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Nitrates and nitrites

1. NAME
   1.1 Substances
   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 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/HIGH RISK CIRCUMSTANCES OF POISONING
   4.1 Uses
      4.1.1 Uses
      4.1.2 Description
   4.2 High risk circumstances of poisoning
   4.3 Occupationally exposed population
5. ROUTES OF ENTRY
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Other
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)
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
8. TOXICOLOGICAL ANALYSES/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 Gastro-intestinal
      9.4.5 Hepatic
      9.4.6 Urinary
         9.4.6.1 Renal
         9.4.6.2 Other
      9.4.7 Endocrine and reproductive systems
      9.4.8 Dermatological
      9.4.9 Eye, ear, 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
      10.5.1 Adults
      10.5.2 Children
   10.6 Management discussion
11. ILLUSTRATIVE CASES
   11.1 Case reports from the literature
12. ADDITIONAL INFORMATION
   12.1 Specific preventive measures
   12.2 Other
13. REFERENCES
14. AUTHOR, REVIEWER, DATE, COMPLETE ADDRESS
    NITRATES AND NITRITES

    International Programme on Chemical Safety
    Poisons Information Monograph (Group Monograph) G016
    Chemical 

    1.  NAME

        1.1  Substances

             Nitrates and nitrites of 

        1.2  Group

             Sodium nitrite
             Potassium nitrite 
             Calcium nitrite 
             Magnesium nitrite 
             Sodium nitrate
             Potassium nitrate 
             Calcium nitrate
             Magnesium nitrate
             Ammonium nitrate

        1.3  Synonyms

             Potassium nitrate: saltpetre; nitre;
             Sodium nitrate: Chilean saltpetre; cubic nitre; soda nitre;
             Ammonium nitrate: Ammonium salpetre;
             Calcium nitrate: Norway salpetre; lime salpetre;
             Magnesium nitrate: nitromagnesite (hydrated form,
             mineral which is occurs in nature); 
             Sodium nitrite: erinitrit;

        1.4  Identification numbers

             1.4.1  CAS number

                    Sodium nitrate:             7631-99-4

             1.4.2  Other numbers

                    Potassium nitrate:          7757-79-1
                    Ammonium nitrate:           6484-52-2
                    Calcium  nitrate:           10124-37-5
                    Calcium  nitrate hydrated:  13477-34-4
                    Magnesium nitrate:          10377-60-3
                    Magnesium nitrate hydrated: 13446-18-9
                    Sodium nitrite:             7632-00-0
                    Potassium nitrite:          7758-09-0
                    Calcium  nitrite:           13780-06-8
                    Calcium  nitrite hydrated:  10031-34-2

                    Magnesium nitrite:          15070-34-5
                    Ammonium nitrite:           13446-48-5

                    RTECS numbers 

                    Sodium nitrate:              WC5600000
                    Potassium nitrate:           TT3700000
                    Ammonium nitrate:            BR9050000
                    Calcium nitrate: 
                    Calcium nitrate hydrated:    EW3000000
                    Magnesium nitrate:           OM3750000
                    Magnesium nitrate hydrated:  OM3756000
                    Sodium nitrite:              RA1225000
                    Potassium nitrite:           TT3750000
                    Ammonium nitrite:            RA0770000

                    UN transportation number 

                    inorganic nitrates: 1477 (class 5.1) 
                    inorganic nitrites: 2627 (class 5.1) 
                    Calcium nitrate: 1454
                    Sodium nitrate: 1498
                    Sodium nitrate & Potassium nitrate mixture: 1499
                    Potassium nitrate: 1486
                    Potassium nitrate & Sodium nitrite mixture: 1487
                    Potassium nitrite: 1488
                    Sodium nitrite: 1500
                    Ammonium nitrate fertilizer: 2067,
                                                 2068,,
                                                 2069,,
                                                 2070,,
                                                 2072 (class 5.1),;
                                                 0223 (class 1.1D),;
                                                 2071 (class 9) 
                    Ammonium nitrite: 0222 (class 1.1D),;
                                                 1942 (class 5.1) 
    Ammonium nitrate liquid (hot concentrated solution): 2426 (class 5.1)

                    EEC number 

                    Potassium nitrite:  007-011-00-X
                    Sodium nitrite:     007-010-00-4

        1.5  Brand names/Trade names

        1.6  Manufacturers/Importers

    2.  SUMMARY

        2.1  Main risks and target organs

             The major acute toxic effect of nitrate and nitrite 
             poisoning is methaemoglobinaemia. Blood is the target organ.
             Methaemoglobin reduces the oxygen-carrying capacity of the 
             blood and in addition, it shifts the oxyhaemoglobin 

             dissociation curve to the left interfering with the unloading 
             of oxygen.
    
             Hypotension and collapse may also occur.
    
             The principal concern with exposure to nitrate is its 
             biological reduction to reactive and toxic nitrite. Nitrate 
             itself is rather harmless.

        2.2  Summary of clinical effects

             Hematological effects include blue-greyish cyanosis that 
             may appear within a few minutes to 45 minutes or more after 
             exposure.
    
             Stupor, coma and convulsions in severe poisoning due to 
             severe hypoxia. Tachycardia, hypotension and collapse may 
             also occur. Nausea, vomiting and abdominal pain may be 
             seen.

        2.3  Diagnosis

             The diagnosis is based on: (i) the clinical presentation 
             of the patient, mainly a central cyanosis in absence of 
             cardiac or pulmonary cause; (ii) the brownish colour of blood 
             and high levels of methaemoglobinaemia (which correlate well 
             with clinical symptoms); and (iii) circumstances of exposure.
             Other relevant laboratory analyses are: arterial blood gases, 
             acid base balance, nitrates could be measured in urine. The 
             levels are usually below 150 mg NO3-/day).

        2.4  First-aid measures and management principles

             Induce emesis and/or gastric lavage if ingestion was 
             recent.
             Administer activated charcoal.
    
             Monitor vital signs, blood pressure, respiration and onset of
             cyanosis.
    
             Administer oxygen if there are clinical signs of
             methaemoglobinaemia.
    
             Methylene blue is the specific antidote indicated in case of
             methaemoglobinemia.

    3.  PHYSICO-CHEMICAL PROPERTIES

        3.1  Origin of substance

             Nitrates can be of natural and synthetic origin.
    
             Nitrate is an important metabolite in the biological nitrogen 
             cycle, produced during nitrification of reduced nitrogen 
             compounds. It is a natural constituent of soil and 
             vegetation. Nitrate is also a normal metabolite in 
             mammals.
    
             Nitrate in soil, ground and surface water derive mainly from 
             mineralization of soil organic matter; some also from 
             application of mineral fertilizers.
    
             The major natural deposit of nitrates is that of sodium
             nitrate (Chilean saltpetre) in northern Chile.
    
             Nitrates are produced on a large scale from nitric acid made 
             from ammonia by catalytic oxidation. Nitrates are formed 
             from the reaction of nitric acid with ammonia or minerals 
             (e.g. phosphate rock) to give ammonium nitrate and water 
             soluble salts used as fertilizers.
    
             Nitrite is also a metabolite in the biological nitrogen 
             cycle; an intermediate in both nitrification and 
             denitrification. It is also a normal metabolite in 
             mammals.
    
             Nitrites in commercial use are all of synthetic origin. They 
             are made mainly by dissolving nitrogen oxides (NO and NO2)
             in  alkaline solutions.
    
             Nitrites can also be prepared by reduction of nitrates.

        3.2  Chemical structure

             The structural formula of nitrate is:
    
    FIGURE 1

             Molecular weight: 62.05
    
             The structural formula of nitrite is: O == N -- O-
             Molecular weight: 46.006

        3.3  Physical properties

             3.3.1  Colour

                    See individual nitrate compounds in Section 3.3.3

             3.3.2  State/form

                    See individual nitrate compounds in Section 3.3.3

             3.3.3  Description

                    NaNO3: melting point = 308C; decomposes at
                    380C; solubility in H20 = 9225 g/100 mL; soluble in
                    alcohol; density = 2.26.
    
                    KNO3: melting point = 334C; decomposes at 400C;
                    solubility in H20 = 13.3; insoluble in alcohol;
                    insoluble in ether; density = 2.109.
    
                    NH4NO3: melting point = 170C; decomposes at 210C;
                    solubility in H2O = 118; solubility in alcohol =
                    3.820; insoluble in ether; density = 1.72.
    
                    Ca(NO3)2: melting point = 561C; solubility in
                    water = 12118; solubility in alcohol = 1415; insoluble
                    in ether.
    
                    Ca(NO3)2.3H20: melting point = 51C
    
                    Ca(NO3)2.4H20: melting point = approx.40C;
                    decomposes at 132C; solubility in water = 266;
                    soluble in alcohol.
    
                    Mg(NO3)2.2H20: melting point = 129C; soluble in
                    water; soluble in alcohol.
    
                    Mg(NO3)2.6H20: melting point = 89C; decomposes
                    at 330C; solubility in water = 125b; soluble in
                    alcohol.
    
                    NaNO2: melting point = 271C; decompose at 320C;
                    solubility in water = 8215; slightly soluble in water;
                    solubility in alcohol = 0.320;
    
                    KNO2: melting point = 440C; decomposes at 350C a;
                    solubility in water = 281; soluble in hot
                    alcohol.
    
                    Ca(NO2)2.H2O: melting point = 100C; solubility
                    in water= 46; slightly soluble in alcohol.
    
                    Ca(NO2)2.4H2O: solubility in water= 75; soluble
                    in alcohol.
    
                    Mg(NO2).3H2O: decomposes at 100C; soluble in
                    cold water; soluble in alcohol.
    

                    Key:
                    a:  decomposition starts at 350C 
                    b: temperature not specified (cold water)
                    upper case number denotes temperature (C)
    
                    (Weast, l982)
    
                    Sodium nitrate: colourless transparent crystals or 
                    white granules or powder, with saline, slightly bitter 
                    taste, deliquesces in moist air.
    
                    Potassium nitrate: colourless transparent prisms or 
                    white, granular or crystalline powder with cooling, 
                    saline pungent taste.
    
                    Ammonium nitrate: odourless, transparent, hygroscopic 
                    deliquescent crystals or white granules. Five solid 
                    phases exist at normal pressure. Orthorhombic at room 
                    temperature.
    
                    Calcium nitrate: deliquescent, colourless granules.
                    Evolve heat when dissolved in water.
    
                    Magnesium nitrate hexahydrate: colourless, clear, 
                    deliquescent crystals.
    
                    Sodium nitrite: white or slightly yellow deliquescent 
                    granules or rods decomposed even by weak acids with 
                    evolution of brown fumes of nitrous anhydride.
    
                    Calcium nitrite: white or yellowish deliquescent 
                    hexagonal crystals.
    
                    Ammonium nitrite: white/yellowish crystals decomposed 
                    in hot water.
    
                    (Budavari, 1996)
    
                    The water solutions of nitrates usually have a pH in 
                    the range of 5 to 8. The water solutions of nitrites 
                    are slightly alkaline (pH 9).

        3.4  Hazardous characteristics

             Under normal conditions, both nitrites (except the 
             ammonium salt) and nitrates are stable compounds. However, 
             at higher temperatures they decompose, and may be explosive 
             at extreme conditions (high temperature and pressure).
             Nitrites also decompose in weak acids. Generally, the 
             presence of chlorides, some metals and organic material 
             destabilize both nitrates and nitrites. Nitrates form NO and 
             NO2 upon thermal decomposition, but ammonium nitrate also 
             forms N2O, N2 and H2O depending on temperature.
    

             Nitrites mainly decompose to N2 and NO. N2O3 can also be 
             formed. Ammonium nitrite is unstable and decomposes to N2 
             and H2O. Nitrites oxidize slowly to nitrates when exposed
             to  air.
    
             Toxic gases can form if buildings, where nitrates or nitrites 
             are stored, catch fire. If these materials are enclosed or 
             contaminated with combustible matter, fire may result in an 
             explosion.
    
             Salts of nitrate are odourless and colourless with a saline 
             taste. They are generally hygroscopic.
    
             Salts of nitrite are colourless or slightly yellow. They are 
             generally hygroscopic.
    
             Environmental concerns:
             Nitrate is a nutrient for algae and other microorganisms, and 
             excesses can contribute towards excessive algal growth in 
             natural waters (eutrophication). Microbial processes in soil 
             and water transform nitrate to nitrogen gas (N2), a process 
             known as denitrification. Some nitrous oxide (N2O) a 
             greenhouse gas, is also formed.

    4.  USES/HIGH RISK CIRCUMSTANCES OF POISONING

        4.1  Uses

             4.1.1  Uses

             4.1.2  Description

                    The major use of nitrate is as fertilizer. It 
                    is also used in the manufacture of nitrites, nitrous 
                    oxide, explosives, pyrotechnics, matches, freezing 
                    mixtures and special cements. It is also used as a 
                    colouring and preserving additive to food, for 
                    coagulation of latexes, in the nuclear industry and 
                    for odour (sulphide) and corrosion control in aqueous 
                    systems.
    
                    Nitrite is used as a food preservative and colouring 
                    agent, e.g. curing of meat, in the manufacture of 
                    diazo dyes and rubber, in the textile industry and in 
                    photography. Nitrite is also used in analytical and 
                    preparative chemistry, as a corrosion inhibitor and as 
                    an antidote in cyanide poisoning.

        4.2  High risk circumstances of poisoning

             Accidental exposure:
             Accidental addition of nitrates/nitrites to food in mistake
             for common salt has resulted in poisoning.
    

             Intentional exposure:
             Employees with access to nitrites at work, e.g. laboratory
             personnel, have occasionally attempted suicide through
             ingestion of nitrite.
    
             Medical exposure:
             Mashed carrot  widely used to treat infant diarrhoea has
             occasionally resulted in intake of toxic amounts of nitrate
             (ECETOC, 1988).
    
             Sodium nitrite given intravenously is traditionally used as
             an antidote in cyanide poisoning (see Section 5.5).
    
             Other types of exposure:
    
             The major concern of nitrate and nitrite is associated with 
             intake of food and water. Drinking water contains variable 
             amounts of nitrate. The statutory limits vary slightly from 
             country to country, but is usually either maximum 10 mg 
             NO3--N/L(= 44.3 mg NO3-/L) in the USA or maximum 50 mg 
             NO3-/L in the EU.
    
             Plants contain nitrate as a normal cell constituent and 
             vegetables are usually the main dietary source of nitrate.
             Normal daily intake varies with dietary customs, 50 to 150 mg 
             NO3-/day seems typical for a western diet. Vegetarians can 
             exceed this, with daily intakes of over 300 mg NO3- (Walker,
             1990).
    
             Dietary exposure to nitrites is normally very low, commonly 
             <2 mg NO2-/day and usually <5 mg/day per capita (<0.1 
             mg/kg/day) (Walker, 1990). Exceptionally, higher levels may 
             result from microbial reduction of nitrates in hygienically 
             poor quality well water or in foods rich in nitrates stored 
             under inappropriate conditions. Bacterial reduction of 
             nitrate secreted in the saliva and gastric juice is usually 
             the source of nitrite (Eisenbrand et al., 1980; Mueller et 
             al., 1986). NAS (1981) estimated that approximately 3.5 mg 
             NO2- is formed per day in an average adult in the USA. This 
             process is dependent upon several factors (e.g. nitrate 
             intake) and varies substantially between individuals.
    
             Several cases have been reported where poisoning has been 
             wholly or partly ascribed to high nitrate or nitrite intake.
             Neonates are at special risk.

        4.3  Occupationally exposed population

             Workers in the fertilizer and explosives industries may 
             be exposed to nitrate through inhalation of dusts containing 
             nitrate salts. Dust can dissolve in sweat and expose skin to 
             concentrated solutions of the salts. This also applies to 
             farmers, although they are only periodically exposed.

    5.  ROUTES OF ENTRY

        5.1  Oral

             Oral intake of nitrate and nitrite in food and drinking 
             water is the major route of entry (see Section 4.5). Suicidal
             attempts by ingestion of sodium nitrite tablets are 
             reported.

        5.2  Inhalation

             The body can take up nitrate and nitrite from inhaled
             dust, e.g. from fertilizers.
    
             Nitrogen oxides are transformed to nitrate/nitrite in the 
             lung (Yoshida & Kasama, 1987; Saul & Archer, 1983), but this 
             exposure gives only 1.3 mg NO3-/day (NAS, 1981).

        5.3  Dermal

             There is no information available on inorganic nitrate 
             and nitrite absorption through intact skin. Absorption could 
             take place through skin damaged by extensive burns (Harris et 
             al., 1979), but no analytical data have confirmed this type 
             of absorption.

        5.4  Eye

             Unknown.

        5.5  Parenteral

             Sodium nitrite given intravenously is traditionally used 
             in the treatment of cyanide poisoning in conjunction with 
             sodium thiosulphate in doses of 300 mg for adults (= 200 mg 
             NO2). For children under 25 kg body weight doses of 10
             mg/kg  (= 7 mg NO2/kg) are regarded as safe treatment. Half
             the  dose may be repeated within 24 to 48 hours (Klaassen et
             al.,  1986).

        5.6  Other

             No data available.

    6.  KINETICS

        6.1  Absorption by route of exposure

             Nitrate and nitrite given orally are absorbed and 
             transferred to the blood in the upper part of the 
             gastrointestinal tract.
    

             Abundant pectin in the food may delay absorption which may 
             then occur lower down in the intestine, with possible 
             increased risk for microbial transformation of nitrate into 
             nitrite.

        6.2  Distribution by route of exposure

             Regardless of route of exposure, nitrate and nitrite are 
             rapidly transferred into the blood. Nitrite is gradually 
             oxidized to nitrate which is readily distributed into most 
             body fluids (urine, saliva, gastric juice, sweat, ileostomy 
             fluid). Distribution of nitrate into plasma, erythrocytes, 
             saliva and urine following an oral dose of sodium nitrate has 
             been demonstrated by Cortas & Wakid (1991).

        6.3  Biological half-life by route of exposure

             Wagner et al. (1983) showed the half-life in the body 
             for an oral dose of nitrate to be approximately 5 hours. As 
             blood absorption depends on food matrix (see Section 6.1) and 
             route of exposure, and as larger doses may increase the 
             urinary excretion rate, the biological half-life for both 
             nitrate and nitrite should be expected to be 3 to 8 
             hours.
    
             Nitrate does not accumulate in the body.

        6.4  Metabolism

             Where bacteria are present and the environment can be 
             anaerobic, nitrate can be reduced to nitrite. The main site 
             for this reaction is mouth and stomach, but nitrite formation 
             in the lower intestine and in the bladder (urinary infection) 
             may also be of some toxicological importance.
    
             Nitrite may be further reduced to nitrogen by bacteria under 
             some conditions. In blood, nitrite transforms haemoglobin to 
             methaemoglobin and is simultaneously oxidized to nitrate.
             Normally methaemoglobin gradually reverts to haemoglobin 
             through enzymatic reactions.
    
             Nitrite has vasodilating properties, probably through 
             transformation into nitric oxide (NO) or a NO-containing 
             molecule acting as a signal factor for smooth muscle 
             relaxation.
    
             Nitrite easily transforms into a nitrosating agent in an 
             acidic environment and can react with a variety of compounds, 
             e.g. ascorbic acid, amines, amides.
    
             Nitrosation can also be mediated by bacteria, e.g. in the 
             stomach. Some reaction products are carcinogenic (e.g. most 
             nitrosoamines and amides.

        6.5  Elimination by route of exposure

             Approximately 60% of oral nitrate is excreted in  urine
             (Wagner et al., 1983). The fate of the rest is  not
             completely known, but bacterial or endogenous  metabolism
             probably accounts for the remainder. A  minor part is
             excreted in sweat. See also Section  6.4.

    7.  TOXICOLOGY

        7.1  Mode of action

             The toxicology of nitrate and nitrite in humans and 
             animals has been thoroughly reviewed in monographs by WHO 
             (1985), ECETOC (1988), BIBRA (1990a, b) and Walker (1990).
             Literature in Russian is reviewed by UNEP (1982a; 1982b).
    
             There are no reports that suggest that nitrate as such has 
             toxicological effects. The main toxicological concern is 
             associated with its conversion to nitrite before or after 
             reaching the human body (see Section 6.4).
    
             The major acute toxic effect from nitrite is development of 
             methaemoglobinaemia, a condition where more than 10% of the 
             haemoglobin is transformed into methaemoglobin. When the 
             conversion exceeds 70% the condition can be fatal.
    
             Nitrite may also cause sudden fall in blood pressure due to 
             its vasodilating properties.
    
             These effects are reversible.
    
             The major concern of possible long-term effects of exposure 
             to nitrate and nitrite is associated with formation of 
             nitroso compounds, many of which are carcinogenic. This 
             formation may take place wherever nitrite and nitrosable 
             compounds are present, but it is favoured by acidic 
             conditions or the presence of some bacteria. The 
             gastrointestinal tract and especially the stomach is regarded 
             as the main formation site, but nitrosation reactions can 
             also take place in an infected urinary bladder.
    
             Nitrosation reactions also occur elsewhere in the body as a 
             result of endogenous formation of nitric oxide and nitrite, 
             but the relative contribution of this source is presently 
             unknown.

        7.2  Toxicity

             7.2.1  Human data

                    7.2.1.1  Adults

                             The lethal oral dose of potassium 
                             nitrate for an adult has been estimated to be 
                             between 4 and 30 g (about 40 to 300 mg NO3- 
                             kg).
    
                             It has been reported that adults have 
                             tolerated large doses of nitrate as sodium
                             and  ammonium salt (> 100 mg NO3-/kg) in
                             some  cases repeated for several days for
                             medical or  experimental purposes with only
                             minor effects  in some subjects (light
                             methaemoglobinemia,  diarrhoea, vomiting).
                             Death and severe effects  of nitrate
                             ingestion are generally associated  with
                             doses above 10 g NO3-.
    
                             Doses between 2 and 9 g NO3- have been 
                             reported to cause methaemoglobinemia. These 
                             values correspond to 33 to 150 mg NO3-/kg 
                             (Walker, 1990).
    
                             The lethal oral dose of nitrite for adults
                             has  been variously reported to be between 
                             0.7 and 6 g NO2- (approximately 10 to
                             100 mg NO2-/kg) (WHO, l985; Corre &
                             Breimer, 1979; Fassett, 1973; De Beer et al.,
                             1975). Lower doses may  apply for children
                             (especially neonates), the  elderly and
                             people with certain enzyme  deficiencies.
    
                             The broad range is due to the wide
                             variability  in individual sensitivity
                             illustrated by the  following examples:
                             Gowans (1990) reported a  fatal case of a
                             17-year-old nurse who probably  ingested 1 g
                             sodium nitrite (= 670 mg NO2-) as  a
                             tablet. In contrast, an adult survived 
                             without lasting problems after ingestion of 
                             9.7 g NO2- (as sodium nitrite) (Vetter, 
                             1951).
    
                             Human volunteers given sodium nitrite 
                             intravenously produced a maximum 
                             methaemoglobin level of 7% after a dose of
                             2.7 mg NO2-/kg and 30% after a dose of 8

                             mg/kg (Kiese & Weger, 1969). (This indicates
                             a lethal dose within the range reported above 
                             (ECETOC, 1988)).
    
                             The first symptoms of oral nitrite poisoning 
                             develop within 15 to 45 minutes (ECETOC, 
                             1988).

                    7.2.1.2  Children

                             Neonates are at special risk for
                             high  nitrate and nitrite levels as their
                             enzyme system for regeneration of
                             haemoglobin is not fully developed. Special
                             care should therefore be taken referring to
                             the values stated in Section 7.2.1.1. 
    
                             Most clinical case data refers to neonates 
                             developing methaemoglobinemia after drinking 
                             water or water-based formulations with high 
                             nitrate or nitrite content. The great
                             majority  of cases (well-water
                             methaemoglobinemia) occurred when nitrate
                             levels in drinking water exceeded 100 mg
                             NO3-/L (Bockman & Bryson, 1989) It is
                             generally acknowledged that water nitrate
                             content of 50 mg/L is safe even for 
                             neonates. Assuming normal liquid intake of
                             150 mL/kg/day by neonates, nitrate intake of
                             7.5 mg NO3-/kg/day is safe.
    
                             Experiments indicate that even twice the 
                             amount is safe, but at a higher intake can 
                             cause methaemoglobinemia.
    
                             Cases of methaemoglobinemia have also been 
                             reported due to feeding babies vegetable 
                             preparations where nitrate has been converted 
                             to nitrite through bacterial
                             action.

             7.2.2  Relevant animal data

                    Animal experiments are difficult to evaluate 
                    and use for assessing the toxicity of nitrate in man 
                    because the toxic doses of nitrate and nitrite depend 
                    upon competing processes, the rates of which are not 
                    necessarily the same in man and animals.
    
                    Thus the kinetics of nitrite formation from nitrate, 
                    and the rates of haemoglobin regeneration, are not 
                    necessarily comparable between animals and humans 

                    (ECETOC, 1988). This is especially so for ruminants
                    where ingested nitrate is reduced in the rumen.
    
                    LD50 values for nitrate in rodents varies between 1.2
                    and 6.6 g NO3-/kg.
    
                    WHO (1974) and JECFA (1980) considered 365 mg NO3-kg 
                    as the highest daily dose over lifetime without 
                    adverse effects in rats. On this basis the ADI (given 
                    by WHO/FAO) is set (see section (7.2.5).
    
                    LD50 values for nitrite in rodents varies between 57
                    to 157 mg NO2-/kg.
    
                    WHO (1974) concluded from long-term studies, that the
                    level causing no toxicological effect was less than
                    100 mg 
    
                    NaNO2-/kg/day (=67 mg NO2-/kg/day).

             7.2.3  Relevant in vitro data

                    No data available on acute toxicity.

             7.2.4  Workplace standards

                    Exposure is usually to dust, so regulations for
                    dust in the working environment apply.

             7.2.5  Acceptable daily intake (ADI)

                    The acceptable daily intake for nitrates (total 
                    for potassium and sodium nitrate) is up to 5 mg/kg, 
                    which corresponds to maximum 3.65 mg NO3-/kg
                    (FAO/WHO,  1985). Walker (1990) suggests this value be
                    changed  to 18.5 mg NO3-/kg, based on a more recent
                    study.
    
                    The guideline value given by WHO (1984) for maximum 
                    concentration of nitrate in drinking water is 10 mg 
                    nitrate (as N) /L (= 44.3 mg NO3-/L)  (WHO,
                    1984).
    
                    The acceptable daily intake for nitrites (total for 
                    potassium and sodium nitrite) is up to 0.2 mg/kg, 
                    which corresponds to maximum 0.13 mg NO2-/kg
                    (FAO/WHO, 1985). Walker (1990) suggests this value be
                    changed to 0.07 mg NO2-/kg based on a more recent
                    study. These values are not applicable to
                    neonates.
    

                    WHO makes no specific recommendations for maximum 
                    nitrite concentration in drinking water, but in the 
                    European Union the statutory maximum concentration is 
                    0.1 mg NO2-/L (EEC, 1980).
    
                    Nitrate or nitrite should not be added to baby food.
                    Vegetables known to have a very high nitrate content 
                    (e.g. spinach) should be avoided in baby food 
                    preparations.

        7.3  Carcinogenicity

             There is no evidence that nitrate or nitrite as such 
             cause cancer in animals (ECETOC, 1988). However, a causative 
             connection between nitrate/nitrite and cancer through the 
             formation of N-nitroso compounds is suspected.
    
             The role of nitrate and nitrite in the etiology of cancer in 
             humans, especially gastric cancer, is addressed in numerous 
             studies which are reviewed and discussed by Walker (1990),
             Forman et al. (1989), ECETOC (1988), IARC (1987) and WHO 
             (1985). Included are also epidemiological studies seeking to 
             find correlation between frequency of cancer and nitrate 
             intake with food and water. Evidence from these sources does 
             not support the hypothesis of a straightforward cause and 
             effect association between nitrate exposure and cancer risk 
             (Forman, 1989).

        7.4  Teratogenicity

             Studies relating congenital malformations and cardio-
             vascular effects to nitrate levels in drinking water have not 
             produced consistent results (WHO, 1985; Black, 1989). Studies 
             with mice given nitrite (up to 1 g/L) in drinking water gave 
             no evidence for teratogenic or mutagenic effects on the 
             fetuses (Shimada, 1989).

        7.5  Mutagenicity

             Nitrates show no mutagenic activity in microbial tests 
             under aerobic conditions. Activity has been reported under 
             anaerobic conditions, probably due to reduction of nitrate 
             into nitrite. Mutagenic activity in vivo of high doses of 
             nitrate is difficult to evaluate because of the possibility 
             of chemical reduction.
    
             Nitrite is mutagenic in a number of in vitro assays against 
             microorganisms or cultured mammalian cells. Mutagenic effects 
             were also observed in an in vivo and in vitro experiment 
             using Syrian hamsters. In vivo assays have been equivocal, 
             both positive and negative results having been reported 
             (Walker, 1990).

        7.6  Interactions

             Methaemoglobinemia can also result from several other 
             chemical compounds; e.g. Acetanilide, o-Aminophenol, p-
             Aminophenol, Aniline, Dimethylaniline, Hydroxylamine, p-
             Nitroaniline, Nitrobenzene, Nitro-glycerine and Amylnitrite 
             (Clayton & Clayton, 1981). Cases have also been reported due 
             to the use and overdose of some medicines, e.g. benzocaine, 
             dapsone. There should thus be potential for synergism 
             between methaemoglobin-forming substances and nitrite, but we 
             are not aware of any studies on this topic.

    8.  TOXICOLOGICAL ANALYSES/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
             Arterial blood sampling reveals a characteristic
             chocolate-brown colour. Methaemoglobin concentrations can be
             quantified by spectrophotometry and should be measured
             immediately.
    

             Biochemical analysis
             Total haemoglobin, blood count.
             Serum electrolytes, especially potassium.
             Acid-base balance.
             Arterial blood gases.
             Urine analysis.
    
             Toxicological analysis
             The most relevant investigation is methaemoglobin
             concentration which correlates well with symptoms and should
             be monitored according to the clinical condition.

        8.6  References

    9.  CLINICAL EFFECTS

        9.1  Acute poisoning

             9.1.1  Ingestion

                    Ingestion is the major route of exposure. The
                    first symptoms may appear within 10 to 45 minutes.
                    Methaemoglobinaemia is the principal and constant
                    feature of nitrate/nitrite poisoning.
    
                    Clinical symptoms may include: nausea, vomiting, 
                    abdominal pain, headache, dizziness, fall in blood 
                    pressure, tachycardia, collapse, bluish-grey cyanosis, 
                    hyperventilation, stupor, convulsions, coma and 
                    death.

             9.1.2  Inhalation

                    No data available.

             9.1.3  Skin exposure

                    No information available on inorganic nitrate 
                    and nitrite absorption through intact skin, although 
                    absorption may take place through skin damaged by 
                    burning (Harris et al., 1979) (see Section 
                    5.3).

             9.1.4  Eye contact

                    No data available.

             9.1.5  Parenteral exposure

                    Lethal methaemoglobineamia developed after the 
                    intravenous injection of 450 mg of sodium nitrite in a 
                    17 month-old child after acute cyanide poisoning 

                    (Berlin et al., 1985) had been mistakenly 
                    diagnosed.
    
                    Administration of 600 mg to an adult for the treatment 
                    of cyanide toxicity resulted in a methaemoglobin level 
                    of 58% (van Heijst et al., 1987).

             9.1.6  Other

                    No data available.

        9.2  Chronic poisoning

             9.2.1  Ingestion

                    No data available.

             9.2.2  Inhalation

                    No data available.

             9.2.3  Skin exposure

                    No data available.

             9.2.4  Eye contact

                    No data available.

             9.2.5  Parenteral exposure

                    No data available.

             9.2.6  Other

                    No data available.

        9.3  Course, prognosis, cause of death

             In mild cases, gastrointestinal symptoms and 
             asymptomatic cyanosis dominate the clinical presentation. In 
             severe cases coma and death can occur in the first hour due 
             to hypoxia (severe methaemoglobinaemia) and circulatory 
             collapse. In case of parenteral administration the onset of 
             methaemoglobinaemia is immediate.
    
             Prognosis is usually good if adequate treatment is provided.
    
             Death due to nitrates and nitrites have resulted from large 
             suicidal ingestions, ingestion of contaminated food, 
             industrial accidents and ingestion of contaminated well water 
             in neonates (Harris et al., 1979; Gosselin et al., 1984; 
             Johnson et al., 1987; Donovan, 1990).

        9.4  Systematic description of clinical effects

             9.4.1  Cardiovascular

                    Acute: Nitrite produces relaxation of smooth 
                    muscle, especially in veins, but also in coronary and 
                    peripheral arteries. Venous pooling in the lower 
                    extremities leads to a decreased cardiac preload and 
                    output inducing hypotension and thus ischemia of vital 
                    organs. Hypotension and syncope induced by large 
                    doses of nitrite is due initially to the pooling of 
                    blood in dilated post-arteriolar vessels, notably 
                    venules and even large veins. This vasodilation is 
                    not blocked by atropine or by any recognized drug.
                    Reflex tachycardia is the rule but a vasovagal reflex 
                    may induce transient bradycardia just before complete 
                    collapse (Gosselin et al., 1984; Donovan, 1990). This 
                    collapse can occur from marked vasodilation, decreased 
                    cardiac output and vital organ anoxia. Arythmias have 
                    been reported (Gowans, 1990) Electrographic changes of 
                    hyperkalemia (peaked T waves) have been reported by 
                    Sporer and Mayer (1991) in a 37-year-old man who had
                    ingested saltpeter (potassium nitrate).

             9.4.2  Respiratory

                    Acute: Tachypnea and hyperventilation may
                    occur. Cyanosis is due to methaemoglobinaemia.

             9.4.3  Neurological

                    9.4.3.1  Central Nervous System (CNS)

                             Headache, dizziness, restlessness, 
                             agitation and confusion are common in
                             moderate  poisoning. In severe cases, stupor, 
                             convulsions and coma can occur as a result of 
                             cerebral anoxia.

                    9.4.3.2  Peripheral nervous system

                             No data available.

                    9.4.3.3  Autonomic nervous system

                             No data available.

                    9.4.3.4  Skeletal and smooth muscle

                             No data available.

             9.4.4  Gastro-intestinal

                    Acute: Nausea, vomiting and abdominal pain are
                    usually the first symptoms.

             9.4.5  Hepatic

                    No data available.

             9.4.6  Urinary

                    9.4.6.1  Renal

                             No data available.

                    9.4.6.2  Other

                             No data available.

             9.4.7  Endocrine and reproductive systems

                    No data available.

             9.4.8  Dermatological

                    Acute: Blue-grey cyanosis is due to
                    methaemoglobinaemia.

             9.4.9  Eye, ear, nose, throat: local effects

                    No data available.

             9.4.10 Haematological

                    Acute: Methaemoglobinaemia is the principal
                    and constant feature of acute nitrate and nitrite 
                    poisoning. Methaemoglobin is haemoglobin in which the 
                    iron has been oxidized to the ferric state, Fe3+, 
                    rendering it incapable of oxygen transport.
                    Methaemoglobin exerts its toxicity in two ways: (a) it 
                    reduces the oxygen-carrying capacity of the blood; (b) 
                    in addition, it shifts the oxyhaemoglobin dissociation 
                    curve to the left, interfering with the unloading of 
                    oxygen (Donovan, 1990; Goldfrank, 1990).
    
                    In mild cases, slate grey cyanosis may be visible only
                    in the lips and mucous membranes.
    
                    The appearance of cyanosis also depends on the total 
                    haemoglobin, oxygen saturation, skin pigmentation, and 
                    ambient lighting.
    

                    Severe methaemoglobinemia exceeding 70% may be
                    associated with fatal outcome.
    
                    Methaemoglobin levels correlate well with symptoms in
                    most cases (Hall et al., 1986):
    
                    0-3%          Normal level
                    3-10%         No clinical symptoms
                    10-15%        None or slate grey cutaneous 
                                   coloration "chocolate brown" blood
                    15-20%        Generalized blue-grey cyanosis, 
                                   usually  asymptomatic
                    20-45%        Headache, fatigue, dizziness, 
                                   exercise  intolerance, syncope
                    45-55%        Increasing CNS depression
                    55-65%        Coma, seizures, cardiac failure, 
                                   cardiac  arrhythmias, metabolic
                                   acidosis
                    > 65%         High incidence of mortality

             9.4.11 Immunological

                    No data available.

             9.4.12 Metabolic

                    9.4.12.1 Acid-base disturbances

                             Acute: Metabolic acidosis secondary
                             to tissue hypoxia may be observed in moderate
                             and severe poisoning (Gosselin et al., 1984;
                             Hall et al., 1986).

                    9.4.12.2 Fluid and electrolyte disturbances

                             Significant hyperkalemia has been
                             observed in one patient after the ingestion
                             of potassium nitrate (saltpeter) (Sporer and
                             Mayer, 1991), due to the high potassium
                             intake.

                    9.4.12.3 Others

                             No data available.

             9.4.13 Allergic reactions

                    No data available.

             9.4.14 Other clinical effects

                    No data available.

             9.4.15 Special risks

                    Nitrate or nitrite poisoning during pregnancy 
                    has not been reported.
    
                    The nitrate content of mothers' milk, and in milk in 
                    general, is low: below 10 mg NO3-/L (Wettig et al., 
                    1988; Geissler et al., 1991).
    
                    Human red cells deficient in glucose-6-phosphate 
                    dehydrogenase are more sensitive to the 
                    methaemoglobin-generating activities of nitrite than 
                    normal red cells (Gosselin et al., 1984). Patients 
                    with congenital NADPH Methb Reductase deficiency are 
                    also particularly susceptible to 
                    nitrates/nitrites.
    
                    Neonates are particularly sensitive to methaemoglobin 
                    induced by nitrates and nitrites due to their 
                    transient deficiency in methaemoglobin reductase, 
                    their low levels of erythrocyte NADH and the greater 
                    susceptibility of haemoglobin F (foetal haemoglobin) 
                    to oxidation (Lukens, 1987; Walley and Flanagan, 
                    1987). Near-adult levels of methaemoglobin reductase 
                    and haemoglobin A are reached by 4 months of age 
                    (Keating et al., 1973; Donovan, 1990).

        9.5  Others

             No data available.

        9.6 Summary

    10. MANAGEMENT

        10.1 General principles

             Patients with severe acute nitrate or nitrite poisoning 
             should be admitted to an intensive care unit because rapid 
             deterioration can occur. Monitor vital signs as respiration, 
             blood pressure and the onset of cyanosis. Monitor acid-base 
             balance and arterial blood gases. Administer oxygen and 
             artificial respiration if necessary.
    
             Symptomatic measures, especially oxygen therapy; gastric 
             lavage or emesis; oral activated charcoal; antidotes for 
             methaemoglobinemia - methylene blue; or exchange transfusion 
             may be considered in severe cases if methylene blue 
             fails.

        10.2 Life supportive procedures and symptomatic treatment

             Supportive measures include treatment of respiratory 
             failure, shock, acid-base disturbances and convulsions.
             Oxygen therapy is indicated if there are clinical signs of 
             methaemoglobinemia.

        10.3 Decontamination

             Ingestion: gastric lavage is indicated in recent 
             ingestion up to four hours. Although activated charcoal is 
             not less effective in adsorbing nitrite than other 
             methaemoglobin-inducing organic compounds, it could be 
             administered per os. If an oro-or naso-gastric tube is in 
             place, administer activated charcoal through the tube after 
             the lavage.
    
             Skin: take off contaminated clothes. Wash skin with copious
             amounts of water.

        10.4 Enhanced elimination

             Data on the use of exchange transfusion for removing 
             nitrates and nitrites from the blood are limited (Harris et 
             al., 1979). The advantages of this mode of therapy is the 
             rapid reduction of circulating methaemoglobin levels and the 
             removal of some of the offending agents. Exchange 
             transfusion may be useful for methylene blue failures or for 
             patients with known G6PD or NADPH methaemoglobin reductase 
             deficiencies (Harris et al., 1979; Harrison, 1977).
    
             No data indicating the benefit of forced diuresis,
             haemodialysis or haemoperfusion are available.

        10.5 Antidote 

             10.5.1 Adults

                    Methylene blue (tetramethyl thionine chloride) 
                    is the specific antidote indicated in 
                    methaemoglobinaemia induced by nitrates and nitrites.
                    It is effective but may have significant side effects 
                    if used inappropriately (see end of this section).
    
                    Treatment with methylene blue is indicated in 
                    symptomatic patients and when methaemoglobinemia 
                    levels are greater than 30% (Curry, 1982; Hall et al., 
                    1986; Donovan, 1990). The initial dosage is 1 to 2 
                    mg/kg or 0.1 to 0.2 mL/kg of a 1% solution, 
                    administered intravenously over 5 to 10 minutes.
                    Clinical improvement and clearing of cyanosis occur 
                    within 1 to 2 hours. Methaemoglobin levels should be 
                    monitored 1 hour after the infusion. If the patient 

                    remains symptomatic and the level is still high, a 
                    second dose may be given (Harris et al., 1979; Hall et 
                    al., 1986; Donovan, 1990). 
    
                    A single case of methaemoglobinemia treated with a 
                    continuous methylene blue infusion has been reported 
                    by Wilson (1976), who described a case of a 36-year-
                    old man who had ingested two sodium nitrite tablets.
                    On admission he had cyanosis and respiratory distress.
                    The patient was treated with oxygen and an infusion of 
                    20 mL of methylene blue (1% Solution) in 500 mL of 
                    dextrose/saline (4%: N/5) given over four hours with 
                    total recovery.
    
                    Methylene blue will be ineffective in reversing 
                    methaemoglobinemia and may produce hemolytic anemia in 
                    patients with glucose-6-phosphate dehydrogenase 
                    deficiency as this enzyme is essential for the 
                    generation of NADPH in the hexose monophosphate 
                    shunt.
    
                    Without NADPH methylene blue cannot act as a reducing 
                    agent in the transformation of methaemoglobin to 
                    haemoglobin (Goldfrank, 1990).
    
                    Ascorbic acid has been mentioned as an alternative 
                    therapy but according to most authors its reducing 
                    effects are too slow to have significant benefits 
                    (Harris et al., 1979; Hall et al., 1986; Donovan, 
                    1990).
    
                    White and Weiss (1991) state that the total dose of 
                    methylene blue should not exceed 7 mg/kg. Methylene 
                    blue therapy may have significant side effects (non 
                    specific): precordial pain, dysnea, restlessness and 
                    methemoglobinemia.

             10.5.2 Children

                    No data available.

        10.6 Management discussion

             Patients with mild cyanosis but without symptomatic 
             evidence of hypoxia and methaemoglobin concentrations of less 
             than 25% will only require close observation and supplemental 
             oxygen (Hall et al., 1986; Goldfrank 1990).
    
             Lloyd (1992) states that toxic methaemoglobinaemia that is 
             not life-threatening is best treated by preventing further 
             administration of the offending chemical and allowing normal 
             metabolic pathways to reduce the methaemoglobin with high 
             flow oxygen treatment as a valuable adjunct to management.

             Levels of 20 to 30% of methaemoglobin resolve spontaneously 
             in two to three days with no further effects. Severe 
             methaemoglobinaemia of toxic or hereditary etiology should be 
             treated with one to two mg/kg of methylene blue intravenously 
             as a 1% solution in saline. It acts as a co-factor in the 
             alternate methaemoglobin reduction pathways involving 
             NADPH.

    11. ILLUSTRATIVE CASES

        11.1 Case reports from the literature

             Gowans (1990) reported a 17-year-old dental nurse who 
             was admitted to the casualty department  with central 
             cyanosis, tachycardia, tachypnea and systolic blood pressure 
             of 90 mmHg. Fifteen minutes after admission, she vomited, 
             aspirated and suffered a respiratory arrest. She was 
             intubated and ventilated. Her blood sample was a chocolate 
             brown color. Forty five minutes after admission, methylene 
             blue was administered intravenously (2 mg/kg over l0 
             minutes), however fifteen minutes later her blood pressure 
             was unrecordable, a series of cardiac arrhythmias ensued and 
             despite the insertion of a temporary pacing wire together 
             with standard resuscitation measures she failed to recover 
             and was certified dead two hours after admission. Biochemical 
             analysis after death revealed that the level of 
             methaemoglobinemia was 35%, implying a much higher level on 
             admission to hospital and the serum nitrite ion level was  13
             mg/L. In this case the dental nurse almost certainly 
             obtained the tablet (s) of 1 g sodium nitrite from the 
             practice in which she was employed.
    
             Kaplan et al. (1990) reported a group of ten patients 
             suffering from moderate to severe methaemoglobinemia after 
             accidental intoxication with sodium nitrite  mistaken for 
             table salt. One patient died in the casualty department but 
             the other nine recovered rapidly after appropriate therapy 
             with methylene blue and ascorbic acid. The two patients most 
             severely affected who survived methaemoglobin levels of 79% 
             and 71%, respectively, required a repeated dose of methylene 
             blue after two hours. All patients improved dramatically and 
             there were no after-effects.
    
             Keating et al. (1973) reported a case of a two-week-old black 
             male infant who was taken to the Emergency Room because his 
             grandmother had noted that his lips and nail beds had "dark 
             color". In the previous 24 hours he had consumed 500 mL of 
             carrot juice. Physical examination revealed an alert, 
             irritable infant with marked cyanosis of the nail and lips.
             Methaemoglobin level was 9 g/l00 mL, representing 60% the 
             total haemoglobin. Methylene blue, 1 mg/kg body weight, was 
             given intravenously and the patient's colour improved 
             promptly. Subsequent methaemoglobin determinations 1 and 12 

             hours later revealed 0.9 and 0 g/100 mL, respectively. The 
             carrot juice fed to the infant was found to contain large 
             quantities of both nitrates and nitrites, 525 ppm and 775 
             ppm, respectively.
    
             Johnson et al. (1987) described a fatal outcome in a 
             two-month-old female infant fed with a powdered formula mixed 
             with well water. For the one-month checkup the mother noted 
             blueness around the infant's mouth and of the feet and hands, 
             some trouble in breathing, and occasional diarrhea and 
             vomiting. The infant was given progressively larger amounts 
             of the powdered formula  prepared with well water, until she 
             began to vomit, and had severe diarrhea and severe cyanosis.
             The parents rushed her to their physician who gave her oxygen 
             for 15 minutes, however the infant did not improve and was 
             referred to a hospital in another town 33 miles distant for 
             further treatment. The infant stopped breathing during the 
             trip, she was given cardiopulmonary resuscitation after 
             arrival at the hospital but could not be resuscitated. The 
             infant's blood was noted to be a chocolate brown colour. The 
             well water at the farm was found to have a concentration of 
             about 664 mg NO3-/L.

    12. ADDITIONAL INFORMATION

        12.1 Specific preventive measures

             Because the consumption of well water with chemical or 
             bacterial contamination may have serious consequences 
             especially for infants, such wells should be tested 
             periodically to ensure their safety, and compliance with 
             national regulations or WHO recommendations for potable 
             water.
    
             Vegetables of known high nitrate content (carrots, spinach, 
             beets, cabbage) might be restricted in infants under four 
             months of age (Keating et al., 1973).
    
             Sodium nitrites tablets (1 g) widely used in the medical and 
             dental profession to prevent rusting of instruments should be 
             recognized as a potent poison and should be kept in secure 
             storage (Gowans, 1990).

        12.2 Other

             No other data.

    13. REFERENCES

        Berlin G, Brodin B, Hilden JO. (1985) Acute dapsone 
        intoxication: A case treated with continuous infusion of Methylene 
        Blue, forced diuresis and plasma exchange. Clinical Toxicology 
        22: 6 537-548
    

        BIBRA (1990a) (British Industrial Biological Research 
        Association). Toxicity profile: Nitrates. BIBRA Information Dept., 
        London.
    
        BIBRA (1990b) (British Industrial Biological Research 
        Association). Toxicity profile: Nitrites. BIBRA Information Dept., 
        London.
    
        Black CA (1989)  Reducing American exposure to nitrate, nitrite 
        and nitroso compounds: The national network to prevent birth 
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    14. AUTHOR, REVIEWER, DATE, COMPLETE ADDRESS 

        Authors:    Oluf Chr. Bockman & Tom Granli
                    (sections Norsk Hydro Research Centre 
                    1, 3, 4, P.O. Box 2560 
                    5, 6, 7) 3901 Porsgrunm 
                    Norway
    
                    Tel: 47-3-562000
                    Fax: 47-2-562327
    
        Date:       October 1991
    
        Author:     Mara Cristina Alonzo
                    Centro de Informacion y Asesoramiento Toxicologico
                    Hospital de Clinicas - Piso 7
                    Av. Italia s/n
                    Montevideo
                    Uruguay
    
                    Tel: 598-2-804000
                    Fax: 598-2-470300 
    
        Date        January 1992
    
        Peer Review:         Newcastle-upon-Tyne, United Kingdom, 
                             February 1992
    
        Peer Review          Berlin, October 1995.
    
        Finalised            IPCS, Septeber 1996
    
        Editor:              M.Ruse (IPCS, May, 1999)
    



    See Also:
       Toxicological Abbreviations