicles (internal combustion engines).Other sources are 
             industrial processes such as manufacture of nitric acid and 
             explosives, smoking, gas-fired appliances and oil stoves.
    
             Burning plastics, shoe polish, nitrocellulose, and welding 
             operations produce oxides of nitrogen (Horvath, 1980).
    
             Nitric oxide is prepared industrially by passing air through 
             an electric arc or by oxidation of ammonia over platinum 
             gauze.
    
             Laboratory preparation is by reacting sodium nitrite with 
             ferrous sulphate.
    
             Nitrous oxide is prepared by thermal decomposition of
             ammonium nitrate.
    
             Nitrogen dioxide is prepared industrially from nitric oxide
             and in the laboratory from lead nitrate.
    
             Nitrogen pentoxide is produced by dehydration of nitric acid
             by phosphorus pentoxide (Budavari, 1996).

        3.2  Chemical structure

             Nitric oxide
             Molecular weight      30.01
    
             Nitrogen dioxide 
             Molecular weight      44.02
    
             Nitrogen pentoxide 
             Molecular weight     108.02

        3.3  Physical properties 

             3.3.1  Colour

                    See section 3.3.3

             3.3.2  State/form

                    See section 3.3.2

             3.3.3  Description

                    Nitrogen dioxide
                    Molecular formula:      NO2
                    Boiling point           21.15C
                    Melting point           -9.3C 
                    Molecular mass          44.02
                    Condensation point      21C
                    Specific gravity at 20C 1.448 (liquid)
    
                    A reddish brown gas. Liquid below 21.15C. 
    
                    Nitrogen pentoxide
                    Molecular formula:      N2O5
                    Boiling point           47.0C
                    Melting point           30C
                    Molecular mass          108.02
    
                    Colourless hexagonal crystals.
    
                    Nitrous oxide
                    Molecular formula:       N2O
                    Boiling point            88.46C 
                    Melting point            -90.81C
                    Vapour pressure (Pascals at 20C) 4.93 (Mellor, 1967)
                    Solubility: Soluble in alcohol and ether. 
    
                    A colourless gas with slightly sweetish odour and
                    taste. 
    
                    Nitric oxide
                    Molecular formula        NO
                    Boiling point:           -151.8 C
                    Molecular mass:          30.01
    
                    A colourless gas.
    
                    (Budavari, 1996)

        3.4  Hazardous characteristics

             Nitrogen dioxide
             It has an irritating odour and is highly poisonous.Under 
             normal atmospheric conditions it exists in equilibrium with 
             nitrogen tetroxide (N204). Heavier than air. Nitrogen
             dioxide  produces nitrous acid (HN02) and nitric acid
             (HN03) on contact with water.
    

             Nitrogen pentoxide
             Sublimes at -32.4C but  undergoes moderately rapid
             decomposition into 02 and the NO2/N204 equilibrium
             mixture at temperatures above -10C. Freely soluble in
             chloroform without appreciable  decomposition.
    
             Nitrous oxide
             Supports combustion.Very stable and rather inert chemically 
             at room temperatures.Dissociation begins above 300C when 
             the gas becomes a strong oxidizing agent.
    
             Nitric oxide
             Burns when heated with hydrogen. It combines with oxygen to
             form nitrogen dioxide and with halogens to form nitrosyl
             halides, e.g. NOCl.
    
             (Budavari, 1996)

    4.  USES/CIRCUMSTANCES OF POISONING

        4.1  Uses

             4.1.1  Uses

             4.1.2  Description

                    Nitric oxide
                    In the manufacture of nitric acid, bleaching of rayon;
                    as a stabilizer (to prevent free radical
                    decomposition) for  propylene, methyl ether etc.
    
                    Nitrogen dioxide 
                    Intermediate in nitric and sulphuric acid production.
                    It is also used in nitration of organic compounds and 
                    explosives in the manufacturing of oxidized cellulose 
                    compounds. Has been used to bleach flour. Proposed as 
                    oxidizing agent in rocket propulsion.
    
                    Nitrogen pentoxide 
                    Used in chloroform solution as a nitrating agent.
    
                    Nitrous oxide
                    To oxidize organic compounds at temperatures above
                    300C  to make nitrites from alkali metals at their
                    boiling  points, in rocket fuel formulations (with
                    carbon  disulphide) and in the preparation of whipped
                    cream. Also used as an anaesthetic gas (Budavari,
                    1996).

        4.2  High risk circumstance of poisoning

             Poisoning occurs following exposure to industrial, 
             manufacturing or agricultural sources which evolve nitrous 
             fumes (oxides of nitrogen). 
    
             Nitrogen dioxide and nitric oxide are the principal hazards.
             Nitrous oxide is narcotic in high concentrations but it is 
             less irritant than other oxides of nitrogen.

        4.3  Occupationally exposed populations

             Occupational exposure usually occurs from manufacture of
             dyes, fertilizers, celluloid and lacquers; and from welding
             glass blowing and food bleaching.
    
             Firemen may be exposed to nitrogen oxide during chemical
             plant fires or from burning mattresses (Ellenhorn &
             Barceloux, 1988).
    
             Nitrogen oxides are also released from processes such as 
             electroplating, engraving, photogravure operations etc.
             (Gosselin et al., 1984).
    
             Severe symptoms and death has been reported in farmers
             working in or near silos. This syndrome, known as silo
             filler's disease, is due to acute exposure to oxides of
             nitrogen produced by silage (Ellenhorn & Barceloux 1988).
    
             Occupational exposure occurs in anaesthesia. 

    5.  ROUTES OF ENTRY

        5.1  Oral

             Not known.

        5.2  Inhalation

             Inhalation of some oxides of nitrogen such as nitric
             oxide and nitrogen dioxide causes poisoning. On contact with
             air,  nitric oxide is converted to highly poisonous nitrogen 
             dioxide. 
    
             The effects of nitrogen dioxide are insidious: inhalation may 
             cause only slight pain or go unnoticed, but may cause death 
             later.

        5.3  Dermal

             Nitric acid , formed when fumes of nitrogen oxides mix
             with sweat, has caused skin burns (Haddad and Winchester,
             1990).

        5.4  Eye

             Fumes of nitrogen oxides can cause eye irritation
             (Haddad and Winchester, 1990).

        5.5  Parenteral

             Not known.

        5.6  Others

             Not known.

    6.  KINETICS

        6.1  Absorption by route of exposure

             Nitrogen oxides are largely absorbed by and react with 
             pulmonary alveolar structures and terminal respiratory 
             bronchioles.
    
             They are less soluble than most irritant gases and have a 
             greater tendency to reach the bronchioles and alveoli (Haddad 
             and Winchester, 1990).

        6.2  Distribution by route of exposure

             Within the lungs, nitrogen oxides react with water to
             form nitrous and nitric acids causing extensive local
             damage.

        6.3  Biological half-life by route of exposure

             The biological half-life of endogenous nitrogen oxides
             in vascular endothelium is very short.

        6.4  Metabolism

             No data available.

        6.5  Elimination by route of exposure

             No data available.

    7.  TOXICOLOGY

        7.1  Mode of Action

             Of the five principal oxides of nitrogen, nitrous oxide
             is  comparatively harmless. The principal target organ for
             other oxides is  the lung. Nitric oxide is less toxic tot he
             lung than nitrogen dioxide. Little is known about toxicology
             of nitrogen  trioxide (N2O3) and nitrogen pentoxide
             (N2O5) (Gosselin et al., 1984).
    
             It is now generally accepted that nitrogen dioxide is the 
             principal causative factor of the pulmonary changes following 
             the inhalation of oxides of nitrogen ("nitrous fumes")
             (Milne,  1969).
    
             Nitrogen oxides are irritant and destructive to lung tissues 
             because they are slowly hydrolysed to acids. The upper 
             respiratory tract is largely spared perhaps because these 
             gases have a low solubility in aqueous media and because they 
             are only slowly hydrolysed.
    
             The mild upper respiratory irritant effect is a result of 
             nitrogen dioxide being converted to nitric acid in the 
             presence of water.
    
             Nitric acid destroys respiratory epithelium and alveolar 
             membranes and may produce metabolic acidosis. The mild 
             initial irritant effects allow widespread dissemination of 
             nitrogen oxides throughout the lungs and result in diffuse 
             delayed inflammation.
    
             Fibrotic destruction of terminal bronchioles (bronchiolitis 
             obliterans) occurs as a late complication (Ellenhorn & 
             Barceloux, 1988).
    
             Nitrogen dioxide decomposition may also produce nitrates
             which  are capable of causing vasodilatation and mild 
             methaemoglobinaemia.

        7.2  Toxicity

             7.2.1  Human data

                    7.2.1.1  Adults

                             The presence of nitrogen dioxide may
                             be difficult  to perceive and it is
                             frequently undetectable at  concentrations
                             causing mucosal irritation. Early  symptoms
                             are often mild, even in cases where  there is
                             serious late toxicity. At levels of  100 to
                             150 ppm toxicity occurs within 30 to 60 

                             minutes and at levels of 200 to 700 ppm 
                             fatalities result after short exposure 
                             (Ellenhorn & Barceloux, 1988). 
    
                             Chest discomfort occurs after exposure to 15
                             ppm for 1 hour and the sensation becomes
                             unpleasant at 25 ppm. After 1 minute at 50
                             ppm subjects feel substernal pain. Longer
                             exposure at this concentration causes
                             reversible inflammatory changes in the lungs.
                             Higher concentrations may be fatal
                             (Dreisbach, 1987).

                    7.2.1.2  Children

                             No data available.

             7.2.2  Relevant animal data

                    In the rat, exposure to 0.5 ppm for 4 hours
                    causes  reversible degranulation of lung cells. Mice
                    exposed  continuously for 3 months to 0.5 ppm become
                    more  susceptible to infection when challenged with 
                    pneumococci. Weight loss occurs in monkeys exposed to 
                    this concentration but other animals are not
                    affected.
    
                    In the rat, continuous exposure to 2 ppm of NO2 for 3 
                    days caused epithelial hyperplasia in the terminal
                    bronchioles. Exposure for more than one year caused
                    thinning of the membrane lining the lungs.
    
                    Intermittent exposure of rats to 4 ppm for a year
                    caused  no discernible permanent damage to the lungs
                    (Dreisbach,  1987).
    
                    Animals exposed to 70 ppm for 8 hours developed 
                    periorbital oedema and corneal opacities (Ellenhorn
                    and  Barceloux, 1988).

             7.2.3  Relevant in vitro data

                    No data available.

             7.2.4  Workplace standards

                    Nitrogen dioxide:
                    Threshold limit value (time weighted average):
                    3 ppm (6 mg/m3)
    
                    Threshold limit value - STEL: 5 ppm (10 mg/m3)
    

                    NIOSH recommends 1 ppm of nitrogen dioxide as a
                    workplace environmental standard (NIOSH, 1976).
    
                    Nitric oxide:
                    Threshold limit value: 25 ppm

             7.2.5  Acceptable daily intake (ADI) and other guideline 
                    levels

                    Not relevant.

        7.3  Carcinogenicity

             Unknown

        7.4  Teratogenicity

             Unknown

        7.5  Mutagenicity

             Unknown

        7.6  Interactions

             Unknown

    8.  TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS

        8.1  Material sampling plan

             8.1.1  Sampling and specimen collection

                    8.1.1.1  Toxicological analyses

                    8.1.1.2  Biomedical analyses

                    8.1.1.3  Arterial blood gas analysis

                    8.1.1.4  Haematological analyses

                    8.1.1.5  Other (unspecified) analyses

             8.1.2  Storage of laboratory samples and specimens

                    8.1.2.1  Toxicological analyses

                    8.1.2.2  Biomedical analyses

                    8.1.2.3  Arterial blood gas analysis

                    8.1.2.4  Haematological analyses

                    8.1.2.5  Other (unspecified) analyses

             8.1.3  Transport of laboratory samples and specimens

                    8.1.3.1  Toxicological analyses

                    8.1.3.2  Biomedical analyses

                    8.1.3.3  Arterial blood gas analysis

                    8.1.3.4  Haematological analyses

                    8.1.3.5  Other (unspecified) analyses

        8.2  Toxicological Analyses and Their Interpretation

             8.2.1  Tests on toxic ingredient(s) of material

                    8.2.1.1  Simple Qualitative Test(s)

                    8.2.1.2  Advanced Qualitative Confirmation Test(s)

                    8.2.1.3  Simple Quantitative Method(s)

                    8.2.1.4  Advanced Quantitative Method(s)

             8.2.2  Tests for biological specimens

                    8.2.2.1  Simple Qualitative Test(s)

                    8.2.2.2  Advanced Qualitative Confirmation Test(s)

                    8.2.2.3  Simple Quantitative Method(s)

                    8.2.2.4  Advanced Quantitative Method(s)

                    8.2.2.5  Other Dedicated Method(s)

             8.2.3  Interpretation of toxicological analyses

        8.3  Biomedical investigations and their interpretation

             8.3.1  Biochemical analysis

                    8.3.1.1  Blood, plasma or serum

                    8.3.1.2  Urine

                    8.3.1.3  Other fluids

             8.3.2  Arterial blood gas analyses

             8.3.3  Haematological analyses

             8.3.4  Interpretation of biomedical investigations

        8.4  Other biomedical (diagnostic) investigations and their 
             interpretation

        8.5 Overall Interpretation of all toxicological analyses and 
             toxicological investigations

             Sample collection
             Collect blood samples to assess arterial blood gases and
             methaemoglobin levels.
    
             Biomedical analysis
             Arterial blood gas studies show hypoxia, hypercapnia and
             acidosis with early changes in the alveolar - arterial oxygen
             gradient.
    
             Pulmonary function tests show obstructive, restrictive and
             diffusion defects as a result of destruction of alveoli,
             interstitium and bronchioles (Ellenhorn & Barceloux,
             1988).

        8.6  References

    9.  CLINICAL EFFECTS

        9.1  Acute poisoning

             9.1.1  Ingestion

                    Unknown

             9.1.2  Inhalation

                    The irritant effects of oxides of nitrogen
                    cause  inflammation of the lungs, leading to profuse
                    exudation  into the alveolar spaces. Pulmonary oedema,
                    rapid  breathing and cyanosis are early features.
    
                    Relapse may occur after 2 to 3 weeks with the onset of
                    bronchiolitis obliterans.
    
                    Chest X-ray shows fluffy confluent bilateral
                    infiltrates  in patients with pulmonary oedema, and a
                    nodular pattern  in cases of bronchiolitis
                    obliterans.

             9.1.3  Skin exposure

                    Skin burns can occur when nitrous fumes mix
                    with sweat to form nitric acid. 

             9.1.4  Eye contact

                    Exposure to nitrogen oxides can cause conjunctivitis. 

             9.1.5  Parenteral exposure

                    Not relevant.

             9.1.6  Other

                    Not relevant.

        9.2  Chronic poisoning

             9.2.1  Ingestion

                    Unknown.

             9.2.2  Inhalation

                    No adverse effects were found in workers
                    exposed for several years at 30 to 35 ppm oxides of
                    nitrogen (ACGIH, 1986).

             9.2.3  Skin exposure

                    No data available.

             9.2.4  Eye contact

                    No data available.

             9.2.5  Parenteral exposure

                    Unknown.

             9.2.6  Other

                    Unknown.

        9.3  Course, prognosis, cause of death

             Clinical features depend on the duration and intensity
             of exposure and follow a triphasic pattern. 
    
             Initially, there is mild irritation of the upper respiratory
             tract. 
    
             Mild cases become asymptomatic within several hours. The 
             severity of initial symptoms does not correlate well with 
             subsequent pulmonary pathology, although patients with mild 
             nitrogen dioxide exposure often recover without any late 
             complications.
    

             After a latent period of 32 hours (in some instances lasting
             up to 72 hours) patients may develop inflammation of the
             lungs and pulmonary oedema.
    
             About 50% patients surviving pulmonary oedema develop
             bronchiolitis obliterans in 2 to 6 weeks.
    
             In a few instances, bronchiolitis obliterans may be the 
             initial presentation with symptoms including progressive 
             dyspnoea, cyanosis, cough and wheezing.
    
             The patient may be even more intensely ill during this
             relapse  than during the initial reaction.
    
             Recovery can take up to 6 months. Emphysematous change 
             persists, depending on the severity of the original
             damage.
    
             Death can occur due to asphyxia within a few hours of the 
             onset of pulmonary oedema.
    
             Exposure to high concentrations in the region of 100 to 500 
             ppm may leads to sudden death from bronchospasm and 
             respiratory failure. Delayed pulmonary oedema can cause 
             death. Several weeks after exposure, bronchiolitis obliterans
             can cause death.

        9.4  Systematic description of clinical effects

             9.4.1  Cardiovascular

                    Rapid and weak pulse, cyanosis, venous
                    congestion and  hypotension occur secondary to anoxia
                    and  haemoconcentration (Gosselin et al. 1984).
                    Hypotension  may occur due to a direct effect of
                    nitrates on blood  vessels (Haddad and Winchester,
                    1990).

             9.4.2  Respiratory

                    Usually no symptoms occur at the time of
                    exposure with  the exception of a slight cough and
                    perhaps fatigue and nausea. Exposure to low
                    concentrations may result in impaired pulmonary
                    defence mechanisms (macrophages, cilia) with
                    complications.
    
                    Only relatively high concentrations of nitrogen oxides 
                    produce prompt coughing, choking, production of mucoid 
                    and frothy sputum, headache, nausea, abdominal pain
                    and dyspnoea and tightness and burning pain in the
                    chest. There may be haemoptysis.
    

                    Inhalation of nitrogen dioxide for a short period
                    causes increased airways resistance (Horvath, 1980).
                    This seems to be due to histamine release (Guidotti,
                    1978).
    
                    A symptom-free period may follow exposure and lasts
                    for  5 to 72 hours. Fatigue, uneasiness, restlessness,
                    cough, tachypnoea and dyspnoea, appear insidiously as
                    adult  respiratory distress syndrome gradually
                    develops.
    
                    Increasingly rapid and shallow respiration, cyanosis, 
                    coughing with frothy expectoration, and physical signs 
                    of bronchospasm and pulmonary oedema such as crackles 
                    and wheezes can be observed. Vital capacity is rapidly 
                    reduced. A serous exudate may develop in the pleural 
                    cavity, but its volume is usually small. Anxiety, 
                    mental confusion, lethargy, and finally loss of 
                    consciousness occur as a result of hypoxia.
    
                    Chest X-ray may show widespread, coarse mottling 
                    throughout the lung fields. Lungs may be
                    radiologically  clear within a few days, in parallel
                    with clinical  improvement (Milne, 1969). Circulatory
                    collapse is  secondary to anoxia and
                    haemoconcentration.
    
                    Death may occur within a few hours of the first
                    evidence  of pulmonary oedema.
    
                    Sometimes a second acute phase follows the initial 
                    pulmonary reaction after a quiescent period of 2 to 6 
                    weeks. Cough, tachypnoea, dyspnoea, fever, tachycardia 
                    and cyanosis at this stage are usually due to 
                    bronchiolar inflammation which may lead to
                    bronchiolitis  obliterans (Milne, 1969).The relapse
                    may be abrupt and  fulminating, leading either to
                    death or a slow  convalescence.
    
                    Chest X-ray reveals widespread bilateral mottling.
    
                    Blood gas analysis indicates hypoxia.
    
                    In non-fatal cases, convalescence may be complicated
                    by  infection, bronchitis, bronchiolitis obliterans, 
                    pneumonia and general weakness. Rarely, diffuse 
                    pulmonary fibrosis may develop. 

             9.4.3  Neurological

                    9.4.3.1  Central Nervous System (CNS)

                             The effects are secondary to
                             hypoxia. There may be confusion.

                    9.4.3.2  Peripheral nervous system

                             Not known

                    9.4.3.3  Autonomic nervous system

                             Not known

                    9.4.3.4  Skeletal and smooth muscle

                             Not known

             9.4.4  Gastrointestinal

                    There may be nausea.

             9.4.5  Hepatic

                    Not known

             9.4.6  Urinary

                    9.4.6.1  Renal

                             Unknown

                    9.4.6.2  Others

                             Unknown

             9.4.7  Endocrine and reproductive systems

                    Unknown

             9.4.8  Dermatological

                    Skin burns from nitric acid may occur due to
                    the mixture of fumes with sweat (Haddad and
                    Winchester, 1990).

             9.4.9  Eye, ears, nose, throat: local effects

                    There may be conjunctivitis and sore throat.

             9.4.10 Haematological

                    Severe haemoconcentration occurs due to the
                    fluid loss  in pulmonary oedema. Leucocytosis can
                    occur even in the  acute initial phase (Haddad and
                    Winchester, 1990).
    
                    Changes in blood chemistry (such as decreased red cell 
                    membrane acetylcholinesterase activity, red cell 
                    glucose-6-phosphate dehydrogenase, total haemoglobin 
                    and haematocrit and an increase in red cell
                    peroxidized  lipids) have been seen in young adults
                    exposed to  nitrogen dioxide 1 or 2 ppm for 3 hours
                    daily for 3  days (Gosselin et al., 1984).
    
                    Methaemoglobinaemia has been reported (Haddad and 
                    Winchester, 1990).

             9.4.11 Immunological

                    Unknown.

             9.4.12 Metabolic

                    9.4.12.1 Acid-base disturbances

                             Metabolic acidosis can occur due to
                             the  formation of nitrous acid and the
                             development  of lactic acidosis (Haddad and
                             Winchester,  1990).

                    9.4.12.2 Fluid and electrolyte disturbances

                             Pulmonary inflammation and oedema
                             result in  fluid loss from blood.

                    9.4.12.3 Others

                             Unknown

             9.4.13 Allergic reactions

                    Unknown

             9.4.14 Other clinical effects

                    Unknown

             9.4.15 Special risks

                    Pregnancy: Unknown.
    
                    Breast feeding: Unknown.
    
                    Enzyme deficiencies: Unknown.

        9.5  Others

             American astronauts on the Apollo - Soyuz mission were
             briefly exposed by accident to nitrogen dioxide. Elevated
             urinary levels of hydroxylysine glycosides suggested collagen
             breakdown in the pulmonary parenchyma (Ellenhorn & Barceloux,
             1988).

        9.6  Summary

    10. MANAGEMENT

        10.1 General principles

             Remove the patient from the source of exposure.
             Establish an adequate airway and maintain respiration.
             Give oxygen and assisted ventilation if necessary.
             Remove secretions.
             Advise strict bed rest.
             Asymptomatic patients should be kept under observation for up
             to 72 hours.

        10.2 Life supportive procedures and symptomatic treatment

             Establish an adequate airway and respiration. Remove
             frothy  exudate from respiratory tract. Give oxygen for
             dyspnoea and  cyanosis. If severe pulmonary oedema is
             present, assisted  ventilation may be needed.
    
             Give normal saline or plasma expanders intravenously or blood
             transfusion to maintain adequate perfusion pressure.
    
             Do frequent sputum cultures. Treat infection with appropriate
             antibiotics.
    
             Correct acid-base abnormalities.
    
             If pulmonary oedema is not present, ensure a urine output of
             at least 1500 ml daily by giving adequate fluids. 
    
             If symptoms of irritation or bronchospasm occur give a
             bronchodilator such as salbutamol by nebulizer.
    
             Give methylprednisolone 20 to 80 mg orally or intravenously.
             Repeat daily for 8 weeks before gradually decreasing the dose
             (Haddad and Winchester, 1990).

        10.3 Decontamination

             Eye contact:
             Irrigate exposed eyes with copious amounts of water.

        10.4 Enhanced elimination

             Not relevant

        10.5 Antidote treatment

             10.5.1 Adults

                    No specific antidote.

             10.5.2 Children

                    No specific antidote.

        10.6 Management discussion

             For bronchospasm, atropine, epinephrine, expectorants,
             and  sedative drugs are ineffective and harmful (Gosselin et
             al., 1984).
    
             Patients must be followed-up for at least 6 weeks since 
             relapses can occur.
    
             Asymptomatic patients could be discharged after 24 to 36 
             hours of observation but they should be followed up within 
             several weeks to assess pulmonary status.

    11. ILLUSTRATIVE CASES

        11.1 Case reports from literature

             Cough, dyspnoea at rest and on exertion, chest pain, 
             headache, haemoptysis and weakness were the symptoms reported
             by 116  people exposed to fumes from a malfunctioning engine 
             (Hedberg et al., 1989).
    
             A chemist exposed to nitrogen dioxide (nitrous fumes) had 
             cough and slight headache only. Twelve hours later he was 
             awakened with dyspnoea and cough. On admission to hospital 
             soon after, he had severe acute pulmonary oedema. He was 
             discharged on the 7th day. On the 20th day after exposure he
             was readmitted with dyspnoea, coughing and sweating. He 
             required intermittent positive pressure ventilation. He was 
             treated with corticosteroids and discharged 28 days later 
             (Milne, 1969). 

    12. ADDITIONAL INFORMATION

        12.1 Specific preventive measures

             Exposure to oxides of nitrogen at workplace should be 
             avoided by appropriate storage of chemicals and by following 
             proper safety standards.

        12.2 Other

             No data available.

    13. REFERENCES

        American Conference of Governmental Industrial Hygienists
        Inc.  (1986).Documentation of the threshold limit values and 
        biological exposure indices.5th Edition.Cincinnati, Ohio. 435  -
        436.
    
        Budavari S ed. (1996) The Merck Index: an encyclopedia of 
        chemicals, drugs, and biologicals, Rahway, New Jersey, Merck and 
        Co. Inc.
    
        Cotlon FA, Wilkinson G ed. (1980) Advanced Inorganic Chemistry, 
        U.S.A., John Wiley and Sons Inc.
    
        Dreishbach RH, Robertson WO ed (1987) Handbook of Poisoning: 
        Prevention, Diagnosis and TreatmentLos Altos, Appleton & Lange.  p
        202.
    
        Ellenhorn MJ & Barceloux DG ed (1988). Medical Toxicology. New 
        York, Elsevier Science Publishing Company, Inc. p 876. 
    
        Gosselin RE, Smith RP, Hodge HC ed.(1984) Clinical Toxicology of 
        Commercial Products. Baltimore, Williams and Wilkins. p III 319-
        326.
    
        Guidotti TL (1978). The higher oxides of nitrogen: inhalation 
        toxicology. Environmental Research 15:43-72
    
        Haddad LM and Winchester JF ed. (1990)Clinical management of 
        poisoning and drug overdose 2nd Edition.W.B. Saunders Company, 
        Philadelphia 1272 - 1280.
    
        Horvath SM (1980) Nitrogen dioxide, pulmonary function and 
        respiratory disease. Bull. N.Y. Acid. Med. 56 (9): 835 - 846.
    
        NIOSH: Criteria for a Recommended Standard - Oxides of nitrogen 
        (1976).DHEW Pub. No (NIOSH) 76 - 149.
    
        Hedberg K, Hedberg CW, Iber C, et al (1989) An outbreak of 
        nitrogen dioxide induced respiratory illness among ice hockey 
        players. JAMA, 262 (21): 3014 - 3017
    

        Lee JD ed. (1964) Concise Inorganic chemistry, 2nd Edition, Great 
        Britain, William Clowes & Sons Ltd. pp. 115 - 119.
    
        Mellor JW ed. (1967) Mellor's Comprehensive Treatise on Inorganic 
        and theoretical chemistry.Volume VIII Supplement II Nitrogen  Part
        II. London, Longmans Green Co. Ltd. pp 189 - 195.
    
        Milne JEH (1969) Nitrogen dioxide inhalation and bronchiolitis 
        obliterans. J. Occupational Medicine 11: 538 - 547.
    
        WHO (1977). Environmental Health Criteria 4. Oxides of nitrogen.
        World Health Organisation. Geneva, Switzerland.

    14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE
        ADDRESSES

    Author(s):       Dr. Ravindra Fernando & Miss. Deepthi Widyaratne
                    National Poisons Information Centre
                    Faculty of Medicine
                    Kynsey Road
                    Colombo 8
                    Sri Lanka.
    
    Date:           January 1992
    
    Peer Review:    London, United Kingdom, September 1992
    
    Editor:         M.Ruse (IPCS, May, 1999)
    




    See Also:
       Toxicological Abbreviations
       Nitrogen oxides (FAO Nutrition Meetings Report Series 40abc)
       NITROGEN OXIDES (JECFA Evaluation)