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Nerium oleander L.

1. NAME
   1.1 Scientific name
   1.2 Family
   1.3 Common name(s) and synonyms
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
   2.5 Poisonous parts
   2.6 Main Toxins
3. CHARACTERISTICS
   3.1 Description of the plant
      3.1.1 Special identification features
      3.1.2 Habitat
      3.1.3 Distribution
   3.2 Poisonous parts of the plant
   3.3 The toxin(s)
      3.3.1 Name(s)
      3.3.2 Description, chemical structure, stability
      3.3.3 Other physico-chemical characteristics
   3.4 Other chemical contents of the plant
4. USES/CIRCUMSTANCES OF POISONING
   4.1 Uses
      4.1.1 Uses
      4.1.2 Description
   4.2 High risk circumstances
   4.3 High risk geographical areas
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. TOXINOLOGY
   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
   7.3 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 Biochemical analyses
         8.1.3.3 Arterial blood gas analysis
         8.1.3.4 Haematological analyses
         8.1.3.5 Other (unspecified) analyses
   8.2 Toxicological Analyses and their Interpretation
      8.2.1 Tests on toxic ingredient(s) of material
         8.2.1.1 Simple Qualitative Test(s)
         8.2.1.2 Advanced Qualitative Confirmation Test(s)
         8.2.1.3 Simple Quantitative Method(s)
         8.2.1.4 Advanced Quantitative Method(s)
      8.2.2 Tests for biological specimens
         8.2.2.1 Simple Qualitative Test(s)
         8.2.2.2 Advanced Qualitative Confirmation Test(s)
         8.2.2.3 Simple Quantitative Method(s)
         8.2.2.4 Advanced Quantitative Method(s)
         8.2.2.5 Other Dedicated Method(s)
      8.2.3 Interpretation of toxicological analyses
   8.3 Biomedical investigations and their interpretation
      8.3.1 Biochemical analysis
         8.3.1.1 Blood, plasma or serum
         8.3.1.2 Urine
         8.3.1.3 Other fluids
      8.3.2 Arterial blood gas analyses
      8.3.3 Haematological analyses
      8.3.4 Interpretation of biomedical investigations
   8.4 Other biomedical (diagnostic) investigations and their interpretation
   8.5 Overall interpretation of all toxicological analyses and toxicological investigations
9. CLINICAL EFFECTS
   9.1 Acute poisoning
      9.1.1 Ingestion
      9.1.2 Inhalation
      9.1.3 Skin exposure
      9.1.4 Eye contact
      9.1.5 Parenteral exposure
      9.1.6 Other
   9.2 Chronic poisoning
      9.2.1 Ingestion
      9.2.2 Inhalation
      9.2.3 Skin exposure
      9.2.4 Eye contact
      9.2.5 Parenteral Exposure
      9.2.6 Other
   9.3 Course, prognosis, cause of death
   9.4 Systematic description of clinical effects
      9.4.1 Cardiovascular
      9.4.2 Respiratory
      9.4.3 Neurological
         9.4.3.1 Central nervous system (CNS)
         9.4.3.2 Peripheral nervous system
         9.4.3.3 Autonomic nervous system
         9.4.3.4 Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary
         9.4.6.1 Renal
         9.4.6.2 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/antitoxin 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 preventative measures
   12.2 Other
13. REFERENCES
14. AUTHOR(S), DATES(S) REVIEWER(S), (INCLUDING UPDATES), COMPLETE ADDRESS(ES):
    NERIUM OLEANDER

    International Programme on Chemical Safety
    Poisons Information Monograph 366
    Plant

    1.  NAME

        1.1  Scientific name

             Nerium oleander L.

        1.2  Family

             Apocynaceae

        1.3  Common name(s) and synonyms

             Adelfa (Puerto Rico, Spain); 
             Alheli Extranjero (Puerto Rico); Baladre
             (Catalunya-Spain); Espirradeira (Brazil);
             Flor de Sao Jose (Brazil); 
             Laurel de jardn (Argentina Uruguay);
             Laurel rosa
             (Argentina, Uruguay); Laurier rose (France);
             Loandro (Brazil); Loureiro rosa (Brazil); 
             Oleana (Hawaii); Oleander (Brazil, UK, USA); 
             Oliwa (Hawaii); Rosa Francesa (Cuba); 
             Rosa Laurel (Mexico);
             Rose bay (UK).

    2.  SUMMARY

        2.1  Main risks and target organs

             N. oleander ingestion causes both cardiac and
             gastrointestinal signs and symptoms.  The main toxic
             principles are the glycosides, which induce cardiac
             arrhythmia and eventually death.

        2.2  Summary of clinical effects

             The clinical picture usually starts with
             gastrointestinal signs:  nausea, vomiting, abdominal pain and
             diarrhoea.  Later, cardiovascular and neurological symptoms
             can occur.  Sinus bradycardia or different degrees of
             atrioventricular (AV) block are the most frequent cardiac
             features.  In severe cases, ectopic beats occur which may be
             followed by ventricular tachycardia and fibrillation.  The
             main neurological symptoms are: tremor, drowsiness and
             ataxia.  Hypotension and unconsciousness may also occur. 
             Seizures have been described.

        2.3  Diagnosis

             Diagnosis is based on the clinical features (malaise,
             vomiting, abdominal pain, bradycardia, dizziness),
             electrocardiographic changes and glycosides investigated by
             digoxin immunoassay.  The triad of gastrointestinal distress,
             circumoral erythema and cardiac dysrhythmia should alert to
             the possibility of N. oleander poisoning.
    
             A plant specimen or parts obtained from gastric lavage or
             vomiting should be collected for botanical identification. 
             N. oleander can be recognized by microscopic examination of
             its epidermis, where stoma cells are typical.

        2.4  First-aid measures and management principles

             Treatment should aim at:
             -gut decontamination by means of emesis or lavage;
             -correction of electrolyte imbalance;
             -correction of severe bradycardia with atropine or electrical
             pacing
             -corrections of ventricular dysrhythmias;
             -administration of digoxin-specific Fab antibodies could be
             considered if available.

        2.5  Poisonous parts

             All parts of this plant, including the sap, either
             fresh, dried or boiled, are toxic.  A single leaf intensively
             chewed has been reported to be lethal.

        2.6  Main Toxins

             The main poisonous principles are cardiac glycosides. 
             The one most studied is oleandrin, but there are more than
             ten other glycosides whose chemical structure is well known: 
             5 -cardenolides, such as oleandrine; 5 a-cardenolides, such
             as uzangenin-type; oleandrigenin (16-Acetylgitoxigenin) (ol). 
             The "ol" being: oleandroside (oleandrin); glucose
             (glucosyloleandrin); gentiobioside (gentiobiosyl oleandrin);
             diginoside (nerigoside); digitoxigenin (digitalose/diginose);
             oleagenine - oleasides (A,E) (diginose, gentiobiose-
             diginose).  Adyregenin is a compound with no cardiac
             effect.

    3.  CHARACTERISTICS

        3.1  Description of the plant

             3.1.1  Special identification features

                    N. oleander is an evergreen shrub reaching
                    four metres in height. Leaves are 10 to 22 cm long,
                    narrow, untoothed and short-stalked, dark or grey-
                    green in colour.  Some cultivars have leaves
                    variegated with white or yellow.  All leaves have a
                    prominent mid rib, are "leathery" in texture and
                    usually arise in groups of three from the stem.  The
                    plant produces terminal flower heads, usually pink or
                    white, however, 400 cultivars have been bred and these
                    display a wide variety of different flower colour: 
                    deep to pale pink, lilac, carmine, purple, salmon,
                    apricot, copper, orange and white (Huxley, 1992). 
                    Each flower is about 5 cm in diameter and five-
                    petalled.  The throat of each flower is fringed with
                    long petal-like projections.  Occasionally double
                    flowers are encountered amongst cultivars.  The fruit
                    consists of a long narrow capsule 10 to 12 cm long and
                    6 to 8 mm in diameter; they open to disperse fluffy
                    seeds.  Fruiting is uncommon in cultivated plants. 
                    The plant exudes a thick white sap when a twig or
                    branch is broken or cut (Font-Quer, 1974; Schvartsman,
                    1979; Lampe & McCann, 1985; Pearn, 1987).

             3.1.2  Habitat

                    Where the species grows in the wild (i.e. in
                    the Mediterranean), it occurs along watercourses,
                    gravely places and damp ravines.  It is widely
                    cultivated particularly in warm temperate and
                    subtropical regions where it grows outdoors in parks,
                    gardens and along road sides.  Elsewhere, where the
                    plant is not frost-tolerant (e.g. in central and
                    western Europe), it may be grown as a conservatory or
                    patio plant.

             3.1.3  Distribution

                    N. oleander is cultivated worldwide as an
                    ornamental plant; it is native only in the
                    Mediterranean region (Kingsbury, 1964; Hardin & Arena,
                    1974).

        3.2  Poisonous parts of the plant

             The whole plant, including the sap, is toxic.

        3.3  The toxin(s)

             3.3.1  Name(s)

                    Oleandrin, a glycoside, is the main toxin.  Its
                    chemical name is 16b-acetoxy-3b-[(2,6 dideoxy-3-0-
                    methyl-a2-L-arabino-hexopyranosyl) oxy]-14-hydroxy-5,
                    14-card-20(22)-enolide (Reynolds, 1989).

             3.3.2  Description, chemical structure, stability

                    Oleandrin:
                    CAS number:  465-16-7
                    Structural formula:  C32H48O9
                    Molecular weight:  576.7
                    Structural name:  oleandrin

             3.3.3  Other physico-chemical characteristics

                    Oleandrin forms colourless, odourless, acicular
                    crystals which are very bitter (Shaw & Pearn, 1979). 
                    The concentration of oleandrin in the plant tissues is
                    approximately 0.08% (Schvartsman, 1979).
    
                    Solubility:  insoluble in water; it has little
                    resistance to light but it is heat-stable (Pearn,
                    1987; Reynolds, 1989).

        3.4  Other chemical contents of the plant

             N. oleander contains at least 2% cardiac glycosides.
    
             Rosagenin may be extracted from the bark and has a
             strychnine-like action.  Several flavones (0.5%) and volatile
             oils (unimportant amount), as well as rubber, fats, sugars
             and hydrocyanic acid, can be isolated from its leaves
             (Schvartsman, 1979; Shaw & Pearn, 1979; Pearn, 1987).

    4.  USES/CIRCUMSTANCES OF POISONING

        4.1  Uses

             4.1.1  Uses

                    Miscellaneous pharmaceutical product
                    Other therapeutic preparation

             4.1.2  Description

                    Preparations containing the active principles
                    were used formerly as rodenticides, insecticides, and
                    as remedies for indigestion, fever, ringworm, malaria,
                    leprosy, venereal diseases and as abortifacients. 
                    Therapeutic use of oleander glycosides as cardiac

                    drugs were assessed and documented in the 1930s (Shaw
                    & Pearn, 1979; Osterloh et al., 1982).  The USSR
                    pharmacopoeia contains an oleandrin solution (solutio
                    Neriolini) and oleandrin tablets, and oleandrin
                    solution (oleandrin 22 mg, alcohol 74 mL, distilled
                    water to 100 mL).  This contains 7 to 9 'frog units'
                    per mL (1 mg oleandrin = 34 to 44 frog units). 
                    Oleandrin tablets each contain 100 mg of the active
                    principle (Reynolds, 1989).

        4.2  High risk circumstances

             The high risk circumstances of exposure are: children
             playing with the ornamental shrub (tasting, chewing,
             ingesting portions of the plant), and inappropriate medicinal
             use of plant infusion.  Intentional poisoning by ingestion of
             plant infusions has been reported.

        4.3  High risk geographical areas

             Although the plant is native to the Mediterranean basin,
             it has been introduced as an ornamental shrub in many
             tropical and subtropical countries (Mahin et al., 1984).  The
             plant is common in Australia and southern Africa and
             ingestion of plant parts is one of the major causes of
             childhood admission to hospital (Shaw & Pearn, 1979).

    5.  ROUTES OF EXPOSURE

        5.1  Oral

             Parts of the plant can be ingested accidentally or in
             suicide attempts (Jouglard et al., 1973; Pronczuk & Laborde,
             1988).  Extracts or herbal teas made of N. oleander have
             been ingested for suicidal or medicinal purposes (Haynes et
             al., 1985; Blum & Rieders, 1987).  Ingestion of water
             contaminated with N. oleander leaves (from a flower bowl),
             meat cooked or stirred with the stems, and honey made by bees
             visiting the flowers have produced toxic effects (Hardin &
             Arena, 1974).

        5.2  Inhalation

             Smoke from burning N. oleander may be toxic (Hardin &
             Arena, 1974; Shaw & Pearn, 1979).

        5.3  Dermal

             No data available.

        5.4  Eye

             No data available.

        5.5  Parenteral

             No data available.

        5.6  Others

             A fatal case, following rectal and oral administration of
             N. oleander extract, has been described (Blum & Rieders,
             1987).

    6.  KINETICS

        6.1  Absorption by route of exposure

             Oleandrin is well absorbed orally (Schvartsman, 1979).

        6.2  Distribution by route of exposure

             Wide body distribution is expected: high concentrations
             of oleandrin have been measured in blood, liver, heart, lung,
             brain, spleen and kidney in a fatal case of N. oleander
             extract poisoning (Blum & Rieders, 1987).

        6.3  Biological half-life by route of exposure

             No data available.

        6.4  Metabolism

             No data available.

        6.5  Elimination and excretion

             Oleandrin is eliminated very slowly from the body (one
             to two weeks) (Shaw & Pearn, 1979).

    7.  TOXINOLOGY

        7.1  Mode of Action

             The cardiac effects of the glycosides are due to direct
             cardiotoxicity and an indirect effect via the vagal nerve. 
             The direct effect is due to the inhibition of the Na-K
             ATP-ase pump (sodium-potassium adenosine triphosphatase
             enzyme system).  This specific action increases intracellular
             sodium ion and serum potassium concentrations.  The sodium
             influx lowers the membrane potential threshold, increasing
             excitability.  The chronotropic effect is primarily central,
             mediated by an increase of vagal tone which decreases the
             rate of sinoatrial node depolarization (Osterloh et al.,
             1982).

        7.2  Toxicity

             7.2.1  Human data

                    7.2.1.1  Adults

                             Between 7 to 20, or a "handful", of
                             the leaves have been ingested by adult
                             patients who were intoxicated but recovered
                             completely; the dose of oleandrin in this
                             sample is not known (Pronczuk & Laborde,
                             1988; Shumaik et al., 1988).

                    7.2.1.2  Children

                             A single leaf may be lethal to a
                             child (Shaw & Pearn, 1979).

             7.2.2  Relevant animal data

                    One leaf of N. oleander may be sufficient to
                    kill a sheep (Shaw & Pearn, 1979).  The lethal dose of
                    N. oleander leaves reported for several animal
                    species is about 0.5 mg/kg.  Animals poisoned by
                    eating the plant often develop bloody diarrhoea, due
                    to a direct effect on the gastrointestinal tract.  The
                    bitter and astringent taste of the plant's leaves
                    means that all but starving creatures are likely to be
                    exposed. (Szabuniewicz et al., 1971; Pearn, 1987).

             7.2.3  Relevant in vitro data

                    No data available.

        7.3  Carcinogenicity

             No data available.

        7.4  Teratogenicity

             No data available.

        7.5  Mutagenicity

             No data available.

        7.6  Interactions

             Pre-medication with digoxin or other cardiac glycosides
             may increase the severity of poisonings.  The well-known
             interaction between digoxin and quinidine (increasing digoxin
             levels) should be considered.

    8.  TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS

        8.1  Material sampling plan

             8.1.1  Sampling and specimen collection

                    8.1.1.1  Toxicological analyses

                             Suspect material, scene residues,
                             vomited or washed out gastric contents should
                             be collected for analysis, as well as
                             preparations containing N. oleander.
    
                             Plasma samples should be taken for the
                             digoxin immunoassay.
    
                             Morphology and anatomy:
    
                             Specimens of the leaves, flowers and branches
                             should be collected for botanical and
                             pharmacognostical identification.  Suspect
                             material and plant portions found in vomit or
                             scene residues should be taken for the
                             macroscopic and microscopic analysis.

                    8.1.1.2  Biomedical analyses

                             Blood and urine should be collected
                             for routine biochemical analysis.  Serum
                             samples should be taken for measurements of
                             the serum potassium concentration.

                    8.1.1.3  Arterial blood gas analysis

                             Blood should be collected for
                             arterial blood gas analysis in unconscious
                             patients.

                    8.1.1.4  Haematological analyses

                             Blood should be collected for
                             routine haematological analyses.

                    8.1.1.5  Other (unspecified) analyses

                             No data available.

             8.1.2  Storage of laboratory samples and specimens

                    8.1.2.1  Toxicological analyses

                             Biological samples should be stored
                             at 4C in a refrigerator.  For macroscopic
                             and microscopic analysis fresh plant material
                             should be kept between sheets of newspaper.
    
                             Dried plant material should be protected from
                             moisture.
    
                             Plant portions found in vomit or scene
                             residues have to be stored in clean bottles
                             or sealed plastic bags.

                    8.1.2.2  Biomedical analyses

                             Biological samples should be stores
                             at 4C in a refrigerator.

                    8.1.2.3  Arterial blood gas analysis

                             Storage is not possible.

                    8.1.2.4  Haematological analyses

                             Samples should be stored at 4C in a
                             refrigerator.

                    8.1.2.5  Other (unspecified) analyses

                             No data available.

             8.1.3  Transport of laboratory samples and specimens

                    8.1.3.1  Toxicological analyses

                             No special requirements.
    
                             For macroscopic and microscopic analysis:
                             no special requirements.

                    8.1.3.2  Biochemical analyses

                             No special requirements.

                    8.1.3.3  Arterial blood gas analysis

                             Transport to the laboratory
                             immediately.

                    8.1.3.4  Haematological analyses

                             No special requirements.

                    8.1.3.5  Other (unspecified) analyses

                             No data available.

        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)

                             A.  Identification of the plant
                             parts (additional to 3.1.1)
    
                             The powdered leaves are characteristically a
                             light yellow green in colour and taste
                             bitter.
    
                             Anatomical:
                             The lower surface of the leaf has
                             characteristic abaxial grooves containing
                             (single-cell hair) and vimicelled trichomes. 
                             The cells of the mesophyllum contain calcium
                             oxalate crystals (35 m).
    
                             B. Identification of toxic, active
                             ingredients in plant or preparation
    
                             (i) Specific reaction:
    
                             - Principle of test (or method):
                             In general cardenolides form with aromatic
                             nitro compounds in alkaline solution (e.g.
                             Kedde-reagent) typical and very specific re,
                             violet-red or blue-violet products
                             (Meisenheimer adducts).
    
                             - Sampling: plant parts, (preferably leaves,
                             flowers, fruit).
    
                             - Chemicals and reagents
    
                             Chemicals:
                             *  dioxane
                             *  dichloromethane (methylene chloride)
                             *  3,5-dinitro benzoic (C2H4N2O6)
                             *  ethanol
                             *  methanol
    

                             *  2 N NaOH (8,4 g NaOH dissolved in 100 mL
                                water)
                             *  oleandrine
                             *  oleander glycoside mixture -1 for TLC-
                                comparison
    
                             Reagents:
                             *  Keddle-reagent: dissolve 3 g of 3,5-
                                dinitro benzoic acid in ethanol.
                                Take 5 mL and mix with 5 mL of a 2 N NaOH
                                directly before use.
    
                             Equipment:
                             *  round bottle flask, 50 mL
                             *  pipettes 0.1 mL and 0.5 mL
                             *  test tubes
                             *  filter-paper or silica gel plate
                                (5  5 cm)
                             *  Extrelut R- column (20 mL, Nr. 11737 Merck
                                AG, D-6100
                             *  Darmstadt
    
                             - Test sample (or specimen) preparation
    
                             *  Extract 1 g of material (suspect material,
                                scene residues) with 20 mL methanol 50%
                                for 15 minutes under reflux on a water
                                bath.
                             *  Filtrate and evaporate the extract to a
                                volume of 10 mL.
                             *  Apply the extract on an ExtrelutR- column
                                and wait for 20 minutes.
                             *  Extract the retain material with 60 mL of
                                dioxan-methanol-dichloromethane
                                [8+1+1].
                             *  Collect the extract and evaporate to 10
                                mL.
    
                                Reference compound
                                Dissolve 10 mg of oleandrine in 10 mL
                                ethanol
                                Dissolve 10 mg of the "Oleander glycoside
                                mixture" in 10 mL ethanol.
    
                             - Procedure:
    
                             *  Spot 100 L of the extract on a filter-paper
                                 or on a silica gel plate [5  5 cm]
                             *  Add 5 drops of the Keddle-reagent
                             *  An immediate blue, red or violet-blue
                                colour indicates the presence of
                                cardenolides (Colour vanish).
    

                                Analytical calibration procedure and
                                calculation of results not necessary.
    
                                Quality control
                                Carry out a blank test by taking 100 L of
                                water instead of the sample.
                                Carry out a positive control test by
                                taking 100 L of a cardenolide solution
                                such as oleandrin in ethanol.
    
                             - Specificity
    
                             A specific reaction with the lactone ring of
                             the cardenolide-molecule.  Cardenolides
                             respond with a blue, red or violet- blue
                             colour reaction.
    
                             - Analytical performance: detection limit
                             3 g of a cardenolide.
    
                             - Analytical assessment of the result: a
                             positive result indicates the presence of a
                             cardenolide.
    
                             - Medical interpretation of the result:
                             consider the possibility of ingestion of
                             cardenolides.
    
                             (ii) Thin Layer Chromatography
    
                             - Principle of test:
                             TLC separation of the Oleander cardenolide
                             mixture, (Wagner & Bladt, 1995), detection in
                             UV-254 and detection of the cardenolide zones
                             with Kedde-reagent.
    
                             - Sampling: 1 to 2 g of the suspect material
                             or residue.
    
                             - Chemicals and reagents
    
                             Chemicals:
    
                             *  chloroform
                             *  dioxane
                             *  dichloromethane (methylene chloride)
                             *  3,5-dinitro benzoic acid
                             *  thyl acetate
                             *  methanol
                             *  2 M sodium hydroxide (8,4 g NaOH dissolved
                                in 100 mL water)
                             *  sulfuric acid (conc.)
                             *  water
    

                             *  TLC-Silicagel 60 F 254 plates (with
                                fluorescence marker) (e.g. Merck
                                Darmstadt, Roth D 7500 Karlsruhe Nr.
                                2-8867 and 2-8864)
                             *  oleandrine
                             *  oleander glycoside mixture -1 for TLC-
                                comparison
    
                             Reagents:
    
                             *  Keddle-reagent: dissolve 3 g of 3,5-
                                dinitro benzoic acid
                             *  in ethanol.
                             *  Take 5 mL and mix with 5 mL of a 2 M NaOH
                                directly
                             *  before spraying.
    
                             *  Solvent system for TLC: ethylacetate-
                                methanol-water
                                [81+11+8]
    
                             *  Reference compounds:
                                Dissolve 10 mg of oleandrine in 10 mL
                                ethanol
                                Dissolve 10 mg of lanatoside C in 10 mL
                                ethanol
                                Dissolve 10 mg of the "Oleander glycoside
                                mixture" in 10 mL ethanol.
    
                             - Equipment:
    
                             *  round bottle flask 50 mL
                             *  TLC tank
                             *  UV lamp (254 nm)
                             *  fume cupboard
                             *  spray apparatus
    
                             - Test sample (or specimen) preparation
    
                             *  Extract 1 g of material (suspect material,
                                scene residues) with 20 mL methanol (50%)
                                for 15 minutes under reflux on a water
                                bath.
                             *  Filtrate and evaporate the extract to a
                                volume of 10 mL.
                             *  Apply the extract on an Extrelut20-
                                column and wait for minutes.
                             *  Extract the retained material with 60 mL
                                of dioxanmethanol- dichloro methane
                                [8+1+1].
                             *  Collect the extract and evaporate to
                                10 mL.
    

                             *  Reference compounds
                                Dissolve 10 mg of oleandrine in 10 mL
                                ethanol
                                Dissolve 10 mg of lanatoside C in 10 mL
                                ethanol
                                Dissolve 10 mg of the "Oleander glycoside
                                mixture" in 10 mL ethanol.
    
                             - Procedure:
                             *  Apply 20 L of each cardenolide reference
                                solution to the TLC plate along the
                                baseline.
                             *  Apply 20 L and 40 L of the test sample
                                preparation to the TLC plate along the
                                baseline.
                             *  Prepare the TLC tank with the solvent
                                mixture.
                             *  Place the prepared TLC plate in the tank
                                and allow to run for 12 cm
                             *  Take the TLC plate out and allow to dry.
    
                             *  Detection
                                Place the plate under UV lamp (UV-254 nm)
                                to visualize the spots and mark with a
                                pencil.  Cardenolides show weak
                                fluorescence quenching.  Spray the TLC
                                with Kedde-reagent and immediately blue,
                                violet-blue and red-violet spots indicate
                                the presence of cardenolides.  Plant
                                extracts show 8-10 Kedde-positive zones in
                                the R-range 0.1 - 0.9.
    
                                Another re-agent used may be conc.
                                Sulfuric acid (unspecified reaction). 
                                Mostly red to red-brown spots indicate the
                                presence of cardenolides.  Plant extracts
                                show at least 8-10 red zones in the
                                R-range 0.1-0.9.
    
                                Calculate the Rf-values of the zones and
                                compare the Rf-values with the reference
                                compound and the Rf-values of the
                                cardenolid compounds given in table 2.
    
                                Analytical calibration procedure and
                                calculation or results is not applicable.
    
                                - Quality control:
                                Carry out positive control test by taking
                                20 L of a cardenolide solution such as
                                oleandrine in ethanol.
    

                                Compare the TLC-fingerprint of an
                                authentic N. oleander cardiac
                                glycosides-extract.
    
                                - Specificity:
                                A specific reaction with the lactone ring
                                of the cardenolide-structure.
                                Cardenolides respond with blue, red or
                                violet-blue colour.
    
                                - Analytical performance:  detection limit
                                3 g of a cardenolide.
    
                                - Analytical assessment of the result:  a
                                positive result indicates the presence of
                                a cardenolide.
    
                                - Medical interpretation of the result: 
                                consider the possibility of ingestion of
                                cardenolides.

                    8.2.1.2  Advanced Qualitative Confirmation Test(s)

                             With the HPLC-method a cardenolide
                             profile of oleander glycosides in plant
                             extracts or oleander-preparations can be
                             achieved.  The analysis is performed on a RP-
                             18 column by gradient elution (acetonitrile-
                             water) and detection in UV-220 nm. (Tittel &
                             Wagner, 1981).
    
                             Depending on habitat, distribution and time
                             of harvest, the cardenolide content in leaves
                             of different origin shows marked differences
                             in the distribution of the major
                             glycosides.

                    8.2.1.3  Simple Quantitative Method(s)

                             - Principle of test:  The purified
                             cardenolide fraction of suspect material or
                             scene residue, is measured after addition of
                             Kedde-reagent at its absorption maximum
                             (540 nm).
    
                             - Sampling: 2 g plant material, suspect
                             material, scene residue, stomach content
    
                             - Chemicals and reagents: chemicals
                             (analytical grade)
                             *  3,5-dinitro benzoic acid (C2H4N2O6)
                             *  ethanol
    

                             *  methanol
                                2 N NaOH (8,4 g of a NaOH are dissolved in
                                100 mL of water)
                             *  water (distilled)
                             *  Aluminium oxide (Al2O3) acidic
    
                             Reagents:
    
                             *  Kedde-reagent:
                             Dissolve 3 g of 3,5-dinitro benzoic acid in
                             ethanol
                             Take 5 mL and mix with 5 mL of a 2 N NaOH
                             directly before spraying.
    
                             Equipment:
    
                             flasks: 5 mL and 20 mL
                             volumetric flasks: 25 mL and 50 mL
                             pipettes: 1,2,3,4 mL
                             chromatographic column [15 mm diameter,
                             200 mm length]
                             with tap and glass filter (medium porosity
                             grade)
                             timer: 2 minutes
                             spectrophotometer visible
                             glass cuvettes (1 cm path length)
    
                             - Test sample (or specimen) preparation:
                                   - Weigh a precise amount of powdered
                                   plant material (2 g).
                                   - add 35 mL of mixture of 24 mL ethanol
                                   + 36 mL water.
                                   - heat for 20 minutes under reflux.
                                   - filtrate after cooling through
                                   filter-paper.
                                   - wash with residue twice with 5 mL
                                   portions of the ethanol-
                                   water mixture (24+36).
                                   - combine the filtrates and add the
                                   ethanol-water mixture to mark in a
                                   volumetric flask 50 mL.
    
                             Preparation of the column:
    
                             - 4.2 g Al2O3 and 20 mL water are shaken
                             in a flask for approximately 5 minutes.
                             - after standing for 5 minutes the
                             supernatant water is discarded.
                             - wash four times the Al2O3-material with
                             50 mL portions of ethanol.
                             - discard the ethanol.
                             add 50 mL of ethanol, shake well and transfer
                             the Al2O3 material into the column.
    

                             wait for 15 minutes, then add 10 mL ethanol.
                             -open the tap and discard the ethanol till
                             approximately 1/2 cm above the column
                             material (Al3O2).  Close the tap.
    
                             Procedure:
    
                             - apply exactly 2 mL of the filtrate to the
                             column.
                             - eluate 4 times with O.5 mL ethanol and
                             finally with 16 mL ethanol.
                             - collect the cardenolide containing
                             fractions in a volumetric flask and make up
                             to 25 mL volume with ethanol and 4 mL Kedde-
                             reagent in a flask as blank (solution).
                             - take exactly 4 mL of the cardenolide
                             fraction and add 4 mL Kedde-reagent, mix
                             thoroughly.
                             - transfer into the glass cuvette.
                             - read the absorbence of the test solution
                             exactly 2 minutes (with timer) after addition
                             of the reagent against the blank at 540 nm as
                             the coloration is time-dependent!
                             - Analytical calibration procedure and
                             calculation or results:
                             - calibrate with four standards of a solution
                             of 10 mg oleandrine 100 mL ethanol.
                             - take 1/2/3/4 mL and add each time 4 mL of
                             the Kedde-reagent.
                             - measure each solution exactly after
                             2 minutes at 540 nm against the blank.
                             - construct a calibration function.
                             - compare the absorbence of the test solution
                             with the calibration function.
                             - alculate the oleandrin amount as:
    
                                      a  1562.5
                             % =      ----------
                                      e  (100-t)
    
                             a = mg oleandrin found in the calibration
                                 function
                             e = sample material in analytical solution
                             t = loss of liquid (%)
    
                             (t = weigh a precise amount of powdered plant
                             material (1 g) and heat: at 110C till the
                             material has a constant weight:  the
                             difference in weight indicates the loss of
                             liquid of the material).
    
                             - Quality control:
    

                             It is important that test and reference
                             solution are measured exactly after 2 minutes
                             after adding the Kedde-reagent (coloration is
                             time dependent!).
    
                             - Specificity: the method is generally
                             applicable for cardenolides.  The total
                             cardenolides are calculated as oleandrine.
    
                             - Analytical performance
                             Mean coefficient of variation 6%.  Detection
                             limit is 1 g of cardenolide.
    
                             - Analytical assessment of the result
                             Consider the presence of cardenolides.
    
                             - Medical interpretation of the result
                             Consider the possibility of ingestion of
                             cardenolides.

                    8.2.1.4  Advanced Quantitative Method(s)

                             Methods for toxic, active
                             ingredients.  With the HPLC-method of
                             external standard a quantitative estimation
                             of the oleander glycosides can be achieved. 
                             The analysis is performed on a RP-18 column
                             isocratic and by gradient elution
                             (acetonitrile-water) and detection in UV-220
                             nm. (Tittel & Wagner, 1981).
    
                             column      -Bondapak .. C-18 (300  4 mm
                                         ID)
                             flow        2 mL/minutes
                             detection   220 nm
                             solvent     acetonitrile-water (40+60)
                                         isocratic
                             oleandrin   Rt 12.5 minutes
                             adynerin    Rt 14 minutes

                             Quantitative estimation of glycosides other
                             than oleandrine and adynerine is possible by
                             linear gradient elution (20 to 50%
                             acetonitrile in 45 minutes).

             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

                             "Basic analyses"
                             "Dedicated analyses"
                             "Optional analyses"

                    8.3.1.2  Urine

                             "Basic analyses"
                             "Dedicated analyses"
                             "Optional analyses"

                    8.3.1.3  Other fluids

             8.3.2  Arterial blood gas analyses

             8.3.3  Haematological analyses

                    "Basic analyses"
                    "Dedicated analyses"
                    "Optional analyses"

             8.3.4  Interpretation of biomedical investigations

        8.4  Other biomedical (diagnostic) investigations and their
             interpretation

        8.5  Overall interpretation of all toxicological analyses and
             toxicological investigations

             Sample collection
             Plant specimens should be collected for botanical
             identification if possible.  They should be transported
             between two newspaper sheets (preferably the leaves and
             flowers).  Plant portions found in vomit should be stored in
             a plastic bag.
    
             Biomedical analysis
             ECG is valuable for diagnosis, prognosis and treatment since
             cardiac effects similar to digitalis glycosides may occur
             (Goldfrank et al., 1994).  The serum potassium concentration
             should be measured because of its prognostic importance.
    

             Toxicological/toxinological analysis
    
             Plasma samples should be taken for digoxin immunoassay.
    
             In a mild case of N. oleander poisoning the apparent
             digoxin level was 1.5 ng/mL (Shumaik et al., 1988).  In a
             fatal case of N. oleander poisoning "digoxin" level was 5.8
             mcg/l.  A cross reactivity between oleander glycosides was
             demonstrated in a radioimmunoassay. Using this method, 5.8
             mcg/l of digoxin corresponds to 580 mcg/l of total cardiac
             glycoside concentration (Osterloh et al., 1982).  Cheung et
             al. (1984) found radioimmunoassay to be a rapid and
             convenient method to confirm N. oleander poisoning, but the
             apparent "digoxin" concentration was not proportional to the
             cardiac glycoside concentration.
    
             Test for active ingredient
             Immunoassay is a rapid and convenient method for confirming
             ingestion of N. oleander.  The competitive immunoassay
             method allows rapid screening of suspected specimens.  This
             method is also useful for confirming the presence of cardiac
             glycosides in serum (Radford et al., 1986).  Cross reactivity
             has been demonstrated between the cardiac glycosides in
             N. oleander and the digoxin radioimmunoassay (Osterloh et
             al., 1982; Haynes et al., 1985).  Oleandrin can be detected
             by thin layer chromatography, with location by fluorescence
             and chromogenically by means of p-anisaldehyde. 
             Quantification can be performed by fluorescence
             spectrophotometry with excitation at 355 nm and fluorescence
             scanning from 340 to 580 nm (Blum & Rieders, 1987).
    
             Test for biological sample
             Parts of the plant can be confirmed by microscopic
             examination of the epidermis, where stoma cells are
             typical.
    
             Biochemical investigations
             Serum electrolytes should be monitored, with special
             attention to potassium.  Serum urea and creatinine should be
             measured in severe cases.
    
             Interpretation
             The most important biochemical measurement is the serum
             potassium concentration.  It has prognostic significance,
             since the elevated potassium facilitates cardiac arrhythmias. 
             Digoxin radioimmunoassay may help to confirm poisoning.

    9.  CLINICAL EFFECTS

        9.1  Acute poisoning

             9.1.1  Ingestion

                    The clinical effects are mainly cardiac and
                    gastrointestinal, resulting in a clinical picture
                    similar to that of digoxin poisoning, including
                    nausea, vomiting, salivation, colic and diarrhoea
                    (Hardin & Arena, 1974).  Parts of the plant may be
                    recognized in the vomit.  Bloody diarrhoea has been
                    described (Shaw & Pearn, 1979).  Circumoral erythema
                    has been described as a typical sign (Lewin et al.,
                    1986).
    
                    Sinus bradycardia is the most frequent cardiovascular
                    sign, and it may progress to atrioventricular block
                    (AV) and asystole.  Ventricular arrhythmias, premature
                    ventricular beats, ventricular tachycardia and
                    ventricular fibrillation can occur in severe cases
                    (Osterloh et al., 1982).
    
                    The triad of gastrointestinal distress, circumoral
                    erythema and cardiac dysrhythmias in a child or adult
                    should alert to the possibility of poisoning by
                    N. oleander (Lewin et al., 1986).
    
                    Central nervous system effects occur frequently and
                    include ataxia, drowsiness, mydriasis, muscular
                    tremors, seizures and coma (Shaw & Pearn, 1979; Lewin,
                    1980).

             9.1.2  Inhalation

                    Inhalation of smoke from burning the plant may
                    cause poisoning.

             9.1.3  Skin exposure

                    Sap contains an unidentified irritant of the
                    mucous membranes of the mouth and intestine (NCPCC,
                    1979).

             9.1.4  Eye contact

                    Severe eye irritation can be caused by the sap
                    (NCPCC, 1979).

             9.1.5  Parenteral exposure

                    No data available.

             9.1.6  Other

                    A fatal case of rectal and oral administration of
                    N. oleander extract has been described (Blum &
                    Rieders, 1987).

        9.2  Chronic poisoning

             9.2.1  Ingestion

                    Chronic poisoning has not been described, even
                    in patients treated with Oleandrin extracts.

             9.2.2  Inhalation

                    No data available.

             9.2.3  Skin exposure

                    No data available.

             9.2.4  Eye contact

                    No data available.

             9.2.5  Parenteral Exposure

                    No data available.

             9.2.6  Other

                    No data available.

        9.3  Course, prognosis, cause of death

             Patients with cardiovascular illness, those who ingest
             more than 0.5 mg/kg of N. oleander leaves and/or those who
             arrive late to hospital are at highest risk.  Serum potassium
             concentrations are of prognostic importance, as in digoxin
             intoxication (Goldfrank et al., 1994).  The presence of
             hyperkalaemia in the initial stage of intoxication worsens
             the prognosis.  Deaths from ingestion of N. oleander occur
             due to dysrhythmias (Lewin et al., 1986).

        9.4  Systematic description of clinical effects

             9.4.1  Cardiovascular

                    ECG changes include sinus bradycardia, varying
                    levels of atrioventricular block, ventricular
                    arrythmias and finally ventricular fibrillation, which
                    is the usual cause of death.

             9.4.2  Respiratory

                    No effects have been described either in acute
                    or chronic poisoning.

             9.4.3  Neurological

                    9.4.3.1  Central nervous system (CNS)

                             Ataxia, drowsiness, mydriasis,
                             seizures and coma.

                    9.4.3.2  Peripheral nervous system

                             No effects have been described either
                             in acute or chronic poisoning.

                    9.4.3.3  Autonomic nervous system

                             Mydriasis, pallor, hypersalivation
                             and other autonomic effects have been
                             described.

                    9.4.3.4  Skeletal and smooth muscle

                             Muscle tremor may occur after acute
                             poisoning.

             9.4.4  Gastrointestinal

                    Nausea, vomiting, colic and diarrhoea are
                    characteristic of acute poisoning.

             9.4.5  Hepatic 

                    No data available.

             9.4.6  Urinary

                    9.4.6.1  Renal

                             No data available.

                    9.4.6.2  Other

                             No data available.

             9.4.7  Endocrine and reproductive systems

                    No data available.

             9.4.8  Dermatological

                    Irritant circumoral erythema has been described
                    as a typical sign.
    
                    Sap contains an unidentified allergen which produces
                    dermatitis
                    (NCPCC, 1979).

             9.4.9  Eye, ear, nose, throat: local effects

                    Local effects:  the sap irritates the eyes and
                    the mucous membranes of the mouth and  intestine
                    (Pearn, 1987).

             9.4.10 Haematological

                    No data available.

             9.4.11 Immunological

                    No data available.

             9.4.12 Metabolic

                    No data available.

                    9.4.12.1 Acid-base disturbances

                             No data available.

                    9.4.12.2 Fluid and electrolyte disturbances

                             Hyperkalaemia may be detected in
                             acute poisoning. Gastrointestinal fluid loss
                             often leads to dehydration and hypovolaemic
                             shock.

                    9.4.12.3 Others

                             No data available.

             9.4.13 Allergic reactions

                    Sap contains an unidentified allergen which
                    produces dermatitis (NCPCC, 1979).

             9.4.14 Other clinical effects

                    No data available.

             9.4.15 Special risks

                    Pregnancy:  Although N. oleander has been
                    ingested as an abortifacient, abortion has not been
                    reported after acute poisoning (Spevak & Soc, 1975).
                    N. oleander poisoning in a cow during the second
                    half of pregnancy did not produce abortion (Mahin et
                    al., 1984).
    
                    Breast feeding: no data available.
    
                    Enzyme deficiencies: no data available.

        9.5  Other

             No data available.

        9.6  Summary

    10. MANAGEMENT

        10.1 General principles

             Even asymptomatic patients should be admitted for
             observation, decontamination and cardiovascular monitoring. 
             Repeated electrocardiograms or continuous ECG monitoring are
             necessary.
    
             The triad of gastrointestinal distress, circumoral erythema,
             and cardiac dysrrhythmias in a child or adult should alert
             the clinician to the possibility of poisoning due to
             N. oleander; the serum concentration of digoxin level
             should be measured.  A positive result in a patient who is
             not taking the cardiac glycosides suggests ingestion of a
             digitalis-like substance (Lewin et al.,  1986).
    
             Treatment should aim at gut decontamination by means
             of emesis or lavage; correction of electrolyte imbalance; and
             correction of severe dysrthymias (Kunkel, 1983).

        10.2 Life supportive procedures and symptomatic/specific treatment

             Management depends on the occurrence of cardiac
             effects.  Bradycardia may require atropine or electrical
             pacing (Kunkel, 1983).
    
             Ventricular arrhythmias could be treated with phenytoin or
             lignocaine.  Phenytoin should be infused intravenously slowly
             in doses of 3.5 to 5.0 mg/kg, at a rate not greater than 50
             mg/minute to repeat once if necessary.  Lignocaine may be
             administered at a dose of 1 mg/kg as a slow intravenous bolus
             followed by continuous infusion of 2 to 4 mg/minute
             (adult).
    

             Treatment of hyperkalaemia should aim at lowering the serum
             potassium level with insulin, glucose, sodium bicarbonate and
             ion-exchange resins.  Haemoperfusion may be considered in
             severe cases.  Calcium chloride is contraindicated (Goldfrank
             et al., 1994).

        10.3 Decontamination

             Emesis or gastric lavage are indicated at an early
             stage if the patient has not vomited copiously or if no
             contraindications exist.  It should be followed by the
             administration of activated charcoal and, possibly, a
             cathartic.  The indication and value of decontamination
             procedures will depend on the time elapsed since ingestion
             (Pronczuk & Laborde, 1988; Goldfrank et al., 1994).

        10.4 Enhanced elimination

             Forced diuresis, haemoperfusion and haemodialysis are
             not effective in increasing digoxin elimination (Goldfrank et
             al., 1994).  The same criteria can be applied to other
             cardiac glycosides of similar chemical structure.

        10.5 Antidote/antitoxin treatment

             10.5.1 Adults

                    Digoxin-specific Fab antibody fragments have been
                    used successfully in an adult patient intoxicated with
                    N. oleander (Shumaik et al., 1988).
    
                    Although not available for routine use in all
                    countries even for digoxin poisoning, Fab fragments
                    are a possibility to consider when N. oleander
                    poisoning is unresponsive to conventional treatment.

             10.5.2 Children

                    No data available.

        10.6 Management discussion

             The use of digoxin-specific Fab fragments deserves
             further evaluation.

    11. ILLUSTRATIVE CASES

        11.1 Case reports from the literature

             An elderly woman was found weak and vomiting and
             developed a tonic seizure followed by cardiac arrest on
             arrival at hospital.  Despite continuous cardiopulmonary
             resuscitation the patient died.  The potassium level was 8.6 

             mEq/L and the apparent digoxin level was 5.8 mcg/L.  Cross
             reactivity between oleandrin and digoxin was calculated at
             29,000:1 in the digoxin-radioimmunoassay (Osterloh et al.,
             1982).
    
             A 37-year-old man ingested a "handful" of N. oleander
             leaves.  Two hours later, he presented with bradycardia (30
             to 45 bpm) with sinoatrial block and junctional escape.  He
             was treated with a single dose of five vials of digoxin-
             specific Fab antibody fragment (Digibind).  The pre-treatment
             apparent digoxin level was 1.5 mcg/L.  After treatment the
             patient improved, with a sinus bradycardia (56 bpm), and
             recovered uneventfully (Shumaik et al., 1988).

    12. ADDITIONAL INFORMATION

        12.1 Specific preventative measures

             Prevent small children from playing with the plant and
             ingesting parts of it.

        12.2 Other

             No data available.

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        experimentally induced oleander poisoning.  Arch Int Pharmacodyn
        Ther, 189: 12-21.
    
        Tittel G and Wagner H (1981)  Qualitative und quantatitve Analyse
        von Herzglykosiddrogen durch HPLC-Verfahren.  Planta Med,
        43: 252-262.
    
        Wagner H and Bladt S (1995)  Plant drug analysis, 2nd ed.  Berlin,
        Springer.

    14. AUTHOR(S), DATES(S) REVIEWER(S), (INCLUDING UPDATES), COMPLETE
        ADDRESS(ES):

        Author: Dr A. Laborde
        CIAT 7 piso
        Hospital de Clinicas
        Av. Italia s/n
        Montevideo
        Uruguay
    
        Tel: 598-2-804000
        Fax: 598-2-470300
    
        Date: November 1989
    
        Peer review:  Singapore, November 1989
    
        Peer review of Section 8:  Algiers, Algeria, November 1992
    
        General edit and botanical review:
    
        Christine Leon
        Medical Toxicology Unit
        Guy's & St Thomas Hospital Trust
        c/o Royal Botanic Gardens, Kew
        Richmond
        Surrey
        TW9 3AB
        United Kingdom
    
        Tel: +44 (0) 181 332 5702
        Fax: +44 (0) 181 332 5768
        e-mail: c.leon@rbgkew.org.uk
    
        Date: July 1997
    


    See Also:
       Toxicological Abbreviations