Tropane Alkaloids en,0

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The EFSA Journal (2008) 691, 1-55

Tropane alkaloids (from Datura sp.) as undesirable substances in animal feed1 Scientific Opinion of the Panel on Contaminants in the Food Chain

Question N EFSA-Q-2003-063

Adopted on 9 April 2008

PANEL MEMBERSJan Alexander, Diane Benford, Andrew Cockburn, Jean-Pierre Cravedi, Eugenia Dogliotti, Alessandro Di Domenico, Maria Luisa Frnandez-Cruz, Peter Frst, Johanna Fink-Gremmels, Corrado Lodovico Galli, Philippe Grandjean, Jadwiga Gzyl, Gerhard Heinemeyer, Niklas Johansson, Antonio Mutti, Josef Schlatter, Rolaf van Leeuwen, Carlos Van Peteghem and Philippe Verger.

SUMMARYThe term tropane alkaloids refers to a group of more than 200 compounds best known for their occurrence in the family Solanaceae comprising over 100 genera and 3000 plant species. They have in common a two-ringed structure characterized by a pyrrolidine and a piperidine ring sharing a single nitrogen atom and two carbons atoms. The nitrogen atom at the end of the molecule, which characterizes the compounds as alkaloids, is in this group characteristically methylated. The most important natural tropane alkaloids are (-)-hyoscyamine and (-)-scopolamine (also known as hyoscine). High concentrations of these alkaloids have been found particularly in Datura stramonium and Datura ferox, as well as in Datura innoxia. The pattern of tropane alkaloids differs significantly and in Datura stramonium (also known as thorn apple or Jimson weed) hyoscyamine prevails in most parts of the plant, whereas in Datura ferox scopolamine is the major alkaloid

For citation purposes: Scientific Opinion of the Panel on Contaminants in the Food Chain on a request from the European Commission on Tropane alkaloids (from Datura sp.) as undesirable substances in animal feed. The EFSA Journal (2008) 691, 1-55. European Food Safety Authority, 2008

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Tropane alkaloids as undesirable substances in animal feed

produced. Datura plants are toxic for animals if ingested in larger amounts. Their seeds, which contain significant amounts of hyoscyamine and scopolamine, can be found as botanical impurities in feed materials, particularly in soybean and linseed products. Very little information on the actual contamination of feed materials is available, and previous reports on adverse health effects in animals refer in most cases to accidental intoxications following the consumption of Datura plants rather than to the contamination of linseed and sobean contaning feed materials. Hence no conclusive exposure assessment could be presented for farm animals. Overall, pigs have been shown to be among the most sensitive species to Datura poisoning. A worst case exposure estimate indicated that adverse pharmacological effects in pigs following exposure to Datura ferox seeds, mainly containing scopolamine, can not be entirely excluded at the current statutory limits of 3000 mg/kg feed. However, the limited data also suggested that it is not likely that the presence of Datura stramonium impurities in animals feed up to the current statutory level of 1000 mg/kg would present a risk to animal health. The mechanism of action of tropane alkaloids relates to their competitive antagonism at muscarinic acetylcholine receptors, preventing the binding of acetylcholine. According to the specificity and selectivity of muscarinergic acetylcholine receptors in different organs, the functions of smooth muscles and exocrine gland cells, as well as the heart rate, respiration and functions in the central nervous system are modulated. Certain tropanes such as atropine (the racemic mixture of (-)- and (+)hyoscyamine) as well as scopolamine (mainly as butylscopolamine bromide) are used in human and veterinary therapy for a variety of related indications. Reports of poisoning of livestock and experimental feeding studies describe as most common symptoms associated with tropane alkaloids exposure dryness of the mucosa in the upper digestive and respiratory tract, constipation and colic (in horses), pupil dilation (mydriasis), alterations in the heart rate and central nervous effects such as restlessness, irritability, ataxia, seizures and respiratory depression. Tropane alkaloids are readily absorbed following oral ingestion, but have a short biological half-life and are rapidly biotransformed or excreted. Moreover, typical pharmacological signs precede a toxic syndrome, and hence exposed animals would not be slaughtered. Therefore, the CONTAM Panel concluded that it is unlikely that residues of tropane alkaloids in edible tissues, milk and eggs constitute a risk for consumers.

Keywords: tropane alkaloids, Datura stramonium, Datura ferox and Datura innoxi, Solanaceae family, (-)-hyoscyamine, (-)-scopolamine, atropine, toxicity, exposure, carry-over, animal health, human health.

The EFSA Journal (2008) 691, 2-55

Tropane alkaloids as undesirable substances in animal feed

TABLE OF CONTENTSBACKGROUND AS PROVIDED BY THE EUROPEAN COMMISSION ............................................................. 4 1. General background ...................................................................................................................... 4 2. Specific background...................................................................................................................... 5 TERMS OF REFERENCE AS PROVIDED BY THE EUROPEAN COMMISSION ................................................. 5 ACKNOWLEDGEMENT ........................................................................................................................... 6 ASSESSMENT ......................................................................................................................................... 7 1. Introduction ................................................................................................................................... 7 2. Methods of analysis..................................................................................................................... 10 3. Current legislation ....................................................................................................................... 11 4. Occurrence in feed materials....................................................................................................... 12 4.1. Biosynthetic pathways and distribution of alkaloids in plants ............................................ 12 4.2. Alkaloid content in various tissues of Datura spp............................................................... 12 4.3. Tropane alkaloids in feed materials .................................................................................... 16 5. Estimating the intake by farm livestock...................................................................................... 17 6. Adverse effects of tropane alkaloids ........................................................................................... 18 6.1. Mechanism of action ........................................................................................................... 18 6.2. Toxicity studies in rodents .................................................................................................. 19 6.3. Adverse effects in livestock ................................................................................................ 20 6.3.1 Adverse effects in pigs ............................................................................................. 21 6.3.2 Adverse effects in poultry......................................................................................... 23 6.3.3. Adverse effects in ruminants .................................................................................... 25 6.3.4. Adverse effects small ruminants............................................................................... 26 6.3.5. Adverse effects in horses.......................................................................................... 27 6.3.6. Adverse effects in other animal species ................................................................... 28 7. Toxicokinetics, metabolism and tissue distribution .................................................................... 29 7.1. Absorption ........................................................................................................................... 29 7.2. Metabolism and excretion ................................................................................................... 29 7.3. Residue formation ............................................................................................................... 30 7.4. Kinetic studies in rodents .................................................................................................... 30 8. Carry-over and residues .............................................................................................................. 31 9. Human intoxications ................................................................................................................... 32 10. Human dietary exposure.............................................................................................................. 33 CONCLUSIONS ..................................................................................................................................... 33 RECOMMENDATIONS ........................................................................................................................... 34 REFERENCES ....................................................................................................................................... 35 ANNEX I. CHEMICAL AND PHYSICAL PROPERTIES OF ()-ATROPINE, (-)-HYOSCYAMINE AND (-)SCOPOLAMINE ..................................................................................................................................... 43 ANNEX II. THE VARIOUS DATURA SPECIES AND THEIR VARIETIES......

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