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Quaternary ammonium

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
2. SUMMARY
   2.1 Main risk 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/CIRCUMSTANCES OF POISONING
   4.1 Uses
      4.1.1 Uses
      4.1.2 Description
   4.2 High risk circumstances
   4.3 Occupationally exposed populations
5. ROUTES OF EXPOSURE
   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 and excretion
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 in take (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 toxiclogical investigations
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 Others
   9.3 Course, prognosis, cause of death
   9.4 Systemic description of clinical effects
      9.4.1 Cardiovascular
      9.4.2 Respiratory
      9.4.3 Neurological
         9.4.3.1 Central nervous system
         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 Acid-base
      9.4.7 Hematological
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 the literature
12. ADDITIONAL INFORMATION
   12.1 Specific preventive measures
   12.2 Other
13. REFERENCES
14. AUTHOR(S), REVIEWER(S), ADDRESS(ES), DATE



    QUATERNARY AMMONIUM COMPOUNDS

    International Programme on Chemical Safety
    Poisons Information Monograph G022 (Group PIM)
    Chemical

    1.  NAME

        1.1  Substance

             Quaternary ammonium compounds

        1.2  Group

             Benzalkonium Chloride
             Benzethonium Chloride
             Cetalkonium Chloride
             Cetrimide
             Cetrimonium Bromide
             Cetylpyridinium Chloride
             Glycidyl Trimethyl Ammonium Chloride
             Stearalkonium Chloride

        1.3  Synonyms

             Group:
             QAC
             Cationic surfactant
             Cationic detergent

             Benzalkonium Chloride:
             Alkyldimethylbenzylammonium chlorides;
             Zephiran chloride (R);
             Alkyldimethyl quaternary ammonium chlorides;
             Hyamine 3500;
             Benzethonium Chloride: 
             Diisobutylphenoxyethoxyethyldimethylbenzylammonium chloride;
             Hyamine 1622(R)
             Cetalkonium Chloride:
             Benzylhexadecyldimethylammonium chloride;
             Cetyldimethylbenzylammonium chloride;
             Hexadecyldimethylbenzylammonium chloride;
             Triton K 12;

             Cetrimide
             Trimethyltetradecylammonium bromide + dodecyl and
             hexadecyltrimethylammonium bromide
             Cetrimonium Bromide:
             Hexadecyltrimethylammonium bromide
             Cetyltrimethylammonium bromide
             Retarder LA

             Cetylpyridinium Chloride:
             1-Hexadecylpyridinium chloride;
             CPC
             Glycidyltrimethylammonium chloride:
             (2,3-epoxypropyl) trimethylammonium chloride
             Stearalkonium Chloride:
             Benzyl dimethyl stearyl ammonium chloride;
             Stearyldimethylbenzylammonium chloride;

        1.4  Identification numbers

             1.4.1  CAS number

                    Benzalkonium Chloride  CAS 8001-54-5

             1.4.2  Other numbers

                    Benzethonium Chloride CAS 121-54-0
                    Cetalkonium Chloride CAS 122-18-9
                    Cetrimide CAS 8044-71-1
                    Cetylpyridinium Chloride (anhydrous) CAS 123-03-5
                    Stearalkonium Chloride  CAS 122-19-0
                    Cetrimonium Bromide CAS 57-09-0

    2.  SUMMARY

        2.1  Main risk and target organs

             Quaternary ammonium compounds can cause toxic effects by
             all routes of exposure including inhalation, ingestion,
             dermal application and irrigation of body cavities. Exposure
             to diluted solutions can cause mild and self-limited
             irritation. Concentrated solutions of quaternary ammonium
             compounds are corrosive and can cause burns to the skin and
             the mucous membranes. They can produce systemic toxicity due
             to their curare-like properties. They can also cause allergic
             reactions.

        2.2  Summary of clinical effects

             Mild to severe caustic burns of the skin and mucous
             membranes can occur depending on the agent and the
             concentration. Other signs may include: nausea, vomiting,
             abdominal pain, anxiety, restlessness, coma, convulsions,
             hypotension, cyanosis and apnoea due to respiratory muscle
             paralysis; death may occur within 1 or 3 hours after
             ingestion of concentrated solutions. Haemolysis and
             methaemoglobinemia have been reported infrequently.

        2.3  Diagnosis

             Diagnosis depends essentially on prior history and
             presentation of specific signs and symptoms. These may
             include gastrointestinal symptoms, pain, burning sensation or
             local ulceration depending on the site of exposure and the
             concentration of the solution.

        2.4  First-aid measures and management principles

             First aid measures include eyes and skin decontamination
             by immediate and prolonged irrigation with copious amounts of
             water or saline.
             Treatment is symptomatic and supportive. There is no specific
             antidote.
    
             Most ingestions of diluted solutions are benign, and mild
             irritation is self-limited. Only clinical observation and
             symptomatic treatment are usually necessary. Emesis and
             gastric decontamination are not indicated.
    
             After ingestion of concentrated solutions or large amounts,
             monitor and support respiratory and cardiovascular function.
             Early oesophagoscopy should be performed to assess the
             severity of burns.

    3.  PHYSICO-CHEMICAL PROPERTIES

        3.1  Origin of substance

             Quaternary ammonium compounds or cationic detergents are
             synthetic derivatives of ammonium chloride (Arena et al.,
             1964).

        3.2  Chemical structure

             General formula:
                                  R1          R3
                                        N. . . . . . . . . . X
                                  R2          R4
    
             Where R1-4 represent(s) alkyl or aryl substituents and X
             represents a halogen, such as bromide, iodide, or chloride
             (Dreisbach & Robertson, 1987; Budavari, 1996).

        3.3  Physical properties

             3.3.1  Colour

                    See 3.3.3

             3.3.2  State/Form

                    See 3.3.3

             3.3.3  Description

                    The quaternary ammonium compounds show a
                    variety of physical, chemical, and biological
                    properties and most compounds are soluble in water
                    miscible solvents.
    
                    Benzalkonium chloride occurs as a white or yellowish
                    white amorphous powder, a thick gel, or gelatinous
                    flakes. It is hygroscopic, soapy to the touch and has
                    a moldy aromatic odour and very bitter taste.
                    Practically insoluble in ether; and very soluble in
                    acetone, ethanol (95%), methanol, propanol and water
                    (Wade & Weller, 1994). Aqueous solutions of
                    benzalkonium chloride foam when shaken, have a low
                    surface tension and possess detergent and emulsifying
                    properties (Wade & Weller, 1994).

        3.4 Hazardous characteristics

             See 3.3.3.

    4.  USES/CIRCUMSTANCES OF POISONING

        4.1  Uses

             4.1.1 Uses

             4.1.2 Description

                    Quaternary ammonium compounds are the active
                    ingredients in disinfectants and sanitizers for homes,
                    farms, hospitals, offices and public transportation
                    vehicles. They are also used as algaecides and
                    slimicides for swimming pools, industrial water
                    reservoirs, and farm ponds. They are included in the
                    last rinse in laundering by some hospitals, diaper
                    services and various institutions.
    
                    Quaternary ammonium compounds are used in a variety of
                    topical preparations in the treatment of minor
                    infections of the eye, mouth and throat and as
                    preservative in preparations for external use.
                    Cetrimide and benzalkonium chloride are used as
                    antiseptics for cleansing wounds, skin and burns
                    (Reynolds, 1996).
    

                    Quaternary ammonium compounds are also used as surface
                    active agents. These compounds are strongly adsorbed
                    by many substances. The positive charge imparts
                    antistatic properties to wool, cotton, and other
                    cellulosic fibres as well as certain synthetic fibres.
                    The compounds are used in hair conditioners, as
                    softeners for textiles and paper products, and as
                    pigment dispersers (Rietschel, 1995).
    
                    The concentration of quaternary ammonium compounds may
                    vary from 0.005 % to 25 % or more.

        4.2  High risk circumstances

             Accidental poisoning can occur when quaternary ammonium
             compounds are stored in ordinary containers, and should be
             stored in distinctive bottles (never in soft drink bottles)
             in a safe place (Adelson & Sunshine, 1952).
    
             Accidental poisoning has been infrequently described after
             irrigation of body cavities (Gilchrist, 1979; Baraka et al.,
             1980; Momblano et al., 1984).
    
             Repeated occupational exposure after handling quaternary
             ammonium compounds as powders or solutions can produce
             sensitization (Shmunes & Levy, 1972; Oritiz-Frutos et al.,
             1996; Placucci et al., 1996; Krogsrud & Larsen, 1997).

        4.3  Occupationally exposed populations

             Physicians, nurses, dentists, veterinarians,
             pharmacists, and laboratory workers (Rietschel, 1995;
             Placucci et al., 1996). Housework and cleaning
             professionals.

    5.  ROUTES OF EXPOSURE

        5.1  Oral

             This is the most common route of entry (Vale & Meredith,
             1985).

        5.2  Inhalation

             Quaternary ammonium compounds are commonly used in
             inhalers and nasal sprays as a wetting agent and as a
             preservative (Kuboyama et al., 1997; Beasley et al.,
             1998).

        5.3  Dermal

             Accidental spillage of quaternary ammonium compounds on
             skin and clothes is common because these compounds are
             present in various household preparations eg, shampoos, dish
             washing material, disinfectants, cleaning agents, and eye and
             nasal preparations. Dermal absorption is very low except
             through damaged skin (Nicola et al., 1997; Fisher & Stillman,
             1972).

        5.4  Eye

             This route of entry may occur (Reynolds, 1996).

        5.5  Parenteral

             Haemolysis after intravenous injection of quaternary
             ammonium compounds has been reported (Reynolds, 1996).

        5.6  Others

             Irrigation of body cavities:
    
             - intra-uterine administration may cause haemolysis
             (Reynolds, 1996)
    
             - irrigation with cetrimide solutions in the treatment of
             hydatid cysts has produced systemic toxicity (Gilchrist,
             1979; Baraka et al., 1980; Momblano et al., 1984).

    6.  KINETICS

        6.1  Absorption by route of exposure

             Oral exposure:
             Quaternary ammonium compounds are poorly absorbed by oral
             route (Craig & Stitzel, 1994).
    
             Dermal exposure:
             Systemic effects from percutaneous absorption through intact
             skin are rare (Wilson & Burr, 1975).
    
             Parenteral:
             Systemic absorption is possible. (Wilson & Burr, 1975).

        6.2  Distribution by route of exposure

             No data available

        6.3  Biological half-life by route of exposure

             No data available

        6.4  Metabolism

             No data available

        6.5  Elimination and excretion 

             Poorly absorbed by oral route and therefore relatively
             large amounts of the agent are eliminated in faeces (Craig &
             Stitzel, 1994).

    7.  TOXICOLOGY

        7.1  Mode of action

             Local corrosive injury may result from the caustic
             nature of these compounds.
             Quaternary ammonium compounds have curare-like depolarising
             properties (Van Berkel & de Wolff, 1988).

             Benzalkonium chloride may cause bronchoconstriction by
             releasing spasmogenic mediators from the mast cells within
             the broncheal wall and stimulating cholinergic and
             noncholinergic nerves to produce bronchoconstriction (Graf et
             al., 1995; Hallen & Graf, 1995).

        7.2  Toxicity

             7.2.1  Human data

                    7.2.1.1  Adults

                             Human fatalities can occur following
                             an oral dose of 100 to 400 mg/kg or a
                             parenteral dose of 5 to 15 mg/kg (Ellenhorn
                             et al., 1997). According to Arena (1964), the
                             fatal dose of quaternary ammonium compounds
                             was estimated to be 1 to 3 g.

                    7.2.1.2  Children

                             No data available

             7.2.2  Relevant animal data

                    LD50 of benzalkonium chloride varies according
                    to the species of animal and also depends on the route
                    of exposure (Wade & Weller, 1994).
    

                         Guinea pig, oral:   200 mg/kg
                         Mouse, ip           10 mg/kg
                         Mouse, iv           10 mg/kg
                         Mouse, oral         175 mg/kg
                         Mouse, sc           62 mg/kg
                         Rat, ip             14.5 mg/kg
                         Rat, iv             13.9 mg/kg
                         Rat, oral           240 mg/kg
                         Rat, sc             400 mg/kg
                         Rat, skin           1.56 g/kg
    
                    Nasal lesions were induced by the intranasal
                    administration of 0.5 to 0.10% of benzalkonium
                    chloride in rats (Kuboyama et al., 1997). Extensive
                    inner ear destruction occurred after a comparatively
                    short period of middle ear exposure to quaternary
                    ammonium compounds in guinea pigs (Aursnes,
                    1982).

             7.2.3  Relevant in vitro data

                    Tanada et al. (1991) studied the adsorption
                    removal of benzalkonium chloride by granular activated
                    carbon for medical waste water treatment; they found
                    significant correlation between the amount of
                    benzalkonium chloride adsorbed in less than 1000 ppm
                    of equilibrium concentration and the micropore volume
                    of activated carbon.

             7.2.4  Workplace standards

                    No data available

             7.2.5  Acceptable daily in take (ADI) and other guideline
                    levels

                    No data available

        7.3  Carcinogenicity

             No data available

        7.4  Teratogenicity

             No data available

        7.5  Mutagenicity

             No data available

        7.6  Interactions

             Some studies indicate that the presence of alcohol
             potentiates the lethal effect (Adelson & Sunshine,
             1952).

    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
             toxiclogical investigations

             Specific laboratory determination for quaternary
             ammonium compounds are not usually available or necessary for
             the treatment of the patient. In severe cases, a complete
             blood count (haemoglobin, red blood cells, leukocytes with
             differential count), methaemoglobin determination, glucose,
             electrolytes, renal and hepatic function and arterial blood
             gases should be performed; chest X-ray and ECG should also be
             obtained.

    9.  CLINICAL EFFECTS

        9.1  Acute poisoning

             9.1.1  Ingestion

                    Serious toxicity is  unlikely with
                    benzalkonium chloride because of the low
                    concentrations found in most preparations (Vale &
                    Meredith, 1985). However, in higher concentrations,
                    mild to severe caustic burns can occur on the lips,
                    tongue, mouth, throat, hypopharynx, oesophagus,
                    stomach depending on the agent and concentration of
                    the solution (Chataigner et al., 1991; Chan, 1994).
                    They may be accompanied by hypersalivation, vomiting,
                    haematemesis, diarrhoea and confusion (van Berkel & de
                    Wolff, 1988). Metabolic acidosis may also occur
                    (Arena, 1964). In severe cases there may be
                    hypotension, shock, respiratory paralysis,
                    convulsions, coma and cardiorespiratory arrest
                    (Mathieu-Nolf et al., 1985). Fatalities have been
                    reported (Chataigner et al., 1991; Hitosugi et al.,
                    1998).

             9.1.2  Inhalation

                    Prolongation of mucociliary clearance occurred,
                    shortly after application of benzalkonium chloride but
                    there was no detectable effect on nasal mucosal
                    function after two weeks of regular use (McMahon et
                    al., 1997).

                    Some studies state that benzalkonium chloride
                    containing nasal preparations can cause nasal
                    stiffness, nasal mucosa swelling, and
                    bronchoconstriction in asthmatic patients (Reynolds,
                    1996).

             9.1.3  Skin exposure

                    Dermal burns have been reported with
                    concentrated cetrimide, including solutions of 12 and
                    17.5% (Mercer, 1983; Nicola et al., 1997).
                    1% solution of cetrimide produced necrosis when
                    applied to the dermis of a 77-year old woman (August,
                    1975).
                    Caustic action can occur with benzalkonium chloride
                    with preparation diluted 1:2,000 or 1:5,000, and with
                    dilution of at least 1:20,000 (Wilson & Burr,
                    1975).

             9.1.4  Eye contact

                    Eye exposure may result in mild discomfort
                    (0.1% solution) to very serious corneal damage (10%
                    solution) depending on the agent and the
                    concentration. High concentrations of benzalkonium
                    chloride can cause ocular toxicity in human eyes
                    (Reynolds, 1996). Some investigations indicate that
                    quaternary ammonium compounds can cause ocular
                    inflammation (Swan, 1944; Rietschel, 1995).

             9.1.5  Parenteral exposure

                    Intravenous administration of quaternary
                    ammonium compounds may cause haemolysis (Reynolds,
                    1996).

             9.1.6  Other

                    Intra-uterine administration may cause
                    haemolysis (Reynolds, 1996).
                    Irrigation with cetrimide solutions in the treatment
                    of hydatid cysts has produced chemical peritonitis
                    (Gilchrist, 1979), methaemoglobinemia with cyanosis
                    (Baraka et al., 1980) and metabolic acidosis (Momblano
                    et al., 1984).

        9.2  Chronic poisoning

             9.2.1  Ingestion

                    Small amounts of quaternary ammonium compounds
                    are ingested from dish washing detergents used in the
                    kitchen. Repeated measurements and calculations
                    indicate an average oral intake of surfactants of
                    about 100 mg/man/year, this level does not cause
                    toxicity (Gloxhuber et al., 1974).

             9.2.2  Inhalation

                    Occupational asthma has been reported after
                    prolonged exposure to benzalkonium chloride (Bernstein
                    et al., 1994).

             9.2.3  Skin exposure

                    People exposed to quaternary ammonium compounds
                    can exhibit irritant contact dermatitis, particularly
                    with benzalkonium chloride (Shmunes & Levy, 1972;
                    Oritiz-Frutos et al., 1996; Placucci et al., 1996;
                    Krogsrud & Larsen, 1997).

             9.2.4  Eye contact

                    No data available

             9.2.5  Parenteral exposure

                    No data available

             9.2.6  Others

                    No data available

        9.3  Course, prognosis, cause of death

             Poisonings due to diluted solutions usually are mild and
             self-limited.
             In high concentrations, mild to severe caustic burns can
             occur. If there is improvement in symptoms after initial
             treatment then the patient is likely to survive if adequate
             treatment is continued. Death in case of heavy exposure is
             usually related to cardiorespiratory collapse,
             bronchoconstriction or acute pulmonary oedema (Ellenhorn,
             1997). In severe cases death may occur within 1 or 3 hours
             after ingestion (Chataigner et al., 1991; Hitosugi et al.,
             1998).

        9.4  Systemic description of clinical effects

             9.4.1  Cardiovascular

                    In acute cases hypotension and cardiac arrest
                    can occur (Mathieu-Nolf et al., 1985; Nicola et al.,
                    1997).

             9.4.2  Respiratory

                    In acute cases pulmonary oedema resulting from
                    aspiration, dyspnea and cyanosis due to paralysis of
                    the respiratory muscles, bronchoconstriction, cough
                    can occur (Adelson & Sunshine, 1952; Chataigner et
                    al., 1991; Chan, 1994).
                    Several cases of bronchoconstriction resulting from
                    nebulised benzalkonium chloride as a preservative in
                    corticosteroid preparations have been reported
                    (Beasley et al., 1986; Beasley et al., 1987; Beasley
                    et al., 1998)
                    Occupational asthma has been reported after prolonged
                    exposure to benzalkonium chloride (Bernstein et al.,
                    1994).

             9.4.3  Neurological

                    9.4.3.1  Central nervous system

                             In acute exposure, central nervous
                             depression progressing to coma may occur and
                             can be preceded by excitement and convulsions
                             (Gloxhuber et al., 1974; Reynolds,
                             1996).

                    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

                             Quaternary ammonium compounds have
                             depolarising muscle relaxant properties and
                             can produce paralysis of the respiratory
                             muscles (Reynolds, 1996).

             9.4.4  Gastrointestinal

                    In acute exposure vomiting, diarrhoea, and
                    abdominal pain may occur. Ingestion of concentrated
                    solution may produce local ulceration on lips, mouth,
                    pharynx, oesophagus, stomach and intestines (Vale &
                    Meredith, 1985; Chataigner et al., 1991).

             9.4.5  Hepatic

                    In acute exposure hepatic necrosis and elevated
                    liver function tests have been reported (Adelson &
                    Sunshine, 1952).

             9.4.6  Acid-base

                    In acute and severe cases metabolic acidosis
                    has been reported (Adelson & Sunshine, 1952; Momblano
                    et al., 1984).

             9.4.7  Hematological

                    Haemolysis and methaemoglobinaemia have been
                    reported in a woman following irrigation with 0.1%
                    cetrimide in the treatment of hydatid cysts (Baraka et
                    al., 1980).
                    Intra-uterine administration of quaternary ammonium
                    compounds may cause haemolysis (Reynolds,
                    1996).

    10. MANAGEMENT

        10.1  General principles

              Treatment is symptomatic and supportive. There is no
              specific antidote.
              Most ingestions of diluted solutions are benign, mild
              irritation is self-limited and only clinical observation and
              symptomatic treatment are usually necessary. Gastric
              decontamination is not indicated.

        10.2  Life-supportive procedures and symptomatic treatment

              When clinically indicated, expansion of circulatory
              blood volume, vasoactive drugs, supplemental oxygen,
              artificial ventilation and treatment of seizures should be
              promptly instituted.
              Endoscopy should be performed as soon as possible and within
              24 hours.
              Symptomatic treatment may include bronchodilators,
              antiemetics and methaemoglobinemia treatment when
              indicated.
    
              Treatment of contact dermatitis and other injuries should be
              performed.

        10.3  Decontamination

              Ingestion
              A significant ingestion is unlikely if spontaneous emesis has
              already occurred. Do not induce emesis or perform gastric
              lavage because of the risk for corrosive injury and
              production of foam (AACT & EAPCCT, 1997).
              For significant ingestions, consideration may be given to
              aspirating the stomach contents; however, the risk of
              gastrointestinal injury could be further compromised by this
              procedure. If undertaken, this should be performed cautiously
              through a thin, flexible nasogastric tube.
              In severe cases, activated charcoal may be considered;
              however, although there are in vitro data demonstrating the
              adsorption of benzalkonium chloride by activated charcoal
              (Tanada et al., 1991), its effective use in the medical
              management of severe quaternary ammonium poisonings has not
              been confirmed. Furthermore this may mask endoscopy
              evaluation.
    
              Eyes and skin
              Irrigate with copious amounts of tepid water or saline.
              Consult an opthalmologist if eye pain persists or if there is
              significant corneal injury on fluorescein examination (Olson,
              1999).

        10.4  Enhanced elimination

              Elimination methods have not been shown to be effective
              (Olson, 1999).

        10.5  Antidote treatment

               10.5.1  Adults

                       There is no specific antidote

               10.5.2  Children

                       There is no specific antidote

        10.6  Management discussion

              For significant ingestions, consideration may be given
              to aspirating the stomach contents; however, the risk of
              gastrointestinal injury could be further compromised by this
              procedure. If undertaken, this should be performed cautiously
              through a thin, flexible nasogastric tube.
              Although there are in vitro data demonstrating the adsorption
              of benzalkonium chloride by activated charcoal (Tanada et

              al., 1991), its effective use in the medical management of
              severe quaternary ammonium poisonings has not been confirmed.
              Furthermore this may mask endoscopy evaluation.

    11. ILLUSTRATIVE CASES

        11.1 Case reports from the literature

             Child, oral ingestion
             Two and a half-month-old twins were mistakenly given an 11%
             solution of benzalkonium chloride orally for candidiasis.
             They had been prescribed a 1:50,000 dilution. Within 24 hours
             both children had developed irritability, fever, anorexia,
             dehydration, cough, circumoral erythema, drooling and
             numerous oral and pharyngeal lesions. One twin developed
             chemical pneumonitis. Both twins were given IV fluids and
             antibiotic support and recovered (Nicola et al., 1997).
    
             Children, oral ingestion
             Five normal newborn breast fed babies were accidentally fed a
             dilute antiseptic solution (chlorhexidine 0.05% with
             cetrimide 1%) in place of sterile water, developing caustic
             burns of the lips, mouth and tongue within minutes; one baby
             became quite severely ill due to acute pulmonary oedema, but
             all survived without sequele (Mucklow, 1988).
    
             Adult, oral ingestion
             While in a tavern, a 45-year-old woman, was served a drink
             made up of 3/4 of an ounce of whisky and 2.5 ounces of
             supposed ginger ale (but it was hyamine 2389). She swallowed
             a mouthful (approximately 1 ounce) and immediately complained
             of feeling ill and vomited. She died approximately 25 minutes
             after ingesting the drink (Adelson & Sunshine, 1952).
    
             Adults, skin exposure
             Two physicians were reported to have become sensitized to
             benzalkonium chloride from handling instruments soaked in the
             disinfectant for cold sterilization. They developed allergic
             conjunctivitis from the presence of benzalkonium chloride in
             ophthalmic solutions (Fisher & Stillman, 1972; Rietschel,
             1995).
    
             Adult, skin exposure
             A physician developed a severe allergic conjunctivitis from
             an ophthalmic solution containing benzalkonium chloride. The
             conjunctivitis became worse with the use of another
             preparation containing this preservative (Fisher & Stillman,
             1972).

    12. ADDITIONAL INFORMATION

        12.1 Specific preventive measures

             Quaternary ammonium compounds should not be stored in
             soft drink containers and should be stored in specific
             bottles and in a safe place. While handling these compounds
             care should be necessary.

        12.2 Other

             No data available

    13. REFERENCES

        AACT & EAPCCT (1997). Position statement: gastric lavage.
        Clin Toxicol, 7: 711-719
    
        Adelson L & Sunshine I (1952) Fatal poisoning due to a cationic
        detergent of the quaternary ammonium compound type. Am J Clin
        Pathol, 22:656-661.
    
        Arena JM (1964) Poisoning and other health hazards associated with
        use of detergents. JAMA, 190:56-58.
    
        Arena JM ed (1986) Poisoning, Toxicology, symptoms, treatments,
        5th ed. Charles c Thomas publishers. USA. pp 684-695.
    
        August PJ (1975) Cutaneous necrosis due to cetrimide application.
        Brit Med J, 1: 70
    
        Aursnes J (1982) Ototoxic effects of quaternary ammonium
        compounds. Acta Oto-Laryngol, 93:421-433.
    
        Baraka A, Yamut F, Wakid N (1980) Cetrimide-induced
        methaemoglobinaemia after surgical excision of hydatid cysts.
        Lancet 88-89.
    
        Beasley R, Rafferty P, Holgate S (1986) Benzalkonium chloride and
        bronchoconstriction. Lancet, 2: 1227
    
        Beasley R (1987) Bronchoconstriction properties of preservatives
        in ipratropium bromide (Atrovent) nebuliser solution. Br Med J,
        294: 1197-8
    
        Beasley R, Fishwick D, Miles JF, Hendeles L (1998) Preservatives
        in nebulizer solutions: risks without benefit. Pharmacotherapy,
        18, 1: 130-9
    

        Bernstein JA, Stauder T, Bernstein DI, Bernstein IL (1994) A
        combined respiratory and cutaneous hypersensitivity syndrome
        induced by work exposure to quaternary amines. J Allergy Clin
        Immun, 2, pt 1: 257-259
    
        Budavari S ed. (1996) The Merck index: an encyclopedia of
        chemicals, drugs and biologicals, 12th ed. Rahay, New Jersey,
        Merck and co., Inc., pp1089-1093.
    
        Chan TYK (1994). Poisoning due to Savlon (Cetrimide) liquid. Human
        Exper Toxicol, 13: 681-682
    
        Chataigner D, Garnier R, Sans S, Efthymiou ML (1991). Intoxication
        aigue accidentelle par un désinfectant hospitalier. 45 cas dont 13
        d'évolution mortelle. La Presse Médicale, 20: 741-743
    
        Craig CR & Stitzel RE (1994). Modern Pharmacology 4th edition
        Little, Brown and Co. Boston ISBN 0-316-15932-8
    
        Dreisbach RH & Robertson WO.(1987) Handbook of poisoning:
        prevention, diagnosis and treatment 12th ed. Appleton and lange,
        California, p369.
    
        Ellenhorn MJ, Schonwald S, Ordog G, Wasserberger J (1997)
        Ellenhorn's medical toxicology: Diagnosis and treatment of human
        poisoning, 2nd ed. Williams and Wilkins, Maryland, USA. pp
        1204-1235.
    
        Fisher AA & Stillman MA (1972) Allergic contact sensitivity to
        benzalkonium chloride. Arch Dermatol, 106:169-171.
    
        Gilchrist DS (1979) Chemical peritonitis after cetrimide washout
        in hydatid-cyst surgery. Lancet, 2: 1374
    
        Gloxhuber CH, Henkel, Dusseldorf CGH (1974) Toxicological
        properties of surfactants. Arch Toxicol, 32:245-270.
    
        Graf P, Hallen H, Juto JE (1995) Benzalkonium chloride in a
        decongestant nasal spray aggravates rhinitis medicaments in
        healthy volunteers. Clin Exp Allergy, 25(5):395-400.
    
        Hallen H & Graf P (1995) Benzalkonium chloride in nasal
        decongestive sprays has a long-lasting adverse effects on the
        nasal mucosa of the healthy volunteers. Clin Exp Allergy,
        25(5):401-5.
    
        Hitosugi M, Maruyama K, Takatsu A (1998) A case of fatal
        benzalkonium chloride poisoning. Int J Legal Med, 111, 5:
        265-266
    

        Krogsrud NE & Larsen AI (1997) Airborne irritant contact
        dermatitis from benzalkonium chloride. Contact Dermatitis,
        36(2):112.
    
        Kuboyama Y, Suzuki K, Hara T (1997) Nasal lesions induced by
        intranasal administration of benzalkonium chloride in rats.
        journal of toxicological sciences. J Toxicol Sci,
        22(2):153-60.
    
        Mathieu-Nolf M, Mathieu D, Leblanc JH, Frimat P, Furon D. Les
        intoxications par les antiseptiques de la classe des ammoniums
        quaternaires sont-elles toujours bénignes ? J Toxicol Clin Exper,
        5: 406
    
        McMahon C, Darby Y, Ryan R, Scadding G (1997) Immediate and short
        term effects of benzalkonium chloride on the human nasal mucosa in
        vivo. Clin Otolaryng, 22(4):318-22.
    
        Mercer DM (1983) Cetrimide burn in an infant. Postgrad Med J,
        59:472-473.
    
        Momblano P, Pradere B, Jarrige N et al (1984) Metabolic acidosis
        induced by cetrimonium bromide. Lancet, 2:1045.
    
        Mucklow ES (1988) Accidental feeding of a  dilute antiseptic
        solution (chlorhexidine 0.05% with cetrimide 1%) to five babies.
        Human Toxicol, 7:567-569.
    
        Nicola B, Nicolas E, Junice R, Glyn V (1997) Paediatric Toxicology
        Handbook of poisoning in children. Macmillan reference ltd,
        London, pp166-169.
    
        Olson KR (1999) Poisoning and drug overdose, 3rd edition Appleton
        & Lange, Stanford, Connecticut, pp 154-5 ISBN 0-8385-0260-1.
    
        Oritiz-Frutos FJ, Argila D, River R, Zamarro O, Miguelez S (1996)
        Allergic contact dermatitis from benzalkonium chloride used as a
        denaturant of ethanol. Contact Dermatitis, 35(5):306.
    
        Placucci F, Benini A, Tosti A (1996) Occupational allergic contact
        dermatitis from disinfectant wipes used in dentistry. Contact
        Dermatitis, 35(5):306.
    
        Reynolds JEF ed (1996) Martindale: the Extra Pharmacopoeia, 31st
        ed. Pharmaceutical Press, London, 117-8.
    
        Rietschel RL (1995) Fisher's Contact Dermatitis, 4th ed. Williams
        & Wilkins, Maryland, USA, pp 69,198,199,275,590-204.
    

        Shmunes E & Levy EJ (1972) Quaternary ammonium compound contact
        dermatitis from deodorant. Arch Dermatol, 105:91-93.
    
        Swan KC (1944) Reactivity of the oc(c)ular tissues to wetting
        agents. Am J Ophthalmol, 27:1118-1122.
    
        Tanada M, Miyoshi T, Nakamura T, Tanada S (1991) Adsorption
        removal of benzalkonium chloride by granular activated carbon for
        medical waste water treatment. Asia Pac J Public Health, 5:
        27-31
    
        Vale JA & Meredith TJ (1985) A concise guide to the management of
        poisoning, 3rd ed. Churchill livingstone, New york,p 42.
    
        Van Berkel M & de Wolff FA (1988). Survival after benzalkonium
        chloride poisoning. Human Toxicol, 7: 191-193
    
        Wade A & Weller PJ ed (1994) A handbook of pharmaceutical
        excipients, 2nd ed. The pharmaceutical press, London, pp
        27-31.
    
        Wilson JT & Burr IM (1975) Benzalkonium chloride poisoning in
        infant twins. Am J Dis Child, 129:1208-1209.

    14. AUTHOR(S), REVIEWER(S), ADDRESS(ES), DATE

        Author:     Satish Kumar Arugonda,
                    School of Pharmacy,
                    University of Otago,
                    Dunedin, New Zealand.
    
        Date:       5th October,1998.
    
        Peer review group: N Besbelli, D Cobaugh, L Fruchtengarten, B
        Groszek, MO Rambourg-Schepens (coordinator), W Temple.
    
        Date: July, 1999