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    WORLD HEALTH ORGANIZATION           FOOD AND AGRICULTURE ORGANIZATION
    ORGANISATION MONDIALE DE LA SANTE   ORGANISATION POUR L'ALIMENTATION 
                                        ET L'AGRICULTURE

                                        WHO/VBC/DS/88.63
                                        ORIGINAL: ENGLISH

                                        Distr.: Limited



   DATA SHEET ON PESTICIDES No. 63

   NICLOSAMIDE



         It must be noted that the issue of a Data Sheet for a
    particular pesticide does not imply endorsement of the pesticide by
    WHO or FAO for any particular use, or exclude its use for other
    purposes not stated. While the information provided is believed to
    be accurate according to data available at the time when the sheet
    was compiled, neither WHO nor FAO are responsible for any errors or
    omissions, or any consequences therefrom.

    The issue of this document does    Ce document ne constitue pas une
    not constitute formal              publication. Il ne doit faire
    publication. It should not be      l'objet d'aucun compte rendu ou
    reviewed, abstracted or quoted     résumé ni d'aucune citation sans
    without the agreement of the       l'autorisation de l'Organisation
    Food and Agriculture               des Nations Unies pour
    Organization of the United         l'Alimentation et l'Agriculture
    Nations or of the World Health     ou de l'Organisation Mondiale de
    Organization.                      la Santé.


    CLASSIFICATION:

    Primary use: Molluscicide

    Secondary use: Anthelmintic, lampricide

    Chemical group: Chloronitrophenol derivative

    Date issued: March 1988

    1.0  GENERAL INFORMATION

    1.1  COMMON NAME: niclosamide (BSI, ISO and BPC - exception Germany,
         niclosamid and clonitralid).

    1.1.1 Identity: The active ingredient may be niclosamide (I), or its 
          ethanolamine salt (II), or piperazine salt (III), or niclosamide 
          monohydrate (IV). 


          IUPAC:  (I)    2'5-dichloro-4'-nitrosalicylanilide

                  (II)   5-chloro-salicyl-(2-chloro-4-nitro) anilide 
                         2-aminoethanol salt

                  (III)  5-chloro-salicyl-(2-chloro-4-nitro) anilide 
                         piperazine salt

                  (IV)   5-chloro-salicyl-(2-chloro-4-nitro) anilide 
                         monohydrate

          CAS:    (I)    5-chloro-N-(2-chloro-4-nitrophenyl)-
                           2-hydroxybenzamide

                  (II)   5-chloro-N-(2-chloro-4-nitrophenyl)-
                         2-hydroxybenzamide with 2-aminoethanol (1:1)

                  (III)  5-chloro-N-(2-chloro-4-nitrophenyl)-
                         2-hydroxybenzamide with piperazine (2:1)

                  (IV)   5-chloro-N-(2-chloro-4-nitrophenyl)-
                         2-hydroxybenzamide with monohydrate (1:1)


          CAS Reg. No.:  (I)   50-65-7

                           (II)  1420-04-8

                           (III) 34892-17-6

                           (IV)  7336-56-2

          Molecular
          formula:         (I)   C13H8Cl2N2O4

                           (II)  C15H15Cl2N3O5
        
                           (III) C30H26Cl4N6O8

                           (IV)  C13H8Cl2N2O4  H2O


          Relative molecular
          mass:
                           (I)   327.1

                           (II)  388.2

                           (III) 740.4

                           (IV)  345.1


          Structural formula:

                       Structural formula (I)
                       Structural formula (II)
                       Structural formula (III)

                       Structural formula (IV)



    1.1.2 Synonyms: Bayer 73R;  Bayer 2353R;  Bayer 25 648R;  BayluscidR;  
          BayluscideR; CestocidR;  Clonitralid;  DichlosaleR;  FenasalR;  
          HL 2447R; IomesanR,  IomezanR; LintexR;  ManosilR;  NasemoR;  
          NiclosamidR; Niclosamide,  PhenasalR;  TredemineR; SulquiR;  
          VermitidR;  VermitinR; YomesanR. 


    1.2  SYNOPSIS: Niclosamide is a relatively selective, non-cumulative 
         chlorinated aromatic amide pesticide; principally used against 
         aquatic snails but also as an antiparasitic drug in human and 
         veterinary medicine.  It is of very low toxicity to mammals (WHO 
         Hazard Class III, table 5), can be toxic to aquatic vertebrates 
         (e.g. fish and amphibians) and crustaceans.  Niclosamide is non-
         persistent in the aquatic environment, has a slight effect on 
         aquatic plants and zooplankton but is not generally phytotoxic 
         at field concentrations.

    1.3  SELECTED PROPERTIES

    1.3.1 Physical characteristics: Niclosamide is a yellowish grey 
          odourless crystalline solid which melts between 224-229 °C. The 
          piperazine salt melts above 240 °C with decomposition.  The 
          ethanolamine salt form is a yellow solid melting at minimum 
          191 °C. 

    1.3.2 Solubility: Niclosamide is not very water soluble, 5-8 mg/L at 
          20 °C, sparingly soluble in ether, ethanol and chloroform, and 
          soluble in acetone; the ethanolamine salt dissolves in distilled 
          water 180-280 mg/L at 20 °C. 

    1.3.3 Stability: In tablets niclosamide undergoes a biodegradation in 
          moist environments but niclosamide itself is stable in an aqueous 
          solution for several months.  The ethanolamine salt is stable to 
          heat, hydrolysed by concentrated acid or alkali, and stable in 
          aquatic environments.

    1.3.4 Vapour pressure: <1 mPa at 20 °C


    1.4  AGRICULTURE, HORTICULTURE AND FORESTRY


    1.4.1 Common formulations: These include an emulsifiable concentrate at 
          250 g a.i./L, a wettable powder at 700 g a.i. (of ethanolamine 
          salt)/kg, and tablets of various dosages up to 1 105 mg of a.i. 
          These tablets are available only on a restricted basis in many 
          countries. 

    1.4.2 Pests controlled: Niclosamide is used effectively against 
          molluscs (especially fresh water snails), and cestode and 
          trematode infestations of humans, livestock, and pets.

    1.4.3 Unintended effects: Niclosamide is toxic to all fish species at 
          0.5 mg/L (48 hours), and to zooplankton and aquatic vegetation at 
          high concentrations. 


    1.5  PUBLIC HEALTH

    1.5.1 Common formulations: As in 1.4.1 above.

    1.5.2 Pests controlled: Niclosamide is used effectively against fresh 
          water snails that are intermediate hosts for schistosomiasis and 
          fascioliasis.  It has also been used in the control of cestodes 
          infecting man. 

    1.5.3 Use pattern - For environmental applications against snails 0.6-
          1.0 mg/L is effective.  In humans over the age of eight, two oral 
          doses of 1 g each, one hour apart for five successive days are 
          usually effective against dwarf tapeworm in individuals six years 
          old and over, and 500 mg for younger children.  In veterinary 
          medicine single doses ranging from 83-500 mg/kg are recommended. 

    1.5.4 Unintended effects: Occasional gastrointestinal upset is the only 
          side effect reported. 

    2.0  TOXICOLOGY AND RISKS

    2.1  TOXICOLOGY - MAMMALS

    2.1.1 Absorption:  Niclosamide is slowly absorbed from the 
          gastrointestinal tract, and through the skin or mucous  
          membranes. 

    2.1.2 Mode of action: In in vitro studies, niclosamide inhibited rat 
          liver mitochondrial synthesis of ATP. 

    2.1.3 Excretion products:  When oral doses of niclosamide ethanolamine 
          salt were given to male rats, one third of the applied dose was 
          absorbed from the gastrointestinal tract.  Excretion of this 
          portion occurred within 24 hours via urine (T 1/2 was six hours).  
          The remaining two thirds of the administered dose was excreted in 
          the faeces.  The major excretion product was 2,5'-dichloro-4'-
          amino-salicylanilide. In vitro studies showed that mouse and 
          sheep liver enzyme systems could reduce but not hydroxylate 
          niclosamide.  Studies done on pregnant rats have shown that foe-
          tuses are unable to metabolize niclosamide until more than 13 
          days old. 

    2.1.4 Toxicity, single dose

          Oral LD50:

                Niclosamide:

                      Rat  (M,F)    5 000  mg/kg  b.w.
                      Mouse  (F)   >1 500  mg/kg  b.w.
                      Rabbit        5 000  mg/kg  b.w.
                      Cat          >1 000  mg/kg  b.w.

                Ethanolamine salt:

                      Rat  (M,F)   10 000  mg/kg  b.w.
                      Rat (M)       5 000  mg/kg  b.w.
                      Rabbit (M,F)  4 000  mg/kg  b.w.
                      Cat     (M,F)   500  mg/kg  b.w.

                Piperazine salt:

                      Rat           5 000  mg/kg  b.w.
                      Mouse  (M)    1 000  mg/kg  b.w.
                      Cat           1 000  mg/kg  b.w.
                      Dog           1 000  mg/kg  b.w.


                Niclosamide monohydrate:

                      Rat (M)       5 000  mg/kg  b.w.
                      Mouse (M,F)  10 000  mg/kg  b.w.


                Dermal LD5O:

                      Rat (F)       2 000 mg/kg  b.w. (700 g/kg w.p.)


                Intraperitoneal LD50:

                      Rat (M)     44-250 mg/kg  b.w. (ethanolamine salt)

                Intravenous LD50:

                      Rat (M)          7 mg/kg  b.w. (ethanolamine salt)


          In studies on dogs and cats given niclosamide intraperitoneally 
          or intravenously, animals were seen to vomit as a result of 
          niclosamide poisoning. 


                Inhalation LD50:

                      Rat (M,F)      2 270 mg/m3/1 hr (ethanolamine salt)
                      Rat (M,F)     >2 260 mg/m3/4 hr (700 g/kg w.p.)

          Symptoms of poisoning were non-specific, and consisted of 
          behavioural disturbances, hypopnea and convulsions. 

          Ocular irritation: Testing in rabbits revealed that the 
          ethanolamine salt, 700 g/kg w.p. and 250 g/kg emulsion 
          concentrate had strong irritative effects upon the mucous 
          membranes of the eye.  They were also found to be corrosive 
          to the cornea. 

    2.1.5 Toxicity, repeated doses

          Oral: A marginal decrease in haemoglobin concentration and 
          erythrocyte count occurred when male and female rats were given 
          niclosamide at 5 000 mg/kg/day for four weeks.  The no-effect 
          level was 2 000 mg/kg/day.  No effects were seen on cats in two 
          studies for up to four weeks with dose levels of niclosamide up 
          to 900 mg/kg/day. 

          Male and female dogs treated with niclosamide showed no toxic 
          effects at doses up to 4 500 and 6 000 mg/day for four weeks. 

          Dermal: No evidence of toxicity was seen in rats treated with 
          niclosamide at 200 mg/kg/day for three weeks. 

    2.1.6 Dietary Studies

          Short term: No effects were seen in rats fed on a diet containing 
          5 or 15 ppm niclosamide ethanolamine salt for 90 days.  Reduction 
          in weight was seen in male rats fed on a diet containing 10 000 
          or 25 000 ppm of niclosamide for 326 or 319 days.  No effects 
          were seen in female rats similarly dosed.  RaLs fed on a diet 
          containing 2 000-20 000 ppm of niclosamide for 14 weeks showed no 
          effects at any dose level.  Male rats given niclosamide 1 000 or 
          2 500 mg/kg/day for 55 or 64 days, followed by feeding on a diet 
          containing 10 000 or 25 000 ppm niclosamide for the remainder 
          of 365-381 days, had reduced body weights in the high dose
          group.  No other damage was observed at either dose. 

          No effects were seen in dogs fed niclosamide or niclosamide 
          ethanolamine salt 100 mg/kg/day for one year. 

          Long term:  No published information available.

    2.1.7 Supplementary studies of toxicity

          Carcinogenicity: Male and female rats and female mice developed 
          no carcinomas when administered the niclosamide ethanolamine salt 
          in feed at dose levels of 14 216-28 433 ppm and 274-549 ppm 
          respectively.  Poor survival of male mice did not permit 
          evaluation of carcinogenic potential of niclosamide in these 
          animals. 

          Teratogenicity:  No embryotoxic or teratogenic effects were seen 
          after doses of 1 000 mg/kg/day on gestation days 7-10, 10-12, or 
          13-16.  Likewise, no teratogenic or embryotoxic effects were seen 
          in rats treated orally with a dose of 1 000 mg/kg/day on days
          4-6, 7-9, or 10-12. 

          Mutagenicity: No indication of mutagenic potential was seen in 
          the progeny of mice subjected to a dominant lethal test with 
          niclosamide ethanolamine salt.  Likewise no mutagenic potential 
          was seen in an Ames test without metabolic activation while 
          slight mutagenic effects were seen with metabolic activation in 
          Salmonella typhimurium.  Both of the above studies used the 
          ethanolamine salt. 

          Other Studies: Studies on goats, one heifer and sheep showed no 
          toxic effects of orally applied niclosamide except some temporary 
          diarrhoea in goats.  An increased rate of absorption and somewhat 
          decreased rate of excretion was found to occur in the ruminants 
          as compared with laboratory animals, but this had no effect on 
          the toxicity of niclosamide. 

    2.1.8 Modifications of toxicity:  No information available.

    2.2  TOXICOLOGY - MAN

    2.2.1 Absorption route: Niclosamide is absorbed from the 
          gastrointestinal tract, through the skin or by inhalation of fine 
          dust or mist. 

    2.2.2 Dangerous doses: No information available.

    2.2.3 Observations on occupationally exposed workers: Skin reactions 
          have occasionally been reported in field workers applying the 250 
          g/L emulsion concentrate.  Skin reactions were not thought to be 
          caused by niclosamide itself but by other formulation 
          ingredients. 

    2.2.4 Observations on exposure of the general population: No 
          information available. 

    2.2.5 Observations on volunteers: Nausea and abdominal pain occurred in 
          about 10% of patients following oral dosage. Single oral doses of 
          2 000 mg niclosamide (radiolabelled) given to male and female 
          volunteers showed that 2-25% of the compound was excreted in 
          urine over four days, with the rest being eliminated with the 
          faeces.  Maximum serum concentrations ranged from 0.25-0.60 µg/ml 
          and metabolites were excreted in the form of glucuronide 
          conjugates.  These included niclosamide, 2',5-dichloro-4'-
          aminosalicylanilide, and 2',5-dichloro-4'
          -acetaminosalicylanilide.  No signs of intoxication were noted in
          adult males or females treated once or twice with niclosamide at 
          1 000 mg/person, or in children treated with 750-1 000 mg/person. 
          Dermal applications had no sensitizing effects on individuals
          suffering from a photoallergy to tribromosalicylanilide.  No 
          methemoglobin formation was observed in males treated orally with
          30 mg niclosamide/kg b.w. 


    2.2.6 Reported mishaps:  No information available.

    2.3  TOXICITY TO NON MAMMALIAN SPECIES

    2.3.1 Fish: Niclosamide is toxic to fish and zooplankton, LC50 being 
          0.05 mg/L (during 24-48 hours); carbaryl potentiates its toxicity 
          in rainbow trout. 

    2.3.2 Birds: Ducklings treated orally with 100 mg niclosamide/bird 
          showed no toxic effects. 

          Oral LD50 (technical material):

               Red-winged blackbird    >60 mg/kg b.w. (in the feed for 18
                                       days)

               Mallard                 >2000 mg/kg b.w. (single dose)

               Ringbilled duck         500 mg/kg b.w. (single dose)

    2.3.3 Others: Niclosamide is toxic to crayfish, frogs, clams, and 
          other aquatic organisms.  It is not harmful to bees if applied as 
          recommended. 


    3.0   FOR REGULATORY AUTHORITIES - RECOMMENDATIONS ON REGULATION OF 
          COMPOUND

    3.1  RECOMMENDED RESTRICTIONS ON AVAILABILITY (For definition of 
         categories see Introduction to Data Sheets) 

         All available formulations, category 5

    3.2  TRANSPORT AND STORAGE

         Formulations in Category 5: Should be transported and stored in 
         clearly labelled, leakproof containers out of reach of children, 
         away from food and drink. 

    3.3  HANDLING

         Formulations in Category 5: No facilities other than those needed 
         for the handling of any other chemical are required. 

    3.4  DISPOSAL AND/OR DECONTAMINATION OF CONTAINERS

         Formulations in Category 5: Containers may be decontaminated but 
         should never be used for food or water (for method see paragraph 
         4.3). If to be disposed of, containers should be burned or crushed 
         and buried below topsoil, away from water sources. 

    3.5  SELECTION, TRAINING AND MEDICAL SUPERVISION OF WORKERS

         Formulations in Category 5: No pre-employment or periodic medical 
         examinations are required.  Special account should be taken of the 
         workers' ability to comprehend and follow instructions.  Training 
         of workers in techniques to avoid contact is essential. 

    3.6  ADDITIONAL REGULATIONS RECOMMENDED IF DISTRIBUTED BY AIRCRAFT

         All formulations: For non-aquatic field applications, pilots and 
         loaders should have special training in application methods.  
         Flagmen should wear overalls and a broad brimmed hat, they should 
         be well away from the dropping zone. 

    3.7  LABELLING

         Formulations in Category 5 - Minimum cautionary statement:

                                CAUTION - POISON

         This product contains niclosamide, a molluscicide and anthelmintic 
         of low toxicity to mammals but no significant hazard to human 
         health.  Very small amounts are absorbed by ingestion.  As a drug 
         it should be taken only on the advice of a physician.  Avoid 
         excessive skin contact.  Wash with soap and water after handling.  
         Store in a tightly closed container out of reach of children and 
         well away from food, animal feed and food utensils.  If a large 
         quantity is ingested call a physician.  There is no specific 
         antidote, if illness follows exposure, treatment must be 
         symptomatic. 


    3.8  RESIDUES IN FOOD: Niclosamide has never been evaluated by the 
         FAO/WHO Joint Meeting on Pesticide Residues in Food and no maximum 
         residue limits in food have been determined. 

    4.0  PREVENTION OF POISONING IN MAN AND EMERGENCY AID


    4.1  PRECAUTIONS IN USE


    4.1.1 General: Niclosamide is a molluscicide and anthelmintic of low 
          toxicity to mammals.  It can be absorbed from the 
          gastrointestinal tract to a very limited extent only.  It is a 
          metabolic poison of no known health hazard to man; 
          therapeutically it is useful against cestoda in humans. 

    4.1.2 Manufacture and formulations: For T.L.V. no information 
          available. 

          Closed systems and forced ventilation may be required to reduce, 
          as much as possible, the exposure of workers to the chemical, 
          because of its initiative properties. 

    4.1.3 Mixers and applicators: When opening a container and when mixing, 
          protective impermeable boots, clean overalls, and impermeable 
          gloves should be worn.  Mixing, if not mechanical, should always 
          be carried out with a paddle of appropriate length.  Avoid 
          contact with mouth, eyes and skin.  Before eating, drinking or 
          smoking, hands and other exposed skin should be thoroughly 
          washed. 

    4.1.4 Other associated workers (including flagmen in aerial operations):

          Persons exposed to niclosamide and associated with its 
          application should observe the precautions described above in 
          4.1.3. 

    4.1.5 Other populations likely to be affected: Other populations are 
          not likely to be exposed to hazardous amounts of niclosamide. 

    4.2  ENTRY OF PERSONS INTO TREATED AREAS: No restriction necessary.

    4.3  SAFE DISPOSAL OF CONTAINERS AND SPILLAGE: Residues in containers 
         should be emptied in a diluted form into a deep pit taking care to 
         avoid contamination of ground waters. The empty container may be 
         decontaminated by rinsing two or three times with water and 
         detergent and scrubbing the sides.  The hands should be protected 
         during this work. Decontaminated containers should not be used for 
         food or drinking water. 

    4.4  EMERGENCY AID

    4.4.1 Early symptoms of poisoning: Niclosamide has apparently not 
          caused human poisoning and has been used in man for therapeutic 
          reasons.  Nausea, abdominal pains and vomiting are infrequent 
          side effects in anthelmintic therapy. 

    4.4.2 Treatment before person is seen by a physician, if symptoms 
          appear following exposure: The person should stop work 
          immediately, remove any contaminated clothing and clean affected 
          skin area.  If a large quantity of material was swallowed and 
          signs of toxicity are apparent, induce vomiting if person is 
          conscious avoiding aspiration of vomit. 

    5.0   FOR MEDICAL AND LABORATORY PERSONNEL

    5.1  MEDICAL DIAGNOSIS AND TREATMENTS OF POISONING

    5.1.1 General information: Niclosamide is a molluscicide and 
          anthelmintic with no known toxic effect in man.  It may be 
          absorbed by ingestion to a limited extent, and is frequently 
          prescribed for cestode infection in humans. (See Review: Andrews, 
          P., Thyssen, J. and Lorke, D., (1983) Pharmac. Ther., 19, 245-
          295.) 

    5.1.2 Signs and symptoms - No information is available on the acute 
          toxic effects; nausea, abdominal cramps and vomiting are 
          infrequent side effects in anthelmintic therapy. 

    5.1.3 Laboratory: Methods for determining primary metabolite levels or 
          the native compound in body fluids or urine have been developed 
          (see references). 

    5.1.4 Treatment: Follow treatment for general poisoning.  In case of 
          eye exposure decontaminate with copious amounts of water. 

    5.1.5 Prognosis: Unknown.

    5.1.6 References to previously reported cases: There have been no 
          previously reported cases. 

    5.2  SURVEILLANCE TESTS - None.

    5.3  LABORATORY METHODS

    5.3.1 Detection and assay of compound and residues: In water and 
          sediment samples GC or HPLC methods can be used: 

          Muir, D. C. G. and Grift N. P., (1980), Int. J. Environ. Anal.  
          Chem., 8, 1-14. 

    5.3.2 Methods for determining the native compound in body fluids or 
          urine 

          Hudson, R. H., (1979) U.S. Fish.  Wildl.  Serv., Invest. Fish 
          Control, 87-89, 5. 

          Luhning, C. W., Harmann, P. D., Sills, J. B., Dawson, V. K, and 
          Allen J., (1979) J. Ass. Off. Analyt. Chem., 62, 1141-1145 

          Dawson, V. K., (1982) Can. J. Fish. Aguat. Sci., 39, 778-782

    5.3.3 Other tests in case of poisoning: None