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Ilex aquifolium L.

1. NAME
   1.1 Scientific name
   1.2 Family
   1.3 Common name(s)
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
   4.2 High risk circumstances
   4.3 High risk geographical areas
5. ROUTES OF ENTRY
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Others
6. KINETICS
   6.1 Absorption by route of exposure
   6.2 Distribution by route of exposure
   6.3 Biological half-life by route of exposure
   6.4 Metabolism
   6.5 Elimination by route of exposure
7. TOXICOLOGY/TOXINOLOGY/PHARMACOLOGY
   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 Animal data
      7.2.3 Relevant vitro data
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
8. TOXICOLOGICAL/TOXINOLOGICAL ANALYSIS
9. CLINICAL EFFECTS
   9.1 Acute poisoning by:
      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 by:
      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 CNS
         9.4.3.2 Peripheral nervous system
         9.4.3.3 Autonomic nervous system
         9.4.3.4 Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary
         9.4.6.1 Renal
         9.4.6.2 Others
      9.4.7 Endocrine and reproductive system
      9.4.8 Dermatological
      9.4.9 Eyes, 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: pregnancy, breast feeding, enzyme
   9.5 Others
10. MANAGEMENT
   10.1 General principles
   10.2 Relevant laboratory analyses and other investigations
      10.2.1 Sample collection
      10.2.2 Biomedical analysis
      10.2.3 Toxicological/Toxinological analysis
      10.2.4 Other investigations
   10.3 Life supportive procedures and symptomatic treatment
   10.4 Decontamination
   10.5 Elimination
   10.6 Antidote treatment
      10.6.1 Adults
      10.6.2 Children
   10.7 Management discussion: alternatives and controversies, research
11. ILLUSTRATIVE CASES
   11.1 Case reports from literature
   11.2 Internally extracted data on cases
   11.3 Internal cases (added by the PC using monograph).
12. ADDITIONAL INFORMATION
   12.1 Availability of antidotes and antisera
   12.2 Specific preventive measures
   12.3 Other
13. REFERENCES
   13.1 Clinical and toxicological
   13.2 Botanical
14. AUTHOR(S), REVIEWER(S), DATES, COMPLETE ADDRESSES



    1.    NAME

      1.1   Scientific name

            Ilex aquifolium

      1.2   Family

            Aquifoliaceae

      1.3   Common name(s)

            UK: European Holly, English Holly, Oregon Holly, Sparked Holly, 
            Christmas Holly, Crocodile Holly, Prick Holly, Holly,
            Common Holly, Holly Green.

            France: Houx, Houx Epineux, Housson, Grand Pardon, Bois Franc, 
            Greou, Agrifous, Agriou, Grifeuil, Agabousse, Alquiroux. 

            Spain: Acebo Comun.

            Germany: Stechpalme, Hulst, Hülse.

            Italy: Aquifolio Comune, Alloro Spinoso, Leccio Spinoso.

    2.    SUMMARY

      2.1   Main risks and target organs

            Poisoning by ilex aquifolium is due to the ingestion of 
            berries, which may induce gastrointestinal symptoms. 
 
      2.2   Summary of clinical effects

            Ingestion of berries may cause nausea, vomiting, abdominal pain 
            and diarrhoea. Stupor and drowsiness have been seen in children 
            after ingestion of large quantities of berries. Although lethal 
            cases have been reported in older literature there are no 
            recent reports of severe poisonings. Ingestion of Ilex 
            aquifolium berries is mostly associated with gastrointestinal 
            symptoms. 

            Mechanical damage to the eye may occur due to the thorny 
            leaves. 

      2.3   Diagnosis

            There are no specific laboratory analyses. Identification of 
            the plant and berries is easy. 

      2.4   First-aid measures and management principles

            Emesis or gastric lavage may be indicated in recent ingestion 
            of more than 5-10 berries in a child. 
            Hospitalization is indicated if large amounts have been 

            ingested. 

            Symptomatic treatment of gastrointestinal symptoms.



      2.5   Poisonous parts

            All parts of the plant contain active principles (Aliharidis, 
            1987). 

      2.6   Main toxins

            Ilex aquifolium contains several toxins:  saponin, phenolic 
            compounds, terpenoides, sterols, alkaloids, anthocyanines 
            (Thomas, 1980, Alikaridis 1987). 

    3.    CHARACTERISTICS

      3.1   Description of the plant

            3.1.1 Special identification features

                  Ilex aquifolium is an evergreen tree 1-20 metres high.

                  Leaves: dark green, shining, hard, thorny on the young 
                  branches. 

                  Flowers: small, white, rosy, fragrant; situated at the 
                  base of the leaves (from April to July). 

                  Fruits: globulose, red berries of 8 mm diameter. Each 
                  berry contains 4 seeds (from August to October-December). 

            3.1.2 Habitat

                  Ilex aquifolium grows in forests, parks, gardens and in 
                  plains and mountain areas. 

            3.1.3 Distribution

                  Native plant of Europe. It is also cultivated as an 
                  ornamental tree in North America and North Africa. 

      3.2   Poisonous parts of the plant

            Leaves, bark, berries contain active principles; no information 
            available on roots.  

      3.3   The toxin(s)

            3.3.1 Name(s)

                  Several active principles have been identified:

                  Phenolic derivatives: vanillic acid, p-hydroxybenzoic 

                  acid (fruit); 

                  Anthocyanines: cyanidin-3-xylosylglucoside (fruit);
                  pelargonidin-3-glucoside (fruit);

                  Flavonoids: quercetin-3-rutinoside (leaves)


                  Terpenoids: alpha-amyrin (bark, leaves, fruit); ursolic 
                  acid (leaves, fruit); oleanolic acid (leaves); ilex 
                  lactone (fruit); 

                  Sterols: ergosterol (leaves); beta-sitosterol (fruit);

                  Alkaloids: theobromine

                  Fatty acids: pentadecanoic acid (leaves); palmitic acid 
                  (leaves); stearic acid (leaves); arachidic acid (leaves); 
                  oleic acid (leaves); linolenic acid (leaves); 

                  Alkanes: (leaves, fruit)

                  Cyanogenic glucosides:

                  2 beta-D-glucopyranosyloxy-p-hydroxy-6,7-dihydromande-
                  lonitrile (fruit, leaves, bark). 

                  (Alkaridis, 1987; Budzikiewicz, 1979; Willems, 1988)

            3.3.2 Description, chemical structure, stability

                  The chemical structure of only some principles is known 
                  in detail. 

                  Ilex lactone: 3-(3'-Hydroxycyclopent-1-enyl-Z-propenic
                  acid-1,5'-lactone (Thomas & Budzikiewicz, 1980).

                  Cyanogenic glucoside: 2 beta-D-glucopyranosyloxy-p-
                  hydroxy-6,7 dihydromandelonitrile (Willems, 1988). 

                  Triterpenester:  27,p-cumaroxy ursolic acid (Budzikiewicz 
                  & Thomas, 1980). 

            3.3.3 Other physico-chemical characteristics

      3.4   Other chemical contents of the plant

    4.    USES/CIRCUMSTANCES OF POISONING

      4.1   Uses

            In folk medicine, Ilex aquifolium (infusion or decoction of 
            dried leaves) is traditionally used for intermittent fevers and 
            rheumatism; for its antipyretic properties; and for its 
            astringent, diuretic and expectorant effects (Alikaridis, 
            1987). Ilex aquifolium is also occasionally used in homeopathic 

            medicine. 
 
      4.2   High risk circumstances

            Intoxications are almost exclusively seen in children after 
            ingestion of berries from Ilex aquifolium cultivated in parks, 
            gardens, or when branches with berries are used ornamentally in 
            homes. 

      4.3   High risk geographical areas

            The plant is native to Europe but is also cultivated in North 
            America and North Africa. 

    5.    ROUTES OF ENTRY

      5.1   Oral

            The only route of poisoning.

      5.2   Inhalation

            No data available.

      5.3   Dermal

            No data available.

      5.4   Eye

            No data available.

      5.5   Parenteral

            No data available.

      5.6   Others

            No data available.

    6.    KINETICS

      6.1   Absorption by route of exposure

            No data available.


      6.2   Distribution by route of exposure

            No data available.

      6.3   Biological half-life by route of exposure

            No data available.

      6.4   Metabolism

            No data available.

      6.5   Elimination by route of exposure

            No data available.





    7.    TOXICOLOGY/TOXINOLOGY/PHARMACOLOGY

      7.1   Mode of action

            The exact mode of action is unknown.  The gastrointestinal 
            symptoms may be due to the saponin. (West et al. 1977).  
            However, no specific toxin responsible for the symptoms has 
            been identified. 

      7.2   Toxicity
      
            7.2.1 Human data

                  7.2.1.1 Adults

                        No data available.

                  7.2.1.2 Children

                        3 - 5 berries may cause gastrointestinal symptoms.  
                        Although 20 to 30 berries are estimated to be a 
                        "lethal dose" no recent references or cases confirm 
                        this data. 

            7.2.2 Animal data

                  No data available.

            7.2.3 Relevant 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

            No data available.

    8.    TOXICOLOGICAL/TOXINOLOGICAL ANALYSIS


    9.    CLINICAL EFFECTS
             
      9.1   Acute poisoning by:
      
            9.1.1 Ingestion

                  Vomiting, diarrhoea, abdominal pain are the most common
                  symptoms after ingestion of berries.

            9.1.2 Inhalation

                  No data available.

            9.1.3 Skin exposure

                  No data available.

            9.1.4 Eye contact

                  No data available.

            9.1.5 Parenteral exposure

                  No data available.

            9.1.6 Other

                  No data available.

      9.2   Chronic poisoning by:

            9.2.1 Ingestion

                  No data available.

            9.2.2 Inhalation

                  No data available.

            9.2.3 Skin exposure

                  No data available.

            9.2.4 Eye contact

                  No data available.

            9.2.5 Parenteral exposure

                  No data available.

            9.2.6 Other

                  No data available.

      9.3   Course, prognosis, cause of death

            Gastrointestinal symptoms appear within hours after the 
            ingestion of berries and may last for 24 h.  Severe symptoms 
            may be observed after ingestion of a large number of berries. 

            Death has been reported in the older literature (Lewin, 1929), 
            but has not been confirmed by more recent reports. 

      9.4   Systematic description of clinical effects

            9.4.1 Cardiovascular

                  No cardiac disturbances reported in humans.

                  Experimental studies performed on frog and rabbit hearts,  
                  showed that extracts of fruits and seeds are similar in 
                  toxicity to digitalis (Waud, 1931-1932). 

            9.4.2 Respiratory

                  No data available.

            9.4.3 Neurological

                  9.4.3.1     CNS

                        Drowsiness and stupor have been observed in cases 
                        with severe gastrointestinal symptoms (Arena 1979; 
                        Rodriguez et al. 1984). 


                  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

                  Vomiting, diarrhoea, abdominal cramps are the common 
                  symptoms after ingestion of berries especially in 
                  children. 

            9.4.5 Hepatic

                  No data available.

            9.4.6 Urinary

                  9.4.6.1     Renal

                        No data available.

                  9.4.6.2     Others

                        No data available.

            9.4.7 Endocrine and reproductive system

                  No data available.
 
            9.4.8 Dermatological

                  No data available.

            9.4.9 Eyes, ear, nose, throat : local effects

                  No data available.

            9.4.10 Haematological

                  A haemolytic principle has been isolated from the leaves 
                  (Balansard and Flandrin, 1951).  However, no haemolysis 
                  has been reported in human poisoning. 

            9.4.11 Immunological

                  No data available.

            9.4.12 Metabolic

                  9.4.12.1    Acid base disturbances

                        No data available.

                  9.4.12.2    Fluid and electrolyte disturbances

                        May be seen in patients with severe 
                        gastrointestinal disturbances 
                        
                  9.4.12.3    Others

                        No data available.

            9.4.13 Allergic reactions

                  No data available.

            9.4.14 Other clinical effects


                  No data available.

            9.4.15 Special risks: pregnancy, breast feeding, enzyme 
            deficiencies 

                  No data available.

      9.5   Others

            No data available.

    10.   MANAGEMENT

      10.1  General principles

            Emesis or gastric lavage is indicated, especially in children 
            if more than 3 -5 berries have been ingested. Treatment is 
            supportive in the symptomatic patient. A sample of the berries 
            and leaves is useful for identification. 

      10.2  Relevant laboratory analyses and other investigations

            10.2.1 Sample collection

                  Sample of vomitus or gastric lavage fluid may be useful 
                  for identification of the berries. 

            10.2.2 Biomedical analysis

                  Control fluid balance and blood electrolytes.

            10.2.3 Toxicological/Toxinological analysis

                  Not relevant.

            10.2.4 Other investigations

                  No data available.

      10.3  Life supportive procedures and symptomatic treatment

            Treatment is symptomatic and supportive : replacement of fluid 
            and electrolyte losses in the case of vomiting and diarrhoea. 

      10.4   Decontamination

            Emesis or gastric lavage followed by activated charcoal may be 
            indicated in children. When more than 3 to 5 berries have been 
            ingested. 

      10.5  Elimination

            No data available.

      10.6  Antidote treatment


            10.6.1 Adults

                  No data available.

            10.6.2 Children

                  No data available.

      10.7  Management discussion: alternatives and controversies, research 
      needs 

            No data available.

    11.   ILLUSTRATIVE CASES

      11.1  Case reports from literature

            No data available.

      11.2  Internally extracted data on cases

            Among 46 children who had ingested berries of Ilex aquifolium, 
            only three showed symptoms: 

            10 month-old child      hypersalivation
            17 month-old child      vomiting and diarrhoea
            2 year-old child        vomiting and abdominal cramps

            Abdominal movements and mydriasis have been reported following
            ingestion by a dog.

      11.3  Internal cases (added by the PC using monograph).

    12.   ADDITIONAL INFORMATION

      12.1  Availability of antidotes and antisera

            No data available.

      12.2  Specific preventive measures

            No data available.

      12.3  Other

            No data available.      

    13.   REFERENCES

      13.1  Clinical and toxicological

      13.2  Botanical

            Alikaridis F (1987).  Natural constituents of ilex species. J 
            Ethnopharmacol 20: 121-144. 

            Arena JM (1979).  Are holly berries toxic? (letter). J Am Med 
            Assoc 242: 2341. 

            Balansard J & Flandrin P (1951).  Heterosides of the leaves of 
            the holly tree (Ilex aquifolium). Chem Abst 45: 7307. 

            Bate-Smith EC (1962).  The phenolic constituents of plants of 
            their taxonomic significance I. Dicotyledons. J Linnean Soc 
            (Botany) 58: 95-173. 

            Bohnic P (1959).  Contribution to the knowledge of the 
            chemistry of holly (Ilex aquifolium). Farm Vestn (L. Jubljana) 
            10: 57-58. 

            Bohnic P (1967).  Determination of theobromine in Ilex 
            aquifolium. Farmacevtski Vestnik 18: 9-20. 

            Budzikiewicz H, Thomas H (1980).  p-cumaroxy-ursolsaure, ein 
            neuer inhaltstoff von Ilex aquifolium. L Z Naturforsch 35b: 
            230-231. 

            Catalano S, Marsili A, Morell I, Pistelli L, Scartoni V.  
            Constituents of the leaves of Ilex aquifolium. Planta Medica 
            33: 416-417. 

            Crombie WM (1958).  Fatty acids in chloroplasts and leaves. J 
            Experim Botany 2: 254-261. 

            Chrelashivili MN, Mgaloblishvili MP (1974).  Reactions of the 
            carbohydrates in leaves of different ages in evergreen plants 
            during fall and winter. Turdy Instituta Bot Academiia Nauk 
            Gruzinskoi SSR 27: 247-259. 

            Fischer R, Linse E (1930).  Microchemical detection of abrutin 
            and ursone in plants. Arch Pharmazie 268: 185-190. 

            Fritzsch S (1983). Les baies toxiques. Thèse de Médecine N° 303
            Strasbourg, France.

            Garnier R. Ressources médicinales de la flore française.  
            Editeurs Vigot Frères. 

            Gessner O (1974).  Gift und Arzneipflanzen von Mitteleuropa. 3e 
            Edition, Heidelberg, Carl Winter, Universitätsverlag. 

            Ishikura N (1971).  Paper chromatographic analysis of 
            anthocyanins in the red epicarp of Ilex aquifolium.  Botanical 
            Magazine, Tokyo 24: 113-117. 

            Jungfleisch, Leroux (1908).  Identity of Ilicic alcohol with 
            alpha amyrin. Comptes rendus hebdomadaires des séances de 
            l'Académie des Sciences 147: 862-864. 

            Knapp R, Liskens HF (1954).  Amino acids from leaf straw of 
            plant species of forests with different soils. 
            Naturwissenschafte 41: 480-481. 

            Lechevalier (1947).  "Le livre des plantes médicinales et 
            vénéneuses de France. Encyclopédie Biologique, Paris. 

            Mitchell J, Rook A (1979).  Botanical dermatology. Greengrass, 
            Vancouver. 

            Nooyen AM (1920).  Urson and its distribution in the plant 
            world. Pharmaceutisch Weekblad 57: 1128-1142. 

            Personne MJ (1884).  Sur un nouvel alcool retiré de la glu du 
            houx. Compte rendus hebdomadaires des séances de l'académie des 
            sciences 98: 1585-1587. 

            Poisindex

            Rodriguez TD, Johnson PN, Jeffrey LP (1984).  Holly berry 
            ingestion : case report. Vet Hum Toxicol 26: 157-158. 

            Santamour FS (1973).  Anthocyanins of holly fruits. 
            Phytochemistry  12: 611-615. 

            Schindler H, Herb M (1955).  Chemistry of Ilex aquifolium. 
            Isolation of ursolic acid and rutin from the leaves. Arch 
            Pharmazie 288: 372-377. 

            Thomas H, Budzikiewicz H (1980).  Ilex lactone, ein 
            bisnormonoterpen neuartiger strukture aus Ilex aquifolium. 
            Phytochemistry 19: 1866-1868. 

            Thomas H, Budzikiewicz H (1980).  Inhaltstoffe der Fruchte von 
            Ilex aquifolium. L Z Pflanzenphysio 99: 271-276. 

            Valadon LRG, Sellens AM, Mummery RS (1975).  Carotenoids of 
            various berries. Ann Botany 39: 785-790. 

            Vermont J (1977).  Toxicologie des plantes à baies ou à fruits 
            bacciformes. Thèse Lyon. 

            Waud RA (1932).  A digitalis-like action of extracts made from 
            holly. J Pharmacol Exp Ther 45: 27. 

            Waud RA (1932).  Further studies on extracts made from holly.  
            Proc Soc Exp Biol Med 30: 393-398. 

            Willems M (1988).  Quantitative determination in Ilex 
            aquifolium. Planta Medica 55: 195. 

    14.   AUTHOR(S), REVIEWER(S), DATES, COMPLETE ADDRESSES

      Author:     Professeur A. Jaeger, Doctor  F. Flesch
                  Centre Anti-Poisons de Strasbourg
                  Hospices Civils - BP. 426
                  67091 Strasbourg
                  France

                  Tel:  33-88161144
                  Fax:  33-88161330
                  Tlx:  770 880 CHU STG

      Date:       26 April 1990

      Peer review: Strasbourg, France, April 1990