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Salicylic acid

1. NAME
   1.1 Substance
   1.2 Group
   1.3 Synonyms
   1.4 Identification numbers
      1.4.1 CAS number
      1.4.2 Other numbers
   1.5 Brand names, Trade names
   1.6 Main manufacturers, main importers
2. SUMMARY
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First aid measures and management principles
3. PHYSICO-CHEMICAL PROPERTIES
   3.1 Origin of the substance
   3.2 Chemical structure
   3.3 Physical properties
      3.3.1 Colour
      3.3.2 State/form
      3.3.3 Description
   3.4 Other characteristics
      3.4.1 Shelf-life of the substance
      3.4.2 Storage conditions
4. USES
   4.1 Indications
      4.1.1 Indications
      4.1.2 Description
   4.2 Therapeutic dosage
      4.2.1 Adults
      4.2.2 Children
   4.3 Contraindications
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 and excretion
7. PHARMACOLOGY AND TOXICOLOGY
   7.1 Mode of action
      7.1.1 Toxicodynamics
      7.1.2 Pharmacodynamics
   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
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
   7.7 Main adverse effects
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)
      8.2.3 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 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 Systemic description of clinical effects
      9.4.1 Cardiovascular
      9.4.2 Respiratory
      9.4.3 Neurological
         9.4.3.1 Central Nervous System (CNS)
         9.4.3.2 Peripheral nervous system
         9.4.3.3 Autonomic nervous system
         9.4.3.4 Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary
         9.4.6.1 Renal
         9.4.6.2 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 Other
   9.6 Summary
10. MANAGEMENT
   10.1 General principles
   10.2 Life supportive procedures and symptomatic/specific treatment
   10.3 Decontamination
   10.4 Enhanced elimination
   10.5 Antidote treatment
      10.5.1 Adults
      10.5.2 Children
   10.7 Management discussion
11. ILLUSTRATIVE CASES
   11.1 Case report from literature
12. ADDITIONAL INFORMATION
   12.1 Specific preventive measures
   12.2 Other
13. REFERENCES
14. AUTHORS
    Salicylic acid

    International Programme on Chemical Safety
    Poisons Information Monograph 642
    Pharmaceutical


    1. NAME

        1.1  Substance

             Salicylic acid

        1.2  Group

             ATC Classification:
             Analgesics,
             Other Analgesic and Antipyretics,
             Salicylic acid and derivatives
             N02AB

        1.3  Synonyms

             Orthohydroxybenzoic acid;
             2-hydroxybenzoic acid;
             Acido Orthoxibenzoico;
             Acidium Salicylicum;
             Salizylsaure

        1.4  Identification numbers

             1.4.1  CAS number

                    69-72-7

             1.4.2  Other numbers

                    RTECS/NIOSH:  VO0525000

        1.5  Brand names, Trade names

             Salicylic Acid Collodion (B.P.). 12g/100 mL
             Salicylic Acid Collodion (U.S.P.)  10g/100 mL
             Salicylic Acid Paint (A.P.F.)  Corn paint
             Lactic and Salicylic Acid paint (A.P.F)
             Salicylic Acid and Resorcinol Cream Aqueous (A.P.F)
             Salicylic Acid and Sulphur Cream Aqueous (A.P.F)
             Salicylic Acid Ear Drops (A.P.F)
             Salicylic Acid Topical Foam (U.S.P.)
             Salicylic Acid Gels  (U.S.P)
             Salicylic Acid Lotion  (B.P.)
             Salicylic Acid and Coal Tar (A.P.F)
             Salicylic Acid Ointment Lotion (B.P.)
             Salicylic Acid and Coal Tar Ointment (A.P.F)
             Salicylic Acid and Sulphur Ointment (B.P.C)
             Salicylic Acid Plaster (U.S.P)
             Pyralvex( Norgine, UK),

             Salactol (Dermal Labor. UK),
             Verrugon (Pickles, UK),
             Cuplex (Smith & Nephew Pharmaceuticals, UK),
             Duofilm (Stiefel, UK),
             Keralyt (Stiefel, UK),
             Monophytol (Laboratories for Applied Biology, UK)  (Reynolds,
             1996)

        1.6  Main manufacturers, main importers

             See 1.5

    2.  SUMMARY

        2.1  Main risks and target organs

             The toxic effects of salicylic acid and salicylates are
             complex. Main risks with oral therapeutic doses are mostly
             gastrointestinal irritation. Hepatic encephalopathy (Reye's
             Syndrome) has been reported in children who had taken aspirin 
             for treatment of viral infections such as influenza. Toxic
             doses of salicylate stimulate the respiratory centre leading
             to respiratory alkalosis. In severe intoxication, metabolic
             acidosis, water and electrolyte loss occur as the principle
             secondary consequences. Central nervous system toxicity
             includes, tinnitus, hearing loss and in very severe cases
             particularly in children convulsions and coma. Target organs
             are  central nervous system, lungs, kidneys and liver.

        2.2  Summary of clinical effects

             Following oral ingestion of  salicylic acid (SA) and or
             any other salicylate, nausea, vomiting, epigastric
             discomfort, tinnitus, loss of hearing, sweating, flushing
             (vasodilatation) tachypnoea and hyperpnoea are commonly
             observed. Local gastrointestinal (GI)  irritation of SA is
             more marked than ASA (acetylsalicylic acid). In severe
             intoxication irritability, tremor, blurred vision, mental
             confusion, delirium, stupor, coma, fever, cerebral oedema and
             cardio-respiratory arrest may occur. Central nervous system
             toxicity and gastrointestinal haemorrhage are more common
             after chronic (therapeutic) intoxication. A marked alteration
             of acid-base balance from respiratory alkalosis to metabolic
             acidosis may be observed. In severe salicylate intoxication
             in adults, non cardiogenic pulmonary oedema, nonfocal
             neurological abnormalities, unexplained ketosis and a
             prolonged prothrombin time can occur. Skin eruption and
             subconjuntival haemorrhage may be seen but marked
             thrombocytopenia is rare. Methyl salicylate poisoning has the
             odour of the drug which can be detected on the breath and in
             the urine and vomit. Central nervous system stimulation,
             intense hyperpnoea and hyperpyrexia are prominent features.


        2.3  Diagnosis

             Symptoms and signs of oral ingestion of SA overdose
             usually commence by nausea, vomiting and epigastric
             discomfort. However, in mild salicylism particularly with
             therapeutic intoxication, tinnitus, loss of hearing,
             dizziness, sweating, and flushing are more common. Severe
             salicylate poisoning is associated with marked respiratory
             and nervous system toxicity. Hyperventilation and respiratory
             alkalosis are more common in adults, whereas hypoventilation
             and metabolic acidosis are more commonly observed in
             children. A rapid screening test for the presence of
             salicylate in the urine may indicate the use of the drug.
    
             Estimation of salicylate concentration in plasma/serum can
             confirm the diagnosis and reveals the severity of
             intoxication. A plasma salicylate concentration of 300 to 500
             mg/L at 6 hour post-ingestion indicates a mild toxicity, 500
             to 800 mg/L moderate toxicity and >800 mg/L is considered as
             severe SA intoxication.

        2.4  First aid measures and management principles

             Inducing vomiting, gastric aspiration and lavage should
             only be considered if large amounts of salicylate has been
             ingested.
    
             Enhancement of elimination using alkaline diuresis and
             repeated doses of activated charcoal, correction of
             dehydration, acidosis and electrolytes. In severe salicylate
             intoxication, haemodialysis and or charcoal haemoperfusion is
             indicated.

    3.  PHYSICO-CHEMICAL PROPERTIES

        3.1  Origin of the substance

             Salicylic acid in the form of esters was found in
             several plants, notably in wintergreen leaves and the bark of
             sweet birch. It was made synthetically by heating sodium
             phenolyate with carbon dioxide under pressure and microbial
             oxidation of  naphthalene (Windholz, 1983).

        3.2  Chemical structure

             Chemical name:
             2-Hydroxy-benzoic acid
    
             Molecular formula: C7H6O3
             Molecular weight:   138.1
    

             Chemical structure:

    STRUCTURAL FORMULA 1

        3.3  Physical properties

             3.3.1  Colour

                    Colourless or white

             3.3.2  State/form

                    Solid-crystals

             3.3.3  Description

                    Colourless acicular crystals or a white
                    crystalline powder. The synthetic form is white but if
                    prepared from natural methyl salicylate, it may have a
                    slightly yellow or pink tint.
    
                    Salicylic acid is a white crystalline powder with a
                    sweetish acrid taste. If prepared from natural methyl
                    salicylate, it may have a faint mint like odour. It is
                    available in forms of ointments, cream, gel,
                    transdermal patches, liquids and plaster.
    
                    Salicylic acid is soluble 1 in 460 to 550 of water, 1
                    in 15 of boiling water, 1 in 3 to 4 in alcohol, 1 in 3
                    in ether and 1 in 45 in chloroform (Reynolds, 1996).

        3.4  Other characteristics

             3.4.1  Shelf-life of the substance

                    Shelf-life is dependent on the manner of
                    storage. It should be stored in well closed containers
                    and protected from light (Reynolds, 1996).

             3.4.2  Storage conditions

                    Store in well closed containers and protect
                    from light (Reynolds, 1996).


    4.  USES

        4.1  Indications

             4.1.1  Indications

                    Analgesic
                    Other analgesic/antipyretic
                    Salicylate; analgesic

             4.1.2  Description

                    Salicylic acid has keratinolytic properties and
                    is applied topically in the treatment of
                    hyperkeratotic and scaling conditions such as
                    dandruff, ichthyosis and psoriasis. Initially a
                    concentration of 2% is used increasing to about 6% if
                    necessary.
    
                    It is often used in conjunction with many other
                    agents, such as benzoic acid, coal tar, resorcinol and
                    sulphur. Salicylic acid is also used in the form of
                    paint and in the form of collodion basis (10 to 17%)
                    or as a plaster (20 to 50%) to destroy warts and
                    corns. It also possesses fungicidal properties and is
                    used topically in the treatment of fungal skin
                    infections such as tinea (Reynolds, 1996).

        4.2  Therapeutic dosage

             4.2.1  Adults

                    The topical preparations such as transdermal
                    patches, gels, ointments, liquids, creams or plasters
                    are usually used in concentrations of 2.5 to 60% for
                    the treatment of psoriasis, warts and other keratinous
                    disorders (Chren & Bickers, 1990).

             4.2.2  Children

                    Since salicylic acid is used topically, the
                    above concentration and dosage may be applied in
                    children with caution.

        4.3  Contraindications

             Due to the severe gastric irritation which salicylic
             acid causes, it is no longer used orally. However, when used
             topically it may cause an allergic contact rash in some
             people. If applied to large areas of skin, it may be absorbed
             into the blood stream and induce salicylism (Parish, 1991).


    5.  ROUTES OF ENTRY

        5.1  Oral

             Salicylic acid causes gastric irritation and thus, 
             there is no oral pharmaceutical available. However, Chinese
             medicated oil (Koong yick Hung Far Oil) which contains 67%
             methyl salicylate has been taken orally (Chan, 1996).

        5.2  Inhalation

             Not relevant.

        5.3  Dermal

             Salicylic acid is readily absorbed from the skin and may
             induce toxicity (salicylism).

        5.4  Eye

             Unknown

        5.5  Parenteral

             Unknown

        5.6  Other

             No data available.

    6.  KINETICS

        6.1  Absorption by route of exposure

             Salicylic acid is readily absorbed from the skin and may
             cause toxicity, particularly in children and the newborn.
             Herbal products such as the chinese medicated oil which
             contains methyl salicylate is also absorbed through
             gastrointestinal mucosa following ingestion (Chan, 1996).

        6.2  Distribution by route of exposure

             About 50 to 80% of salicylate in the blood is bound to
             plasma proteins, while the rest remains in the active ionized
             state; protein binding is concentration dependent. Saturation
             of binding sites lead to more free salicylate and increased
             toxicity. The apparent volume of distribution is 0.1 to 0.2
             L/kg. Acidosis increases the volume of distribution because
             of the enhancement of tissue penetration of salicylate (Levy
             & Tsuchiya, 1972).


        6.3  Biological half-life by route of exposure

             The plasma salicylate half-life following therapeutic
             doses is 2 to 4.5 hours, but in overdosage, increases to 18
             to 36 hours (Done, 1960). When the metabolic pathway is
             saturated (conjugation with glycin),  zero order kinetics
             apply and thus the elimination half-life cannot be derived
             correctly.

        6.4  Metabolism

             At low dosage,  approximately 80% of salicylic acid is
             metabolised in the liver. Conjugation with glycine, forms
             salicyluric acid and when conjugated with glucuronic acid,
             acyl and phenolic glucuronide are formed. Small amounts of
             salicylic acid are also hydroxylated to gentisic acid. With
             large doses, the kinetics switch from first order to zero
             order (Michaelis-Menten) kinetics (Levy & Tsuchiya, 1972).

        6.5  Elimination and excretion

             Salicylates are excreted mainly by the kidney as
             salicylic acid, salicyluric acid, salicylic glucuronides and
             gentisic acid. The proportion excreted of each metabolite,
             depends upon urinary pH. With urinary alkalinisation,
             salicylic acid excretion is enhanced (Prescott et al., 1982).

    7.  PHARMACOLOGY AND TOXICOLOGY

        7.1  Mode of action

             7.1.1  Toxicodynamics

                    Marked hyperventilation occurs as a result of
                    direct stimulation of the respiratory centre. Indirect
                    stimulation of respiration is caused by an increased
                    production of CO2 as a result of salicylate-induced
                    uncoupling of oxidative phosphorylation. Respiratory
                    alkalosis develops as a result of the direct and
                    indirect stimulation of the respiratory centre. In an
                    attempt to compensate, bicarbonate accompanied by
                    sodium, potassium and water, is excreted in the urine.
                    Dehydration and hypokalemia result, but more
                    importantly, the loss of bicarbonate diminishes the
                    buffering capacity of the body and allows the
                    development of a metabolic acidosis (Proudfoot &
                    Brown, 1969; Davidson, 1971; Proudfoot, 1983). The
                    pyretic effect of toxic doses of salicylate is a
                    direct result of the uncoupling of oxidative
                    phosphorylation. High doses of salicylate have
                    additional toxic effects on the central nervous system
                    consisting of stimulation(including convulsions)
                    followed by depression, confusion, dizziness,

                    asterixis, delirium, psychosis, stupor and coma
                    (Anderson et al., 1976; Anderson, 1981). Very high
                    doses of salicylates have a depressive effect on the
                    medulla and may cause central respiratory paralysis as
                    well as sudden circulatory collapse secondary to
                    vasomotor depression. The loss of buffering capacity
                    and the effects of salicylate on carbohydrate, lipid
                    and protein metabolism lead to the development of a
                    metabolic acidosis or, more commonly in practice, a
                    mixed acid-base disturbance (Proudfoot & Brown, 1969;
                    Meredith & Vale, 1981; Proudfoot, 1983). Both hypo-
                    and hyper-glycaemia may occur in salicylate poisoning.
                    The former most probably due to an increased tissue
                    demand for glucose oxidation due to the uncoupling of
                    oxidative phosphorylation. Neuroglycopenia can occur
                    in the presence of normal blood glucose concentrations
                    (Thurston et al., 1970). If hepatic glycogen stores
                    are adequate, catecholamines production stimulates
                    glycogenolysis leading to hyperglycemia which can
                    persist for several days (Cotton & Fahlberg, 1964).
                    Salicylate intoxication is often accompanied by
                    hypothrombinaemia due to a warfarin like action of
                    salicylate on the vitamin K1 epoxide cycle, which
                    rarely causes clinical problems (Proudfoot, 1983).

             7.1.2  Pharmacodynamics

                    Salicylic acid alleviates pain, lowers an
                    elevated body temperature and inflammation by
                    inhibiting the synthesis of prostaglandins that occur
                    in inflamed tissues. Salicylate inhibits the
                    conversion of arachidonic acid  to the unstable
                    endoperoxide intermediate PG G2, which is catalyzed by
                    the enzyme cyclo oxygenase. Platelets are especially
                    susceptible to this action as they are incapable of
                    regenerating the enzyme, presumably they have little
                    or no capacity for protein biosynthesis (Brantmark et
                    al., 1981). Cyclo oxygenase(COX) is present in two
                    main isoforms. COX-1 is the isoform  of the enzyme and
                    is present under normal physiological conditions. COX-
                    2 is the inducible isoform of  the enzyme and is
                    induced in settings of inflammation (i.e. production
                    of eicosanoids and kinins). Inhibition of COX-1
                    results in unwanted side effects, particularly those
                    leading to gastric ulcer. Current pharmacological
                    research, in the NSAID field is centering on finding a
                    selective COX-2 inhibitor. Meloxicam is a selective
                    COX-2 inhibitor  that has been marketed in France and
                    some other countries (Insel, 1996).


        7.2  Toxicity

             7.2.1  Human data

                    7.2.1.1  Adults

                             Since salicylic acid is available
                             only in topical preparations, human data on 
                             toxicity have not been reported. However, the
                             chinese medicated oil (Koong Yick Hung Far
                             Oil), which contains 67% methyl salicylate
                             induced severe salicylate poisoning
                             (Chan,1996). Salicylic acid concentrations
                             above 800 mg/L after 6 hours post exposure is
                             severely toxic and may be lethal
                             (Balali-Mood, 1981).

                    7.2.1.2  Children

                             Salicylate intoxication is often
                             more serious in small children (<4 years)
                             than in older children, due to an early
                             development of a metabolic acidosis rather
                             than a respiratory alkalosis (Winters et al.,
                             1959).

             7.2.2  Relevant animal data

                    None relevant.

             7.2.3  Relevant in vitro data

                    None relevant.

        7.3  Carcinogenicity

             No data available.

        7.4  Teratogenicity

             There is no evidence that moderate therapeutic doses of
             salicylates cause fetal damage in human beings; however,
             babies born to women who ingest salicylates for long periods
             may have a significantly reduced mass at birth. In addition,
             there is an increase in prenatal mortality, anaemia,
             antepartum and postpartum haemorrhage, prolonged gestation
             and complicated deliveries. These effects occur when
             salicylates are administered during the third trimester, and
             thus its use during this period of pregnancy should be
             avoided (Insel, 1996).


        7.5  Mutagenicity

             No data available

        7.6  Interactions

             Salicylic acid is highly protein-bound and may increase
             the unbound or free drug concentrations of other drugs such
             as hypoglycemics, anticoagulants and methotrexate(an
             antimetabolite chemotherapeutic drug), reaching toxic levels
             of these agents. The uricosuric activity of phenylbutazone,
             probenecide and sulphinpyrazone is strongly antagonized by
             salicylate and maybe completely diminished by small doses due
             to decreased tubular reabsorption of uric acid (Insel, 1996).
             In a report of two cases of severe salicylate poisoning,
             asystole occurred shortly after the intravenous
             administration of diazepam (Berk & Anderson, 1989).

        7.7  Main adverse effects

             Salicylic acid is a gastric irritant and because of the
             serious damage it may cause to the stomach lining, it has not
             been used orally. Topical use of salicylic acid may induce
             allergic contact dermatitis (Davies, 1985). Salicylic acid
             may cause excessive drying and irritation in some people
             (Parish, 1991). Some individuals, especially asthmatics
             exhibit sensitivity to salicylates. Urticaria, angioneurotic
             oedema, rhinitis, severe and even fatal paroxysmal,
             bronchospasm and dyspnea may occur (Reynolds, 1996).

    8.  TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS

        8.1  Material sampling plan

             8.1.1  Sampling and specimen collection

                    8.1.1.1  Toxicological analyses

                             Screen residues or suspected
                             materials, plasma, urine and stomach
                             contents. Avoid sodium azide
                             preservation.

                    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

                             Keep biological samples in a
                             refrigerator prior to analysis.

                    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

                             No special conditions.

                    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)

                             Trinder's reagent: Dissolve 40 g of
                             Hg(II) Cl2 in 850 mL of hot water. After
                             cooling down, add 120 mL of HCl 1 mol/L and
                             40 g of hydrated ferric nitrate. When the
                             ferric nitrate has been dissolved, add water
                             to 1000 mL. Add 0.1 mL Trinder's reagent to 1
                             mL of urine and mix. A violet colour
                             indicates the presence of salicylates. For
                             stomach contents and serum residues, boil a
                             portion of the specimen with 2 mL of
                             hydrochloric acid 0.1 mol/L for 10 minutes,
                             cool and filter, if necessary neutralise with
                             sodium hydroxide 0.1 mol/L. Add 100 µl of
                             Trinders' reagent to the clear neutralized
                             solution. A violet colour indicates presence
                             of salicylate.


                    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)

             8.2.3  Interpretation of toxicological analyses

        8.3  Biomedical investigations and their interpretation

             8.3.1  Biochemical analysis

                    8.3.1.1  Blood, plasma or serum

                             Platelet function and coagulation
                             tests, in order to estimate the degree of
                             inhibition of platelet aggregation and
                             hypoprothrombinaemia may be
                             required.

                    8.3.1.2  Urine

                    8.3.1.3  Other fluids

             8.3.2  Arterial blood gas analyses

                    In adults with severe salicylate poisoning an
                    initial respiratory alkalosis is followed by metabolic
                    acidosis. In children, metabolic acidosis is more
                    common than in adults. Acid-base disturbances are
                    usually mixed in mild to moderate salicylate poisoning
                    (Proudfoot  & Brown, 1969; Proudfoot, 1983).

             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 investigations

             Following the qualitative test for salicylate, the
             plasma/serum salicylate concentration should be determined on
             admission, and at regular intervals to assess the severity of
             intoxication, prognosis and approach to treatment. Salicylate
             concentration may continue to rise even up to 24 hours post
             ingestion (Balali-Mood, 1981). However, based on severe
             intoxication plasma salicylate concentrations at 6 hours
             after an overdose could be divided into three groups:
    
             1. 300 to 500 mg/L      mild toxicity
             2. 500 to 800 mg/mL     moderate toxicity
             3. >800 mg/L            severe toxicity (Proudfoot, 1983).
    
             Clinical findings and  acid-base disturbances should be
             considered when interpreting the plasma salicylate
             concentration and deciding upon management (Meredith & Vale,
             1981). The Done nomogram categorizes the severity of
             poisoning for single ingestion based on peak salicylate
             concentrations. In patients with significant acidosis and in
             patients who ingest multiple doses or sustained release
             preparations, the Done nomogram will tend to underestimate
             the severity of salicylate intoxication (Todd et al., 1981).
             Development of the nomogram was based on the assumption that
             salicylates are eliminated by a first order process, whereas
             in fact they are partially eliminated through natural
             processes. This may lead to overprediction  of the severity
             of toxicity. Therefore, the Done-nomogram is not commonly
             used. Following ingestion of enteric-coated tablets, plasma
             salicylate concentrations on admission are not a reliable
             guide to the severity of poisoning. Salicylate concentration
             may not peak until more than 12 hours after such an overdose
             (Springer & Groll, 1980; Todd et al., 1981).
    
             Hypokalemia, hypo/hyperglycaemia, hypocalcaemia and acid-base
             disturbances may occur during salicylate poisoning. It is
             therefore essential to investigate electrolyte (and if
             possible osmolality) and arterial blood gas analysis. Other
             biochemical analyses such as liver and kidney function tests
             are required as clinically indicated (Cotton & Fahlbeg, 1964;
             Balali-Mood, 1981; Proudfoot, 1983).

        8.6  References


    9.  CLINICAL EFFECTS

        9.1  Acute poisoning

             9.1.1  Ingestion

                    Initial symptoms of salicylate poisoning may be
                    nausea and vomiting, epigastric pain and occasionally
                    haematemesis. Hyperventilation, sweating, flushing,
                    fever, irritability, tinnitus and loss of hearing are
                    the common clinical features of mild to moderate
                    salicylate intoxication. In severe intoxication,
                    hypoventilation, stupor, hallucination, convulsions,
                    papiloedema and coma particularly in children may
                    occur. Metabolic acidosis, non-cardiogenic pulmonary
                    oedema, hepatotoxicity and cardiac dysrhythmias may
                    also occur (Balali-Mood, 1981; Meredith & Vale, 1981).

             9.1.2  Inhalation

                    No data available

             9.1.3  Skin exposure

                    Severe poisoning has been reported as a result
                    of the use of salicylic acid ointment for
                    dermatological problems and in the treatment of skin
                    burns (Editorial of JAMA, 1964; Taylor & Halprin,
                    1975; Pluskwa et al., 1984).

             9.1.4  Eye contact

                    No data available

             9.1.5  Parenteral exposure

                    No data available

             9.1.6  Other

                    None

        9.2  Chronic poisoning

             9.2.1  Ingestion

                    Chronic salicylate poisoning occurred as a
                    result of excessive therapeutic administration over a
                    period of 12 hours or more were reported (Dove &
                    Jones, 1982). Metabolic pathways of salicylic acid
                    become saturated and thus plasma concentration
                    increases, producing toxicity. Small children are at
                    particular risk of overdose especially when fever,

                    sweating and tachycardia of salicylate intoxication
                    are attributed to the underlying illness and are used
                    as indications for increasing the dose (Proudfoot,
                    1983). Children may become intoxicated through breast
                    milk (Clark & Wilson, 1981). The presenting signs of
                    chronic salicylate poisoning can include metabolic
                    acidosis, hypoglycemia, lethargy, coma and fits
                    (English et al., 1996).

             9.2.2  Inhalation

                    No data available

             9.2.3  Skin exposure

                    Chronic usage of salicylic acid and or methyl
                    salicylate in skin and rheumatic diseases may cause
                    intoxication through percutaneous absorption. Life
                    threatening salicylate poisoning caused by
                    percutaneous absorption of salicylic acid (10%
                    ointment) in a 7-year-old boy with ichthyosis vulgaris
                    was reported (German et al., 1996). Application of
                    teething gels containing salicylic acid induced
                    intoxication (Paynter & Alexandre, 1979).

             9.2.4  Eye contact

                    No data available

             9.2.5  Parenteral exposure

                    No data available

             9.2.6  Other

                    None

        9.3  Course, prognosis, cause of death

             If a large quantity of a salicylate has been taken,
             nausea, vomiting, tinnitus, deafness, sweating,
             vasodilatation and hyperventilation may develop. Acid-base
             disturbances, electrolyte imbalance, non cardiogenic
             pulmonary oedema, hypoventilation and hallucination, stupor,
             irritability, coma and convulsions particularly in children
             and older patients can proceed death. Loss of consciousness
             in adults is very rare and when occurs indicates poor
             prognosis. A review of 51 fatal cases of acute salicylate
             poisoning in Ontario during 1983 and 1984, discovered that
             salicylate was the most common cause of death, due to the
             ingestion of single drugs. Autopsy results showed that 50% of
             the patients had pulmonary abnormalities, 28% had lesions of
             the gastrointestinal tract, 18% had nervous system

             abnormalities and 25.6% had no pathological changes
             (McGuigan, 1987). Mortality from chronic salicylate
             intoxication is considerably higher (25%) than from acute
             overdose (1 to 2%) (Anderson et al., 1976). Death is often
             due to sudden cardiac arrest or occasionally due to multiple
             complications following severe brain damage (Proudfoot,
             1983).

        9.4  Systemic description of clinical effects

             9.4.1  Cardiovascular

                    Sudden cardiovascular collapse is a recognized
                    complication of salicylate poisoning (Anderson et
                    al.1976, Proudfoot et al, 1983). Two patients with
                    severe salicylate intoxication developed asystole
                    shortly after intravenous diazepam administration
                    (Berk & Anderson, 1989). Transient myocardial
                    dysfunction (global left ventricular shortening
                    fraction of 23%) with pulmonary edema was found in a
                    13-month-old boy with salicylate poisoning (Ralston et
                    al., 1995).

             9.4.2  Respiratory

                    Non-cardiogenic pulmonary oedema may occur in
                    salicylate intoxicated patients who are over 30 years
                    of age. Cigarette smoking, chronic salicylate
                    ingestion, metabolic acidosis and the presence of
                    neurological symptoms and signs on admission are
                    strong risk factors for the subsequent development of
                    pulmonary oedema. The exact mechanism is unknown.
                    Three possible explanations are: (i) A direct toxic
                    effect on pulmonary microvasculature; (ii) Interaction
                    with endogenous mediators such as prostaglandins; and
                    (iii) A central nervous system mediated effect
                    (Walters et al., 1983).

             9.4.3  Neurological

                    9.4.3.1  Central Nervous System (CNS)

                             In moderate to severe salicylate
                             intoxication, CNS stimulation (irritability
                             and convulsions) followed by depression,
                             confusion, dizziness, delirium, psychosis,
                             asterixis, stupor and coma occur usually when
                             metabolic acidosis is the dominant acid-base
                             abnormality (Proudfoot & Brown, 1969). These
                             features are thought to be due to reduced
                             ionisation of salicylic acid and a shift of
                             salicylate from the plasma into the brain.
                             Very high doses of salicylate have a

                             depressive effect on the medulla and may
                             cause central respiratory paralysis as well
                             as sudden circulatory collapse, secondary to
                             vasomotor depression (Proudfoot,
                             1983).

                    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  Gastrointestinal

                    Ingestion of salicylate may result in
                    epigastric discomfort, nausea and vomiting. Salicylic
                    acid has more irritant effects on gastric mucosa than
                    acetylsalicylic acid and thus has been withdrawn from
                    oral administration for many years. Acetylsalicylic
                    acid may also cause gastric irritation. Perforated
                    peptic ulcer also occurs extremely rarely (Robins et
                    al., 1985).

             9.4.5  Hepatic

                    Hepatotoxicity may occur both after the
                    therapeutic use of salicylate or following its
                    overdosage. Liver biopsy revealed acute hepatocellular
                    necrosis with periportal inflammation and fatty
                    changes in hepatocytes (Wofe et al.,1974). Hepatic
                    encephalopathy (Reye's Syndrome) has been reported in
                    children taking aspirin for treatment of viral
                    infections such as influenza.

             9.4.6  Urinary

                    9.4.6.1  Renal

                             Oliguria sometimes occurs, which is
                             mostly due to dehydration(Temple et al,
                             1976). Renal failure may rarely occur in
                             individuals without volume depletion, pre-
                             existing renal and or systemic diseases (Rupp
                             et al., 1983).


                    9.4.6.2  Other

                             None.

             9.4.7  Endocrine and reproductive systems

                    High doses of salicylate cause release of
                    adrenaline from the adrenal medulla; this is thought
                    to be partly responsible for the observed
                    hypoglycaemia due to glycogenolysis that sometimes
                    occurs. Large doses of salicylate stimulate
                    corticosteroids secretion by the adrenal cortex
                    (Temple, 1981).

             9.4.8  Dermatological

                    Toxic epidermal necrosis in 13 patients
                    associated with the use of salicylate have been
                    reported (Lowney et al., 1967).

             9.4.9  Eye, ear, nose, throat: local effects

                    Eye: Transient myopia occurred in a patient
                    following ingestion of 2.7 g acetylsalicylic acid
                    (Sandford-Smith, 1974). Bilateral subconjunctival
                    haemorrhage has been reported (Black & Bensinger,
                    1982).
    
                    Ear: Tinnitus and hearing loss caused by salicylate in
                    overdose are due to increased labyrinthine pressure
                    (Waltner, 1955). It may also be due to an effect on
                    the hair cells of the cochlea. There is a relationship
                    between the hearing loss and the plasma salicylate
                    concentration (Meyers et al., 1965).
    
                    There has been no reports on the local effects of
                    salicylate on the nose and throat.

             9.4.10 Haematological

                    Salicylates prolong the bleeding time due to
                    inhibition of collagen glucosyltransferase present in
                    membranes of platelets. As a result, the adherence of
                    platelets to connective tissue or collagen fibres is
                    diminished. Salicylate overdose reduces the
                    concentration of vitamin K-dependent coagulation
                    factors, particularly prothrombin (Brantmark et al.,
                    1981).


             9.4.11 Immunological

                    Salicylates have the capacity to supress a
                    variety of antigen-antibody reactions such as: the
                    inhibition of antibody production, of antigen-antibody
                    aggregation and of antigen induced release of
                    histamine. Salicylates also induce a non specific
                    stabilization of capillary permeability during
                    immunological insults. The concentration of salicylate
                    causing this effect is high, and their relationship 
                    to the antirheumatic efficacy of salicylates is yet to
                    be determined.

             9.4.12 Metabolic

                    9.4.12.1 Acid-base disturbances

                             Respiratory alkalosis is more often
                             observed in adults than in children.
                             Metabolic acidosis develops sooner in
                             children than in adults (Winters et al.,
                             1959; Proudfoot & Brown, 1969). However, in
                             severe salicylate poisoning in adults,
                             metabolic acidosis may also occur. High
                             concentrations of salicylate may lower
                             bicarbonate by not  more than 2 to 3 mmols.
                             The acidosis is not therefore due to the
                             presence of salicylic acid itself. The
                             principle cause is competitive inhibition of
                             NAD+-dependent dehydrogenases including
                             lactate and oxoglutarate dehydrogenase and
                             the other oxidative enzymes such as succinate
                             dehydrogenase (Grisolia et al., 1969).
                             Salicylate enhances entry and oxidation of
                             fatty acids in liver cells,leading to
                             increased ketogenesis. Competitive inhibition
                             of amino acyl-tRNA synthetases in pairs and
                             amino acid  incorporation results in
                             amino-acidaemia (Smith & Dawkins, 1971).
                             Dehydration and vasomotor depression results
                             in poor renal perfusion and accumulation of
                             sulphuric and phosphoric acids (Tenney &
                             Miller, 1995; Winters et al., 1959).

                    9.4.12.2 Fluid and electrolyte disturbances

                             Increased renal secretion of
                             sodium, potassium and water accompanies loss
                             of bicarbonate in the urine. Fluid loss also
                             results from vomiting, sweating and
                             hyperventilation. Dehydration is commonly
                             associated with hypernatraemia. Water loss
                             may be considerable from 2 to 3 L/m2 surface

                             area in moderate to severe poisoning and up
                             to 6 L/m2 in severely poisoned patients
                             (Temple, 1978).

                    9.4.12.3 Others

                             (1) Oxidative Phosphorylation
                             The uncoupling of oxidative phosphorylation
                             by salicylate results in the inhibition of a
                             number of ATP-dependent reactions and an
                             increase in O2 uptake and CO2 production.
                             (2) Nitrogen compound metabolism
                             Toxic doses of salicylate cause a significant
                             nitrogen imbalance, characterized by amino
                             aciduria, though this is due in part to
                             stimulation of active tubular absorption
                             because of reduced ATP formation.
                             (3) Fat metabolism
                             Salicylates enhance oxidation of fatty acids
                             in muscle, liver and other tissues together
                             with a decrease of concentrations of plasma,
                             free fatty acids, phospholipids and
                             cholesterol (Insel, 1996).

             9.4.13 Allergic reactions

                    Some people particularly asthmatics, exhibit
                    marked sensitivity to salicylate, resulting in various
                    reactions including urticaria and other skin
                    eruptions, angioneuritis, oedema, rhinitis and severe
                    and even fatal paroxysmal bronchospasm and dyspnea,
                    hypotension, shock and syncope (Reynolds, 1996).
                    Despite the fact that the symptoms (such as the ones
                    mentioned above) resemble anaphylaxis, this reaction
                    does not appear to be immunological in nature. It may
                    be a shunt towards the lipoxygenase pathway leading to
                    an increased production of leukotrienes and other
                    inflammatory mediators. Although, this hypothesis is
                    unproved and it does not explain why only a minority
                    of patients with asthma or other predisposing
                    conditions display the reaction. Even so, results in a
                    small number of patients suggest that blockade of
                    5-lipoxygenase with the drug zileuton may prevent
                    symptoms and signs of aspirin intolerance (Insel,
                    1996).

             9.4.14 Other clinical effects

                    The relationship between the use of salicylate
                    and Reye's syndrome in children and adolescents
                    (mostly 5 to 15 years) has been demonstrated by
                    epidemiological studies (Sullivan-Bolyai & Corey,
                    1981).


             9.4.15 Special risks

                    Salicylate intoxication may occur through
                    placental transfer(Lynd, 1976) and breast milk (Clark
                    & Wilson, 1981).

        9.5  Other

             None.

        9.6  Summary

    10. MANAGEMENT

        10.1 General principles

             Management of acute salicylic acid poisoning includes
             prevention of absorption, correction of acid-base, fluid and
             electrolyte imbalance and enhancing of the drug elimination.
             Respiratory alkalosis needs no specific treatment, but severe
             acidosis requires at least a partial correction with sodium
             bicarbonate. Hypokalaemia may be aggravated by administration
             of sodium bicarbonate. Thus, potassium may need repletion.
             However, if large amounts of water and electrolytes are given
             to the patient, the sodium and water load may precipitate 
             pulmonary oedema (Balali-Mood, 1981; Proudfoot, 1983).
             Sedative and depressive drugs must be avoided. Tetany may be
             corrected with the use of calcium gluconate(Meredith & Vale,
             1981). Due to the delayed effects of salicylate overdose, the
             patient must be kept under observation for at least 24 hours
             (Balali-Mood, 1981).

        10.2 Life supportive procedures and symptomatic/specific treatment

             If non-cardiogenic pulmonary oedema occurs, mechanical
             ventilation with positive end-expiratory pressure (PEEP) may
             be required. Correction of electrolyte and acid-base
             disturbances is essential. ECG monitoring  and in very severe
             cases intensive care therapy is needed. Sponging and any
             other physical countermeasure for hyperpyrexia may be
             required. Antipyretics must be avoided (Balali-Mood, 1981;
             Proudfoot, 1983).

        10.3 Decontamination

             Inducing emesis and when the patient reaches the
             hospital, gastric aspiration and lavage, is only recommend if
             the patient ingested large amounts of salicylate (American
             Academy of Clinical Toxicology and the European Association
             of Poisons Centres and Clinical Toxicologists, 1997). It is
             not necessary if a non-oral route of entry such as dermal
             absorption, caused intoxication.
    

             Although activated charcoal proved to be equally effective as
             emesis and gastric lavage in volunteers (Danel & Henry,
             1988), it may only be exploited therapeutically if the
             patient presents soon after ingestion. Repeated doses of
             activated charcoal (50 to 75 g immediately and 1 g/kg 4
             hourly) will increase the non renal elimination of salicylate
             and will greatly  diminish the plasma half-life (Hillman &
             Prescott, 1985). Although multiple doses of activated
             charcoal in pigs following high dose intravenous aspirin
             administration did not enhance salicylate clearance (Johnson
             et al., 1995), it was found effective in the poisoned
             patients (Montoya-Carbera et al., 1995). Addition of sodium
             sulphate as a saline catharatic to activated charcoal was
             found to have no effect on the prevention of salicylate in
             six healthy volunteers (Sketsis et al., 1982). However, it
             may be used as a cathartic in a single dose with the initial
             dose of plain activated charcoal to prevent constipation,
             although sorbitol may be considered as a safer cathartic to
             be used.

        10.4 Enhanced elimination

             Forced alkaline diuresis was employed in the management
             of salicylate poisoning (Lawson et al., 1969; Berg, 1977).
             Fluid retention may occur during forced diuresis and increase
             the risk of pulmonary oedema in severe salicylate
             intoxication (Heffner & Sahn, 1981; Balali-Mood, 1981). It is
             now recognised that the urine pH is of  far greater
             importance than the volume of urine excreted (Balali-Mood,
             1981; Prescott et al., 1982). To achieve maximum excretion of
             salicylate, a urine pH of more than 8 is required
             (Balali-Mood , 1981). Urinary alkalinisation requires close
             supervision in the ward/intensive-care unit. In patients with
             cardiac and or renal impairment, and in those who are in
             shock, haemodialysis/haemoperfusion should be considered.
             Haemodialysis should also be considered in severely poisoned
             patients with features of central nervous system toxicity,
             pulmonary oedema, cerebral oedema and in cases of plasma
             salicylate concentrations of more than 800 mg/L (Proudfoot,
             1983). Haemodialysis is preferred to haemoperfusion because
             it corrects acid-base and electrolyte abnormalities more
             rapidly and may avoid the need for the administration of
             large amounts of sodium bicarbonate (Winchester et al.,
             1981). Peritoneal dialysis is less effective than alkaline
             diuresis and is two to three times less effective than
             haemodialysis, and its use is not recommended (Winchester et
             al., 1977).


        10.5 Antidote treatment

             10.5.1 Adults

                    There is no specific antidote.

             10.5.2 Children

                    There is no specific antidote.

        10.7 Management discussion

             Salicylate poisoning particularly in chronic cases may
             be missed. Systemic inflammatory response syndrome  (SIRS) is
             characterised by body temperature abnormalities, tachypnea or
             hyperventilation, tachycardia, and leukocytosis or
             leukopenia. Chronic salicylate poisoning should be considered
             as a cause of SIRS in the absence of a source of infection,
             since survival depends on prompt diagnosis and management
             (Chalasani et al., 1996). Chronic salicylate poisoning
             particularly those with metabolic acidosis, hypoglycaemia,
             lethargy, coma and fits in malaria endemic areas may mimic
             severe malaria as was investigated in Kenya (English et al.,
             1996). Although the clinical value of screening for
             salicylates in acute poisoning was emphasized (Chan et al.,
             1995), determination of plasma salicylate concentration is
             required to confirm the diagnosis and  to estimate the
             severity of salicylate intoxication. Prevention of absorption
             by emesis, gastric aspiration and lavage  after ingestion may
             be required. Estimation of serial plasma salicylate poisoning
             following overdosage in adults revealed that the peak
             concentration may be delayed up to 24 hours post ingestion
             (Balali-Mood, 1981). Alkalization of the urine (pH> 8) and
             repeated doses of activated charcoal will enhance salicylate
             elimination (Balali-Mood, 1981; Prescott et al., 1982;
             Hillman & Prescott, 1985). In severe salicylate intoxication
             (plasma salicylate concentrations >800 mg/L), haemodialysis
             is also recommended.

    11. ILLUSTRATIVE CASES

        11.1 Case report from literature

             Salicylate poisoning has been very common and thousands
             of cases have been reported in the literature since the early
             20th century. Cases of salicylic acid dermal absorption which
             induced intoxication particularly in children have also been
             reported (Davies et al., 1979; Clark & Wilson, 1981).
             Salicylic acid intoxication caused by teething ointment was
             also reported (Paynter & Alexander, 1979).


    12. ADDITIONAL INFORMATION

        12.1 Specific preventive measures

             Since salicylic acid is only available in external
             usage forms care should be taken to use it under supervision.
             Drugs must be kept in a safe place, not to be reached by
             children. Parents and patients need to be warned of the
             potential risks of chronic usage of salicylic acid
             preparations.

        12.2 Other

             None.

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    14. AUTHORS

        Authors:    Mahdi Balali-Mood & Kia Balali-Mood
                    Poisons Control Centre
                    Imam Reza Hospital
                    Faculty of Medicine
                    Mashhad University of Medical Sciences
                    Mashhad 91735
                    Islamic Republic of Iran
    
                    Tel:     +98-51-889301/98973
                    Fax:     +98-51-883714/93038
    
        Date:       August 1996
    
        Reviewer:   Bill Watson, Kansas City, USA
    
        Date:       1996
    
        Peer review: INTOX Meeting, London, UK,  March, 1998
    
        Editor:     Dr M.Ruse (September, 1998)
    


    See Also:
       Toxicological Abbreviations
       Salicylic acid (ICSC)
       SALICYLIC ACID (JECFA Evaluation)