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:
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