This report contains the collective views of an international group of
    experts and does not necessarily represent the decisions or the stated
    policy of the United Nations Environment Programme, the International
    Labour Organisation, or the World Health Organization.

    Published under the joint sponsorship of
    the United Nations Environment Programme,
    the International Labour Organisation,
    and the World Health Organization

    First draft prepared by Dr J. Sekizawa, Dr M. Takeda
    and Dr K. Matsumoto (National Institute of
    Hygienic Sciences, Japan) and Dr M. Eto
    (Kyushu University, Japan), with the assistance
    of Dr J. Miyamoto and Dr M. Matsuo (Sumitomo
    Chemical Company)

    World Health Orgnization
    Geneva, 1992

         The International Programme on Chemical Safety (IPCS) is a
    joint venture of the United Nations Environment Programme, the
    International Labour Organisation, and the World Health
    Organization. The main objective of the IPCS is to carry out and
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    toxicology. Other activities carried out by the IPCS include the
    development of know-how for coping with chemical accidents,
    coordination of laboratory testing and epidemiological studies, and
    promotion of research on the mechanisms of the biological action of

    WHO Library Cataloguing in Publication Data


        (Environmental health criteria ; 132)

        1.Trichlorfon - poisoning 2. Trichlorfon - toxicity 
        3.Environmental exposure      I.Series

        ISBN 92 4 157132 2        (NLM Classification: WA 240)
        ISSN 0250-863X

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    names of proprietary products are distinguished by initial capital





         1.1   Summary and evaluation
               1.1.1   Exposure
               1.1.2   Uptake, metabolism,
                       and excretion
               1.1.3   Effects on organisms
                       in the environment
               1.1.4   Effects on experimental
                       animals and  in vitro
                       test systems
                1.1.5  Effects on human beings
         1.2   Conclusions
         1.3   Recommendations


         2.1   Identity
         2.2   Physical and chemical properties
         2.3   Conversion factors
         2.4   Analytical methods


         3.1   Natural occurrence
         3.2   Industrial production
         3.3   Uses


         4.1   Transport and distribution
               4.1.1   Air
               4.1.2   Water
               4.1.3   Soil
         4.2   Abiotic degradation
         4.3   Biodegradation
         4.4   Environmental fate


         5.1   Environmental levels
               5.1.1   Air
               5.1.2   Water
               5.1.3   Soil
               5.1.4   Residues in plants
                       and animals
         5.2   Residues in food
               5.2.1   Crops
               5.2.2   Milk
               5.2.3   Meat
               5.2.4   Poultry and eggs
               5.2.5   Fish
         5.3   Occupational exposure


         6.1   Absorption and distribution
               6.1.1   Animal
               6.1.2   Human
         6.2   Biotransformation
         6.3   Elimination and excretion
         6.4   Reaction with body components
               6.4.1    In vitro studies
               6.4.2    In vivo studies


         7.1   Microorganisms
         7.2   Invertebrates
         7.3   Aquatic vertebrates
         7.4   Terrestrial vertebrates
         7.5   Ecosystems


         8.1   Acute toxicity
         8.2   Short-term exposure
         8.3   Skin and eye irritation;
               8.3.1   Skin irritation
               8.3.2   Skin sensitization
               8.3.3   Eye irritation
         8.4   Long-term exposure
               8.4.1   Oral administration

               8.4.2   Intraperitoneal administration
               8.4.3   Dermal administration
         8.5   Mutagenicity
               8.5.1   DNA methylation
               8.5.2   Mutagenicity
         8.6   Carcinogenicity
         8.7   Teratogenicity and
               reproductive toxicity
               8.7.1   Mouse
               8.7.2   Rat
               8.7.3   Hamster
               8.7.4   Rabbit
               8.7.5   Congenital tremor
         8.8   Neurotoxicity
         8.9   Immunological studies
         8.10  Toxicity of dichlorvos
         8.11  Mechanism of toxicity -
               mode of action


         9.1   Acute poisoning -
               poisoning incidents
         9.2   Therapeutic use of
         9.3   Occupational exposures
         9.4   Treatment of acute trichlorfon poisoning



    ANNEX I.    Treatment of organophosphate
                insecticide poisoning in man

    ANNEX II.   No-observed-effect levels (NOELs)
                in animals treated with





    Dr V. Benes, Department of Toxicology and Reference Laboratory,
    Institute of Hygiene and Epidemiology, Prague, Czech and Slovak 
    Federal Republic

    Dr C. Carrington, Division of Toxicological Review and Evaluation,
    Food and Drug Administration, Washington DC, USA  (Joint Rapporteur)

    Dr W. Dedek, Department of Chemical Toxicology Academic of Sciences,
    Leipzig, Germany

    Dr S. Dobson, Institute of Terrestrial Ecology, Monks Wood
    Experimental Station, Huntingdon, United Kingdom

    Dr D.J. Ecobichon, Department of Pharmacology and Therapeutics, McGill
    University, Montreal, Canada

    Dr M. Eto, Department of Agricultural Chemistry, Kyushu University,
    Fukuoka-shi, Japan  (Vice-Chairman)

    Dr Bo Holmstedt, Department of Toxicology, Swedish Medical Research
    Council, Karolinska Institute, Stockholm, Sweden

    Dr S.K. Kashyap, National Institute of Occupational Health, Ahmedabad,

    Dr J. Miyamoto, Takarazuka Research Centre, Hyogo, Japan

    Dr H. Spencer, United States Environmental Protection Agency,
    Washington DC, USA  (Chairman)

    Dr M. Takeda, National Institute of Hygienic Sciences, Tokyo, Japan


    Dr M. Matsuo, Biochemistry and Toxicology Laboratory, Sumitomo 
    Chemical Co. Ltd, Osaka-shi, Japan (representing GIFAP)


    Dr J. Sekizawa, National Institute of Hygienic Sciences, Tokyo, Japan
     (Joint Rapporteur)

    Dr K.W. Jager, IPCS, World Health Organization, Geneva, Switzerland


         Every effort has been made to present information in the criteria
    documents as accurately as possible without unduly delaying their
    publication. In the interest of all users of the Environmental Health
    Criteria documents, readers are kindly requested to communicate any
    errors that may have occurred to the Director of the International
    Programme on Chemical Safety, World Health Organization, Geneva,
    Switzerland, in order that they may be included in corrigenda, which
    will appear in subsequent volumes.

                                   *  *  *

         A detailed data profile and a legal file can be obtained from the
    International Register of Potentially Toxic Chemicals, Palais des
    Nations, 1211 Geneva 10, Switzerland (Telephone no. 7988400 - 


         A WHO Task Group on Environmental Health Criteria for Trichlorfon
    and Fenitrothion met at the World Health Organization, Geneva, from 10
    to 14 December 1990. Dr K.W. Jager, IPCS, welcomed the participants on
    behalf of Dr M. Mercier, Director of the IPCS, and the three IPCS
    cooperating organizations (UNEP/ILO/WHO). The Group reviewed and
    revised the drafts and made evaluations of the risks for human health
    and the environment from exposure to trichlorfon and fenitrothion.

         The first draft of the EHC on trichlorfon was prepared
    collaboratively by Dr M. Eto of the Kyushu University, Dr J. Miyamoto
    and Dr M. Matsuo of the Sumitomo Chemical Company, and Dr M. Takeda
    and Dr K. Matsumoto of the National Institute of Hygienic Sciences of
    Japan. The scientific editing was performed by Dr J. Sekizawa of the
    National Institute of Hygienic Sciences of Japan. Dr K.W. Jager of the
    International Programme on Chemical Safety, assisted in the
    preparation of the second draft, incorporating comments received
    following the circulation of the first drafts to the IPCS contact
    points for Environmental Health Criteria  documents.

         Dr K.W. Jager of the IPCS Central Unit was responsible for the 
    scientific content of the documents, and Mrs M.O. Head of Oxford  for
    the editing.

         The fact that Sumitomo Chemical Company Limited, Japan
    (trichlorfon and fenitrothion) and Bayer AG, Germany (trichlorfon)
    made available to the IPCS and the Task Group their proprietary 
    toxicological information on the products under discussion is 
    gratefully acknowledged. This allowed the Task Group to make its 
    evaluation on the basis of more complete data.

         The efforts of all who helped in the preparation and finalization
    of the documents are gratefully acknowledged.


         The major transformation product of trichlorfon in mammals,
    including human beings, is dichlorvos, the cholinesterase inhibiting
    activity of which is at least 100 times that of trichlorfon (Hofer,
    1981). Trichlorfon can be said to act in the mammalian body as a "slow
    release source" for dichlorvos, which may be of essential importance
    for, among others, its schistosomicidal effect (Nordgren, 1981;
    Nordgren et al., 1978).

         Only information directly related to trichlorfon will be
    discussed and evaluated in this publication.

         For an evaluation of the health and environmental hazards of 
    dichlorvos, the reader should refer to EHC No. 79: Dichlorvos (WHO,
    1989). A more complete treatise on the effects of organophosphorus
    insecticides in general, especially their short- and long-term effects
    on the nervous system, and their treatment, can be found in EHC No.
    63:   Organophosphorus insecticides - A  general introduction (WHO,

         A comprehensive review of Russian literature up to 1983, on the
    toxicity and hazards of trichlorfon, has been published by the 
    International Register of Potentially Toxic Chemicals (IRPTC/GKNT,


    1.1  Summary and evaluation

    1.1.1  Exposure

         Trichlorfon is an organophosphorus insecticide that has been in 
    use since the early 1950s. In agriculture, it is mainly used against 
    insect pests in field and fruit crops. Trichlorfon is also used to 
    control forest insects and for the control of parasites in domestic 
    animals. Under the name of metrifonate, trichlorfon is used for the 
    treatment of human infestation by  Schistosoma haematobium.  It is
    considered to be a slow release reservoir of dichlorvos. Trichlorfon 
    is available in the form of an emulsifiable concentrate, powder, dust,
    granules, a solution, and ultra-low volume concentrates.

         The air concentration of trichlorfon insecticide may be as high
    as 0.1 mg/m3, soon after spraying, but levels decrease within days
    to below 0.01 mg/m3. Levels of trichlorfon in run-off water from 
    sprayed areas may be as high as 50 µg/litre, though levels in surface 
    waters are usually much lower and decrease rapidly.

         Trichlorfon degrades rapidly in soil, and levels generally
    decrease to negligible amounts within one month of application. It is
    relatively stable in water below pH 5.5. At higher pH, trichlorfon is
    transformed to dichlorvos. While microorganisms and plants may
    metabolize trichlorfon, the most important route of removal is abiotic 

         With a few exceptions, levels of trichlorfon on crops are below
    10 mg/kg, the day after application, and fall to below 0.1 mg/kg,
    during the two weeks following.

         Milk from cows treated with trichlorfon for pest control may 
    contain residues as high as 1.2 mg/litre, 2 h after application, but
    the  levels decline to below 0.1 mg/litre, 24 h after treatment.
    Significant  levels of trichlorfon have not been found in meat from
    treated  animals. Eggs from treated hens have been found to contain
    0.05 mg  trichlorfon/kg.

    1.1.2  Uptake, metabolism, and excretion

         Trichlorfon is readily absorbed via all routes of exposure (oral,
    dermal, inhalation) and is rapidly distributed to the tissues of the 
    body. Peak blood concentrations were detected within 1-2 h, almost 
    total disappearance from the blood stream occurring in a matter of 
    1.5-4 h. The biological half-life of trichlorfon in the mammalian 
    blood was estimated to be in the range of 30 min.

         Trichlorfon undergoes transformation to dichlorvos (2,2-dichloro
    vinyl dimethyl phosphate), via dehydrochlorination, in water,

    biological fluids, and tissues, at pH values higher than 5.5.
    Dichlorvos is the physiologically active anticholinesterase. The main
    routes of degradation are demethylation, P-C bond cleavage, and ester
    hydrolysis via dichlorvos. The major metabolites of trichlorfon found
     in vivo are demethyl trichlorfon, demethyl dichlorvos, dimethyl 
    hydrogen phosphate, methyl hydrogen phosphate, phosphoric acid, and
    trichloroethanol. The last metabolite is found in the urine as a
    glucuronide conjugate.

         Trichlorfon and metabolic products are primarily eliminated via 
    the urine. Studies conducted with radiolabelled (14C-methyl and
    32P-) trichlorfon revealed that the bulk of the chemical was
    eliminated in the form of water-soluble material, little being
    chloroform-soluble. Some 66-70% of the water-soluble products appeared
    in the urine within 12 h while 24% of the 14C-methyl material was
    eliminated in the expired air as carbon dioxide (CO2). Low levels of
    trichlorfon and metabolites have been detected in bovine milk
    following oral and  dermal treatment of the animals.

    1.1.3  Effects on organisms in the environment

         Trichlorfon is moderately toxic for fish (96-h LC50 values
    range between 0.45 mg/litre and 51 mg/litre) and moderately to highly 
    toxic for aquatic arthropods (48-h/96-h LC50 values range between 
    0.75 µg/litre and 7800 µg/litre). However, reported concentrations of
    trichlorfon in surface waters, after application in forests at  6
    kg/ha, fall short of these ranges. Thus, in normal usage, trichlorfon
    will have little or no effect on populations of aquatic organisms,
    since other groups, such as molluscs and microorganisms are less
    sensitive than arthropods. LD50 values from laboratory studies
    ranging from 40 mg/kg to 180 mg/kg indicate that trichlorfon is
    moderately toxic for birds. However, in field studies, no effects  on
    numbers, breeding pairs, nesting success, or mortality of forest 
    songbirds were seen following aerial application of trichlorfon. An 
    observed reduction in singing and increased feeding activity may  have
    been the result of a reduction in food organisms. There is no 
    indication that trichlorfon will adversely affect organisms in the 
    terrestrial environment, other than arthropods. There is no 
    information on effects on beneficial arthropods.

    1.1.4  Effects on experimental animals and in vitro test systems

         Trichlorfon is an insecticide that is moderately toxic for 
    experimental animals. Oral LD50 values for technical trichlorfon in 
    laboratory animals range from 400 to 800 mg/kg body weight and dermal
    LD50 values for the rat are greater than 2000 mg/kg body weight.

         Trichlorfon poisoning causes the usual organophosphate
    cholinergic signs attributed to accumulation of acetylcholine at nerve 

         Technical trichlorfon was shown to be moderately irritating to
    the eyes of rats, but was not irritating in skin tests on rabbits.
    Skin sensitization potential was demonstrated in guinea-pigs.

         Short-term, oral toxicity studies were carried out on rats, dogs,
    monkeys, rabbits, and guinea-pigs. In a 16-week study on rats, a
    4-year study on dogs, and a 26-week study on monkeys,
    no-observed-effect levels (NOELs) of 100 mg/kg diet, 50 mg/kg diet,
    and 0.2 mg/kg body weight (based on plasma, erythrocyte, or brain ChE 
    activity) respectively, were determined. Inhalation exposure of rats,
    over 3 weeks, indicated a NOEL of 12.7 mg/m3, based on the
    inhibition of plasma, erythrocyte, and brain ChE activity. Long-term 
    toxicity/carcinogenicity studies were carried out on mice, rats,
    monkeys, and hamsters after oral, intraperitoneal, or dermal 
    administration. An adverse effect on the gonads was seen following 
    the oral exposure of mice and rats at dose levels of 30 mg/kg body 
    weight and 400 mg/kg diet, respectively. In a 24-month study on rats
    and a 10-year study on monkeys, NOAELs of 50 mg/kg diet and 0.2 mg/kg
    body weight, respectively, were determined. Available data do not
    provide evidence of carcinogenicity following the long-term exposure
    of test animals by several routes of administration.

         Under physiological conditions, trichlorfon has been reported to 
    have a DNA-alkylating property. The trichlorfon mutagenicity results
    have been both positive and negative. Dichlorvos may be responsible,
    either in part or in full, for the effects observed. Most of the  in
    vitro mutagenicity studies on both bacterial and mammalian cells were
    positive while few of the  in vivo studies produced a positive

         Studies on mice, rats, and hamsters indicate that trichlorfon 
    produces a teratogenic response in rats at doses high enough to
    produce maternal toxicity. Exposure of rats to 145 mg trichlorfon/kg 
    diet, during gestation, caused fetal malformations. A gavage dose of 
    400 mg/kg body weight in hamsters also produced both maternal 
    toxicity and a teratogenic response. The lowest dose by gavage that 
    produced teratogenic effects in rats was 80 mg/kg body weight. The 
    effects appear to be time specific in the gestation period. A NOEL of
    8 mg/kg was determined in this gavage study.

         NOELs of 8 mg/kg body weight and 200 mg/kg body weight were
    demonstrated for rats and hamsters, respectively. Teratogenic 
    responses involving the central nervous system have also been 
    reported for the pig and guinea-pig.

         However, no teratogenic effects were observed in a 3-generation 
    reproduction study on rats, in which high dose levels induced adverse 
    reproductive effects. The NOEL in this study was 300 mg/kg diet.

         Very high doses have produced neurotoxic effects in animals.

         The active transformation product in mammals is dichlorvos, which
    is estimated to be at least 100 times more potent as an 
    anticholinesterase than trichlorfon.

    1.1.5  Effects on human beings

         Several cases of acute poisoning from intentional (suicide) or 
    accidental exposure have occurred. Signs and symptoms of intoxication
    were characteristic of AChE inhibition, such as  exhaustion, weakness,
    confusion, excessive sweating and salivation, abdominal pains,
    vomiting, pinpoint pupils, and muscle spasms. In  severe cases of
    poisoning, unconsciousness and convulsions developed and death usually
    resulted from respiratory failure. In cases where victims survived due
    to medical intervention, a delayed polyneuropathy, associated with
    weakness of the lower limbs, sometimes occurred a few weeks after
    exposure. In fatal cases, autopsy findings showed ischaemic changes in
    the brain, spinal cord, and vegetative ganglia, damage to the myelin
    sheath in the spinal cord and brain peduncles, and structural changes
    in the axons of peripheral nerves.

         A few cases of occupational poisoning have occurred, mainly 
    through the neglect of safety precautions. Occupational exposure at 
    a work-place where air concentrations exceeded 0.5 mg/m3 resulted  in
    decreased plasma cholinesterase and changes in the EEG pattern.
    However, these were completely reversible on cessation of exposure. No
    cases of skin sensitization have been reported.

         This compound has been extensively used for the treatment of 
    schistosomiasis in humans. Administration of a single dose (7-12
    mg/kg) resulted in cholinesterase inhibition in plasma and 
    erythrocytes in the range of 40-60%, without cholinergic symptoms.
    However, mild symptoms were observed in cases with a repeated dose
    regimen. A high dose level (24 mg/kg) caused severe cholinergic

    1.2  Conclusions

         -    Trichlorfon is a moderately toxic organophosphorus ester
              insecticide. Over-exposure from handling during manufacture
              or use and accidental or intentional ingestion may cause
              serious poisoning.

         -    Trichlorfon exposure of the general population occurs mainly
              as a result of agricultural and veterinary practices, and in
              the treatment of  Schistosoma  haematobium.

         -    The reported trichlorfon intakes are far below the
              Acceptable Daily Intake established by FAO/WHO and should
              not constitute a health hazard for the general population.

         -    With good work practices, hygienic measures, and safety
              precautions, trichlorfon is unlikely to present a hazard for
              those occupationally exposed.

         -    Despite its high toxicity for non-target arthropods,
              trichlorfon has been used with few or no adverse effects on
              populations of organisms in the environment.

    1.3  Recommendations

         -    For the health and welfare of workers and the general
              population, the handling and application of trichlorfon
              should only be entrusted to competently supervised and
              well-trained operators, who will follow adequate safety
              measures and apply trichlorfon according to good application

         -    The manufacture, formulation, agricultural use, and disposal
              of trichlorfon should be carefully managed to minimize
              contamination of the environment, particularly surface

         -    Regularly exposed worker and patient populations should
              undergo periodic health evaluations.

         -    Application rates of trichlorfon should be limited, to avoid
              effects on non-target arthropods. The insecticide should
              never be sprayed over water bodies or streams.


    2.1  Identity

         Trichlorfon was first prepared by Lorenz in 1952 and then by 
    Barthel in 1954 by the reaction of dimethyl phosphite with chloral. It
    is a racemic mixture of dimethyl 2,2,2-trichloro-1-
    hydroxyethylphosphonate. Two molecules of trichlorfon are associated
    together (Lorenz et al., 1955).

    Chemical structure:


    Chemical formula:             C4H8Cl3O4P

    Relative molecular mass:      257.44

    Common name:                  trichlorfon (ISO)

    Chemical name:                dimethyl 2,2,2-trichloro-1-

    Synonyms:                     chlorofos, DEP, DETF, dipterex,
                                  dimethyl 1-hydroxy- 2,2,2-trichloro
                                  ethanephosphonate,  O, O-dimethyl
                                  phosphonate, metrifonate, foschlor,
                                  trichlorofon, trichlorphon

    Trade names:                  Agroforotox, Anthon, L 13/59,
                                  Bilarcil, Cekufon, Danex, Dipterex,
                                  Ditriphon, Dylox, Dyrex, Dyvon,
                                  Masoten, Metrifonate, Neguvon,
                                  Proxol, Tugon, Wotex

    CAS registry number:          52-68-6

    RTECS registry number:        TA 0700000

    Impurities:                   The purity of technical trichlofon
                                  was reported to be more than 98%
                                  (FAO/WHO, 1972). The main
                                  impurities are 2,2-dichlorovinyl
                                  dimethyl phosphate: dichlorvos (0-
                                  0.2%), trichloroacetaldehyde (0-
                                  0.05%), dichloroacetaldehyde (0-
                                  0.03%), methyl hydrogen 2,2,2-
                                  nate; demethyl trichlorfon (0-0.3%),
                                  and water (less than 0.3%). The
                                  technical product also contains
                                  phosphoric acid, 2,2,2-trichloro-1-
                                  hydroxyethylphosphonic acid, and
                                  dimethyl phosphite (FAO/WHO,
                                  1972; Melnikov et al., 1975).

    2.2  Physical and chemical properties

         Trichlorfon is a colourless crystalline powder that is stable at 
    room temperature. It is slowly hydrolysed in acid media; the half-life
    is 526 days at pH 1-5 and 20 °C (Mühlmann & Schrader, 1957). Cleavage
    of one of the methyl ester groups takes place by acid hydrolysis. In
    alkaline media, however, trichlorfon is rapidly converted to
    dichlorvos and then hydrolytic products (see section 4.2).

         Some physical properties are given in Table 1.

    2.3  Conversion factors

              1 ppm = 11.4 mg/m3
              1 mg/m3 = 0.088 ppm, at 25 °C and 760 mmHg.

    2.4 Analytical methods

         There are several methods for the determination of trichlorfon,
    some of which are listed in Table 2. For formulation analysis,
    potentiometric titration of liberated chloride with standard silver 
    nitrate AgNO3 has been recommended (Macdougall, 1964; Bennewitz &
    Foth, 1967). The total chlorine content is determined by refluxing 
    with aqueous NaOH. On the other hand, treatment with ethanol amine at
    room temperature gives one molecule of hydrogen chloride from each
    molecule of trichlorfon. Polarography is also used (Giang & Caswell,
    1957). However, extraction with ethyl acetate and gas-chromatographic
    determination are generally applied (Zweig & Sherma, 1972).

    Table 1.  Physical and chemical properties of trichlorfona
    Physical state                    colourless crystals

    Melting point (°C)                83-84

    Boiling point (°C)                100 (0.1 mmHg)

    Vapour pressure (20 °C)           7.8 x 10-6 mmHg

    Volatility (20 °C)                0.022 mg/m3

    Density                                1.73

    Solubility in g/100 ml (25 °C)    water               15.4
                                      benzene             15.2
                                      chloroform          75.0
                                      diethyl ether       17.0
                                       n-hexane            0.08

    Partition coefficient             log Pow 0.57

    Corrosiveness                     corrosive to metals
    a  From: Giang et al. (1954); FAO/WHO (1972); Dedek (1981); IARC

         Extraction with acetonitrile, reextraction with ether and
    gas-chromatographic determination with flame photometric detection
    (FPD) or flame thermionic detection (FTD) are standard procedures for
    the determination of residues. Trichlorfon is thermally decomposed
    during chromatography to give dimethyl phosphite which is then
    determined (Ferreira & Fernandes, 1980). Chloral generated by
    decomposition can be determined by electron-capture detector (Zweig &
    Sherma, 1972).

         Acetylation or trimethylsilylation can stabilize trichlorfon for
    gas chromatography without decomposition (Vilceanu et al., 1973; 
    Bowman & Dame, 1974). Trichlorfon itself has been successfully 
    determined at a high sensitivity using a column, such as Thermon 3000
    on Shimalite TPA. More recently, a GC- FTD method, based on on-column
    derivation by acetic anhydride, has been reported by Conrad et al.
    (1987). The response is linear over ranges of 0.1-2.0 ng. The method
    is applicable for the determination of trichlorfon in technical
    products and formulations, as well as for residues in crops and animal
    tissue samples.

    Table 2.  Summary of analytical methods for the determination of trichlorfon
    Sample         Sample preparation                       Analytical              Detection  Recovery (%)     Comments            Reference
    medium                                                  conditions              limit      (added level,
                                                            (Detector, column,                 mg/kg)
                                                            column temperature
    Formlation     refluxing with concentration NaOH        potentiometric                                      determination       MacDougall
                                                            titration with AgNO3                                of trichlorfon      (1964)
                                                            of total Cl-                                        in formulations

                   standing with ethanolamine for 1 h at    potentiometric                                      distinguishable     Bennewitz
                   room temperature                         titration of liberated                              between             & Foth
                                                            HCl with AgNO3                                      trichlorfon         (1967)
                                                                                                                and dichlorvos

                   ethyl acetate ext.a                      FTD-GC, 25%             0.01 µg    ±1-2%            determination       Zweig &
                                                            carbowax 20W,           accuracy                    of trichlorfon      Sherma
                                                            1.5 m (5 ft)                                        in powder           (1972)
                                                            195 °C, N2,                                         formulation
                                                            120 ml/min

                   dissolving in CHCl3 and sililating with  FID-GC, 3% XE-60,       relative   1.3%             determination       Bowman &
                   bis-(trimethylsilyl)-trifluoracetamide   1.2 m, 110 °C, He       standard                    of trichlorfon      Dame
                                                            50 ml/min               deviation                   in soluble          (1974)

                   acetylating with acetic                  FTD-GC, 15%             pg                          determination       Vilceanu et
                   anhydridepyridine mixture                Apiezon L, 1 m,                                     of trichlorfon      al. (1973)
                   (2:0.5) in CH3CN                         160-200 °C, N2,                                     after acetylation
                                                            60 ml/min

    Residues       0.1 N H2SO4 diethyl ether                FTD-GC 16% XF-1150,     0.1 mg/kg  74-86 (0.1)      the extracts        Zweig &
    in food                                                 2 m (6 ft)                         102-5 (12.5)     should be           Sherma
                                                            135 °C, He                                          dialysed for        (1972)
                                                            25 ml/min                                           24 h before

    Table 2 (continued)
    Sample         Sample preparation                       Analytical              Detection  Recovery (%)     Comments            Reference
    medium                                                  conditions              limit      (added level,
                                                            (Detector, column,                 mg/kg)
                                                            column temperature
    Crops,         CH3CN+H2O/CHCH3 ext.a hexane -           FTD-GC, 20%             5 µg/kg    90-100 (0.2)     some metabolites    Takase et
    fish,          CH3CN partition CH3CN:+H2O,              carbowax 20 M,                     fat 72 (0.2)     are also            al. (1972)
    chicken        evaporation, aq. layer/heptane           1m, 150 °C, N2                                      determined
                   washing NaCl, ether ext.a                60 ml/min

    Crops,         CHCl3 ext.; reext. with activated        FPD-GC, 16%             2 µg/kg    100 (0.002-0.25) determination       Devine
    soil,          carbon/acetone (hexane sat.a NaCl ext.   XF-1150, 2 m,           (water)    water, 94-104    of trichlorfon      (1973)
    animal         CHCl3 + NaCl ext.; aq. phase/CHCl3 ext.  125 °C                  50 µg/kg   (0.05-0.2)       in forest
    tissues,       for animal tissue)                                               (others)   soil, 90-99      environmental
    water                                                                                      (0.05-50)        samples
                                                                                               plants, 82

    Fruit          acetone ext.; 2% Na2SO4/hexane then      FTD-or FPD-GC, 5%       0.1 mg/kg  90-102%          clean-up is         Ferreira &
                   ethyl acetate N2 40 ml/min               carbowax-20 M,                     (1.0)            not necessary       Fernandes
                                                            3 m, 160-180 °C                                     for ethyl           (1980)

    Livestock      CH3CN ext.; 5% Na2SO4/CHCl3 ext.a        FPD-GC, 3%              2 µg/kg    90 (egg)-102     Salithion           Imanaka et
    products       haxane-CH3CN partition aq.               Thermon 3000,                      (milk) (0.4)     (same               al. (1981)
                   CH3CN/CH2Cl2 ext.a                       0.3 m, 120-170 °C,                                  retention
                                                            N2 60 ml/min                                        time) can be
                                                                                                                removed by
                                                                                                                washing with

    Table 2 (continued)
    Sample         Sample preparation                       Analytical              Detection  Recovery (%)     Comments            Reference
    medium                                                  conditions              limit      (added level,
                                                            (Detector, column,                 mg/kg)
                                                            column temperature
    Milk           CHCl3 ext.                               TLC, benzenemethyl      5 µg/kg    75-100           semi-quantitative   Fechner et
                                                            acetate (3:1),                     (0.02-0.4)       determination       al. (1971)
                                                            enzymic determination                               separating
                                                            after activation                                    dichlorvos
                                                            with ammonia

    Feed           0.1% HCl ext.a; CHCl3 reext.a            FPD-GC DB-1             0.01 mg/kg 88 (50 ppm)      feed samples        Cox et al.
                                                            (FSOT) 0.53 min x                                                       (1989)
                                                            30 m 120-150 °C
                                                            (6 °C/min) He
                                                            10 ml/min

    Crops          acetone or CH3CN ext.; conc.a + NaCl     FTD-GC, methyl          0.01 ng    70-99            sep-pak             Ishizaka et
                   reext.a with diethyl ether; Sep-pak C18  silicon or                         (0.1 mg/kg)      cartridge is        al. (1986)
                   (silica gel) benzene/MeOH                phenylmethyl                                        very useful
                                                            silicon;                                            for simple
                                                            (FSOT) 0.53 mm x                                    clean-up
                                                            10 m, 160 °C

    Serum          Serum+0.1 mix well; M HCl (1=1)          FTD-GC, CBP-1           2.5 ng/ml                   extraction is       Ameno et
                   Sep-pak C18 (silica gel) 0.1 M HCl,      (FSOT) 0.53 mm x                                    not necessary       al. (1989)
                   10% & 50% aq. MeOH                       12 m 120 °C He                                      for wide
                                                            30 ml/min                                           range of
                                                                                                                curve (5 approx
                                                                                                                500 ng/ml)
    a  ext. = extraction.
       reext. = reextraction.
       sat. = saturated.
       conc. = concentration.

         The simultaneous detection (µg/kg) and identification of
    trichlorfon and other organophosphorus pesticides extracted from 
    foods can be accomplished by using gas chromatography-mass
    spectrometry (Stan, 1977; Stan et al., 1977). Although the molecular 
    ion cannot be measured by the electron impact (EI) ionization mass 
    spectrum, an intense peak of the protonated molecular ion (M+1)+ is
    observed in the chemical ionization (CI) mass spectrum. Thus, the 
    latter is more sensitive and selective than the former in residue 
    determination. Field desorption mass spectrum shows the protonated 
    dimer ion (2M+1)+ of trichlorfon besides the (M+1) ion (Schulten &
    Sun, 1981). The occurrence of such ions is helpful in confirming the
    identification of trichlorfon.

         Thin-layer chromatography (TLC) is particularly useful for 
    qualitative analysis. Systematic separation schemes for many 
    organophosphorus pesticides have been proposed (Guth, 1967; Getz  &
    Wheeler, 1968; Antoine & Mees, 1971; Ambrus et al., 1981). Levels of
    0.1 µg trichlorfon can be detected using nitrobenzyl-pyridine reagent
    or silver nitrate and UV irradiation on silica gel or  polyamide TLC.
    A TLC-enzyme inhibition technique, that can be used for the
    determination of residues in organophosphorus pesticides was reviewed
    by Mendoza (1973). Trichlorfon itself is not a good inhibitor of
    cholinesterase (Winterlin et al., 1968), but treatment with ammonia on
    the plate, converting it into dichlorvos, is performed to enhance its
    sensitivity (Fechner et al., 1971).

         Although high performance liquid chromatography (HPLC) has 
    recently become an important technique in pesticide analysis, few 
    data are available for trichlorfon (Szalontai, 1976; Daldrup et al.,
    1981, 1982).

         Colorimetric methods have been applied for determining
    trichlorfon, based on the phosphomolybdate reaction (Sissons & 
    Telling, 1970) and the Fujiwara reaction (Cerna, 1963; Giang et al.,

         A method to preconcentrate water samples for the measurement of
    trichlorfon was reported by Dedek et al. (1987).

         The use of gas chromatographic detectors in HPLC has recently 
    received increasing attention because of the growing need for high 
    sensitivity and selectivity. The on-line combination of HPLC and 
    these detectors, using a thermo spraying interface (TSP), has been 
    applied successfully, because the advent of miniaturized HPLC systems
    has alleviated many of the difficulties including a loss of
    sensitivity associated with direct mobile phase introduction. In most 
    cases, the techniques of HPLC separation, GC-FTD detection, and GC-MS
    confirmation can be successfully used in the analyses with
    TSP-HPLC-FTD and TSP-HPLC-MS (Gluckman et al., 1986).

         The TSP-HPLC-FTD system has been successfully used to determine
    a polar and thermally unstable pesticide like trichlorfon in many
    samples, because high sensitivity and less matrix interference are
    achieved than with the HPLC-ultraviolet spectrophotometry (UV) system
    for pesticide residues. According to Gluckman's report (1986),
    trichlorfon can be detected at a level of 40 pg by TSP-HPLC-FTD and
    the residues in tomatoes and cabbage can be determined without any

         The characterization of several organophosphorus pesticides has 
    been achieved using positive and negative ion "filament on"
    TSP-HPLC-MS. When ammonia gas is used as a reagent one, the base  peak
    is [M + NH4]+ in the positive ion mode (PIM) for the
    organophosphorus pesticides examined, while the pesticides exhibited 
    different fragmentation behaviour in the negative ion mode (NIM)
    ([M]- in the base peak). PIM shows a higher sensitivity for these
    compounds than NIM.

         Trichlorfon and other organophosphorus pesticides can be detected
    at levels of 20-50 ng (minimum detection limit; s/n = 3) in the
    reconstructed ion chromatography of PIM-HPLC-MS. Since, a 100-fold to
    1000-fold increase in sensitivity will be expected using single ion
    monitoring (SIM), the detection limits in PIM-TSP- HPLC-MS are rather
    similar to those in GC-NCI-MS and in direct liquid introduction
    (DLI)-HPLC-NCI-MS (Barcelo, 1987; Barcelo et al., 1988; Betowski &
    Jones, 1988).

         The Joint FAO/WHO Codex Alimentarius Commission has given
    recommendations for the methods of analysis to be used in the 
    determination of trichlorfon residues (FAO/WHO, 1989).

         Because of the transformation of trichlorfon into dichlorvos, it
    is  necessary to have a method for the simultaneous quantification of 
    both of these compounds in biological studies. Such a method has been
    worked out by Nordgren (1981), and Nordgren et al. (1978, 1980, 1981),
    and has been correlated with the degree of enzyme inhibition. Similar
    methods have been used by Yakoub (1990).


    3.1  Natural occurrence

         Trichlorfon is not a natural product. However, it is found as a 
    metabolite of the insecticide butonate: butyric acid ester of
    trichlorfon (Dedek et al., 1979).

    3.2  Industrial production

         Trichlorfon was introduced as a commercial chemical in 1952. It
    is manufactured by reacting dimethyl phosphite with chloral (Barthel
    et al., 1954; Lorenz et al., 1955).

         There is no record of the world production of trichlorfon. It is 
    produced in Germany, Japan, and Spain and is believed to be produced
    also in Argentina, Brazil, China, Israel, Mexico, the Republic of
    Korea, and the USSR. The total production in western Europe was
    estimated to be about 2000 tonnes in 1977. The production in Japan has
    ranged from 613 to 1095 tonnes per year over the last decade (Japan
    Plant Protection Association, 1985, 1986, 1989).

    3.3 Uses

         Trichlorfon is a broad-spectrum insecticide that is particularly 
    effective against  Diptera.  In agriculture, it is used mainly
    against insect pests in field and fruit crops. Trichlorfon is also
    used to control forest insects, in public health, and for the control
    of endo- and ectoparasites in/on domestic animals and fish.

         Under the generic name of metrifonate, trichlorfon is used as an 
    antihelminthic in humans and is one of the treatments of choice for 
    infestation by  Schistosoma haematobium, primarily in Africa
    (Snellen, 1981; Davis, 1986; Aden Abdi et al., 1987; Wilkins &  Moore,
    1987; Aden Abdi & Gustafsson, 1989; Yakoub, 1990; Aden  Abdi, 1990).
    The usual regimen consists of three doses of 7.5 or 10 mg/kg, given at
    intervals of 14-21 days. Because of the lower costs in comparison with
    other treatments, metrifonate is particularly attractive for mass
    treatments. It has been given to millions of patients with
    schistosomiasis with only occasional mild side effects (Nordgren,
    1981). In order to obtain better patient compliance, Aden Abdi (1990)
    recently proposed a regimen of 3 x 5 mg, administered in one day (see
    section 9.2).

         Metrifonate is also under consideration as a treatment for 
    Alzheimer's disease (Hallak & Giacobini, 1989; Becker et al., 1990; 
    Pomponi et al., 1990).

         Table 3 gives an indication of the world-wide consumption of 
    trichlorfon. Although the quantity is not reported, trichlorfon is
    used also in several other countries including Finland, Hungary,

    Malaysia, Mongolia, and the USSR. According to a Battelle report
    (1987), the total consumption of trichlorfon in 13 countries in 1987
    was 851 tonnes as shown in Table 4, which also includes data from
    other sources.

         The following formulations are used in agriculture: 50%
    emulsifiable concentrate, 95, 80, and 50% soluble powders, 50% 
    wettable powders, 5 and 4% dusts, 5, 2.5, and 1% granules, 75, 50, 40,
    and 25% ultra-low volume concentrates. Some formulations mixed with
    other organophosphorus insecticides, such as malathion and ESP, or
    with carbamate insecticides, such as carbaryl, are also used.

         The following formulations are used for animal treatments:  90,
    80, and 50% soluble powders, 6% suspension, 11% solution, 50% 
    injectable solution tablets. A 1% fly bait is also available, and a 
    0.1% preparation against house-ants. For antihelminthic prep arations,
    trichlorfon can be used in combination with atropine, fenbendazole, or

         Tablets containing 100 mg active ingredient metrifonate are used 
    in the treatment of schistosomiasis in humans.

    Table 3.  World usage of trichlorfon
    Year       Usage (tonne)      References


    1980           3159         Battelle (1982)

    1983           2349         Battelle (1984)

    1987            851         Battelle (1987)


    Table 4.  Usage of trichlorfona
    Country                 Usage    Year     Main use
    France                   -       1987
    Italy                  10.2      1987     vines
    Turkey                 16.4      1987     vegetables
    FRGb                   19.9      1984     sugar beet
    United Kingdomb         0.8      1984     sugar beet
    Spain                 155.3      1987     vines, vegetables,

    Czechoslovakiac          -       1983
    Swedenc                 5.7      1982     agriculture, hygiene
    Japan                 279.7      1987     potatoes, other

    Korea, Republic        79.0               forests, apples
    India                    -
    Indonesia               6.0      1987     soybeans
    Thailandc              19.0      1978
    Philippinesb             -       1984
    USA                   454.0d     1978     field crops, alfalfa,
                                              forests, cotton,
                            1.8      1987     alfalfa
    Mexico                133.1      1987     maize, cotton,
                                              tobacco, tomatoes,
                                              sugar cane, soybeans
    Brazil                145.3               soybeans, cotton,
    Egypt                    -
    South Africa           24.6               maize
    Kenyac                   -       1983
    a  From: Battelle (1987).
    b  From: Battelle (1984).
    c  Information through IRPTC (International Register of
       Potentially Toxic Chemicals).
    d  From: IARC (1983).


         Following aerial application, trichlorfon is distributed to the
    air, soil, water, trees, plants, and other media. With rainfall,
    trichlorfon penetrates into the lower soil layers and moves into the
    aquatic environment.

    4.1  Transport and distribution

    4.1.1  Air

         The air/water partition coefficient of trichlorfon was determined 
    to be <5.0 x 10-7, indicating that the distributed amount in air is 
    much smaller than that in water and is, in fact, negligible (Kawamoto 
    & Urano, 1989).

    4.1.2  Water

         One and two days after the aerial application of trichlorfon to
    a  forest at the rate of 1.0 kg/ha, a small amount of the compound was 
    found in creek water (Pieper & Richmond, 1976). Trichlorfon was also
    detected in water samples in sprayed forests in Canada (Sergeant &
    Zitko, 1979).

         Rainfall caused run-off of trichlorfon from the sprayed steppe 
    zone into ponds (IRPTC/GKNT, 1983). In an agricultural region of the
    USSR, trichlorfon migrated into drainage water and was transferred
    across a significant distance, depending on the rainfall (Zakharov,

    4.1.3  Soil

         Because of its high water-solubility (15.4 g/100 ml), there was 
    some downward movement of trichlorfon through soil with water. When
    sprayed twice on an apple orchard, the insecticide was detected in
    soil layers of 0-10 cm and 10-20 cm depth, 10 days after the last 
    treatment (Naishtein et al., 1973).

         Trichlorfon applied to the soil surface at the rate of 2.4 kg
    a.i./ha  did not move significantly into the lower layers by leaching
    (Baida, 1970); when applied at a high rate of 60 kg/ha, the compound 
    penetrated into the 60-cm layer of the soil (Naishtein, 1976).

         It has been shown, in different soils, that the disappearance of
    the insecticide (initial concentration; 10 mg/kg) is very rapid during
    the first few days following application and considerably slower
    thereafter. The levels of trichlorfon residues in a soil without
    plants were 5.2, 2.1, and 0.9 mg/kg on the 5th, 11th, and 21st days
    after application, respectively. However, in soils with tomato,
    cabbage, and potato plants, trichlorfon levels decreased more rapidly
    to 2.1, 1.0, and 0.6 mg/kg, respectively, on the 5th day, 0.7, 0.5,

    and 0.3 mg/kg on the 11th day, and 0.6, 0.3, and 0.2 mg/kg on the 21st
    day after treatment. Only a small amount of trichlorfon was detected 
    after 30 days. The rate of disappearance in soils was dependent on 
    the vegetation (Ivanova & Molozhanova, 1974).

    4.2 Abiotic degradation

         The proposed degradation pathways of trichlorfon in the
    environment are shown in Fig. 1.

         In alkaline buffers and seawater (pH 8.1), trichlorfon is
    rearranged via dehydrochlorination to yield the more potent
    cholinesterase inhibitor, dichlorvos; however, in acidic buffers or in 
    fresh water (pH 5.3), it is stable. At more alkaline pH values, the 
    anticholinesterase activity disappears slowly (Ecobichon, 1979). At 
    pH 5.5 and above, degradation to dichlorvos occurs at detectable 
    rates (Dedek, 1981).

         On photolysis in water under ultraviolet radiation (UVR),
    trichlorfon was rapidly converted to dichlorvos (2) and two
    unidentified products. These two products decomposed further on
    prolonged irradiation. Photodegradation appears to be much slower  in
    the solid state than in aqueous solution (Giovanoli-Jakubczak et  al.,

         [32P]-trichlorfon on glass plates was photodecomposed by 7% 
    after a 5-h exposure to UVR (500 W, 200-600 nm) and by 6% after  a
    20-h exposure to sunlight. A trace amount of dimethyl hydrogen 
    phosphate (5) (see Fig. 1) and methyl hydrogen phosphate (7) were 
    identified as photodegradation-products, whereas dichlorvos (2) was 
    not detected among the photodegradation-products on the glass plates 
    in either case (Dedek et al., 1979).

         Trichlorfon is fairly stable in acidic solutions, but unstable in 
    neutral and basic solutions. The half-life of chloroform-extractable 
    radioactivity in buffer solutions at 40 °C is 46.4 days at pH 2, 16
    days at pH 5, 3.75 days at pH 6, 19 h at pH 7, 8.8 h at pH 8, and 75
    min at pH 10. Dichlorvos (2), the demethylated derivative  of
    trichlorfon (6), dimethyl hydrogen phosphate (5) and methyl hydrogen
    phosphate (7) were identified as degradation products, but they were
    not quantified (see Fig. 1; Dedek et al., 1979).

         In other studies, the half-life of trichlorfon at 100 mg/litre in 
    sterilized water-ethanol (99:1) phosphate buffers at 25 ± 3 °C, was 
    reported to be more than 1000 weeks at pH 4.5, 3.5 weeks at pH 6.0,
    0.4 weeks at pH 7.0, and 0.13 weeks at pH 8.0. It was concluded that
    the disappearance was mainly due to the conversion of trichlorfon to
    dichlorvos via dehydrochlorination (Chapman & Cole, 1982). In another
    study, the half-lives for the formation of dichlorvos from trichlorfon
    at pH 7, pH 7.5, and pH 8 were reported by Hofer (1981) to be 27, 9,
    and 3 h, respectively.

    FIGURE 1

         Formulated trichlorfon was applied to sterilized and
    non-sterilized soils with a 60% moisture content, and incubated at
    ambient temper ature under natural sunlight. At concentrations of both
    13 and  132 mg/kg, the levels of insecticide decreased to less than
    the detection limit within 40 and 50 days, respectively, under both 
    sterilized and non-sterilized conditions. It appears that the
    insecticide is readily subjected to abiotic degradation in soil
    (Yurovskaya & Zhulinskaya, 1974).

    4.3  Biodegradation

         The metabolic fate of [14C]-trichlorfon labelled at the methoxy 
    group has been studied in culture media of nodule-forming bacteria,
    such as  Rhizobium leguminosarum and  Rhizobium trifolii.  After 
    incubation for 10 days at 30 °C, the unchanged parent compound
    (19-25%) together with dimethyl hydrogen phosphate (18- 25%) (5) and
    methyl hydrogen phosphate (0.6-1%) (7) was recovered from the media.
    In addition, a trace amount of [14C] carbon dioxide was  evolved
    during the same period (Salama et al., 1975) (see Fig. 1).

         In contrast, a demethylated derivative (6) of trichlorfon and 
    2,2,2- trichlorohydroxyethylphosphonic acid (3) were shown to be the
    major metabolites in the culture media of  Aspergillus niger,
     Penicillium notatum, and  Fusarium spp. (Zayed et al., 1965).

    4.4  Environmental fate

         The metabolism of [14C]-trichlorfon labelled at the methoxy
    group has been studied in plants of the broad bean  (Vicia faba) and
    clover  (Trifolium alexandrinum).  The roots of the plants were
    immersed in a phosphate buffer at pH 6 containing [14C]-trichlorfon
    at a concentration of 50 mg/litre, and grown for 5 or 10 days in the 
    greenhouse. At harvest, the buffer solution as well as the roots of 
    the two plants contained unchanged parent compound and dimethyl 
    hydrogen phosphate (5) together with a trace amount of methyl 
    hydrogen phosphate (7) (Salama et al., 1975) (see Fig. 1).

         Following the application of [32P]-trichlorfon to stems or
    leaves, the insecticide disappeared from tomato, potato, and cotton
    plants with half-lives of 20-57 h in the greenhouse, and from plums,
    apples, cherries, peas, and wheat plants with half-lives of 0.5-7.5
    days in the field. Characterization of metabolites was not possible
    because of their volatility (Dedek et al., 1979).

         When formulated trichlorfon (0.2%) was sprayed on cabbage and 
    onion plants at a rate of 1200 litre/ha, rapid conversion to
    dichlorvos occurred. One day after treatment, the treated leaves of
    cabbage and onion plants contained the highest residues of dichlorvos
    (0.09-0.51 mg/kg) together with the parent compound (0.79-3.1 mg/kg).
    Trichlorfon disappeared from the leaves with a half-life of less than
    3 days, and dichlorvos decreased to less than the detection limit 
    within 15 days (Baida, 1975).


    5.1  Environmental levels

    5.1.1  Air

         When 2% trichlorfon was applied at a rate of 30 ml/m2, its 
    vapour was detected in the air. The initial concentration of 0.1
    mg/m3 decreased rapidly to 0.05-0.01 mg/m3 within 2-3 days.
    Trichlorfon was not detected after 30 days (Degtyareva et al., 1977).
    After handspraying in a vineyard at 2 and 6 kg/ha, air concentrations 
    of 0.0003 and 0.001 mg/m3, respectively, were measured. Average 
    daily concentrations of trichlorfon and its maximum single
    concentration in the Ukrainian Republic were 0.0003 and 0.0004
    mg/m3, respectively (IRPTC/GKNT, 1983).

    5.1.2  Water

         When an 18% aqueous solution of trichlorfon was sprayed on a 
    forest at a rate of approximately 1 kg/ha from a helicopter, the 
    residues were 23.4-51.9 and 8.7-12.1 µg/litre in the creek water on 
    the first and second day after application, respectively (Pieper & 
    Richmond, 1976).

         According to the monitoring programmes in Canada in 1976 and 
    1977, water samples in the forests where trichlorfon was sprayed were
    contaminated with 0.062-1.0 µg/litre of the insecticide in most of the
    year's samples in 1976, but the concentration in samples in 1977 were
    considerably lower, with a maximum value of 0.058 µg/litre (Sergeant
    & Zitko, 1979).

         Trichlorfon was measured in soil water at 0.001 (1970), 0.02
    (1971), and 0.001 mg/litre (1972) on average 1.5-2 months after 
    application (IRPTC/GKNT, 1983).

         When trichlorfon was sprayed over a mixed boreal forest in New 
    Brunswick (Canada) at a rate of 1.14 kg/ha, concentrations in stream 
    water were approximately 95 µg/litre initially and below detection 
    limit (0.05 µg/litre) two weeks after treatment (Sundaram & Varty,

    5.1.3  Soil

         Trichlorfon was one of the chemicals found at hazardous waste 
    sites in the USA (Kokoszka & Flood, 1989). Levels were not specified.

         After the spraying of a vineyard at 2 or 6 kg/ha, trichlorfon 
    levels measured in the soil were 0.24 and 0.48 mg/kg, respectively, on
    the day of treatment. One day later, the levels in the soil were 0.49
    and 1.03 mg/kg, and 15 days later, 0.002 and 0.02 mg/kg. The average
    level of trichlorfon in the soil in the Kherson Region was 0.01 mg/kg

    (1970), 0.17 mg/kg (1971) and 0.002 mg/kg (1972). After spraying a
    forest at 0.8 kg/ha over a 200-ha area (160 kg  total), monitoring
    soil over the area gave estimates of 29.9 kg  trichlorfon remaining in
    the soil, 5 days after application and 0.43  and 0.25 kg after 10 and
    14 days, respectively. All the trichlorfon  measured was in the top 10
    cm of soil. No trichlorfon was found  18 days after spraying
    (IRPTC/GKNT, 1983).

         After aerial spraying of trichlorfon over a mixed boreal forest
    in  New Brunswick (Canada) at a rate of 1.14 kg/ha, residues in soil 
    dissipated from 3 mg/kg initially to levels below the detection limit
    (0.05 mg/kg) in about two weeks (Sundaram & Varty, 1989).

    5.1.4  Residues in plants and animals

         An 18% aqueous solution of trichlorfon was applied by helicopter 
    at 6.1 litre/ha to a forest. The residues on days 1, 2, 8, and 15
    after aerial treatment were 11.2-12.6 mg/kg, 3.8-10.4 mg/kg, 0.8-1.6
    mg/kg and below detection limit-0.6 mg/kg, respectively, on  Douglas
    fir, 68.2-81.7 mg/kg, 40.3-59.4 mg/kg, 3.9-4.5 mg/kg and  below
    detection limit, respectively, on willow, and 43.1-113.0 mg/kg,
    4.3-30.0 mg/kg, 5.3-6.3 mg/kg, and below the detection limit-2.1
    mg/kg, respectively, on grasses (detection limit: 0.1 mg/kg) (Pieper
    & Richmond, 1976).

         Trichlorfon was detected in all song birds caught in the area
    (60.7 ha), 76 h after spraying at the rate of 1.1 kg/ha. The residues 
    of trichlorfon were found at 0.01 mg/kg for blue jays and crested
    fly-catchers and at 0.013-0.04 mg/kg for baltimore oriols (Kurtz & 
    Studholme, 1974).

         When trichlorfon was sprayed at a rate of 1.14 kg a.i./ha over a 
    mixed boreal forest in New Brunswick (Canada), the initial residues 
    in foliage ranged from 10.8 to 17.3 mg/kg fresh weight, but dissipated
    rapidly to 2.6 to 6.5 mg/kg in three days (Sundaram & Varty, 1989).

    5.2  Residues in food

    5.2.1  Crops

         The results of supervised trials involving foliar treatment of 
    various crops with trichlorfon are summarized in Table 5.

         Leafy vegetables, such as lettuce, spinach, and Chinese raddish 
    leaves showed high residues of trichlorfon (several mg/kg or more)
    shortly after application. The trichlorfon residues in Chinese raddish
    leaves were about ten times higher than those in the roots. Among
    fruits, strawberries, raspberries, black currants, and red currants
    were found to contain higher trichlorfon residues than other fruits,
    such as citrus. The results in Table 5 showed that the residues
    decreased rapidly with time after application.

         During the period 1987-88, 764 home-grown and imported wheat 
    samples were analysed for pesticide residues in the United Kingdom.
    Trichlorfon was not found at, or above, the reporting limit of 0.1
    mg/kg (Osborne et al., 1989).

         Following normal field application (in a field trial) of
    trichlorfon in Portugal to Portuguese cabbage and broccoli, residue
    levels decreased to below the MRL of 0.5 mg/kg in 10 days for the
    Portuguese cabbage and two weeks for the broccoli. The difference in
    time is mainly ascribed to the much larger surface area exposed in the
    case of the broccoli (Magalhaes et al., 1989).

         The surveillance of trichlorfon residues on over twenty crops in 
    Hungary revealed that about 90.1% of the samples contained residues 
    at levels below 0.02 mg/kg (Anon. 1978a).

         Trichlorfon residues on spinach and lettuce after spraying were 
    somewhat higher in green-house crops than in field crops in West 
    Germany (Stobwasser & Kirchhoff, 1968).

         No trichlorfon residues were found in a survey of pesticide 
    residues on crops (total samples: 697) collected from a Tokyo market 
    from April 1984 to March 1989 (detection limit: 0.005 mg/kg) (Nagayama
    et al., 1986, 1987, 1988, 1989).

         Cucumber vines were sprayed to run-off with 0.05% trichlorfon 
    aqueous solution, and the fruits sampled over a period of time. The 
    half-life of trichlorfon was 1.76 days (Hameed et al., 1980).

         Grape products were prepared in a laboratory from grapes
    harvested 1 day after the last application of trichlorfon. Trichlorfon 
    residues were detected at levels of 140%, 120%, 159%, and 0.4% of the
    originally applied concentration in the grape juice, raisins, wines,
    and brandies, respectively, and the dichlorvos concentrations in the
    wines were higher than those in the grapes from which the wines were
    made (Hiramatsu & Furutani, 1978).

         Residues of 0.0002-0.006 mg trichlorfon and dichlorvos/kg were 
    detected in 8 out of 40 flower honeys in Bulgaria (Tsvetkova et al.,

    Table 5.  Residues of trichlorfon in crops
    Crop/       Application (spray)                                 Residues (mg/kg) on the day of spraying                      Reference
    Country                                                         or at intervals [days] after applicationa
                no.      kg/ha    formulationb                                                                          
                                               0         1/3        4/6        7/9        10/12    13/15      17/19     21
    Finland              ns                                         0.6                            0.5        0.4       0.2      Anon. (1978b)
                                                                                                              [18-21]   [27-29]

    Japan       6        2-5      EC-50                             0.14-0.05  0.08-0.03                                         FAO/WHO (1979)
                8        2-5                                        0.23-0.07  0.05-0.03

    USSR        4        2.0      EC                     0.79-0.27  0.17                  0.09     0.07                 0.007    Baida (1975)

    Chinese cabbage
    Japan       3        2.0      EC-50                                                            0.13-0.04  0.09-0.02          Hiramatsu &
                                                                                                              [18-21]            Furutani (1977)
                5        2.0                                                              0.06     0.05                          FAO/WHO (1979)
                6        2.0                                                              0.13     0.09
                1        0.75                            0.19-0.12             0.05                0.03

    Finland     1        1.2      WP-80        34-26     5.6        0.75       0.25       0.13                          0.01     Abbasov (1972)

    USA         1        0.6      WP-50        1.6       0.8        0.3        0.7                 0.3                  0.2      FAO/WHO (1976)
                1        1.2                   0.8       0.8        0.6        nd                  0.3
                1        0.6                             1.2                   0.3                 0.3                  nd
                5        1.2                                                              0.5
                6        1.2                                                                       nd
                7        1.2                                                              0.2

    Table 5 (continued)
    Crop/       Application (spray)                                 Residues (mg/kg) on the day of spraying                      Reference
    Country                                                         or at intervals [days] after applicationa
                no.      kg/ha    formulationb                                                                          
                                               0         1/3        4/6        7/9        10/12    13/15      17/19     21
    Head lettuce
    Finland     1        1.2      WP-50        22.8                 1.5        0.31                0.04                 0.01     FAO/WHO (1976)
                1        1.2                   31.2                 1.1        0.17                0.06                 nd

    FRG         1        0.75     EC-50        8.1       1.8        0.54       0.41       0.20     nd                   nd       FAO/WHO (1976)
                1        0.75                  15.9      4.6        0.21       0.08       0.14     0.05                 nd
                1        0.45                  5.8       1.8        0.22       0.09       nd       nd                   nd
                1        0.45                  4.8       4.3        0.27       nd         nd       nd                   nd

    Leaf lettuce
    Finland     1        1.2      WP-80        33.5                 2.6        0.61                                     0.03     FAO/WHO (1976)
                1        1.2                   26.4                 1.3        0.23                                     0.02

    USA         2        1.2      WP-50                  6.3        1.3        nd                  nd                            FAO/WHO (1976)
                2        1.2                             3.5        1.1        nd                  nd
                2        1.2                             3.8-0.8    0.8-0.1    0.4-nd
                2        1.2                             97.6       9.2        6.0                 3.9

    Red cabbage
    Netherlands 1        1.0      WP-80                                        0.05-0.03                                         Anon. (1978c)

    Savoy cabbage
    Netherlands 1        1.0      WP-50                                        0.36-0.12                                         Anon. (1978c)

    Hungary     1        0.8      WP-50                  0.2        0.02       0.01/0.01                                         FAO/WHO (1976)

    Table 5 (continued)
    Crop/       Application (spray)                                 Residues (mg/kg) on the day of spraying                      Reference
    Country                                                         or at intervals [days] after applicationa
                no.      kg/ha    formulationb                                                                          
                                               0         1/3        4/6        7/9        10/12    13/15      17/19     21
    Netherlands 3        1.2      WP-80        0.4-0.15  0.4-0.15              0.13-0.08                                         Anon. (1978c)
                4        1.2                   0.9-0.08  0.1-0.08              0.05-0.03

    Netherlands 1        1.0      WP-80                                        0.33-0.12                                         Anon. (1978c)

    Netherlands 1        1.0      WP-80                                        0.02-0.01                                         Anon. (1978c)

    Netherlands 1        1.0      WP-80                             5.3-3.4                                                      FAO/WHO (1976)
                1        1.0                                        6.2-2.1

    Netherlands 1        1.1      WP-50        33.3-23.3 5.5-2.9    3.4-1.2    1.3-0.4    0.9-0.2  0.4-0.2    0.5-0.1            FAO/WHO (1976)
                1        1.1                   4.5-1.9   3.1-1.2    0.8-0.4    0.5-0.25   0.3-0.2  0.1-0.06

    (under frame)
    FRG         1        0.75     WP-50                  4.4                              2.4                           1.6      FAO/WHO (1976)
                1        0.75                  30        21.5       5.2        1.2        2.2                           0.25

    Canada      2        1.1      WP                                0.6        0.2                 nd                            FAO/WHO (1976)
                2        1.1                                        39         3.5                 nd

    Table 5 (continued)
    Crop/       Application (spray)                                 Residues (mg/kg) on the day of spraying                      Reference
    Country                                                         or at intervals [days] after applicationa
                no.      kg/ha    formulationb                                                                          
                                               0         1/3        4/6        7/9        10/12    13/15      17/19     21
    FRG         1        0.75                                       2.0        1.6        0.7      0.35                          FAO/WHO (1976)
                1        0.75                                       0.4        0.02
                1    ca. 1.5      WP-80                             19.8       1.8
                1        0.75     WP-50        34        6.0        0.85       0.15       0.15
                1        0.75     WP-50        30                   1.7        0.3        0.08
                1        0.75                  30        13.2       5.6        1.0        1.0

    Netherlands 1        0.5      WP-50        6.5-5.7   2.7-1.2    2.1-0.08   0.6-0.1    0.3-0.2                                FAO/WHO (1976)
                1        0.63                  2.2-1.8   1.1-0.4    0.6-nd     0.2-0.1    0.2-nd
                1        1.9                   1.4-0.5              0.3-0.05   0.01-nd
                1        0.7                   1.4-0.6   0.3-0.2    0.4-nd     0.7-nd

    USA         2        1.1                                        11.2       0.3                 0.3                           FAO/WHO (1976)
                2        1.1                                                   0.9                 0.4
                2        1.1                                        1.8        0.2                 nd

    Lima bean
    USA         1        2.22     EC                                                                                    0.07-0.02FAO/WHO (1976)

    Chinese radish
    (leaf)      5        2.0      EC-50                  2.76-0.22  0.26-0.09  0.07-0.02                                         FAO/WHO (1979)

    (root)      5        2.0                             0.12-0.07  0.07-0.03  0.05-0.01

    (leaf)      8        2.0                             1.4-0.9    0.77-0.1   0.09-0.03

    Table 5 (continued)
    Crop/       Application (spray)                                 Residues (mg/kg) on the day of spraying                      Reference
    Country                                                         or at intervals [days] after applicationa
                no.      kg/ha    formulationb                                                                          
                                               0         1/3        4/6        7/9        10/12    13/15      17/19     21
    Chinese radish
    (root)      8        2.0                             0.12-0.08  0.04-0.03  0.04-0.01                                         FAO/WHO (1979)

    (leaf)      8        1.5-2.0   not stated            1.4-0.22   0.77-0.10  0.09-0.03

    USSR        4        2.0      EC                     2.7-3.1    0.90-1.2   0.02-0.77           nd-0.04              nd [30]  Baida (1975)

    Japan       6        2.0      EC-50                                        0.03-0.02  0.02-nd                                FAO/WHO (1979)

    Egg plant
    Japan       5        1.0      EC-50                             0.03-0.02  0.01-nd    nd                                     FAO/WHO (1979)
                8        1.0                                        0.02       0.007-nd

    Green pepper
    Hungary     1        1.0      WP-50        0.13      0.06       0.05       0.03       0.02     0.02                          Anon. (1978a)

    Netherlands 1        1.2      WP-50                  0.03-nd                                                                 FAO/WHO (1976)
                1        1.2                             0.13-nd                                                                 Abbasov (1972)

    Netherlands 1        1.2      WP                                                      0.9-0.6                                Anon. (1978c)
                1        1.2                                                              1.9-0.1                                Anon. (1978c)

    Table 5 (continued)
    Crop/       Application (spray)                                 Residues (mg/kg) on the day of spraying                      Reference
    Country                                                         or at intervals [days] after applicationa
                no.      kg/ha    formulationb                                                                          
                                               0         1/3        4/6        7/9        10/12    13/15      17/19     21
    Japan       1-5      1.0      EC-50        1.6-0.8   1.4-0.28   0.9-0.4    0.4-0.26            0.15-0.1                      Hiramatsu &
    (unsacked)                                                                                                                   Furutani (1978)

    (sacked)                                   0.1 5     0.07       0.08       0.06                0.06

    USA         1        4.5      WP-80                                                                                 nd       Iwata at el. (1979)

    USA         1        4.5      WP-80                                                                                 nd       Iwata et el. (1979)

    Japan       5        3.0      EC-50                                                                                 nd       FAO/WHO (1979)

    Japan       3        3g/tree  EC-50                  0.57-0.53  0.36                           0.3-0.25                      FAO/WHO (1979)

    Finland     2        0.8g/    not stated                                                       5.6                           Anon. (1978b)
                         0.5-0.6g/                                                                            2.9-0.7            Anon. (1978b)
                         plant                                                                                [18-21]

    Table 5 (continued)
    Crop/       Application (spray)                                 Residues (mg/kg) on the day of spraying                      Reference
    Country                                                         or at intervals [days] after applicationa
                no.      kg/ha    formulationb                                                                          
                                               0         1/3        4/6        7/9        10/12    13/15      17/19     21
    Japan       3        2.0      EC-50                                                            1.4        0.31               FAO/WHO (1979)
                5        2.0                                        4.6                            0.75
                3        3.0                                                                       2.12       0.46
                5        3.0                                                   3.31                1.06
                1        1.6-2.4                                                                              0.02
                3        2-3      not stated                                              2.1-1.4             0.46-0.33
                5        2-3      not stated                        4.6-3.3               1.1-0.74

    Water melon
    not stated  6        2.0      EC-50                                        0.008                                             FAO/WHO (1979)

    Black currant
    Finland              1.3g/    not stated                                                       2.6                  0.2      Anon.(1978b)
                         plant                                                                                          [27-29]

    Red current
    Finland              1.6g/    not stated                                                       25                   12       Anon.(1978b)
                         plant                                                                                          [27-29]

    USA         1        1.1      5% bait      37.5                 3.1        1.9                                      0.1      van Middalem et
                                                                                                                                 al. (1972)

    Table 5 (continued)
    Crop/       Application (spray)                                 Residues (mg/kg) on the day of spraying                      Reference
    Country                                                         or at intervals [days] after applicationa
                no.      kg/ha    formulationb                                                                          
                                               0         1/3        4/6        7/9        10/12    13/15      17/19     21
    USA         4        3.7-1.4  WP-50                  79         4                                                            Isaac at al. (1965)

    Sugar beet
    Japan       6        1.5      EC-50                                        0.05-0.02           0.04-0.02                     FAO/WHO (1979)
                8        1.5                                                   0.04-0.02           0.024-0.020

    Finland     2        0.64     not stated                                                                            0.05     Anon. (1978b)
                6        1.5      not stated                        0.24-0.06                      0.07-0.02
                8        1.5      not stated                        0.26-0.05                      0.08-0.02
    a  nd = not detectable;
       ns = not stated.
    b  WP = Wettable powder;
       EC = Emulsifiable concentrate.
    5.2.2  Milk

         The results of supervised trials in which cows were treated with 
    trichlorfon via several routes of exposure and the residues in the
    milk  measured are summerized in Table 6.

         Trichlorfon residues in cow's milk were mainly studied in animals
    that were administered the pesticide orally. The reports showed
    relatively high levels and a gradual disappearance of trichlorfon in
    the milk of treated cows. The residue values in  FAO/WHO report (1979)
    were much higher than those in others (Table 6).

         To control botflies, a 11.2% aqueous solution of trichlorfon was 
    applied dermally to lactating cows. Maximum residues of trichlorfon 
    and dichlorvos were found in the first milking (0.2 and 0.03 mg/litre,
    respectively) and were still detectable in the third milking. Storage 
    and short-term heating of the milk did not essentially degrade the 
    insecticide, but, with boiling, an accelerated transformation of 
    trichlorfon to dichlorvos took place (Fechner et al., 1968).

         Treatment of cows with 0.25 or 0.5% aqueous solution of 
    trichlorfon resulted in residues in milk of 0.02 and 0.7 mg/litre,
    respectively, within the first 72 h following treatment. The levels of 
    trichlorfon were higher in the morning than in the evening flow
    (IRPTC/GKNT, 1983).

         The trichlorfon residues in cow's milk were in direct proportion 
    to the veterinary use of the insecticide on the cows. Heat processing 
    of milk had little effect on trichlorfon residues. However,
    evaporation or spray drying of the milk reduced the residue levels 
    considerably (Konrad et al., 1975).

    5.2.3  Meat

         Trichlorfon residues in pigs and sheep treated with the chemical 
    under supervised trial conditions are shown in Table 7. The results 
    revealed that trichlorfon residues in pork rapidly disappear; they
    were  below the detection limit (0.01 mg/kg) 24 h after subcutaneous 
    application of 25 mg/kg body weight. The residues following spray 
    treatment of sheep against harmful insects decreased to below the 
    detection limit (0.01 mg/kg) after 168 h (Dedek & Schwarz, 1970a).

         32P-labelled trichlorfon was poured evenly on to 600 cm2
    areas of the freshly shorn backs of sheep at a rate of 20 mg/kg. Only
    a minimal concentration (0.1 mg/kg) of the insecticide was detected in 
    the blood of the sheep. However, trichlorfon levels in the blood of
    cattle were higher than those in the blood of sheep at a similar dose.
    When special solvents were used for the preparation of the trichlor
    fon solution and the dose was increased to 50 mg/kg, the level of 
    residues in the blood of the sheep increased to 1.2 mg/litre (Dedek 
    & Schwarz, 1970b).

        Table 6.  Residues of trichlorfon in milk of cows after application

    Method of                                           Residues (mg/kg) in milk after application                                   Reference
                     mg/kg  1 h    2 h      3 h   4 h   6 h   8 h       9 h    10 h   12 h      20 h     24 h   32-72 h  96 h  168 h
    Dermal           80            0.1-0.25                   0.05-0.25                                                  0.05        Mollhoff

    Dermal           36                                       0.1-0.2                                    0.05                        Mollhoff

    Dermal           100                                      0.1-0.2                           0.05-0.1        0.01                 Mollhoff

    Dermal           100                                                              0.05-0.1  0.05                                 Mollhoff

    Oral             3      0.033           0.091       0.080           0.052                            0.003  0.001                Nakahara 
                                                                                                                                     et al.

    Oral             30     0.56            0.33        0.25            0.16                             0.007  0.001                Nakahara 
                                                                                                                                     et al.

    Oral             1a     0.034           0.029                       0.021                            0.009  0.001                Nakahara
                                                                                                                                     et al.

    Intramuscularb   25            2.4            1.3   0.7   0.5              0.25                      0.1                         Dedek &

    Table 6. (continued)
    Method of                                           Residues (mg/kg) in milk after application                                   Reference
                     mg/kg  1 h    2 h      3 h   4 h   6 h   8 h       9 h    10 h   12 h      20 h     24 h   32-72 h  96 h  168 h

    Pour-ond         20            1.2            0.5   0.3   0.2              0.1                       0.05                        FAO/WHOc

    Pour-one         20            0.2            0.3   0.35  0.35             0.2                       0.1                         FAO/WHOc

    Pour-onf         30                                                        0.45                                      0.05  0.01  Dedek &
    a  1 mg trichlorfon/kg body weight for 5 days.
    b  50% trichlorfon in polyethylene glycol.
    c  Data cited to fit in this table.
    d  2% trichlorfon in mineral oil.
    e  2% trichlorfon in vegetable oil.
    f  5.7% in aqueous solution.
         Six USSR reports were available concerning supervised trials on 
    pigs (7 mg/kg in meat and 12 mg/kg in fat after unspecified treatment;
    Yonova & Zhecheva, 1974), and sheep (Nepoklonov & Bukshtynov, 1971).
    According to the English summaries of the reports, the trichlorfon was
    rapidly absorbed and distributed among various organs and tissues,
    then metabolized and eliminated.

    5.2.4  Poultry and eggs

         The trichlorfon contents of the organs of hens treated externally 
    with 1-8% aqueous solutions were 0.03-1.5 mg/kg, 0.01-0.7 mg/kg,
    0.04-1.0 mg/kg, 0.02-0.8 mg/kg, 0.01-1.5 mg/kg or 0.02-0.9 mg/kg in
    the muscle, liver, lung, heart, kidney and brain, respectively, within
    the first 5 days after application. The eggs from hens treated 
    externally with 6-8% trichlorfon contained trichlorfon levels of
    0.01-0.05 mg/kg (IRPTC/GKNT, 1983).

         Residues of trichlorfon one day after the spraying of chickens at 
    the rate of 150 mg/kg body weight were as follows (mg/kg): egg shell,
    0.48; egg white, 0.27; egg yolk, not detectable. Trichlorfon was
    preserved in chicken carcasses kept for six months at -10 °C, but it
    quickly decomposed when the carcasses were boiled (Dmitriyev, 1970).

    5.2.5  Fish

         Trichlorfon residues in eels were determined 1 and 5 days after 
    ponds were treated with a 1 mg/litre aqueous solution of the 
    insecticide. The results showed that the insecticide decomposed in  a
    short time to form dichlorvos in neutral and weakly alkaline water. In
    pond water with a pH of 8-10, less than 10% of the applied 
    trichlorfon was degraded after 30 min and dichlorvos was detected. The
    residues of trichlorfon and dichlorvos in the eels were 0.009-0.032
    mg/kg and <0.005-0.02 mg/kg, respectively, on the first day 
    following treatment, and 0.011 mg/kg and 0.009-0.032 mg/kg,
    respectively, on the 4th day after treatment. There was a good 
    correlation between the residual amounts of trichlorfon in the eels 
    and the concentrations in the water. Residues of trichlorfon and 
    dichlorvos, which were detected on the skin of eels in water at pH
    7.0, could be removed by rinsing. Insecticide residues were found in
    the internal organs of only one out of 7 eels caught in the field
    pond. Carps exposed to an aqueous solution of trichlorfon at 0.25
    mg/kg were examined on the 2nd, 4th, and 9th days after exposure.
    Residues of trichlorfon and dichlorvos could not be detected in the
    fish on the second day (Nakahara et al., 1973).

    Table 7.  Residues of trichlorfon in various meats after experimental application
    Animal   Method of     mg/kg or                        Residues (mg/kg) after application                            Reference
             application   g/m3                                                                                         
                                      1 h    2 h    3 h    4 h   6 h   12 h   24 h   48 h  72 h   120 h   168 h   240 h

    Hen      spray         150 g/m3                              1.26         0.96   ND                                  Dmitriyev

    Pig      subcu-        25 mg/kg   6      5      3-4    2-3   1     0.1    0.01                                       Dedek &
             taneous                                                                                                     Schwarz

    Sheep    spray         4 g/m3                                             2.3          0.8    0.6     trace   NDa    Nepoklonov&
    a  ND = not detectable.
    5.3  Occupational exposure

         A thousand-fold dilution of 50% trichlorfon emulsifiable
    concentrate was applied to apple trees by operators using a speed 
    sprayer or a power sprayer; the operators wore their usual working 
    clothes or special protective clothes, plus rubber gloves, full length 
    rubber boots, and masks with, or without, charcoal filters. The 
    plasma and red blood cell cholinesterase activity of the operators 
    following both kinds of spraying did not show any significant  changes
    compared with pre-exposure values. The calculated cumulative
    trichlorfon exposures per person with a speed sprayer and a power
    sprayer were 177 ± 54.0 mg and 1179 ± 398 mg, respectively (Kawai et
    al., 1982).

         Occupational exposures to levels exceeding 0.5 mg/m3 have been 
    reported (Lu et al., 1984; Hu et al., 1986).


    6.1  Absorption and distribution

    6.1.1  Animal

         In cattle, percutaneous absorption of 32P-labelled trichlorfon
    after pour-on application is extremely affected by the solvent used
    (Dedek & Schwarz, 1967). With a 2% aqueous solution, only very little
    trichlorfon ended up in the blood (about 0.15 mg/litre). In contrast,
    trichlorfon in a 2% mineral oil solution, was absorbed rapidly,
    reaching a maximum concentration in the blood of 3.1 mg/litre at 42
    min. The percutaneous absorption rate was considerably slower in
    sheep, than in cattle (Dedek & Schwarz, 1970). In  in vitro 
    absorption studies on isolated cattle skin, partition of trichlorfon
    was dependent on the relative solubilities in the water (blood) and
    organic phases (Dedek & Schwarz, 1967).

         Trichlorfon administered orally to mammals is rapidly absorbed,
    degraded, and eliminated. When 32P-labelled trichlorfon was
    administered orally to a cow (25 mg/kg), the radioactivity appeared in
    the blood within half an hour and reached a maximum (15.1 mg/litre
    trichlorfon equivalent) between 1 and 3 h. It, then decreased rapidly
    (less than 1 mg/litre) within 24 h of treatment (Robbins et al.,
    1956). In the liver and brain of a mouse treated orally with
    32P-trichlorfon (6.2 mg/mouse), chloroform extractable radioactivity
    of 188 mg/kg and 28.2 mg/kg trichlorfon equivalents, respectively, was
    found, 15 min after treatment (Miyata & Saito, 1973). The
    radioactivity decreased rapidly to 6.4 and 1.61 mg/kg trichlorfon
    equivalents, respectively, at 4 h. The biological half-life of
    trichlorfon in mice was about 80 min, when it was administered orally.

         Thirty minutes after radiolabelled trichlorfon was given by
    stomach tube to pregnant guinea-pigs on days 35 and 52 of gestation,
    the compound had rapidly become distributed to the main organs of the
    animals, the highest concentrations being present in the liver,
    kidney, and lung. Thirty minutes after dosing, there was a substantial
    uptake of trichlorfon into the fetus, and this became more pronounced
    at the later stage of gestation (52 days), the concentration in fetal
    liver equalling that in the placenta at that time (Berge & Nafstad,

    6.1.2  Human

         In the blood of a patient who ingested 10 g of trichlorfon, the
    concentration of the insecticide was 270 µg/litre after 24 h,
    following which it rapidly decreased and was undetectable after 94 h
    (Fournier et al., 1978). In a 70-year-old woman who died from acute
    trichlorfon poisoning, caused by the ingestion of a 50% emulsifiable 
    concentrate, the levels of trichlorfon in the organs (µg/g) were 310 
    in the blood, 487 in the liver, 465 in the brain, 416 in the kidney,

    and 2240 in the urine. In addition, about 7.2 g of trichlorfon was
    found in the stomach contents (Yashiki et al., 1982).

         A 76-year-old male, who had attempted suicide by ingesting about
    50 ml of trichlorfon, died approximately 8 h later. The trichlorfon
    concentration was found to be 215 µg/g in a blood sample and 15.0 mg/g
    in a gastric lavage liquid sample, both of which were collected about
    1 h after intake (Yashiki et al., 1988).

         Following the administration of metrifonate to humans at doses of
    7.5-10 mg/kg body weight, peak levels of trichlorfon in the plasma (8
    µg/ml) were reached in 2 h or less. Detectable levels were still
    present in the body after 8 h (Nordgren, 1981).

         Four groups of 4 healthy human volunteers each were given
    metrifonate at 2.5, 5, 7.5, or 15 mg/kg (single dose). Peak plasma
    levels of 5-10, 5-15, 10-25, or 15-100 µmol/litre were observed after
    each of the respective doses. There was no evidence of dose- dependent
    kinetics (Aden Abdi, 1990).

    6.2  Biotransformation

         Trichlorfon(1) rearranges readily to form dichlorvos
    (2,2-dichlorovinyl dimethyl phosphate)(2) via dehydrochlorination
    (Lorenz et al., 1955; Metcalf et al., 1959; Nordgren et al., 1978;
    Hofer, 1981; Nordgren, 1981). This transformation occurs under
    physiological conditions (Miyamoto, 1959). Dichlorvos has been found
    in animal tissues  in vivo at less than 5% of the administered dose
    following trichlorfon treatment (Metcalf et al., 1959; Nordgren et
    al., 1978; Dedek, 1981). However, it could not be detected very often
    and only its degradation products, such as demethyl dichlorvos
    (2,2-dichlorovinyl methyl hydrogen phosphate)(4) were found, as
    evidence of the formation of dichlorvos  in vivo (Arthur & Casida,
    1957; Bull & Ridgway, 1969; Miyata & Saito, 1973; Otto et al., 1980).
    Dichlorvos is also formed from trichlorfon in humans. Following the
    administration of metrifonate, dichlorvos was found in erythrocytes
    and plasma at levels corresponding to 0.2-1% of the metrifonate
    concentrations (Nordgren, 1981; Aden Abdi, 1990).

         In  in vitro experiments, the conversion of trichlorfon into
    dichlorvos was demonstrated by incubating with serum (Dedek & Schwarz,
    1966), with the soluble fraction from cow and chicken liver
    homogenates (Akhtar, 1982), and with the digestive juice of the
    silkworm larvae (Sugiyama & Shigematsu, 1969). Demethylation also
    occurred with liver homogenates. The half-life of trichlorfon in the
    blood of various mammals  in vitro ranged up to 30 min (Dedek &
    Schwarz, 1966). Using housefly homogenate, another metabolite was
    produced with the same mass spectrum as dichlorvos, but a different
    Rf value on TLC; it was proposed that this was dimethyl
    2,2-dichloro-1-hydroxyvinylphosphonate (Lange, 1980).

         The main metabolites of 32P-trichlorfon found in mammals were
    demethyl trichlorfon (Fig. 2)(6), demethyl dichlorvos(4), dimethyl
    hydrogen phosphate(5), methyl hydrogen phosphate(7) and phosphoric
    acid(8) (Hassan et al., 1965; Bull & Ridgway, 1969; Miyata & Saito,
    1973). The percentages of the water-extractable metabolites found in
    the whole body in mice, 0.5 and 4 h after oral administration of 6.2
    mg 32P-trichlorfon, were respectively, demethyl trichlorfon (4.3,
    4.0), demethyl dichlorvos (20.8, 9.9), dimethyl hydrogen phosphate
    (34.6, 47.8), methyl hydrogen phosphate (14.3, 17.8), phosphoric acid
    (22.4, 20.9), and unknown compounds (3.6, 0.0) (Miyata & Saito, 1973).

         The glucuronide of trichloroethanol(9) was isolated from the
    urine of a dog in amounts equivalent to 67% of the administered dose
    of trichlorfon, indicating the occurrence of hydrolytic P-C bond
    cleavage (Arthur & Casida, 1957). Another glucuronide containing
    phosphorus and chlorine atoms in 1:2 ratio was found in the urine of
    rabbits administered with trichlorfon (Miyamoto, 1961).

         Thus, the main degradation routes of trichlorfon are
    demethylation, P-C bond cleavage, and ester hydrolysis via dichlorvos.
    Proposed metabolic pathways of trichlorfon, together with the
    established metabolic pathways of dichlorvos, are illustrated in
    Fig. 2.

    6.3  Elimination and excretion

         Trichlorfon administered to mammals is rapidly eliminated,
    primarily via the urine. About 66% of the dose administered orally to
    cows was eliminated in the urine within 12 h. Following oral
    administration (6.2 mg/animal) of 32P-trichlorfon to mice, 70% of
    the total dose was eliminated in the urine and faeces in 12 h (Miyata
    & Saito, 1973). More than 80% of the eliminated compound was present
    in the urine. The majority of the eliminated radioactive compounds in
    both the urine and faeces were degradation products, and only a small
    percentage of them were chloroform extractable. The biological
    half-life of trichlorfon administered orally to mice was estimated to
    be about 80 min (Robbins et al., 1956).

         When methyl-14C-trichlorfon was administered intraperitoneally 
    to rats, 24% of the radioactive carbon was eliminated as carbon
    dioxide in the expired air, within 10 h; 32% was present in the urine
    as formate and dimethyl hydrogen phosphate, within 24 h (Hassan &
    Zayed, 1965).

         Residues of trichlorfon were detected in the milk following the
    oral treatment of cows. Less than 0.2% of the total dose administered
    was recovered in the milk at the end of 144 h (Robbins et al., 1956).
    Single doses of 3 or 30 mg/kg body weight resulted in maximum residues
    in the milk of 0.09 mg/kg in 3 h and 0.55 mg/kg in 1 h, respectively;
    the residues then decreased rapidly to 0.003-0.007 mg/kg at 24 h. A
    small amount of dichlorvos (0.04 mg/kg) was detected as a metabolite

    FIGURE 2

    in the milk, 1-3 h after the higher dose (Nakahara et al., 1972). When
    lactating cows were treated dermally by washing with 11.2%
    trichlorfon, 6-8 h before milking, trichlorfon residues (equal to or
    more than 0.2 mg/kg) and dichlorvos residues (0.03 mg/kg) were found
    in the first milking (Fechner et al., 1968). Trichlorfon was detected
    up to the third milking, 32 h after application, but neither
    trichlorfon nor dichlorvos could be demonstrated in the fourth

    6.4  Reaction with body components

    6.4.1  In vitro studies

         Several investigators have reported the considerable inhibitory
    activity of trichlorfon on acetylcholinesterase  in vitro.  The
    pI50 for acetylcholinesterase was 5.5 and the bimolecular rate
    constant for rat brain acetylcholinesterase was 3.18 × 104/min
    (Arthur & Casida, 1957; Buchet & Lauwerys, 1970). The activity is,
    however, strongly pH-dependent and is about 30-fold more active at pH
    7.4-7.6 than at pH 6.0-6.5. At the lower pH range, trichlorfon is more
    stable with practically no inhibiting activity against
    cholinesterases. In contrast, dichlorvos is equally active at this pH
    range (Metcalf et al., 1959; Miyamoto 1959; Reiner et al., 1975).
    However, the rates of non-enzymatic reactivation of the enzymes after
    inhibition by trichlorfon and dichlorvos are similar. Thus, it is now
    believed that the  in vitro inhibitory activity of trichlorfon is due
    to its rapid, spontaneous, non-enzymatic conversion into dichlorvos.

         Frohlich et al. (1990) determined the competitive and
    uncompetitive constants for the action of trichlorfon on bee
     p-nitrophenyl acetate hydrolysing esterase to be 4.5 × 10-6
    mol/litre and 1.6 × 10-5 mol/litre, respectively.

         The inhibition constant for trichlorfon and chicken liver fluora
    cetanilidase was determined to be 2.5 × 10-6 mol/litre (Nakamura &
    Ueda, 1967).

    6.4.2  In vivo studies

         In rats given trichlorfon intraperitoneally at 150 mg/kg,
    considerable increases in the activities of superoxide dismutase
    (× 1.94) and microsomal cytochrome P-450 (× 2.09), and in lipid
    peroxidation (× 1.44) in the liver were observed, 2.5 h after
    treatment (Matkovics et al., 1980).

         In  in vivo studies on mice receiving a diet containing 100 mg
    trichlorfon/kg, the cholinesterase activities in the brain,
    erythrocytes, and plasma were, respectively, 72.1, 115.7, and 92.7% of
    control values after one-day (24 h) and 79.9, 83.8, and 81.0%,
    respectively, after 20 days (Tsumuki et al., 1970).

         A mixture of trichlorfon and phenothiazine, which was
    administered to horses with feed as an antihelminthic at a single dose
    level of 35.8 mg/kg, reduced the cholinesterase activity in whole
    blood and plasma to 32 and 20%, respectively, by 24 h. The activity
    increased to about 80% after 4 weeks (Bello et al., 1974).

         In humans who received an oral dose of 7.5 mg trichlorfon/kg  on
    two successive days, the maximum inhibition of erythrocyte and plasma
    cholinesterase was 52 and 94%, respectively. The red cell
    cholinesterase activity recovered very slowly to reach only 66% of the
    pretreatment level, 28 days after treatment, while that of the plasma
    cholinesterase recovered rapidly to reach 78% at 22 days (Lebrun &
    Cerf, 1960).

         When 14CH3-labelled trichlorfon was adminstered intravenously
    to rats at 40 mg/kg, the radioactive carbon (14C) was found mainly
    in the liver (25 mg/kg) and kidneys (11.6 mg/kg), 3 h after treatment
    (Dedek & Lohs, 1970). Similar results were obtained with intra
    peritoneal treatment. Only about 1% of the radioactivity found in the
    organs was extractable with acetone, indicating that most of the 14C
    in the tissues was bound to body components. The bound 14C in the
    organs investigated was less than 10% of the total dose. It
    disappeared rather rapidly and the bound radioactivity decreased to
    about one-tenth by 17 h. In another study, about 10% of the phosphorus
    portion, administered orally to mice as 32P-trichlorfon, was found
    bound to tissue (Miyata & Saito, 1973).


         Acute toxicity data for trichlorfon on aquatic and terrestrial
    non-target organisms are summarized in Tables 8 and 9, respectively.

    7.1  Microorganisms

         When trichlorfon was applied to a cotton field at 0.5 g/m2, the
    total count of soil fungi and the counts of some fungal species, such
    as  Aspergillus niger, Fusarium oxysporum, and  A. fumigatus were
    elevated 3 days after treatment. A depressed effect was observed in
     Myrothecium verrucaria.  After 40 days, trichlorfon did not have any
    significant effects on the total count of soil fungi (Abdel-Kader et
    al., 1978). Trichlorfon at 8-16 mg/kg in agar affected the mycelial
    growth of 4 fungi  (A. fumigatus, F. moniliforme, Penicillium
    italicum, and  Sclerotium cepivorum), even 10 days after application
    (El-Hissy & Abdel-Kader, 1980).

         In field pond trials, Grygierek & Wasilewska (1981) found that
    trichlorfon applied at 1 mg/litre reduced zooplankton numbers within
    the first 24 h of application and bottom fauna after 1 week. Rotifers
    ( Keratella sp.) and cladocerans ( Bosmina) were especially
    sensitive to the chemical. The renewal of the affected fauna
    communities took about 1 month. When the pond was treated with
    trichlorfon at 300-800 µg/litre, the numbers of cladocerans and
    copepods decreased, whereas rotifers and phytoplankton increased
    markedly in number. However, the total biomass was not affected (Grahl
    et al., 1981).

         Cain & Cain (1984) incubated the green alga  Chlamydomonas
     moewusii in a medium containing trichlorfon at concentrations up to
    80 µmol/litre (21 mg/litre). At the highest concentration, growth of
    the algae was 76% of control levels. Zygospore germination of
     Chlamydomonas was unaffected at 80 µmol/litre (21 mg/litre) (108% of

    7.2  Invertebrates

         Trichlorfon is highly toxic for aquatic arthropods with LC50
    values ranging from 0.75 to 7800 µg/litre in 48-/96-h tests (Table 8).

         The toxicity of trichlorfon for amphipods increased 2-fold when
    the pH of the media was increased from 7.5 to 8.5; similarly the
    toxicity for stonefly naiads increased about 20-fold when the pH was
    increased from 6.5 to 8.5 (Woodward & Mauck, 1980). Trichlorfon is
    less toxic for mollusca, the 48-h LC50 values ranging up to 25.4
    mg/litre. Prolonged exposure (10 days) resulted in a 10-40 times
    increase in toxicity (Singh & Agarwal, 1981).

        Table 8.  Acute toxicity of trichlorfon for non-target aquatic organisms

    Species         Size                Toxicity    (mg/litre)   Formulationa   Systemb  Temperature   pH       Hardnessc Reference

     Colpidium                            MAD           10                                   20                           Dive
     campylum                                                                                                             et al.


    Rainbow trout                       96-h LC50      4.85       T             S            12                           Marking
     (Salmo                                                                                                               & Mauck
     gairdneri)                                                                                                           (1975)

    Cutthroat trout                     96-h LC50      1.68       T             S            12          7.5      40      Woodward
     (Salmo clarki)                     96-h LC50      3.25       T             S            12          7.5      40      & Mauck
                                        96-h LC50      5.75       T             S             7          7.5      40      (1980)
                                        96-h LC50      4.75       T             S            12          6.5      40
                                        96-h LC50      0.375      T             S            12          8.5      40
                                        96-h LC50      0.620      T             S            12          7.8     320

    Cherry salmon   2.8 g               12-h LC50     10.2       50%EC          SS           17.6                         Kimura
     (Onchorhyncus  2.8 g               24-h LC50      1.1       50%EC          SS           17.6                         et el.
     masou)         2.8 g               48-h LC50      1.1       50%EC          SS           17.6                         (1971)
                    2.8 g               96-h LC50      1.1       50%EC          SS           17.6

    Carp            egg                 24-h LC50     15          EC            S            25        6.9-7.2            Hashimoto
     (Cyprinus      0.60 cm             24-h LC50     11          EC            S            25        6.9-7.2            et al. 
      carpio)       0.73 cm             24-h LC50      8.8        EC            S            25        6.9-7.2            (1982)
                    1.16 cm, 0.013 g    24-h LC50     14          EC            S            25        6.9-7.2
                    1.52 cm, 0.038 g    24-h LC50     15          EC            S            25        6.9-7.2
                    2.51 cm, 0.23 g     24-h LC50     14          EC            S            25        6.9-7.2
                    3.86 cm, 0.87 g     24-h LC50     15          EC            S            25        6.9-7.2
                    5.22 cm, 2.34 g     24-h LC50     15          EC            S            25        6.9-7.2

    Table 8. (continued)

    Species         Size                Toxicity    (mg/litre)   Formulationa   Systemb  Temperature   pH       Hardnessc Reference
    Carp                                48-h LC50   1200         4%D            S            25                           Nishiuchi
     (Cyprinus                          48-h LC50     30         50%EC          S            25                           (1979a)
      carpio)                           48-h LC50     50         80%WP          S            25

    Carp            5.3 cm, 2.2 g       24-h LC50     40                        S            15                           Nishiuchi
     (Cyprinus      5.3 cm, 2.2 g       24-h LC50     40                        S            20                           (1977)
      carpio)       5.3 cm, 2.2 g       24-h LC50     28                        S            25
                    5.3 cm, 2.2 g       24-h LC50     25                        S            30
                    5.3 cm, 2.2 g       24-h LC50     25                        S            35

    Fathead minnow                      96-h LC50     51                                                                  Livingston
     (Pimephales                                                                                                          (1977)

    American eel    black stage         96-h LC50      1.32                     S            22        7.2-7.6   40-48    Spehar et 
     (Anguilla      glass stage         96-h LC50      1.31                     S            22        7.2.-7.6  40-48    al. (1981)
      rostrata)     yellow phase        96-h LC50      8.57                     S            22        7.2.-7.6  40-48    Hinton &

    Striped bass    6 cm, 2.7 g         24-h LC50     10.4       50%SP          S            21          8.2      35      Wellborn
     (Roccus        6 cm, 2.7 g         48-h LC50      9.2       50%SP          S            21          8.2      35      Jr. (1969)
      saxatilis)    6 cm, 2.7 g         96-h LC50      5.2       50%SP          S            21          8.2      35

    Bluegill        0.87-2.4 g          24-h LC50     41.0a      50%SP          S            18           7      51.3     McCann &
     (Lepomis                                                                                                             Jasper
     macrochirus)                                                                                                         (1972)


    Water flea                          3-h LC50       0.18       4%P           S            25                           Nishiuchi
     (Daphnia                           3-h LC50       0.030     50%EC          S            25                           (1979b)
      pulex)                            3-h LC50       0.019     80%WP          S            25

    Table 8. (continued)

    Species         Size                Toxicity    (mg/litre)   Formulationa   Systemb  Temperature   pH       Hardnessc Reference
    Water flea                          1-h LC50       0.088      EC            S            25                           Nishiuchi
     (Daphnia                           3-h LC50       0.014      EC            S            25                           (1979c)
      carinata)                         6-h LC50       0.0064     EC            S            25
                                        24-h LC50      0.0012     EC            S            25
                                        48-h LC50      0.00075    EC            S            25

    Amphipod                            96-h LC50      0.108      T             S            12          7.5     40       Woodward 
     (Garnmarus                         96-h LC50      0.052      T             S            12          8.5     40       & Mauck
     pseudolimnaeus)                                                                                                      (1980)

    Mayfly          9.3 mm, 5.6 mg      3-h LC50       1.8        EC            S            25                           Nishiuchi 
     (Cloeon        9.3 mm, 5.6 mg      6-h LC50       0.75       EC            S            25                           & Asano
      diptrum)      9.3 mm, 5.6 mg      24-h LC50      0.075      EC            S            25                           (1979)
                    9.3 mm, 5.6 mg      48-h LC50      0.056      EC            S            25

    Dragon fly      2.3 cm, 0.62 g      48-h LC50      0.042      EC                         25                           Nishiuchi
     (Orthetrum                                                                                                           (1981)

     (Sympetrum     2.1 cm, 0.56 g      48-h LC50      0.15       EC                         25                           Nishiuchi
     frequens)                                                                                                            (1981)

     (Sigara        5.9 mm, 6.1 mg      48-h LC50      0.15       EC                         25                           Nishiuchi
      substriata)                                                                                                         (1981)

     (Micronecta    3.2 mm, 1.8 mg      48-h LC50      0.075      EC                         25                           Nishiuchi
      sedula)                                                                                                             (1981)

    Stonefly                            96-h LC50      0.100      T             S            12          8.5     40       Woodward 
     (Pteronarcella                     96-h LC50      0.0098     T             S            12          7.5     40       & Mauck
      badia)                            96-h LC50      0.0053     T             S            12          6.5     40       (1980)

    Table 8. (continued)

    Species         Size                Toxicity    (mg/litre)   Formulationa   Systemb  Temperature   pH       Hardnessc Reference
     (Eretes        1.5 cm, 0.20 g      48-h LC50      0.32       EC                         25                           Nishiuchi
      sticticus)                                                                                                            (1981)

    Crayfish        adults, 15-38 g     96-h LC50      7.8        T             S            19          7.8     35       Andreu-Moliner
     (Procambarus                                                                                                         (1986)


    Snail           2.9 cm, 1.6 g       48-h LC50      1.8        EC                         22                           Nishiuchi
     (Semisulcospira                                                                                                      & Yoshida
      libertina)                                                                                                          (1972)

    Snail           2.4 cm, 3.3 g       48-h LC50      4.8        EC                         22                           Nishiuchi 
     (Cipangopaludina                                                                                                     & Yoshida
      malleata)                                                                                                           (1972)

    Red snail       0.72 cm. 1.1 g      48-h LC50      1.8        EC                         22                           Nishiuchi &
     (Indoplanorbis                                                                                                       Yoshida
     exustus)                                                                                                             (1972)

    Physa-snail     0.91 cm, 0.11 g     48-h LC50      3.2        EC                         22                           Nishiuchi 
     (Physa acuta)                                                                                                        & Yoshida

                                        10-day LC50    0.05                                 15-20        7.3              Mandoul et
                                                                                                                          al. (1967)

    Snail           1.2 cm              48-h LC50      2.2                                                                Singh &
     (Lymnaea       1.2 cm              72-h LC50      0.65                                                               Agarwal
     acuminata)     1.2 cm              96-h LC50      0.3                                                                (1981)
                    1.2 cm              168-h LC50     0.22
                    1.2 cm              240-h LC50     0.058

    Table 8. (continued)

    Species         Size                Toxicity    (mg/litre)   Formulationa   Systemb  Temperature   pH       Hardnessc Reference
     (Pila globosa) 3.5 cm              48-h LC50     25.4                                                                Singh &
                    3.5 cm              72-h LC50     19.0                                                                Agarwal
                    3.5 cm              96-h LC50      8.0                                                                (1981)
                    3.5 cm              168-h LC50     2.8
                    3.5 cm              240-h LC50     2.2

     (Gryphaea                          10-day LC50    2.45                                 9-19                 SW       Mandoul et
      angulata)                                                                                                           al. (1967)
    a  T = Technical.
       EC = Emulsifiable concentrate.
       D = Dust.
       WP = Wettable powder.
       SP = Soluble powder.
       P = Powder.

    b  S = Static.
       SS = Semi-static.
       SW = Sea water.
       MAD = Minimal active dose.

    c  Hardness (mg/litre as CaCO3).
         Trichlorfon at concentrations of up to 30 mg/litre did not affect
    byssal attachment in seed mussels ( Mytilus edulis) (Roberts, 1975).

         Trichlorfon showed cholinomimetic properties on the excitor or
    inhibitor receptors of acetylcholine in the isolated heart, median
    dorsal radula protractor muscle, and rectum of the snail  Pila globosa
    (Singh & Agarwal, 1979).

         When freshwater snail,  Lymnaea acuminata, was exposed to 10 or
    20 mg trichlorfon/litre for 48 h, the rate of oxygen consumption and
    the concentration of glycogen were both reduced, while the levels of
    lactic acid and reducing sugars were enhanced. The effects persisted
    for 7 days after withdrawal of the trichlorfon. On the basis of these
    observations, Mahendru & Agarwal (1981) concluded that trichlorfon may
    affect not only cholinesterase activity but also other enzyme systems,
    such as the ones involved in carbohydrate metabolism.

    7.3  Aquatic vertebrates

         Trichlorfon is moderately toxic for fish, the 96-h LC50 values
    ranging from 0.4 to 51 mg/litre (Table 8). The effects of trichlorfon
    on the susceptibility of the developmental stages of carp were not
    remarkable (Hashimoto et al., 1982). However, with regard to  water
    quality, the toxicity for fish increased as the water temperature, pH,
    and hardness increased. The increase in toxicity was affected least
    (3.4 fold) by increasing the temperature from 7 to 12 °C and most
    (13-fold) by changing the pH from 6.5 to 8.5 (Woodward & Mauck, 1980).

         Cherry salmon fingerlings (Onchorhyncus masou) were exposed to
    one-tenth (0.105 mg/litre) and one-third (0.310 mg/litre) of the 96-h
    LC50 value (1.1 mg/litre) of trichlorfon for 6 weeks in a
    flow-through system. Trichlorfon initially retarded the growth of the
    fish at both concentrations, but then the fish grew normally, and the
    condition factors (weight-length coefficent) of the test fish did not
    differ significantly from those of the controls after 6 weeks of
    exposure to trichlorfon. Histopathological examination showed that the
    liver cells were swollen with an obscure cell contour at the beginning
    of the study, but no compound-induced histopathological changes were
    observed after 6 weeks of exposure (Kimura et al., 1971).

         When bluegill fingerlings were exposed to formulations of
    trichlorfon, haemorrhage along, and fractures of, the caudal vertebrae
    (usually extended over three vertebrae) occurred 4-8 h after treatment
    at concentrations of 8-52 mg/litre (McCann & Jasper, 1972).

         Matton & Laham (1969) treated 1-inch rainbow trout larvae for 16
    h with 10-100 mg trichlorfon/litre, or for 40 h with 5 mg/litre.
    Histochemical examination revealed that the acetylcholinesterase
    activity was inhibited in the septa of the myotomes and at the
    myoneural junctions. Furthermore, pathological changes were observed
    in the heart, liver, blood cells, pseudogills, and muscular tissues.

    7.4  Terrestrial vertebrates

         Trichlorfon is relatively toxic for birds with oral LD50 values
    of 40-180 mg/kg body weight (Table 9). Peakall & Bart (1983) reported
    a 5-day LD50 value of 720 mg/kg for Bobwhite quail.

         Residues of trichlorfon and dichlorvos in the bodies of
    canopy-feeder birds (Baltimore orioles, crested fly-catcher, and blue
    jay) were 0.005-0.04 mg/kg, 3 days following an aerial application of
    trichlorfon at 1.12 kg/ha (Kurtz & Studholme, 1974).

         Following aerial spraying of trichlorfon at 1.12 kg/ha, the brain
    cholinesterase activity was about 20% less than that in the controls
    in 2 out of 10 bird-species; in the other 8 species, the activity was
    not depressed, even immediately after spraying (Zinkl et al., 1977).

         According to a survey based on two, 1-h counts in 20-ha plots, 5
    days before and after the spraying of 1120 g trichlorfon/ha, a
    virtually identical change in the number of bird species and the total 
    number of hearings was observed. The application of trichlorfon
    resulted in a slight drop in song-bird activity (165 to 151). It did
    not produce any effects on cholinesterase activity in fly-catchers and
    only 10% inhibition in northern oriols, after 3 days. There was a
    considerable decrease in the singing of male birds after spraying; a
    marked increase in feeding activity immediately following spraying was
    noted. However, examination of the data on individual species does not
    show any consistent pattern: the great crested fly-catcher decreased
    but other fly-catchers did not, the American redstart decreased, but
    another canopy species, the red-eyed vireo, did not. No significant
    effects on the numbers of breeding pairs, bird abundance, nesting
    success, or mortality were found. Brain ChE levels were reduced by 20%
    in 6 out of 103 birds collected during the 5-day period following
    spray (Peakall & Bart, 1983).

         Japanese quail were given trichlorfon daily for 20 days at an
    oral dose of 5 mg/kg body weight. Haematological examinations were
    made on the 5th, 10th, 15th, and 20th day of treatment and on the 5th,
    10th, 15th, and 30th day after stopping treatment. The number of
    erythrocytes dropped on the 5th and 10th days, and the values of the
    haematocrit and haemoglobin fell on the 5th day. A significant
    increase in erythroblast contents was found on the 5th and 10th day.
    No other significant changes of the above parameters were observed up
    to the 30th day after treatment. The numbers of leukocytes,
    lymphocytes, neutrophils, and monocytes sharply increased from the 5th
    to 15th day of treatment, and quickly dropped to normal ranges on the
    10th day after stopping treatment (Gromysz-Kalkowska et al., 1985).

        Table 9.  Acute toxicity of trichlorfon for non-target terrestrial organisms

    Species                  Size          Application                       Toxicity        Formulationa   Temperature  Reference
    Red-winged blackbird                   oral                       LD50    37-75 mg/kg                                Schafer Jr et al.
     (Agelaius phoeniceus)                                                                                               (1983)

                                           oral                       LD50    40 mg/kg                                   Schafer (1972)

    European starling                      oral                       LD50    43 mg/kg                                   Schafer Jr et al.
     (Sturnus vulgaris)                                                                                                  (1983)

                                           oral                       LD50    47 mg/kg                                   Schafer (1972)

     (Columbia livia)         250-380 g    oral                       LD50    179.9 mg/kg                                Hattori (1974)

    White leghorn hen         1.5-2.0 kg   oral                       LD50    75 mg/kg                                   Kimmerle & Löser
                                           intraperitoneal            LD50    75 mg/kg                                   (1974)

    Japanese quail                         oral                       LD50    50 mg/kg                                   Gromysz-Kalkowska
     (Coturnix coturnix                                                                                                  (1985)

    Honey-bee                              sprayed on glass plate     LC50    0.600 W/V%                                 Abdelwahab et
     (Apis mellifera, L)                                                                                                 al. (1973)

                                           weathered residues (3 h)   24-h    17% mortality      50%SP          26       Johansen (1972)
                              128.6 mg     topical                    LD50    28.5 µg/g            T            16       Ahmad &
                                                                                                                         Johansen (1973)

    Alfalfa leafcutter bee                 weathered residues (3 h)   24-h    5% mortality       50%SP          31       Johansen (1972)
     (Megachile rotundate, F) 22.2 mg      topical                    LD50    250 µg/g             T            16       Ahmad &
                              26.1 mg                                 LD50    515 µg/g             T            16       Johansen (1973)

    Table 9. (continued)

    Species                  Size          Application                       Toxicity        Formulationa   Temperature  Reference
    Alkali bee                             weathered residues (3 h)   24-h    31% mortality      50%SP          31       Johansen (1972)
     (Nomia melanderi,
    a   SP = Soluble powder.
        T = Technical grade.
    7.5  Ecosystems

         Trichlorfon applied to ponds at the rate of 1 mg/litre water
    destroyed the food invertebrates for fish. Large numbers of
    zoo-plankton, rotifers, and crustacea, died in the first 24 h after
    treatment, whereas benthos died during the first week. The affected
    fauna, community recovered slowly. Trichlorfon treatment deprived the
    fish of valuable foods, such as crustacean and bottom fauna, for as
    long as 1 month after treatment (Grygierek & Wasilewska, 1981).


         A more complete treatise on the effects of organophosphorus
    insecticides in general, especially their short- and long-term effects
    on the nervous system, will be found in the WHO Environmental Health
    Criteria 63:  Organophosphorus insecticides - A general introduction
    (WHO, 1986).

         No-observed-effect levels in animals treated with trichlorfon
    under various conditions are summarized in Annex II.

    8.1  Acute toxicity

         LD50 values for trichlorfon in different species and following
    different routes of administration are shown in Table 10. Species
    differences in LD50 values seem to be rather small.

         The acute toxicity of trichlorfon is due to the inhibition of
    acetylcholinesterase at the nerve endings by the degradation product
    dichlorvos, leading to accumulation of endogenous acetylcholine. The
    effects are manifested by muscarinic and central nervous system signs
    and symptoms (Taylor, 1980). In the rat, the toxic effects produced by
    trichlorfon are characteristics of organophosphorus poisoning, i.e.,
    muscular fibrillation, salivation, lacrimation, incontinence,
    diarrhoea, respiratory distress, prostration, gasping, tonic and
    clonic convulsion, coma, and death. Trichlorfon caused rapid onset of
    poisoning, effects occurring within 5 min at approximate LD50 doses
    (Edson & Noakes, 1960).

         Only a slight increase in mortality was noted in weanling
    Holtzman rats compared with that in adults, when treated with
    trichlorfon (Brodeur & DuBois, 1963).

         Trichlorfon has a low dermal toxicity (LD50: > 2000 mg/kg)
    compared with that of dichlorvos (LD50: 75-900 mg/kg). The
    difference in lipid solubility between the two compounds may be a
    major factor accounting for this difference (Holmstedt et al., 1978).

         Since trichlorfon is used as a parasiticide in livestock, studies
    have been conducted to assess the effects of the chemical on
    cholinesterase activity and clinical conditions. Administration to
    horses of a single dose of trichlorfon of 60 or 80 mg/kg body weight,
    by stomach tube, resulted in moderately severe and severe colic,
    respectively, whereas a single dose of 80 mg/kg mixed into the feed
    was associated with only a transient softening of the faeces. Doses of
    40 mg/kg or less, by either method of administration, were generally
    tolerated without notable adverse effects except for the softening of
    the faeces, which tended to be self-limiting. Clinical trials at dose
    rates of 35-40 mg/kg in horses, including pregnant and nonpregnant
    mares, stallions, suckling and weanling foals, and yearlings, did not
    cause any notable adverse effects (Drudge et al., 1976).

        Table 10.  Acute toxicity of trichlorfon for several animal species
    Animal      Sex    Route         Parameter   Value          Reference
    Mouse       M      oral           LD50       800 mg/kg      Haley et al. (1975)
                F                                800 mg/kg
                M      ip             LD50       600 mg/kg      Soliman et al. (1984)

    Rat         M      oral           LD50       660 mg/kg      Benes & Cerna (1970)
                M      oral           LD50       630 mg/kg      Gaines (1969)
                F                                560 mg/kg
                M,F    dermal         LD50     >2000 mg/kg
                M      dermal         LD50      2800 mg/kg      Edson & Noakes (1960)
                M      ip (23-day     LD50       190 mg/kg      Brodeur & Dubois
                       old)                                     (1963)
                       ip (adult)                250 mg/kg
                M,F    inhalation     LC50       533 mg/m3      Kimmerle (1975a)
                       (4 h)

    Guineapig   M,F    ip             LD50       300 mg/kg      DuBois & Cotter

    Rabbit      M      dermal         LD50      5000 mg/kg      Deichmann & Lampe

    Dog         M      oral           LD50       420 mg/kg      Deichmann & Lampe
         Pretreatment of female and castrated male sheep with 1.5 mg
    trichlorfon/kg body weight by intravenous injection, which was
    insufficient to produce a significant depression of erythrocyte
    cholinesterase activity, produced toxic effects that were additive to
    those of coumaphos, subsequently administered at 4 mg/kg per day
    (Silvestri et al., 1975a,b).

         Horses treated with trichlorfon (39.7 mg/kg body weight) combined
    with mebendazole (8.8 mg/kg body weight) did not show any, or only a
    few, side-effects, except ChE inhibition, whereas horses given higher
    dosages (up to 5 times this dose) showed dosage-related increases in
    the severity of clinical signs and inhibition of erythrocyte
    cholinesterase activity. Depression of the activity was detected
    within 1 h of treatment. The maximum depression ranged from 42% (at
    the initial dosage) to 75% (at a 5 times higher dosage). Recovery of
    base-line activity did not occur in any of the horses within 32 days
    after treatment (Gingerich & Mia, 1981).

    8.2  Short-term exposure

         Wistar albino rats (10 males per group) were fed trichlorfon at
    0, 1, 5, 25, or 125 mg/kg diet for 16 weeks. Trichlorfon failed to
    cause erythrocyte cholinesterase depression at 125 mg/kg. No effects
    were noted on food consumption or growth, or during gross examination
    of the tissues (Edson & Noakes, 1960).

         Rats (13/sex per group) were fed trichlorfon at dietary levels of
    0, 20, 100, or 300 mg/kg diet for 16 weeks. Significant cholinesterase
    depression was noted at 300 mg/kg. No effects were observed at the 100
    mg/kg level on growth, behaviour, food consumption, or on gross and
    microscopic examination of tissues (Doull & Dubois, 1956).

         After oral administration of trichlorfon to guinea-pig (100 mg/kg
    body weight per day for 60 days) the haemoglobin content was decreased
    by 13.5% while the haematocrit value remained unchanged. Trichlorfon
    also decreased the serum cholinesterase activity by 50% and increased
    the activity of alkaline phosphatase by 36% (Krustev et al., 1976).

         Two dogs were administered 45 mg trichlorfon/kg body weight,
    orally, for 6 days per week over 3 months. No cumulative effects were
    noted. The serum cholinesterase level was 60% of normal at the end of
    the study period. No deaths occurred (Deichmann & Lampe, 1955). In
    another study, dogs (one male and one female per group, 2 males and 2
    females serving as controls) were fed trichlorfon at levels of 0, 50,
    200, or 500 mg/kg diet for 12 weeks. Plasma and erythrocyte
    cholinesterase activity was depressed at 500 mg/kg diet and unaffected
    at 200 mg/kg  diet. Recovery of enzyme activity was complete 6 weeks
    after the feeding of trichlorfon stopped (Williams et al., 1959).

         Rats (10/sex per group) were exposed for 6 h a day over a 3-week
    period (total of 15 exposures) to an atmosphere containing trichlorfon
    at concentrations of 0, 12.7, 35.4, and 103.5 mg/m3. Exposure to a
    concentration of 103.5 mg/m3 slightly affected the health of the
    animals (no details available). Body weight gain, parameters of
    haematological and clinical chemistry examinations, and urinalyses
    were not influenced at any exposure level. Cholinesterase inhibition
    of 42, 31, and 22% was found in the plasma, erythrocytes, and the
    brain, respectively, in male animals at 103.5 mg/m3; female animals
    showed dose-dependent inhibition values of 39, 26, and 26% at 35.4
    mg/m3 and 48, 44, and 47% at 103.5 mg/m3 in the plasma,
    erythrocyte, and brain, respectively. The only significant alteration
    in relative organ weight was found in male animals showing
    dose-related increases in relative spleen weights of about 20 and 25%
    at the 35.4 and 103.5 mg/m3 exposure levels, respectively. No
    abnormal histological findings were observed in any of the tissues
    examined microscopically (Kimmerle, 1975b).

         In a 13-week study to evaluate target organ toxicity,
    dose-response, and maximum tolerated dose for a 2-year study, groups

    of 10 male and 10 female Fischer rats and B6C3F1 mice (8-week-old)
    were administered trichlorfon in the feed at 0, 62, 185, 555, 1666, or
    5000 mg/kg, for 7 days a week. All the rats and mice survived the
    13-week treatment, except one male mouse at 5000 mg/kg and one female
    mouse at 1666 mg/kg. The body weights of the 5000 mg/kg groups of male
    and female rats and mice were significantly lower compared with those
    of their respective controls. Plasma and erythrocyte cholinesterase
    activity was reduced in a dose-related manner in the rats and mice.
    Neurotoxicity tests showed that motor activity and grip strength were
    reduced in the 1666 and 5000 mg/kg groups of male and female rats and
    mice. No histo pathological changes were observed in the brain, spinal
    cord, and sciatic nerve and other organ systems. Absolute and relative
    liver, kidney, and spleen weights were increased in the 1666 and 5000
    mg/kg groups of male and female rats and mice. The weight increase was
    not accompanied by any histopathological findings. Two-year
    carcinogenicity studies on trichlorfon administered in the diet to
    male and female Fischer rats and B6C3F1 mice are in progress (Chan &
    Peters, 1989).

         Groups of 7 male and 7 female Wistar rats were fed 1, 5, 10, 30,
    50, or 100 mg trichlorfon/kg body weight in their diet for 12 weeks.
    A dose of 100 mg/kg, daily, inhibited the cholinesterase activity in
    all tissues examined, namely erythrocytes, serum, brain, heart, liver,
    and gastrocnemius muscle, but the extent of the inhibition differed
    between tissues. No significant histological changes were found in the
    parenchymatous organs, such as the brain, heart, lung, pituitary
    gland, thyroid gland, liver, intestine, stomach, kidney, adrenal
    gland, and testes. Despite the marked inhibition of the tissue
    cholinesterase activity in the treated animals, no changes were
    observed in nocturnal behaviour, reactivity to external stimuli,
    conjunctival and pinna reflexes, and the avoidance reflexes to painful
    stimuli (Shimamoto & Hattori, 1965).

         Groups of 5 male and 5 female Rhesus monkeys ( Macaca mulatta)
    were each administered technical trichlorfon by oral intubation at
    dose levels of 0, 0.1, or 0.2 mg/kg body weight per day for 26 weeks,
    in order to determine a no-observed-effect level on the cholinesterase
    activity in erythrocytes. There were no effects on appearance,
    behaviour, nutritional state, feed and water consumption, and body
    weight gain. No treatment-related changes were found in haematology,
    liver and kidney function, and erythrocyte cholinesterase activity.
    The NOEL in this study was 0.2 mg/kg body weight per day (Hoffmann et
    al., 1988).

    8.3  Skin and eye irritation; sensitization

    8.3.1  Skin irritation

         A skin irritation test was conducted with technical trichlorfon
    applied to the intact and abraded skin of 6 albino rabbits. The

    contact time was 24 h and the animals were observed for 7 days.
    Technical trichlorfon did not irritate the skin (Thyssen, 1981).

         Technical trichlorfon was tested on 6 New Zealand White rabbits
    for its dermal primary irritation potential. The test material was
    kept in contact with the shaved skin under an occlusion patch for 4 h,
    and scoring was performed for 72 h. The results indicated that
    technical trichlorfon is not a primary dermal irritant (Bond, 1986).

    8.3.2  Skin sensitization

         Technical trichlorfon was evaluated in a Magnusson and Kligman
    maximization test on guinea-pigs. The concentrations used were:
    intra-dermal induction, 1%; topical induction, 25%; first challenge,
    25%; and second challenge, 12.5%. The results showed that technical
    trichlorfon is a sensitizer for guinea-pigs (Mihail, 1985).

         Technical trichlorfon was investigated in the open epicutaneous
    test on guinea-pigs for skin-sensitizing potential. Induction (4
    weeks, 5 days per week) was carried out using 0, 1, 3, or 10% test
    compound. Challenges were done with the same concentrations 4, 6, and
    8 weeks after the start of the induction. The 3 and 10% dilutions of
    trichlorfon had a skin-sensitizing effect, but not the 1% dilution
    (Mihail, 1986a).

    8.3.3  Eye irritation

         An irritation test was performed using technical trichlorfon on
    6 albino rats. The exposure times were 5 minutes and 24 h. Technical
    trichlorfon had a moderately irritating effect on the mucosae of the
    eye (Thyssen, 1981).

    8.4  Long-term exposure

         Several reviews on long-term toxicity studies on trichlorfon have
    been published (FAO/WHO, 1972, 1976, 1979; Holmstedt et al., 1978;
    Machemer, 1981; IARC, 1983).

    8.4.1  Oral administration  Mouse

         A group of 30 male and 28 female AB/Jena strain mice, 8 weeks of
    age, received 30 mg trichlorfon/kg body weight, by gavage, twice
    weekly for 75 weeks. A group of 30 male and 29 female mice served as
    controls. All surviving animals were killed in week 80. Inhibition of
    body weight gain and shortening of survival time were noted in the
    treated group. There was no statistically significant difference in
    the incidence of tumours between treated and control mice (Teichmann
    & Hauschild, 1978).

         Groups of 60 male and 60 female Charles River CD-1 mice
    (6-week-old) were given 100, 300, or 1000 mg trichlorfon/kg diet for
    90 weeks, except for males in the 1000 mg/kg group which were treated
    for 82 weeks. A group of 60 male and 60 female mice served as
    controls. Inhibition of body weight gain was observed in females given
    300 or 1000 mg trichlorfon/kg diet. Cholinesterase activity was
    depressed in both sexes at 1000 mg/kg diet. The no-observed-effect
    level was 100 mg/kg diet. No significant microscopic alterations were
    reported. There was no statistically significant difference in the
    incidence of tumours between treated and control mice (Machemer,

         Groups of 50 CD-1 mice per sex and dose level were given
    technical grade trichlorfon at 0, 300, 900, or 2700 mg/kg diet
    (analytical concentrations 0, 275, 891, or 2707 mg/kg diet) for 104
    weeks. There were no significant differences between groups in feed
    consumption, haematological parameters, or mortality. Increased
    incidences of urine stain and ear lesions in males, and vaginal
    discharge in females, were regarded as non-specific cholinergic
    effects. The body weights of the 2700 mg/kg female mice were
    significantly increased throughout the study. There was a
    compound-related increase in liver weight in the 900 and 2700 mg/kg
    females with no corresponding light-microscopic changes, regarded as
    a compound-adaptive mechanism. All trichlorfon-treated groups showed
    significant blood cholinesterase depression throughout the study: 20%,
    in the 300 mg/kg females, and up to 74% in the 2700 mg/kg group; this
    latter dose was compatible with a maximum tolerated dose. No
    compound-related tumorigenicity was found in this study (Hayes, 1988).  Rat

         Groups of 25 male and 25 female, 4-week-old, Sprague-Dawley rats
    were fed trichlorfon in the diet at doses of 0, 50, 250, 500, or 1000
    mg/kg diet. The treatment continued for 17 months for the males and 24
    months for the females. Survival time was shortened in both males and
    females given 1000 mg/kg diet. Retarded growth rate was observed in
    males given 1000 mg/kg diet: their weight was 15% less than the
    controls. Depression of cholinesterase activity was noticed in both
    sexes given doses of 500 or 1000 mg/kg. Female rats fed 500 or 1000
    mg/kg diet exhibited an absence of primary follicules and primitive
    ova and male rats fed 1000 mg/kg diet showed depression of
    spermatogenesis. Necrotizing arteritis was observed in both sexes at
    doses of 500 or 1000 mg/kg. However, no treatment-related
    toxicological changes were reported in rats given 50 or 250 mg/kg
    diet. The incidences of mammary tumours in female rats were 14, 8, 20,
    21, and 25% in groups given 0, 50, 250, 500, and 1000 mg/kg diet,
    respectively. The time to onset of the appearance of tumours was
    dose-dependent, being 1.7 years for the controls while at dietary
    levels of 50, 250, 500, and 1000 mg/kg, the onset occurred after 1.6,
    1.8, 1.5, and 1.1 years, respectively (Doull et al., 1962b).

         Another long-term toxicity study was reported in which groups
    each of 25 male and 50 female, 4-week-old, Sprague-Dawley rats were
    fed trichlorfon at doses of 0, 100, 200, or 400 mg/kg diet for 18
    months. Toxicological changes, such as cystic granular alterations of
    the ovaries and depression of oocytogenesis were seen only in rats fed
    400 mg/kg diet. From these 2 studies, it was concluded that
    trichlorfon given orally to rats may enhance some of the normal aging
    processes in the reproductive tissues in the females and possibly in
    the males (Doull et al., 1965).

         Groups each comprising 50 male and 50 female, Long-Evans rats, 4
    weeks of age, were fed trichlorfon at doses of 50, 250, 500, or 1000
    mg/kg diet. A group of 100 male and 100 female rats served as
    controls. There were neither shortening of survival times nor retarded
    growth in rats given 1000 mg/kg diet. Depression of cholinesterase
    activity in both sexes at 1000 mg/kg diet was the only finding related
    to the treatment. There were no morphological changes considered to be
    compound-related. All surviving animals were killed after 24 months of
    treatment. There was no statistically significant difference in the
    incidence of tumours between treated and control rats (Lorke & Löser,
    1966; Grundmann & Hobik, 1966).

         A group of 30 male and 35 female albino rats, 10 weeks of age,
    received 22 mg trichlorfon/kg body weight in saline, by gavage, twice
    weekly for 90 weeks. A group of 25 male and 26 female rats served as
    controls. All surviving animals were killed in week 118. Survival time
    was reduced in the treated group. There were neither biochemical nor
    morphological changes attributable to the treatment, and no
    statistically significant differences in the incidence of tumours
    between treated and control rats (Teichmann et al., 1978).

         Groups of 50 male and 50 female Fischer 344 rats, were fed diets
    containing mean analytical concentrations of 0, 92.2, 273, or 1518 mg
    trichlorfon/kg feed. Dosages were provided as nominal 0, 100, 300,
    1750 mg/kg diet. The top dosage was started as 1000 mg/kg for 27
    weeks, changed to 1250 mg/kg for 5 weeks, changed to 1500 mg/kg for 8
    weeks, and then changed to 1750 mg/kg for the remaining 65 weeks.
    Satellite groups of 20 animals per sex served as controls and, at the
    highest dose level, the animals were treated for one year and then
    sacrificed to provide interim data. Mortality was unaffected by
    treatment. Decreased food consumption was slight in females up to 66
    weeks and depressed body weight gain occurred in high-dose males.
    Increased cholesterol levels were observed in males at doses of 300
    mg/kg or more while slight anaemia was present in both sexes at 1750
    mg/kg. Cholinesterase activity in plasma, red cells, and the brain was
    significantly reduced in both sexes at 1750 mg/kg. Both liver and
    kidney weights were increased at 1750 mg/kg in both sexes.
    Histological changes were not present in the liver; however, chronic
    nephropathy occurred at the highest dose level. Hyperplasia of the
    upper small intestine and gastritis occurred at 300 mg/kg and above.

    A NOEL equal to 4.45 mg/kg body weight for males and 5.82 mg/kg body
    weight for females was established for the study (Hayes, 1989).
    Tumorigenicity for this study was not assessed by the Task Group.  Dog

         Groups each consisting of 2 male and 2 female Beagle dogs were
    given trichlorfon in the diet at doses of 0, 50, 250, 500, or 1000
    mg/kg diet for 12 months. Depression of cholinesterase activity was
    observed at the 500 and 1000 mg/kg diet levels. Spermatogenesis was
    inhibited in males given 1000 mg/kg diet (Doull et al., 1962a).

         Groups of 4 male and 4 female Beagle dogs were fed dietary
    trichlorfon at levels of 0, 50, 200, 800, or 3200 mg/kg diet for 4
    years. Cholinesterase activity was depressed in dogs of both sexes at
    doses higher than 200 mg/kg diet. Increased mortality, retarded growth
    rate, reduced weights of adrenal glands and testes, and impairment of
    the kidney function were observed at 800 and 3200 mg/kg diet. In
    addition, cholinergic symptoms, such as tremors, cramps, and
    salivation were noteworthy at the 3200 mg/kg level. Only one female
    dog in the latter group survived for 4 years. Liver injury was
    detected biochemically in dogs that died during the study (Löser,
    1970).  Monkey

         Groups of 5 male and 5 female Rhesus monkeys ( Macaca mulatta)
    were administered technical trichlorfon by gavage at dose levels of 0,
    0.2, 1, or 5 mg/kg body weight per day, 6 days per week for 10 years.
    At the 5 mg/kg level, transient pupillary constriction was seen in 2
    animals during the first month, and muscular fasciculations in one. At
    this dose level, a lowering of the erythrocyte count occurred in both
    sexes and, towards the end of the study, the body weights were lower
    in this group. Plasma-, erythrocyte-, and brain-cholinesterase
    activity was inhibited in the 5 and 1 mg/kg groups, while in the 0.2
    mg/kg group inhibition occurred only in erythrocytes in the males.
    Liver biopsies done during the first 3 years of the study did not
    reveal any evidence of changed liver morphology in any of the groups.
    No trichlorfon-related mortality occurred. Complete gross and
    microscopic examination of the tissues of the treated groups gave a
    non-neoplastic pathology similar to that in the control group. No
    significant pathology, including tumorigenicity, related to the
    administration of trichlorfon was observed in the treated animals,
    compared with the controls (Griffin, 1988).

    8.4.2  Intraperitoneal administration  Mouse

         A group of 30 male and 30 female AB/Jena strain mice, 8 weeks of
    age, received 28.2 mg trichlorfon/kg body weight by ip injection,

    twice weekly, for 75 weeks. A group of 30 male and 30 female control
    mice were given saline intraperitoneally. All surviving animals were
    killed in week 80. Inhibition of body weight gain and reduced survival
    time were noted in the treated group. There was no statistically
    significant difference in the incidences of tumours between treated
    and control mice (Teichmann & Hauschild, 1978).  Rat

         In a study by Teichmann et al. (1978), a group of 30 male and 35
    female albino rats, 10 weeks of age, received 12 mg trichlorfon/kg
    body weight intraperitoneally, twice weekly, for 90 weeks, while a
    group of 25 male and 25 female control rats was given saline. All
    surviving animals were killed in week 118. Survival time was reduced
    in the treated group. There was no statistically significant
    difference in the incidences of tumours between treated and control
    rats.  Hamster

         Syrian golden hamsters, (23 males and 25 females per group) 7-8
    weeks of age, were given 20 mg trichlorfon/kg body weight
    intraperitoneally, once weekly, for 90 weeks. A group of 22 male and
    23 female control hamsters were given saline. All surviving animals
    were killed in week 100. Inhibition of body weight gain and reduced
    survival time were noted in the treated group. There was no
    statistically significant difference in the incidences of tumours
    between treated and control hamsters (Teichmann & Schmidt, 1978).

    8.4.3  Dermal administration  Mouse

         A group of 30 male and 30 female AB/Jena strain mice, 8 weeks of
    age, received 0.25 ml 1% solution of trichlorfon in acetone, dermally,
    twice weekly, for 75 weeks. A group of 30 male and 30 female mice
    served as controls. All surviving animals were killed in week 80.
    Inhibition of body weight gain and reduced survival time were noted in
    the treated group. There was no statistically significant difference
    in the incidences of tumours between treated and control mice
    (Teichmann & Hauschild, 1978).

    8.5  Mutagenicity

    8.5.1  DNA methylation

          In vitro studies using chemical agents or isolated nucleic
    acids with dichlorvos showed that the methylating capability of
    dichlorvos was less, by a factor of 10-100, than that of strongly
    genotoxic agents (WHO, 1989).  In vivo studies using the
    determination of 14C-N7-methylguanine in the urine have been used

    to calculate the  in vivo methylation capability of dichlorvos for
    DNA (WHO, 1989) and trichlorfon (Dedek et al., 1976). However, it has
    been shown that the excretion of 14CH3-labelled purines in the
    urine does not constitute evidence for the methylation of the purines
    of DNA, because a natural biosynthetic pathway will give rise to
    urinary methylated purines via the C1-pool (Wright et al., 1979;
    WHO, 1989). Consequently, only the measurement of 14C methylated
    purines in the DNA of organs would provide acceptable results for the
    evaluation of the  in vivo methylating capability of alkylating
    agents (Wright et al., 1979).

         Such studies have been performed by Dedek (1981) for trichlorfon
    with ip administration of 0.48, 0.40, or 0.065 mmol/kg to male mice
    (strain AB Jena/Halle). The extent of methylation in liver DNA was
    found to be maximal after 6 h in amounts of 6-8 and 0.8 µmol
    N7-MeG/mol guanine for the high and the low dose, respectively, that
    is 6-8 methylations in the N7 position per 106 guanine bases.
    However, the alkylation at N7 of guanine by small groups, such as
    the methyl group, does not show a good correlation with genotoxic

         For obtaining a dose-independent measure of alkylation activity,
    the covalent binding index may be used, which is defined as:

                    micromol bound per mol of nucleotides
              CBI =                                      
                    millimol administered per kg animal

         For the strong alkylating agent methyl methanesulfonate (MMS),
    the CBI values for guanine N7 have been estimated to be between 135
    and 556, depending on the route of administration and the time
    intervals. The corresponding CBI values for trichlorfon were 2.3 to
    5.1 (Dedek, 1981; Dedek et al., 1984).

         Trichlorfon has a DNA-alkylating property and may react with DNA
     in vitro to cause depurination and excision (Rosenkranz &
    Rosenkranz, 1972).

    8.5.2  Mutagenicity

         Data on mutagenicity tests  in vitro as well as  in vivo have
    accumulated during the past 20 years. Results indicate that
    trichlorfon is partly positive and partly negative, depending on the
    purity of the test material, test system, dosage, or source, and
    possible effects derived from its degradation products (IARC, 1983).
    Results are summarized in Table 11.

         Trichlorfon induces gene mutation in  S. typhimurium and  E.
    coli Poole et al., 1977; Carere et al., 1978a; Benigni et al., 1980;
    Shirasu et al., 1982; Morya et al., 1983) and in  S. cerevisiae
    (Riccio et al., 1981; Gilot-Delhalle et al., 1983). It also induces a

    mitotic crossing over, gene conversion, and mitotic recombination
    (Waters et al., 1980). The positive results in microorganisms indicate
    that trichlorfon induces mainly base-pair substitution or mutation in
    the absence of metabolic activation. Trichlorfon also induces a
    chlorophyl mutation (Panda & Sharma, 1980) and chromosomal damage in
    plants (Logvinenko & Morgun, 1978; de Kergommeaux, 1983).

          In vitro studies with mammalian cells indicate that trichlorfon
    induces unscheduled DNA synthesis (UDS) in human epithelial cells
    (Benigni & Dogliotti, 1980; Aquilina et al., 1984) and in human
    fibroblasts (Waters et al., 1982). It induces sister chromatid
    exchanges (SCE) in Chinese hamster ovary (CHO) cells (Chen et al.,
    1981; Waters et al., 1982), and chromosomal aberrations in CHO (Sasaki
    et al., 1980; Ishidate et al., 1981) and human lymphocytes (Kurinniy
    & Pilinskaya, 1977).

         Trichlorfon has also been shown to cause cell transformation in
    C3H1OT1/2 CL8 cells (Waters et al., 1981, 1982), and forward mutations
    in mouse lymphoma L51784 cells in the absence of metabolic activation
    (McGregor et al., 1988).

          In vivo studies indicate that trichlorfon induces chromosomal
    aberrations in mouse bone marrow cells (Kurinniy, 1975; Kuzmenko et
    al., 1980; Ryazanova & Gafurova, 1980; Nehéz et al., 1987). However,
    negative results have been reported in a bone marrow micronucleus test
    after intraperitoneal injection of trichlorfon in doses up to 400
    mg/kg (Paik & Lee, 1977; Jones et al., 1982; Waters et al., 1982). In
    the dominant lethal test on mice, trichlorfon was reported to induce
    a significant increase in post implantation losses only after
    administration of relatively high doses, i.e., 405 mg/kg, as a single
    dose, or 54 mg/kg, daily, for 3 weeks (Dedek et al., 1975; Fischer et
    al., 1977). The reproducibility of such effects, however, was not
    supported by other investigators (Becker & Schöneich, 1980). A
    short-term study on mice indicated that trichlorfon did not induce any
    chromosomal damage in either bone marrow or germ cells after treatment
    with 0.5 mg/litre in the drinking-water, continuously, for 7 weeks
    (Degraeve et al., 1984).

         Cytogenetic studies on lymphocytes obtained from persons
    suffering from acute intoxication or those occupationally exposed to
    trichlorfon showed variable increases in the frequency of chromosomal
    aberrations (Trinh Van Bao et al., 1979; Kiraly et al., 1974).

         In conclusion, trichlorfon is mutagenic for microorganisms or
    mammalian cells in  in vitro assay systems. However, the data are not
    consistent, probably because of the purity of the test material and
    possible effects derived from its degradation products, such as
    dichlorvos.  In vivo studies indicate that trichlorfon induces
    chromosomal damage only at relatively high dose levels. In short-term
    studies, however, no such effects were found in bone marrow cells or
    in germ cells.

        Table 11.  Summary of mutagenicity studies on trichlorfon
    Test system                                          Result                Reference
    Rec-assay                    P. mirabilis              +      Adler et al. (1976); Braun et al. (1982)
                                 S. typhimurium            +      Braun et al. (1982)
                                 B. subtilis               -      Shirasu et al. (1976)
    Spot-test                    E. coli                   -      Nagy et al. (1975)
                                 S. typhimurium            -      Carere et al. (1978a)
    Point mutation               E. coli                   +      Hanna & Dyer (1975); Batzinger & Bueding (1977);
                                                                  Kawachi et al. (1980); Nagy et al. (1975); 
                                                                  Moriya et al. (1983)
                                 S. typhimurium            +      Poole et al. (1977); Benigni et al. (1980); Carere et al.
                                                                  (1978a); Kawachi et al. (1980); Shirasu et al. (1982)
                                 A. nidulans               -      Morpurgo et al. (1977); Moriya et al. (1983)
                                 S. coelicolor             +      Carere et al. (1978a,b); Benigni et al. (1980)
                                 S. cerevisiae             +      Riccio et al. (1981)
                                 S. pombe                  +      Gilot-Delhalle et al. (1983)
    Mitotic crossing over        A. nidulans               +      Morpurgo et al. (1977); Benigni et al. (1980)
                                 S. cerevisiae             +      Riccio et al. (1981); Waters et al. (1982)
    Gene conversion              S. cerevisiae             +      Riccio et al. (1981); Jones et al. (1982);
                                                                  Waters et al. (1982)
    Mitotic recombination        S. cerevisiae             +      Poole et al. (1977); Riccio et al. (1981);
                                                                  Simmon (1979); Waters et al. (1982)


    Chlorophyl gene mutation     H. vulgare                +      Panda & Sharma (1980)
    Chromosome damage            H. vulgare                +      Panda & Sharma (1980)
                                Wheat                      +      Logvinenko & Morgun (1978)
    Clastogenesis                Vicia faba                +      Amer & Ali (1983); de Kergommeaux et al. (1983)

    Mammalian cells in vitro
    UDS                         Human epithelial cells     +      Benigni & Dogliotti (1980)
                                Human fibroblasts          +      Waters et al. (1982)
    SCE                         Chinese hamster cells      +      Chen et al. (1981, 1982); Waters et al. (1982)

    Table 11 (continued).
    Test system                                          Result                Reference
    Mammalian cells in vitro
    Chromosome damage           Chinese hamster cells      +      Sasaki et al. (1980); Ishidate et al. (1981)
                                Human lymphocytes          +      Kurinniy & Pilinskaya (1977)
    Gene mutation               Mouse lymphoma             +      Paik & Lee (1977); Jones et al. (1982);
                                                                  Waters et al. (1982)
    Forward mutation assay      Mouse lymphoma cells       +      McGregor et al. (1988)

    Gene mutation                D. melanogaster           -      Benes & Sram (1969); Brzheskii (1973); Lamb (1977)
                                                                  Valencia (1977); Waters et al. (1980)
    Recessive lethal             D. melanogaster           -      Lamb (1977); Waters et al. (1980)

    Micronucleus test           Mouse bone marrow          -      Paik & Lee (1977); Herbold (1979a); 
                                                                  Waters et al. (1982); Jones et al. (1982); 
    Chromosome damage           Mouse bone marrow          -      Degraeve et al. (1981, 1985)
                                                           +      Kurinniy (1975); Nehez et al. (1982, 1987);
                                                                  Degraeve et al. (1981)
                                Hamster bone marrow        -      Dzwonkowska & Hübner (1986); Volkner (1987)
    Dominant lethal             Mice                       -      Arnold et al. (1971); Epstein et al. (1972); 
                                                                  Herbold (1979b); Becker & Schoeneich (1980);
                                                                  Degraeve et al. (1981, 1984a); Moutschen-Dahmen (1981)
                                                           +      Schiemann (1975); Dedek et al. (1975)
    Chromosome damage           Mouse testes               -      Degraeve et al. (1981, 1984b, 1985)
                                                           +      Bulsiewicz et al. (1976);
                                                           +      Fischer et al. (1977)
    Chromosome damage           Human lymphocytes          +      Trinh Van Bao et al. (1974); Kiraly et al. (1979)
    8.6  Carcinogenicity

         All long-term studies available for this evaluation have been
    described in section 8.4; many of these studies are inadequate as
    carcinogenicity studies, or the available reports give insufficient
    detail for an evaluation.

         A weak, dose-related increase in the incidence of mammary tumours
    was reported in female rats fed trichlorfon in the diet (Doull et al.,
    1962b). However, reports adequate for evaluation did not show any
    evidence for the carcinogenicity of trichlorfon in rats, mice, or
    hamsters after oral, intraperitoneal, or skin application.

         The carcinogenicity of dichlorvos, the major conversion product
    of trichlorfon in the mammalian body, has been discussed in WHO (1989)
    and US NTP (1989) (see section 8.10).

    8.7  Teratogenicity and reproductive toxicity

    8.7.1  Mouse

         A single dose of 360 mg trichlorfon/kg, injected
    intraperitoneally in 33 AS/Jena mice on the first day of gestation,
    caused embryo-toxicity. Post-implantation losses were increased with
    60, 120, 240 mg/kg ip on day 9 of gestation (13-15 mice/group), with
    120 or 240 mg/kg ip on days 1-7 (25-30 mice/group), and were more
    pronounced with 240 mg/kg ip (23 mice) on days 7-14 of gestation.
    There were no serious malformations (Scheufler, 1975).

         Nehéz et al. (1987) showed that 4 consecutive intraperitoneal
    doses of 51.5 mg trichlorfon/kg body weight administered to AB
    Jena/Halle mice (12-21 per group) on days 2, 3, 4, and 5, or days 6,
    8, 10, and 12 of gestation produced a very weak embryotoxic effect
    (slightly elevated post-implantation losses,  P <0.05), but no
    teratogenic activity was found.

         A dose of 500 or 600 mg trichlorfon/kg body weight, given daily
    to CD-1 mice by oral gavage on days 10-14 of gestation, produced a
    reduction in fetal weight and a slightly increased incidence of cleft
    palate. This malformation was found in 4/67 fetuses from dams given
    500 mg/kg, in 7/205 fetuses from dams given 600 mg/kg, and in 3/402
    fetuses from control dams (Staples & Goulding, 1979).

         When trichlorfon was administered by gavage to CD-1 mice (15-24
    per group) on days 7-16 of gestation, at a daily dose of 200, 300, or
    400 mg/kg, and to CD rats (15-24 per group) at 50, 100, or 200 mg/kg
    per day on days 7-19 or 8-20 of gestation, trichlorfon was
    teratogenic, fetotoxic, and lethal at the two highest dose levels. At
    the lowest dose level, which was not maternally toxic, there was a
    significant increase in the number of calcified centres in the

    forepaws and hindpaws indicating fetotoxicity and a delay in
    maturation (Courtney et al., 1986).

         Clemens & Hartnagel (1986) reviewed this study and suggested that
    no major or minor birth defects had been demonstrated, and that the
    embryotoxicity, fetotoxicity, and rib variations in the mouse study
    occurred at maternally toxic dose levels. The fact that a very small
    number of fetuses was assessed made conclusions difficult.

         Intragastric exposure of male CFW mice (30/group) to 30 mg
    trichlorfon/kg for 5-260 days resulted in a significant regression of
    the seminiferous epithelium in the testes after 100 days of treatment.
    No regeneration of the gonads was observed, 40 days after exposure
    ceased (Wenda-Rozewicka, 1983).

    8.7.2  Rat

         A single dose of 80 mg trichlorfon/kg, given to groups of 11
    Wistar rats by oral gavage on day 13 of gestation, produced an
    increased incidence of embryonic death and fetal malformations, such
    as exencephaly and nonclosing eyelids. When 80 mg trichlorfon/kg was
    similarly administered on day 9, these effects were not significant.
    A daily dose of 8 mg/kg during gestation did not produce any
    teratogenic manifestations (Martson & Voronina, 1976).

         When trichlorfon was administered in the diet to groups of 9-26
    CD rats on days 6-15 of gestation at a daily intake of 76, 145, 375,
    432 or 519 mg/kg body weight, both maternal and fetal body weights
    were reduced with ingestion of 432 or 519 mg/kg. There was a 
    dose-related increase in the incidence of fetal malformations with
    ingestion of 145 mg/kg or more. The predominant malformations were
    exencephaly, meningocoele, hydrocephaly, syndactily, micrognathia,
    cleft palate, and skeletal system alterations. No adverse effects were
    found with a dose of 76 mg/kg (Staples et al., 1976).

         A daily dose of 480 mg trichlorfon/kg, given to 34 CD rats by
    gavage on days 6-15 of gestation, produced a high incidence (86%) of
    fetal malformations, such as generalized oedema, herniation of the
    brain, hydroencephaly, micrognathia, cleft palate, and skeletal system
    alterations (Staples & Goulding, 1979).

         Groups of 25 naturally inseminated, female Long Evans rats were
    exposed by gavage to technical trichlorfon at 0, 10, 30, or 100 mg/kg
    body weight per day from day 6 to day 16 of gestation, and sacrificed
    on day 20. None of the doses had a lethal effect. Although at 100
    mg/kg diarrhoea was caused in some of the animals, embryonic and fetal
    development were not affected at this dose level (Machemer, 1979a).

         Groups of 33 naturally inseminated, female Charles River rats
    were exposed to technical trichlorfon at 0, 500, 1125, or 2500 mg/kg
    (equivalent to 0, 45, 102, or 227 mg/kg body weight per day) from day

    6 to day 15 of gestation, and sacrificed on day 20. Trichlorfon was
    maternally toxic at dietary levels of 500, 1125, and 2500 mg/kg. There
    was no evidence of trichlorfon-related embryotoxicity (increased
    resorption), fetotoxicity (decreased fetal weight), or teratogenicity
    (malformations) at exposure levels up to and including 2500 mg/kg.
    There was an increase in the incidence of delayed ossification and
    curved, wavy, and/or bulbous ribs at 2500 mg/kg. On the basis of the
    results of this study, 1125 mg/kg, equivalent to 102 mg/kg body weight
    per day, is considered the no-effect dose, in terms of reproductive
    liability in this study (Kowalski et al., 1987).

         A 3-generation (2 litters per generation) rat reproduction study
    with levels of 0, 100, 300, 1000, or 3000 mg trichlorfon/kg in the
    diet resulted in adverse effects on reproduction at 1000 mg/kg, and
    above. At 1000 mg/kg, there was evidence of reduced fertility, smaller
    litters, and reduced bodyweight of pups. At 3000 mg/kg, the pregnancy
    rate was markedly decreased and the pups were smaller and lighter in
    weight with none surviving to the weanling stage. No effects were
    noted at 300 mg/kg or below. Microscopic examination of tissues from
    the F3b generation did not indicate any adverse effects (Löser, 1969;
    Spicer & Urwin, 1971).

    8.7.3  Hamster

         When 200, 300, or 400 mg trichlorfon/kg body weight was given by
    gavage to groups of 10-30 female golden hamsters, each day, on days
    7-11 of gestation, the 300 and 400 mg/kg doses produced a reduction in
    maternal food consumption. At 400 mg/kg, there were signs of maternal
    toxicity and 3 out of 30 animals died; fetal death and malformations
    (cleft palate, patagium, and fused ribs) were increased. At 300 mg/kg,
    only one fetus (out of 105) had malformations. A dose of 200 mg/kg
    body weight did not produce any adverse effects (Staples & Goulding,

    8.7.4  Rabbit

         Groups of 15 naturally inseminated, female Himalayan rabbits were
    exposed by gavage to technical trichlorfon at 0, 5, 15, or 45 mg/kg
    body weight per day from day 6 to day 18 of gestation and sacrificed
    on day 29. The average weight gain of the dosed groups was reduced,
    but doses of 5 and 15 mg/kg were tolerated well. Because of maternal
    toxic effects, two abortions occurred at 45 mg/kg, but the fetuses
    delivered in this dose group developed normally. The
    no-observed-effect level with respect to embryonic development was 15
    mg/kg body weight per day. There were no indications that trichlorfon
    produced any teratogenic effects in this study (Machemer, 1979b).

         Groups of 20, artificially inseminated, female American Dutch
    rabbits were orally exposed to 0, 10, 35, or 110 mg technical
    trichlorfon/kg body weight per day from day 6 to day 18 of gestation
    and sacrificed on day 28. The highest dose (110 mg/kg) was not well

    tolerated and resulted in adverse clinical signs and death,
    significantly reduced overall body weight gain and food consumption,
    and significantly inhibited cholinesterase. At 35 mg/kg, cholin
    esterase was significantly inhibited and one death occurred that was
    possibly treatment-related. A dose of 10 mg/kg was devoid of overt
    maternal toxicity, while 110 mg/kg was embryotoxic and fetotoxic, but
    not teratogenic; 35 mg/kg was a NOEL for developmental toxicity and 10
    mg/kg for maternal toxicity (Clemens et al., 1990).

    8.7.5  Congenital tremor

         Several outbreaks of congenital tremor in piglets have been
    described in herds in which the sows had been treated with
    antiparasitic trichlorfon preparations between days 45 and 63 of
    pregnancy (Kronevi et al., 1975; Dobson, 1977; Bölske et al., 1978;
    Hansen et al., 1978; Knox et al., 1978). Clinically, the disease was
    characterized by ataxia and tremor and a pronounced hypoplasia of the
    cerebellum was found, as well as a reduction in the size of the spinal

         This disease was reproduced experimentally. Four sows were dosed
    with Neguvon Vet at 60 mg/kg body weight, mixed in the morning feed on
    day 55 and on day 70 of pregnancy. All 40 piglets born alive showed
    ataxia and tremor, and, at autopsy, hypoplasia of the cerebellum. In
    97 control litters, none of the 892 live-born piglets showed nervous
    signs (Knox et al., 1978). Similar experimental results were obtained
    following exposure of pigs to multiple oral doses of 50-75 mg
    trichlorfon/kg between approximately 45 and 63 days after conception
    (Pope et al., 1986; Berge et al., 1987a; Rasmussen et al., 1978). A
    similar, but less severe effect resulted from the post-natal exposure
    of piglets from week 3 to week 6 to 50 mg/kg body weight per day.
    Recovery of animals exposed prenatally was slow; 35 days after birth
    they had not reached control values for cerebral and cerebellar
    weight. There was still regional loss of Purkinje cells in the
    cerebellum (Berge et al., 1987b).

         Ten pregnant, white guinea-pigs were given 6 doses of 100 mg
    trichlorfon/kg body weight by gavage on days 36, 37, 38, 51, 52, and
    53 of pregnancy; 7 additional animals served as controls. The pups
    developed trembling and locomotor disturbances. Post-mortem
    examination of the pups revealed significantly decreased weights of
    the total brain and the cerebellum, compared with controls. There was
    also a significant weight reduction, particularly of the medulla
    oblongata, but also of the hippocampus, the thalamus, and the
    colliculi. Histological examination of the cerebellum revealed
    reduction of the external granular layer, and the molecular layer,
    together with a regional absence of Purkinje cells. The activities of
    the neurotransmitter enzymes cholineacetyltransferase and glutamate
    decarboxylase in the cerebellum were reduced compared with the control
    values (Berge et al., 1986). Pregnant, albino guinea-pigs were given
    radiolabelled trichlorfon on days 37 or 52 of pregnancy and examined

    by whole body autoradiography 15, 30, and 45 min after administration.
    Trichlorfon had not accumulated in the fetal guinea-pig brain (Berge
    & Nafstad, 1986).

    8.8  Neurotoxicity

         Olajos et al. (1979) reported that the administration of a
    divided dose of 300 mg/kg to hens (200 + 100 mg/kg given
    subcutaneously, 3 days apart) resulted in levels of neurotoxic
    esterase (NTE) inhibition (46-68% at 24 h) approaching the 70% level
    that has been correlated with the development of organophosphorus-
    ester-induced delayed neurotoxicity (OPIDN), and moderate clinical
    signs (ataxia) resembling the early stages of OPIDN. Shiraishi et al.
    (1983) produced a peripheral neuropathy in a single monkey (1 out of
    1) with a single dose of 250 mg/kg.

         Based on a review of the literature on trichlorfon and dichlorvos
    (both animal studies and cases of human poisoning), Johnson (1981,
    1990), Caroldi & Lotti (1981), and WHO (1989) concluded that only
    doses that exceed the lethal dose are likely to result in a level of
    NTE inhibition at which OPIDN would be expected. Johnson summarized
    reports of neurotoxicity studies on trichlorfon in hens as follows: 
    The acute maximum tolerated cholinergic dose (200 mg/kg
    subcutaneously) produced no marked neuropathy in hens; however,
    moderate neuropathy was seen when a further dose of 100 mg/kg was
    given subcutaneously, 3 days later. Histological signs of severe
    degeneration were seen in the sciatic nerve and spinal cord of the
    ataxic bird at autopsy after 3 weeks. Slight changes were reported in
    sections of the brain stem of the birds given 200 mg/kg, orally, or
    100 mg/kg, subcutaneously (Olajos et al., 1979). But these did not
    appear to be entirely typical of organophosphorus neuropathy and no
    lesions were reported for the spinal cord or sciatic nerve. Inhibition
    of NTE in the spinal cord was only measured in later studies (Hierons
    & Johnson, 1978) and lagged markedly behind that in the brain.

         The ability of trichlorfon to induce delayed neurotoxicity was
    assessed in adult White Leghorn hens, administered single subcutaneous
    doses of 100 or 300 mg/kg, and assessed for visible signs of
    neurotoxicity 24 h after treatment, prior to killing and collection of
    samples of brain and spinal (cervical, thoracic) cord for the
    measurement of AChE and NTE activities. In short-term studies, hens
    received trichlorfon (100 mg/kg) every 72 h for a total of 6 doses.
    Three days after the terminal dose, the hens were killed and the
    brains, spinal cords, and distal sciatic nerves were removed for
    enzymatic and histological examination. While trichlorfon markedly
    inhibited tissue AChE, no reduction in NTE was detected and no overt
    signs of neurotoxicity were observed. In the short-term studies,
    trichlorfon did not cause any obvious neurotoxicity, an observation
    supported by minimal changes in the spinal cord and sciatic nerve
    morphology, no impairment of walking ability, and no inhibition of the
    brain and spinal cord NTE (Slott & Ecobichon, 1984).

         A number of other reports indicate that trichlorfon is either not
    neurotoxic, or produces a neurotoxic effect that is distinct from
    OPIDN. In addition to the Slott & Ecobichon study, several short-term
    dosing regimens that resulted in severe cholinergic toxicity by either
    the oral (Olajos et al., 1979) or dermal (Francis et al., 1985) route
    did not result in neuropathy. Oral doses of 100 mg trichlorfon/kg were
    also reported not to result in significant NTE inhibition (Olajos et
    al., 1979; Olajos & Rosenblum, 1981). Finally, rats, which are much
    less sensitive to agents that cause delayed neurotoxicity, exhibited
    electrophysiological signs of neurotoxicity without accompanying
    histological changes when given oral doses of 30 mg/kg for 3 weeks
    (Lehotzky, 1982) or ip injections of trichlorfon at 200 mg/kg per day
    for 5-15 days (Averbook & Anderson, 1983).

         Other adverse neurobehavioural effects that have been observed
    may be due to acetylcholinesterase inhibition. Dési (1983) exposed
    adult CFY rats (10 males and 10 females per group) at levels of 16 and
    32 mg/kg for 3 months. The lower dose resulted in increased high
    frequency EEC activity, and enhanced central excitability and the
    higher dose in increased low-frequency EEG activity and a significant
    overall increase in EEG activity as well as indications of depressed
    cortical excitability. In animals treated orally with trichlorfon at
    30 mg/kg per day, increased locomotor activity in the open field and
    decreased rotorod performance were observed transiently. While the
    animals were able to acquire the conditioned escape reflex, latency of
    the escape responses in the conditioned escape reflex was markedly
    increased (Lehotzky, 1982).

    8.9  Immunological studies

         Exposure of female mice (BALB/cByJ & C57BL/6J strain; 4 per
    group) to 175 mg trichlorfon/100 ml drinking-water for 14 days had no
    effect on immune function, measured by response to influenza virus
    (Reiss et al., 1987). The dose used was considered to be effective for
    prophylactic treatment against helminthic infestation.

    8.10  Toxicity of dichlorvos

         The major transformation product of trichlorfon in mammals,
    including human beings, is dichlorvos, which is at least 100 times
    more active as a cholinesterase inhibitor than trichlorfon (Hofer,
    1981). An evaluation of the health and environmental hazards of
    dichlorvos can be found in WHO (1989). For completeness sake, however,
    the summary on effects on experimental animals and  in vitro test
    systems from this publication is reproduced below.

         "Dichlorvos is moderately to highly toxic when administered in
    single doses to a variety of animals species by several routes. It
    directly inhibits acetylcholinesterase (AChE) activity in the nervous
    system and in other tissues. Maximum inhibition generally occurs
    within 1 h, and is followed by rapid recovery. The oral LD50 for the

    rat is 30-110 mg/kg body weight, depending on the solvent used. The
    hazard classification of dichlorvos by WHO is based on an oral LD50
    for the rat of 56 mg/kg body weight. The signs of intoxication are
    typical of organophosphorus poisoning, i.e., salivation, lachrymation,
    diarrhoea, tremors, and terminal convulsions, with death occurring
    from respiratory failure. The signs of intoxication are usually
    apparent shortly after dosing, and, at lethal doses, death  occurs
    within 1 h. Survivors recover completely within 24 h.

         Potentiation is slight when dichlorvos is given orally in
    combination with other organophosphates, but in combination with
    malathion it is marked.

         In short-term toxicity studies on the mouse, rat, dog, pig, and
    monkey, inhibition of plasma, red blood cell, and brain ChE are the
    most important signs of toxicity. After oral administration, a dose of
    approximately 0.5 mg/kg body weight (range, 0.3-0.7 mg/kg) did not
    produce ChE inhibition. In a 2-year study on dogs, ChE inhibition was
    noted at 3.2 mg/kg body weight or more.

         Flea collar dermatitis has been described in dogs and cats
    wearing dichlorvos-impregnated PVC flea collars. This was a primary
    irritant contact dermatitis that may have been caused by dichlorvos.

         Many short-term, inhalation studies on different animal species
    have been carried out. Air concentrations in the range of 0.2-1
    mg/m3 do not affect ChE activity significantly. Other effects, such
    as growth inhibition and increase in liver weight, have been reported
    at dose levels at least 10-20 times higher.

         It is possible to produce clinical neuropathy in hens, but the
    doses of dichlorvos required are far in excess of the LD50. The
    effects are associated with high inhibition of neurotoxic esterase
    (NTE) in the brain and spinal cord. In the rat, however, neuropathic
    changes in the white matter of the brain have been reported following
    repeated daily oral application of an LD50 dose.

         Immune suppression has been reported in rabbits. At present, no
    evaluation as to the relevance for human beings can be given; more
    attention to this aspect is needed.

         In a long-term study, rats fed dichlorvos in the diet for 2 years
    showed no signs of intoxication. Hepatocellular fatty vacuolization of
    the liver and ChE inhibition were significant at the two highest dose
    levels (2.5 and 12.5 mg/kg body weight).

         In a carefully conducted, long-term, inhalation study on rats
    with whole body exposure (23 h/day, for 2 years), results were
    comparable with those seen in the oral study. No effects were seen at
    0.05 mg/m3, inhibition of ChE activity took place at 0.48 mg/m3 or

         In several reproduction studies on rats and domestic animals, no
    effects were seen on reproduction, and there was no embryotoxicity at
    dose levels that did not cause maternal toxicity. At toxic doses,
    dichlorvos may cause reversible disturbances of spermatogenesis in
    mice and rats. It was not teratogenic in several studies carried out
    on rats and rabbits.

         Dichlorvos is an alkylating agent and binds  in vitro to
    bacterial and mammalian nucleic acids. It is mutagenic in a number of
    microbial systems, but there is no evidence of mutagenicity in intact
    mammals, where it is rapidly degraded by esterases in blood and other

         Dichlorvos carcinogenicity has been investigated in mice (oral
    studies) and rats (oral and inhalation studies). The dose levels used
    in 2-year, oral studies were up to 800 mg/litre drinking-water or 600
    mg/kg diet for mice, and up to 280 mg/litre drinking-water or 234
    mg/kg diet for rats. In a rat inhalation study, dichlorvos
    concentrations in air of up to 4.7 mg/m3 were tested for 2 years. No
    statistically significant increase in tumour incidence was found. In
    two recent carcinogenicity studies on mice and rats, dichlorvos was
    administered by intubation at dose levels between 10 and 40 mg/kg body
    weight (mice) and 4 and 8 mg/kg body weight (rat) for up to 2 years.
    Only preliminary information has been provided. The evidence for
    carcinogenicity in these new studies is difficult to interpret at this
    time. Only when complete and final reports become available will it be
    possible to draw more definitive conclusions.a

    a  The US-NTP Peer Review Panel reviewed these studies and came to
         the following conclusions:  "Under the conditions of these 2-year
         gavage studies, there was some evidence of carcinogenic activity
         of dichlorvos for male F344/N rats, as shown by increased
         incidences of adenomas of the exocrine pancreas and mononuclear
         cell leukemia. There was equivocal evidence of carcinogenic  
         activity of dichlorvos for female F344/N rats, as shown by
         increased incidences of adenomas of the exocrine pancreas and
         mammary gland fibroadenomas. There was some evidence of
         carcinogenic activity of dichlorvos for male B6C3F1 mice and
         clear evidence for female B6C3F1 mice, as shown by increased
         incidences of forestomach squamous cell papillomas." (US-NTP,

         In a recent evaluation of current data, IARC (in press) concluded
         that there is sufficient evidence for the carcinogenicity of
         dichlorvos in experimental animals, but that there is inadequate
         evidence for the carcinogenicity of dichlorvos in humans.
         From acute and short-term studies, it is clear that the
    metabolites of dichlorvos are all less toxic than the parent compound.
    Only dichloroacetaldehyde was positive in a few mutagenicity tests."

    8.11  Mechanism of toxicity - mode of action

         While trichlorfon itself is not a potent anticholinesterase
    agent, the inhibiting activity of this chemical is attributed to the
    transformation product dichlorvos. The slow conversion of trichlorfon
    to dichlorvos results in the inhibition of both central and peripheral
    cholinergic nerve acetylcholinesterase, with the accumulation of the
    neurotransmitter, acetylcholine, at nerve endings, and the generation
    of characteristic signs and symptoms of toxicity. A full description
    of the mechanism of action of organophosphorus ester insecticides can
    be found in Environmental Health Criteria No. 63:  Organophosphorus
     Insections - A General Introduction (WHO, 1986), and that of
    dichlorvos in Environmental Health Criteria No. 79: Dichlorvos (WHO,
    1989). The muscarinic, nicotinic, and the central nervous
    system-induced signs and symptoms observed in humans have been
    described extensively (Ecobichon et al., 1977; Hayes, 1982; Hayes &
    Laws, 1991).

         Transformation of trichlorfon to dichlorvos in vivo was studied
    in relation to its effects on the cholinesterase activity,
    acetylcholine content, and acetylcholine-turnover in the mouse brain.
    An ip injection of 10 mg dichlorvos/kg caused toxic signs, such as
    salivation, diarrhoea and, in some cases, difficulties in breathing,
    which were clearly recognized about 15 min after administration and
    disappeared almost completely towards the end of 60 min. After an ip
    injection of 125 mg trichlorfon/kg, the above mentioned signs were
    most intense at around 30 min; and almost complete recovery was
    observed towards the end of 2 h. The cholinesterase activity and
    acetylcholine levels reached their minimum and maximum, respectively,
    at 15 min after the injection of dichlorvos and about 45 min after the
    injection of trichlorfon. The delayed decrease in acetylcholine
    turnover following to ip injection of trichlorfon was also
    demonstrated by measuring the acetylcholine-synthesizing rate in the
    brain following intravenous injection of 2H6-choline compared with
    dichlorvos pretreatment. The level of dichlorvos in the brain of mice
    administered trichlorfon ip reached its maximum a few minutes after
    the maximal level of trichlorfon itself; both compounds decreased over
    similar curves during a 120-min period (Nordgren et al., 1978).

         Thirty minutes after intraventricular injection of trichlorfon
    (2.5 mg) in the rat, the activity of the cholinesterase decreased to
    20% in the hippocampus; 22% in the medulla; 50% in the cerebellum; 58%
    in the striatum, and 72% in the cortex. Levels of acetylcholine
    reached a maximum at 45 min in the hippocampus and cortex, and peaked
    in the striatum at 60 min. The greatest increases were seen in the
    hippocampus and cortex with 60 and 55%, respectively (Hallak &
    Giacobini, 1987).

         The administration of 80 mg trichlorfon/kg im to male
    Sprague-Dawley rats was found to produce an increase in acetylcholine
    levels, which peaked at about 170% of control levels, 30 min after
    exposure (Hallak & Giacobini, 1989). Acetylcholine levels returned to
    normal within 120 min of exposure. A second dose at 120 min resulted
    in a second surge in the acetylcholine levels.


         Trichlorfon is one of the organophosphorus compounds for which
    not only acutely toxic effects have been described, but also delayed
    neurotoxicity in humans (WHO, 1986).

         In addition to the reports describing cases of human poisoning,
    there is wide experience concerning the therapeutic use of trichlorfon
    and the side-effects arising from this use.

    9.1  Acute poisoning - poisoning incidents

         Several hundred cases of acute trichlorfon poisoning, some of
    them lethal, have been described in the literature. These were either
    accidental, intentional (suicide), or due to gross neglect of
    prescriptions or safety precautions. A critical detailed review of
    these cases is given by Johnson (1981) and Hayes (1982).

         In all cases, the onset of poisoning was rapid, early signs and
    symptoms being exhaustion, headache, weakness, confusion, vomiting,
    abdominal pain, excessive sweating, and salivation. The pupils are
    small. Difficulty in breathing may be experienced, because of either
    congestion of the lungs or weakness of the respiratory muscles. In
    severe cases of poisoning, muscle spasms, unconsciousness, and
    convulsions may develop and death may result from respiratory failure.

         In the case of trichlorfon, unconsciousness is disproportionately
    common and prolonged and the incidence of mental disturbances is high;
    moreover polyneuropathy has been found at a later stage, in
    approximately 21% of cases (Hayes, 1982). However, after reviewing the
    literature, Johnson (1981; 1990) concluded that only doses of
    trichlorfon that exceed the lethal dose, and where the victim survived
    because of treatment, are likely to result in a level of NTE
    inhibition at which delayed neurotoxicity would be expected.

         The onset of polyneuropathy has occurred as early as 3 days after
    ingestion and as late as 26 days (Hayes, 1982), the majority of cases
    following recovery from the acute effects. The clinical,
    electrophysiological, and histopathological features of the neuropathy
    were similar to the syndrome resulting from TOCP exposure (Hierons &
    Johnson, 1978; Shiraishi et al., 1983; Vasilescu et al., 1984;
    Niedziella et al., 1985). Hayes (1982) discusses the possibility that
    the polyneuropathy could be caused by other chemical compounds,
    present as impurities in the technical product or formulation. Johnson
    (1981) mentions higher alkyl analogs as an example. No confirmation
    for this hypothesis can be found.

         In a case of trichlorfon poisoning, a 21-year-old female
    attempted suicide by drinking about 50 ml of a 50% formulation of
    trichlorfon. She lost consciousness and recovered after 8 h. Two weeks
    after ingestion, the patient developed a tingling sensation in all

    extremities followed by weakness in the lower limbs and knees,
    characterized as motor dominant polyneuropathy (Shiraishi et al.,

         Progressive neuropathy developed 2-8 weeks after acute poisoning
    (i.e., unconsciousness for 16 h) in a 20-year-old man who had taken
    orally a handful of granular solid formulation (trichlorfon content:
    80%). The clinical symptoms were typical of the delayed neuropathy
    that is caused by organophosphates, such as tri- o-cresyl-phosphate,
    with normal conduction velocity in surviving motor nerve fibres as an
    electrophysiological finding. However, a single dose of the above
    granular solid sample did not produce acute delayed neurotoxicity in
    hens (Hierons & Johnson, 1978).

         A 42-year-old man was in deep coma after ingestion of 100-200 ml
    Soldep (25% trichlorfon) and had to be artificially ventilated for 37
    days. Plasma cholinesterase activity was significantly decreased.
    Three weeks after ingestion, there was severe weakness of the lower
    limbs. The EMG (at 40 and 70 days, 4,6,9, and 14 months) indicated
    denervation in the lower extremities and peripheral motorneuron
    lesions in the upper extremities. Twenty-one months after poisoning,
    there was a slow improvement in mobility and the patient was able to
    walk by himself for a short distance (Bátora et al., 1988).

         Akimov & Kolesnichenko (1985) examined the morphological changes
    in the nervous system of 14 patients who had died from acute
    chlorophos poisoning. They found congested blood vessels with
    perivascular oedema and degeneration of the collagenous- and elastic
    fibres of the vascular walls. Diffuse cellular changes, such as
    swelling and ischaemic changes, were found in the brain, spinal cord,
    and vegetative ganglia. There was a moderate destruction of the myelin
    sheaths in the lateral columns of the spinal cord and the brain
    peduncles, and there were structural changes in the axons of the
    peripheral nerves.

         Csik et al. (1986) observed 70 cases of trichlorfon poisoning
    (mainly suicide attempts) between 1971 and 1983. Twenty-five of them
    were re-examined in 1984. Nine of these (36%) had severe residual
    signs of delayed polyneuropathy, mainly of the distal motor type. In
    one case, signs of CNS lesions had persisted. Four had had complaints
    (paraesthesia, weakness of hands) 2-3 months after poisoning, but were
    healthy at the time of re-examination.

    9.2  Therapeutic use of trichlorfon

         Under the name metrifonate, trichlorfon is used to treat
    infection by  Schistosomiasis haematobium in humans (WHO, 1985).
    Metrifonate has, by now, been given to millions of patients in the
    tropics in the treatment of schistosomiasis.

         Following a dose of 7-12 mg/kg, severe cholinergic symptoms are
    rare in spite of almost complete inhibition of plasma cholinesterase
    and 40-60% inhibition of erythrocyte acetylcholin esterase (Nordgren
    et al., 1981; Davis, 1986). However, trials in which several doses
    were administered on either the same day or one day apart resulted in
    abdominal colic, nausea, salivation, dizziness, and headache, which
    precluded further treatment (Aden-Abdi et al., 1987), and the
    subject-reported incidence of one or more of these effects after a
    single dose of 10 mg/kg (46%) was generally higher than in subjects
    given a vitamin placebo (34%) (Wilkins & Moore, 1987). There is one
    report of a possible human birth defect resulting from metrifonate
    treatment (Monson & Alexander, 1984).

         In another report on 6000 people, mostly in South Africa and
    South America, who had been treated with trichlorfon for a few years
    to control various intestinal and body parasites, the dosages varied
    from 7.5 up to 70 mg/kg. The dose of 7.5 mg/kg, given 2-4 times at
    two-week intervals, caused cholinesterase inhibition, weakness,
    nausea, diarrhoea, and abdominal pain. Higher doses (24 mg/kg) caused
    more severe symptoms including tachycardia, salivation, colic pain,
    vomiting, nausea, fatigue, tremors, and sweating. The effects were not
    cumulative and recovery in all cases was rapid. In a few human cases,
    an indication was given that spermatogenesis (size and shape of sperm)
    and sperm mobility might be affected (Wegner, 1970).

         In a large-scale programme in rural villages in Somalia,
    metrifonate was given at a current dosage regimen of 3 single doses of
    7.5 mg/kg each, on three separate days at intervals of 2 weeks (Aden
    Abdi & Gustafsson, 1989). In a large number of cases, the results were
    not satisfactory, due to poor patient compliance with the treatment
    regimen. In an attempt to simplify this regimen, 5 mg/kg, given thrice
    during one day, gave the best results as regards safety and the cure
    rates were comparable with those with the standard regimen (Aden Abdi,

         In a clinical trial on 20 patients with Alzheimer disease, Becker
    et al. (1990) gave single oral doses of 2.5, 5, 7.5, or 15 mg
    metrifonate/kg per week, for 1-3 months. A statistically significant
    improvement was obtained with the 5 mg/kg per week dose level. A 60%
    depression in red cell ChE and 80% depression in plasma ChE were
    accompanied by only minor side effects (nausea, vomiting, and/or
    diarrhoea); there were no effects at 2.5 mg/kg, 5 patients were
    affected at 5 mg/kg, 9 at 7.5 mg/kg, and 13 at 15 mg/kg per week.

    9.3  Occupational exposures

         Few cases of occupational poisoning by trichlorfon have been
    reported. See section 5.3 for occupational exposures.

         Occupational exposure to trichlorfon at a factory where air
    concentrations exceeded 0.5 mg/m3, but where skin contamination also

    occurred, resulted in decreased plasma cholinesterase levels and
    changes in EEG patterns; particularly slow and paroxysmal waves were
    observed (Lu et al., 1984; Hu et al., 1986). Both the biochemical and
    electrophysiological indices returned to normal after exposure ceased.

          Although trichlorfon has been widely used for many years, no
    cases of skin sensitization have been reported (Mihail, 1986b).

    9.4  Treatment of acute trichlorfon poisoning

         The advice on the treatment of organophosphate poisoning from EHC
    63: Organophosphorus Insecticides - A general introduction has been
    reproduced in Annex I.


         Trichlorfon was evaluated by the Joint FAO/WHO Expert Committee
    on Pesticide Residues (JMPR) in 1971, 1975, and 1978 (FAO/WHO, 1972,
    1976, 1979). In 1978, the JMPR established an Acceptable Daily Intake
    (ADI) for man of 0-0.01 mg/kg body weight, based on the fact that the
    following levels cause no toxicological effects:

         Rat: 50 mg/kg in the diet equivalent to 2.5 mg/kg body weight.
         Dog: 50 mg/kg in the diet equivalent to 1.25 mg/kg body weight.

         In 1986, the FAO/WHO CODEX Committee advised a range of maximum
    residue limits (MRLs) for specified food commodities (FAO/WHO, 1986).
    These ranged from 0.05 to 2 mg/kg product.

         Trichlorfon was evaluated by an IARC Working Group in 1983. There
    were no data on its carcinogenicity in humans and the evidence of
    carcinogenicity in experimental animals was inadequate. Trichlorfon
    was classified in Group 3, i.e., cannot be classified as to its
    carcinogenicity to humans (IARC, 1983, 1987).

         WHO classified technical trichlorfon as "slightly hazardous"
    (Class III) (WHO, 1990). A data sheet on trichlorfon (No. 27) has been
    published by the WHO (WHO/FAO, 1977).


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    (From EHC 63:  Organophosphorus Insecticides - A
                   General Introduction)

         All cases of organophosphorus poisoning should be dealt with as
    an emergency and the patient sent to hospital as quickly as possible.
    Although symptoms may develop rapidly, delay in onset or a steady
    increase in severity may be seen up to 48 h after ingestion of some
    formulated organophosphorus insecticides.

         Extensive descriptions of treatment of poisoning by
    organophosphorus insecticides are given in several major references
    (Kagan, 1977; Taylor, 1980; UK DHSS, 1983; Plestina, 1984) and will
    also be included in the IPCS Health and Safety Guides to be prepared
    for selected organophosphorus insecticides.

         The treatment is based on:

         (a)  minimizing the absorption;
         (b)  general supportive treatment; and
         (c)  specific pharmacological treatment.

    I.1  Minimizing the absorption

         When dermal exposure occurs, decontamination procedures include
    removal of contaminated clothes and washing of the skin with alkaline
    soap or with a sodium bicarbonate solution. Particular care should be
    taken in cleaning the skin area where venepuncture is performed. Blood
    might be contaminated with direct-acting organophosphorus esters and,
    therefore, inaccurate measures of ChE inhibition might result.
    Extensive eye irrigation with water or saline should also be
    performed. In the case of ingestion, vomiting might be induced, if the
    patient is conscious, by the administration of ipecacuanha syrup
    (10-30 ml) followed by 200 ml water. This treatment is, however,
    contraindicated in the case of pesticides dissolved in hydrocarbon
    solvents. Gastric lavage (with addition of bicarbonate solution or
    activated charcoal) can also be performed, particularly in unconscious
    patients, taking care to prevent aspiration of fluids into the lungs
    (i.e., only after a tracheal tube has been put into place).

         The volume of fluid introduced into the stomach should be
    recorded and samples of gastric lavage frozen and stored for
    subsequent chemical analysis. If the formulation of the pesticide
    involved is available, it should also be stored for further analysis
    (i.e., detection of toxicologically relevant impurities). A purgative 
    can be administered to remove the ingested compound.

    I.2  General supportive treatment

         Artificial respiration (via a tracheal tube) should be started at
    the first sign of respiratory failure and maintained for as long as

         Cautious administration of fluids is advised, as well as general
    supportive and symptomatic pharmacological treatment and absolute

    I.3  Specific pharmacological treatment

    I.3.1  Atropine

         Atropine should be given, beginning with 2 mg iv and given at
    15-30-min intervals. The dose and the frequency of atropine treatment
    varies from case to case, but should maintain the patient fully
    atropinized (dilated pupils, dry mouth, skin flushing, etc.).
    Continuous infusion of atropine may be necessary in extreme cases and
    total daily doses up to several hundred mg may be necessary during the
    first few days of treatment.

    I.3.2  Oxime reactivators

         Cholinesterase reactivators (e.g., pralidoxime, obidoxime)
    specifically restore AChE activity inhibited by organophosphates. This
    is not the case with enzymes inhibited by carbamates. The treatment
    should begin as soon as possible, because oximes are not effective on
    "aged" phosphorylated ChEs. However, if absorption, distribution, and
    metabolism are thought to be delayed for any reasons, oximes can be
    administered for several days after intoxication. Effective treatment
    with oximes reduces the required dose of atropine. Pralidoxime is the
    most widely available oxime. A dose of 1 g pralidoxime can be given
    either im or iv and repeated 2-3 times per day or, in extreme cases,
    more often. If possible, blood samples should be taken for AChE
    determinations before and during treatment. Skin should be carefully
    cleansed before sampling. Results of the assays should influence the
    decision whether to continue oxime therapy after the first 2 days.

         There are indications that oxime therapy may possibly have
    beneficial effects on CNS-derived symptoms.

    I.3.3  Diazepam

         Diazepam should be included in the therapy of all but the mildest 
    cases. Besides relieving anxiety, it appears to counteract some
    aspects of CNS-derived symptoms that are not affected by atropine.
    Doses of 10 mg sc or iv are appropriate and may be repeated as
    required (Vale & Scott, 1974). Other centrally acting drugs and drugs
    that may depress respiration are not recommended in the absence of
    artificial respiration procedures.

    I.3.4  Notes on the recommended treatment

    I.3.4.1  Effects of atropine and oxime

         The combined effect far exceeds the benefit of either drug

    I.3.4.2  Response to atropine

         The response of the eye pupil may be unreliable in cases of
    organophosphorus poisoning. A flushed skin and drying of secretions
    are the best guide to the effectiveness of atropinization. Although
    repeated dosing may well be necessary, excessive doses at any one time
    may cause toxic side-effects. Pulse-rate should not exceed 120/min.

    I.3.4.3  Persistence of treatment

         Some organophosphorus pesticides are very lipophilic and may be
    taken into, and then released from, fat depots over a period of many
    days. It is therefore quite incorrect to abandon oxime treatment after
    1-2 days on the supposition that all inhibited enzyme will be aged.
    Ecobichon et al. (1977) noted prompt improvement in both condition and
    blood-ChEs in response to pralidoxime given on the 11th-15th days
    after major symptoms of poisoning appeared due to extended exposure to
    fenitrothion (a dimethyl phosphate with a short half-life for aging of
    inhibited AChE).

    I.3.4.4  Dosage of atropine and oxime

         The recommended doses above pertain to exposures, usually for an
    occupational setting, but, in the case of very severe exposure or 
    massive ingestion (accidental or deliberate), the therapeutic doses
    may be extended considerably. Warriner et al. (1977) reported the case
    of a patient who drank a large quantity of dicrotophos, in error,
    while drunk. Therapeutic dosages were progressively increased up to 6
    mg atropine iv every 15 min together with continuous iv infusion  of
    pralidoxime chloride at 0.5 g/h for 72 h, from days 3 to 6 after
    intoxication. After considerable improvement, the patient relapsed and
    further aggressive therapy was given at a declining rate from days 10
    to 16 (atropine) and to day 23 (oxime), respectively. In total, 92 g
    of pralidoxime chloride and 3912 mg of atropine were given and the
    patient was discharged on the thirty-third day with no apparent

    References to Annex I.

    ECOBICHON, D.J., OZERE, R.L., REID, E., & CROCKER, J.F.S (1977)Acute
    fenitrothion poisoning.  Can. Med. Assoc. J., 116: 377-379.

    KAGAN, JU.S. (1977) [ Toxicology of organophosphorus pesticides],
    Moscow, Meditsina, pp. 111-121, 219-233, 260-269 (in Russian).

    PLESTINA, R. (1984)  Prevention, diagnosis, and treatment of
     insecticide poisoning, Geneva, World Health Organization
    (Unpublished document VBC/84.889).

    TAYLOR, P. (1980) Anticholinesterase agents. In: Goodman, L.S. &
    Gilman, A., ed.  The pharmacological basis of therapeutics, 6th ed.,
    New York, Macmillan Publishing Company, pp. 100-119.

    UK DHSS (1983)  Pesticide poisoning: notes for the guidance of medical
     practitioners, London, United Kingdom Department of Health and
    Social Security, pp. 41-47.

    VALE, J.A. & SCOTT, G.W. (1974) Organophosphorus poisoning.  Guy's
     Hosp. Rep., 123: 13-25.

    WARRINER, R.A., III, NIES, A.S., & HAYES, W.J., Jr (1977) Severe
    organophosphate poisoning complicated by alcohol and terpentine
    ingestion.  Arch. environ. Health, 32: 203-205.


    Annex II  No-observed-effect levels (NOELS) in animals treated
    with trichlorfon

    Animal           Exposurea                NOEL (paramater)             Reference
    Rat              16 weeks               100 mg/kg diet (ChE)         Doull & Dubois (1956)

    Dog              12 weeks               200 mg/kg diet               Williams et al. (1959)
                                            (plasma, Er-ChE)

    Rat              6h/day over 3 weeks    12.7 mg/m3 by inhalation     Kimmerle (1975b)
                                            (plasma, Er, brain ChE)

    Beagle dog       12 months              250 mg/kg diet (ChE)         Doull et al. (1962a)

    Beagle dog       4 years                50 mg/kg diet (ChE)          Löser (1970)

    Rhesus monkey    26 weeks               0.2 mg/kg body weight        Hoffmann et al. (1988)
                                            oral intubation (Er-ChE)
    CD-1 mouse       90 weeks               100 mg/kg diet (ChE)         Machemer (1981)
                                            1000 mg/kg diet
                                            (tumour incidence)

    CD-1 mouse       104 weeks              2700 mg/kg diet              Hayes (1988)

    Sprague-Dawley   17 months (m)          250 mg/kg diet (ChE,         Doull et al. (1962b)
    rat              24 months (f)          survival, spermatogenesis,
                                            ovarian changes) 50 mg/kg
                                            diet (mammary tumours)

    Annex II. (continued)

    Animal           Exposurea                NOEL (paramater)             Reference
    Sprague-Dawley   18 months              200 mg/kg diet               Doull et al. (1965)
    rat                                     (ovarian changes)

    Long-Evans rat   24 months              500 mg/kg diet (ChE)         Lorke & Löser (1966);
                                            1000 mg/kg diet              Grundmann & Hobik (1966)
    Rat              twice/week             22 mg/kg body weight         Teichmann et al. (1978)
                     for 90 weeks           by gavage
                                            (incidence of tumours)

    Fischer 344      105 weeks              100 mg/kg diet               Hayes (1989)
    rat                                     (morphological

    Rhesus monkey    6 days/week            0.2 mg/kg body weight        Griffin (1988)
                     for 10 years           oral intubation

    AB/Jena mouse    twice/week             28.2 mg/body weight          Teichmann & Hauschild
                     for 75 weeks           ip injection                 (1978)
                                            (incidence of tumours)

    Rat              twice/week             12.0 mg/kg body weight       Teichmann et al. (1978)
                     for 90 weeks           ip injection
                                            (incidence of tumours)

    Syrian Golden    once/week              20 mg/kg body weight         Teichmann & Schmidt
    hamster          for 90 weeks           ip injection                 (1978)
                                            (incidence of tumours)

    Annex II. (continued)

    Animal           Exposurea                NOEL (paramater)             Reference
    AB/Jena mouse    twice/week             0.25 ml of 1% solution       Teichmann & Hauschild
                     for 75 weeks           in acetone dermal            (1978)
                                            (incidence of tumours)

    a    m = male.
         f = female.

    1.  Résumé et évaluation

    1.1  Exposition

         Le trichlorfon est un insecticide organophosphoré utilisé depuis
    le début des années 1950. En agriculture, on l'emploie principalement
    contre les ravageurs des cultures de plein champ et des vergers. On
    l'utilise également comme insecticide en forêt et pour débarrasser des
    animaux domestiques de leurs parasites. Sous le nom de métrifonate, il
    est utilisé pour traiter l'infestation humaine à  Schistosoma
     haematobium.  Il agit en libérant lentement du dichlorvos. Le
    trichlorfon est commercialisé sous forme de concentré émulsionnable,
    de poudre dispersable, de poudre pour poudrage, de granulés, de
    solution et de concentré à très bas volume.

         Peu après l'épandage, la concentration atmosphérique du
    trichlorfon peut atteindre 0,1 mg/m3 mais cette valeur diminue
    rapidement pour tomber à moins de 0,01 mg/m3 en quelques jours. Les
    eaux de ruissellement provenant des zones traitées peuvent contenir
    des concentrations de trichlorfon atteignant 50 µg/litre, mais la
    teneur des eaux de surface est généralement beaucoup faible et diminue

         Le trichlorfon se décompose rapidement dans le sol et sa
    concentration y devient généralement négligeable dans le mois qui suit
    l'épandage. Il est relativement stable dans l'eau aux pH inférieurs à
    5,5. A pH plus élevé, il se transforme de dichlorvos. Les
    microorganismes et les plantes métabolisent probablement le
    trichlorfon mais son mode d'élimination principal est l'hydrolyse

         A quelques exceptions près, la concentration de trichlorfon sur
    les récoltes est inférieure à 10 mg/kg dans le jour qui suit
    l'épandage et tombe en-dessous de 0,1 mg/kg une quinzaine jours après.

         Le lait des vaches que l'on a traitées au trichlorfon pour les
    débarrasser de leur vermine peut contenir des résidus atteignant 1,2
    mg/litre deux heures après l'application, mais cette valeur tombe
    en-dessous de 0,1 mg/litre dans les 24 heures. On n'a pas constaté la
    présence de concentrations importantes de trichlorfon dans la viande
    des animaux traités. Dans les oeufs de poules traitées on a mesuré des
    concentrations de 0,05 mg/kg.

    1.2  Absorption, métabolisme et excrétion

         Le trichlorfon est rapidement absorbé par l'ensemble des voies
    d'exposition (orale, dermique, respiratoire) et il se répartit
    rapidement dans les tissus de l'organisme. Le taux sanguin passe par
    un maximum au bout d'une à deux heures, le produit disparaissant

    presque totalement du courant sanguin au bout 1,5 à 4 heures. La
    demi-vie biologique du trichlorfon dans le sang des mammifères a été
    estimée à environ 30 minutes.

         Dans l'eau, les liquides biologiques et les tissus, à des valeurs
    du  pH supérieures à 5,5 le trichlorfon subit une transformation en
    dichlorvos (phosphate de 2,2-dichlorovinyle et de diméthyle) par
    déshydrochloration. C'est le dichlorvos qui constitue le principe
    actif antichlolinestérasique. Les principales voies de dégradation
    sont la déméthylation, la coupure de la liaison phosphore-carbone et
    l'hydrolyse de l'ester via le dichlorvos. Les principaux métabolites
    du trichlorfon que l'on trouve  in vivo sont le déméthyltrichlorfon,
    le déméthyldichlorvos, l'hydrogénophosphate de diméthyle,
    l'hydrogénophosphate de méthyle l'acide phosphorique et de
    trichloréthanol. Ce dernier métabolite se retrouve dans l'urine,
    conjugué sous forme de glucuronide.

         Le trichlorfon et ses métabolites sont principalement éliminés
    par voie urinaire. Des études effectuées avec du trichlorfon
    radiomarqué (14C-méthyl et 32P) ont montré que la majeure partie
    du produit s'éliminait sous la forme de dérivés hydrosolubles et une
    faible fraction sous la forme de dérivés solubles dans le chloroforme.
    Environ 66 à 70 % des produits hydrosolubles apparaissent dans l'urine
    dans les 12 heures, 24 % du produit radiomarqué au niveau du
    groupement méthyl étant éliminés dans l'air expiré sous forme de
    dioxyde de carbone (CO2). Après avoir traité des vaches soit par
    administration orale soit par voie cutanée, on a retrouvé dans leur
    lait de faibles quantités de trichlorfon et de ses métabolites.

    1.3  Effets sur les êtres vivants dans leur milieu naturel

         Le trichlorfon est modérément toxique pour les poissons (les
    valeurs de la CL50 à 96 heures vont de 0,45 mg/litre à 51 mg/litre)
    et modérément à fortement toxique pour les arthropodes aquatiques
    (valeur de la CL50 à 48 et 96 heures comprises en entre 0,75
    µg/litre et 7800 µg/litre). Toutefois les concentrations dont il est
    fait état dans les eaux superficielles après épandage dans des forêts
    à la dose de 6kg/ha, sont inférieures à ces valeurs. Il s'en suit
    qu'en utilisation normale, le trichlorfon n'aura guère d'effets sur
    les organismes aquatiques car les autres types d'organismes tels que
    les mollusques et les microorganismes sont moins sensibles que les
    arthropodes. Les valeurs de la DL50 tirées d'études en laboratoire
    se situent entre 40 et 180 mg/kg et montrent donc que le trichlorfon
    est modérément toxique pour les oiseaux. Toutefois des études menées
    sur le terrain après épandage de trichlorfon par voie aérienne sur des
    forêts, n'ont révélé aucun effet sur l'effectif, la formation de
    couples, le nichage ou la mortalité des oiseaux chanteurs. La
    diminution du chant et l'accroissement de l'activité trophique qui ont
    été constatés sont peut-être la conséquence d'une réduction du nombre
    de proies. Rien n'indique que le trichlorfon puisse avoir un effet
    nocif sur la faune terrestre, à part les arthropodes. On ne possède

    aucune donnée au sujet des effets de cet insecticide sur les
    arthropodes utiles.

    1.4  Effets sur les animaux d'expérience et sur les systèmes
         d'épreuves in vitro

         Le trichlorfon est un insecticide modérément toxique pour les
    animaux d'expérience. Chez l'animal de laboratoire, les valeurs de la
    DL50 pour le trichlorfon technique s'étagent de 400 à 800 mg/kg de
    poids corporel et pour le rat, la DL50 cutanée dépasse 2000 mg/kg de
    poids corporel.

         L'intoxication par le trichlorfon offre le tableau clinique
    habituel  de l'atteinte cholinergique due aux organophosphorés et qui
    résulte d'une accumulation d'acétylcholine au niveau des terminaisons

         On a montré que le trichlorfon technique était modérément
    irritant pour la conjonctive chez le rat, aucun effet de ce genre
    n'ayant été noté lors de tests cutanés sur des lapins. Sa capacité de
    sensibilisation cutanée a été mise en évidence chez le cobaye.

         Des études de toxicité par voie orale de brève durée ont été
    effectuées sur des rats, des chiens, des singes, des lapins et des
    cobayes. Lors d'une étude de 16 semaines sur des rats, de 4 ans sur
    des chiens et de 26 semaines sur des singes, on a fixé respectivement
    à 100 mg/kg de nourriture, 5' mg/kg de nourriture et 0,2 mg/kg de
    nourriture la dose sans effet observé (sur la base de l'activité
    cholinestérasique, plasmatique, érythrocytaire ou cérébrale). En
    exposant par voie respiratoire des rats pendant trois semaines, on a
    obtenu une dose sans effet observé de 12,7 mg/m3 en se basant sur
    l'inhibition de l'activité cholinestérasique du plasma, des
    érythrocytes et du cerveau. Des études de toxicité et de
    cancérogénicité à long terme ont été menées sur des souris, des rats,
    des singes et des hamsters à qui l'on a administré du trichlorfon par
    voie orale,intrapéritonéale ou percutanée. Après exposition par voie
    orale des souris et des rats à des doses de 30 mg/kg de poids corporel
    et de 400 mg/kg de nourriture respectivement, on a observé des
    anomalies au niveau des gonades. Lors d'une étude de 24 mois sur des
    rats et de 10 ans sur des singes, on a obtenu des doses sans effet
    observé respectivement égales à 50 mg/kg de nourriture et 0,2 mg/kg de
    poids corporel. Les données sont on dispose ne permettent pas de
    conclure que la substance est cancérogène après administration à des
    animaux de laboratoire pendant une longue période par diverses voies.

         Dans les conditions physiologiques , le trichlorfon est
    susceptible d'alkyler l'ADN. Les tests de mutagénicité ont donné des
    résultats tantôt positifs tantôt négatifs. Il a peut que les effets
    observés soient imputables en tout ou partie au dichlorvos. La plupart
    des études de mutagénicité effectuées  in vitro sur des bactéries ou
    des cellules mammaliennes ont donné des résultats positifs alors que
    rares sont les études in vivo qui ont donné de tels résultats.

         L'expérimentation sur la souris, le rat et le hamster montre que
    le trichlorfon suscite une réaction tératogène chez le rat à des doses
    suffisantes pour être toxiques chez la mère. Après avoir administré à
    des rattes en cours de gestation une dose de 145 mg de trichlorfon par
    kg de nourriture, on a observé des malformations chez les foetus. Une
    dose de 400 mg/kg de poids corporel administrée par gavage à des
    hamsters a également été toxique pour les mères et a provoqué des
    effets tératogènes. La dose la plus faible administrée par gavage et
    ayant provoqué des effets tératogènes chez le rat était de 80 mg/kg de
    poids corporel. Au cours de la période de gestation, les effets
    produits présentent une spécificité chronologique. Cette étude a
    permis de fixer à 8 mg/kg la dose sans effet observé.

         Des doses sans effet observé respectivement égales à 8 mg/kg et
    à 200 mg/kg de poids corporel ont été observées chez le rat et le
    hamster. Chez le porc et le cobaye, on a constaté une action
    tératogène sur le système nerveux central.

         Cependant, aucun effet tératogène n'a été observé lors d'une
    étude de reproduction portant sur trois générations de rats, au cours
    de laquelle on a relevé des effets nocifs sur la fonction de
    reproduction. Dans cette étude, la dose sans effet observé était de
    300 mg/kg de nourriture.

         A très hautes doses, le trichlorfon produit des effets
    neurotoxiques chez l'animal.

         Chez les mammifères, le métabolite actif est le dichlorvos, dont
    l'activité anticholinestérasique est au moins 100 fois plus forte que
    celle du trichlorfon.

    1.5  Effets sur l'homme

         Plusieurs cas d'intoxication aiguë délibérée (suicide) ou
    accidentelle se sont produits. L'intoxication présente une
    symptomatologie caractéristique de l'inhibition de la cholinestérase:
    épuisement, faiblesse, confusion, sueur et salivation profuses,
    douleurs abdominales, vomissements, myosis et spasmes musculaires.
    Dans les cas graves, l'intoxication entraîne la perte de conscience et
    des convulsions et la mort survient généralement par insuffisance
    respiratoire. Chez les victimes qui ont survécu à l'intoxication grâce
    à une intervention médicale, on a observé quelquefois, plusieurs
    semaines après l'exposition, une polyneuropathie retardée accompagnée
    d'une faiblesse des membres inférieurs. Dans les cas mortels,
    l'autopsie a révélé des foyers d'ischémie dans le cerveau, la moelle
    épinière et les ganglions végétatifs, ainsi que des lésions de la
    gaine de myéline dans la moelle épinière et les pédoncules cérébraux,
    avec des altérations dans la structure des axones des nerfs

         Les quelques cas d'intoxication d'origine professionnelle qui se
    sont produits, s'expliquent essentiellement par des négligences au
    niveau de la sécurité. L'exposition professionnelle sur les lieux de
    travail à des concentrations atmosphériques supérieures à 0,5 mg/m3
    a entraîné une réduction de la cholinestérase plasmatique et une
    altération du tracé électroencéphalographique. Toutefois ces anomalies
    ont complètement régressé à l'arrêt de l'exposition. Aucun cas de
    sensibilisation cutanée n'a été signalé.

         Ce composé est très largement utilisé pour le traitement de la
    schistosomiase chez l'homme. L'administration d'une dose unique (7 à
    12 mg/kg) entraîne une inhibition de la cholinestérase plasmatique et
    érythrocytaire à hauteur de 40-60 %, sans entraîner de symptômes
    cholinergiques. Toutefois, des symptômes légers ont été observés chez
    des malades qui avaient pris de ce produit à plusieurs reprises. A
    forte dose (24 mg/kg) on a observé de graves symptômes cholinergiques

    2.  Conclusions

         -    Le trichlorfon est un insecticide organophosphoré modérément
              toxique. Une intoxication grave peut survenir par suite
              d'une exposition excessive au produit lors de sa
              manipulation, de sa fabrication ou de son utilisation ou par
              suite d'une ingestion accidentelle ou délibérée.

         -    L'exposition au trichlorfon de la population générale
              résulte principalement de son utilisation en agriculture et
              en médecine vétérinaire et dans le traitement de la
              schistosomiase (bilharziose).

         -    Les quantités de trichlorfon qui sont absorbées sont très
              inférieures à la dose journalière adminissible fixée par la
              FAO et l'OMS et ne devraient pas constituer une menace pour
              la santé publique.

         -    Si l'on adopte de bonnes méthodes de travail et, que l'on
              respecte les précautions d'hygiène et de sécurité, le
              trichlorfon n'est vraisemblablement pas dangereux pour les
              personnes qui sont exposées de par leur profession.

         -    Bien que le trichlorfon soit très toxique pour les
              arthropodes non visés, son utilisation n'entraîne guère
              d'effets nocifs sur la faune et la flore.

    3.  Recommandations

         -    Afin de préserver la santé et le bien-être des ouvriers et
              de la population en général, il importe de confier la
              manipulation et l'épandage du trichlorfon exclusivement à
              des personnes correctement encadrées et expérimentées, qui

              sauront appliquer les mesures de sécurité indispeurables et
              utiliser convenablementle produit.

         -    Des précautions sont à observer lors de la production, de la
              formulation, de l'utilisation en agriculture et du rejet du
              trichlorfon afin de contaminer le moins possible
              l'environnement et plus spécialement des eaux de surface.

         -    Les travailleurs qui sont régulièrement exposés au
              trichlorfon ainsi que les malades traités avec ce produit
              doivent subir des examens médicaux périodiques.

         -    Les doses d'emploi en agriculture devront rester faibles
              afin d'éviter la destruction des arthropodes non visés. 
              L'insecticide ne devra jamais être épandu sur des étendues
              ou des cours d'eau.


    1.  Resumen y evaluación

    1.1  Exposición

         El triclorfón es un insecticida organofosforado que lleva
    utilizándose desde principios de los años cincuenta. En agricultura
    sirve principalmente para combatir las plagas de insectos en los
    cultivos extensivos y en los frutales. Se utiliza asimismo para
    combatir los insectos de los bosques y los parásitos de los animales
    domésticos. Bajo la denominación de metrifonato, se emplea para tratar
    la infestación del hombre por  Schistosoma haematobium.  Se considera
    un reservorio de liberación lenta de diclorvos. El triclorfón se
    presenta en forma de solución concentrada emulsionable, polvos para
    disolución o aplicación en seco, gránulos, solución y soluciones
    concentradas de volumen muy reducido.

         La concentración de triclorfón insecticida en el aire puede
    alcanzar 0,1 mg/m3 al poco tiempo del rociamiento, pero a los pocos
    días los niveles se sitúan alrededor de 0,01 mg/m3. En las aguas de
    escorrentía de zonas rociadas, la concentración de triclorfón puede
    alcanzar los 50 µg/litro; en cambio en las aguas de superficie suele
    ser mucho más baja y disminuye rápidamente.

         El triclorfón se degrada rápidamente en el suelo; las
    concentraciones suelen disminuir hasta cantidades insignificantes
    durante el mes que sigue  a la aplicación. Es relativamente estable en
    agua si el pH es inferior a 5,5; con un pH más elevado se transforma
    en diclorvos. Aunque los microorganismos y las plantas pueden
    metabolizar el triclorfón, la vía de eliminación más importante es la
    hidrólisis abiótica.

         Salvo raras excepciones, las concentraciones de triclorfón en los
    cultivos son inferiores a 10 mg/kg al día siguiente de la aplicación,
    e inferiores a 0,1 mg/kg durante las dos semanas siguientes.

         La leche de vacas tratadas con triclorfón para combatir plagas
    puede contener hasta 1,2 mg de residuos/litro a las dos horas de la
    aplicación, pero las cifras descienden hasta menos de 0,1 mg/litro a
    las 24 horas del tratamiento. No se han encontrado concentraciones
    importantes de este compuesto en la carne de animales tratados. En los
    huevos de gallinas tratadas se han comprobado valores de 0,05 mg de

    1.2  Ingestión, metabolismo y excreción

         El triclorfón se absorbe fácilmente por todas las vías de
    exposición (oral, cutánea, respiratoria) y se distribuye rápidamente
    a los tejidos del cuerpo. Se detectaron concentraciones máximas en la
    sangre al cabo de 1-2 h, y la sustancia desapareció casi por completo

    del torrente sanguíneo en cuestión de 1,5-4 h. Se calculó que la
    semivida biológica del triclorfón en la sangre de mamíferos es de
    alrededor de 30 minutos.

         Por deshidrocloración, el triclorfón se transforma en diclorvos
    (2,2-diclorovinil dimetil fosfato) en el agua y en los humores y
    tejidos de los seres vivos, si el pH es superior a 5,5. El diclorvos
    es la anticolinesterasa fisiológicamente activa. Las principales rutas
    de degradación son la desmetilación, la escisión del enlace P-C y la
    hidrólisis del éster con el diclorvos como producto intermediario. Los
    principales metabolitos del triclorfón que se encuentran  in vivo son
    el demetil triclorfón, el demetil diclorvos, el dimetil
    hidrogenofosfato, el metil hidrogenofosfato, el ácido fosfórico y el
    tricloroetanol. El último metabolito se encuentra en la orina en forma
    de conjugado de glucurónido.

         El triclorfón y sus productos metabólicos se eliminan
    principalmente con la orina. Los estudios realizados con triclorfón
    radiomarcado (14C-metilo y 32P-metilo) revelaron que la mayor
    parte de la sustancia se eliminaba en forma hidrosoluble, y una
    pequeña parte en forma soluble en cloroformo. Alrededor del 66%-70% de
    los productos hidrosolubles aparecían en la orina al cabo de 12 horas,
    mientras que el 24% del material marcado con 14C-metilo se eliminaba
    en el aire espirado en forma de dióxido de carbono (CO2). Se han
    detectado concentraciones bajas de triclorfón y sus metabolitos en la
    leche de bóvidos tras el tratamiento de éstos por vía oral y cutánea.

    1.3  Efectos en organismos del medio ambiente

         El triclorfón es moderadamente tóxico para los peces (los valores 
    de la CL50 a las 96 h varían entre 0,45 mg/litro y 51 mg/litro) y de
    toxicidad moderada a elevada para los artrópodos acuáticos (la CL50
    a las 48 h/96 h varía entre 0,75 µg/litro y 7800 µg/litro). En cambio,
    los valores observados en aguas de superficie tras aplicar el
    compuesto en bosques a razón de 6 kg/ha quedan por debajo de estos
    límites. Así pues, si es objeto de un uso normal, el triclorfón tendrá
    un efecto muy reducido o nulo en las poblaciones de organismos
    acuáticos, puesto que otros grupos como los moluscos y los
    microorganismos, son menos sensibles que los artrópodos. Los valores
    de la DL50 obtenidos en estudios de laboratorio (de 40 a 180 mg/kg)
    indican que este compuesto es moderadamente tóxico para las aves. En
    cambio, en estudios de campo no se observó efecto alguno en la
    población total, el número de parejas en época de cría, la viabilidad
    de los nidos ni la mortalidad de las aves canoras de los bosques
    tratados mediante aplicaciones aéreas del insecticida. Se observó
    cierta disminución de la actividad canora y mayor actividad de
    búsqueda de alimento, tal vez por haberse reducido las poblaciones de
    los organismos de que se nutren. Nada indica que el triclorfón
    perjudique a los organismos terrestres excepto los artrópodos. No se
    dispone de información sobre sus efectos en artrópodos beneficiosos.

    1.4  Efectos en animales de laboratorio y en sistemas de
         ensayo in vitro

         El triclorfón es un insecticida moderadamente tóxico para los
    animales de laboratorio. Los valores de la DL50 para el producto
    técnico administrado por vía oral a éstos varían entre 400 y 800 mg/kg
    de peso corporal; en la rata, los valores de la DL50 cuando se
    administra por vía cutánea superan los 2000 mg/kg de peso corporal.

         La intoxicación por este compuesto origina los signos
    colinérgicos comúnmente relacionados con los organofosfatos y que se
    atribuyen a la acumulación de acetilcolina en las terminaciones

         Se ha demostrado que el triclorfón técnico es moderadamente
    irritante para los ojos de la rata, aunque no para la piel del conejo.
    Se ha observado potencial de sensibilización cutánea en conejillos de

         Se llevaron a cabo estudios de corto plazo sobre toxicidad por
    vía oral en ratas, perros, monos, conejos y conejillos de Indias. En
    uno de 16 semanas en ratas, en otro de 4 años en perros y en un
    tercero de 26 semanas en monos, se registraron respectivamente las
    siguientes concentraciones sin efectos observados (NOEL):  100 mg/kg
    de ración alimenticia, 50 mg/kg de ración alimenticia y 0,2 mg/kg de
    peso corporal (calculados respecto de la actividad de la colinesterasa
    en plasma, eritrocitos o encéfalo). La exposición de ratas por
    inhalación durante más de tres semanas indicó una NOEL de 12,7
    mg/m3, calculados respecto de la inhibición de la actividad de la
    colinesterasa en plasma, eritrocitos y encéfalo. Se llevaron a cabo
    estudios de toxicidad/carcinogenicidad a largo plazo en ratones,
    ratas, monos y hámsters tras la administración oral, intraperitoneal
    o cutánea. Se observaron efectos adversos en las gónadas de ratones y
    ratas expuestos por vía oral a 30 mg/kg de peso corporal y 400 mg/kg
    de ración alimenticia, respectivamente. En un estudio de 24 meses en
    ratas y otro de 10 años en monos, se determinaron valores de NOEL de
    50 mg/kg de ración alimentaria y de 0,2 mg/kg de peso corporal,
    respectivamente. Los datos disponibles no aportan pruebas de
    carcinogenicidad tras la exposición prolongada de animales de
    laboratorio por diversas vías de administración.

         Se ha comunicado que, en condiciones fisiológicas, el triclorfón 
    tiene la propiedad de alquilizar al ADN. Los ensayos de mutagenicidad
    han dado resultados tanto positivos como negativos. Es posible que el
    diclorvos sea la causa, parcial o totalmente, de los efectos
    observados. La mayoría de los estudios de mutagenicidad  in vitro en
    células tanto bacterianas como de mamíferos dieron resultado positivo;
    en cambio, pocos de los estudios in vivo dieron ese resultado.

         Investigaciones realizadas en el ratón, la rata y el hámster
    indican  que, en dosis lo bastante elevadas como para producir

    toxicidad materna, el triclorfón produce una respuesta teratógena en
    ratas. La exposición de ratas gestantes a dosis de 145 mg/kg de ración
    alimenticia provocó malformaciones fetales. La administración oral
    forzada de 400 mg/kg de peso corporal a hámsters produjo también
    toxicidad materna y respuesta teratógena. Por esta vía, la dosis más
    baja que produjo efectos teratógenos en la rata fue de 80 mg/kg de
    peso corporal. Los efectos son específicos según el momento del
    periodo de gestación en que se ingiere el producto. En este estudio de
    administración oral forzada se obtuvo una NOEL de 8 mg/kg.

         En ratas y hámsters se han encontrado, respectivamente, NOEL de
    8 mg/kg de peso corporal y 200 mg/kg de peso corporal. También se han
    comunicado respuestas teratógenas que afectaban al sistema nervioso
    central en el cerdo y el conejillo de Indias.

         En cambio, no se observaron efectos teratógenos en un estudio de
    reproducción en tres generaciones de ratas, en el que con dosis
    elevadas se indujeron efectos reproductivos adversos. La NOEL en este
    estudio fue de 300 mg/kg de ración alimenticia.

         Con dosis muy elevadas se han producido efectos neurotóxicos en

         En los mamíferos, el producto activo de la transformación es el
    diclorvos, cuya actividad como anticolinesterasa es como mínimo 100
    veces mayor que la del triclorfón.

    1.5  Efectos en el ser humano

         Se han producido varios casos de envenenamiento agudo por
    exposición intencional (suicidio) o accidental. Los signos y síntomas
    de la intoxicación fueron los característicos de la inhibición de la
    acetilcolinesterasa:  agotamiento, debilidad, confusión, sudación y
    salivación excesivas, dolores abdominales, vómitos, pupilas
    puntiformes y espasmos musculares. En casos graves se observaron
    pérdida de la consciencia y convulsiones, y la muerte se produjo en
    general por fallo respiratorio. En las víctimas que sobrevivieron
    gracias a la intervención médica, a veces se observó una
    polineuropatía diferida, acompañada de debilidad de los miembros
    inferiores, la cual apareció algunas semanas después de la exposición.
    En los casos mortales, la autopsia reveló alteraciones isquémicas en
    el encéfalo, la médula espinal y los ganglios vegetativos, lesiones de
    la vaina mielínica en la médula espinal y los pedúnculos cerebrales,
    y cambios estructurales en los axones de los nervios periféricos.

         Se han producido algunos casos de envenenamiento ocupacional,
    principalmente por no observar las normas de seguridad. La exposición
    en un lugar de trabajo con concentraciones en el aire superiores a 0,5
    mg/m3 ocasionó la disminución de la colinesterasa plasmática y
    cambios del trazado electroencefalográfico. No obstante, estos signos

    desaparecieron por completo al cesar la exposición. No se ha
    comunicado ningún caso de sensibilización cutánea.

         Este compuesto se ha usado extensamente para tratar la
    esquistosomiasis del ser humano. La administración de una dosis única
    (7-12 mg/kg) inhibió entre el 40 y el 60% de la colinesterasa del
    plasma y los eritrocitos, sin que aparecieran síntomas colinérgicos.
    En cambio, se observaron síntomas leves en personas tratadas con dosis
    repetidas. Las dosis elevadas (24 mg/kg) produjeron síntomas
    colinérgicos graves.

    2.  Conclusiones

         -    El insecticida triclorfón es un éster organofosforado
              moderadamente tóxico. La exposición excesiva que puede
              producirse al fabricarlo o utilizarlo y la ingestión
              accidental o intencional pueden provocar envenenamientos

         -    La exposición de la población general al triclorfón se
              produce principalmente como resultado de las prácticas
              agrícolas y veterinarias y del tratamiento de la infestación
              por  Schistosoma haematobium.

         -    Las ingestas de triclorfón comunicadas se encuentran muy por
              debajo de la ingesta diaria admisible establecida por la
              FAO/OMS y en principio no constituyen un riesgo para la
              salud de la población general.

         -    Si se siguen prácticas correctas de trabajo, medidas
              higiénicas y precauciones de seguridad, es poco probable que
              el triclorfón represente un riesgo para las personas
              expuestas por su trabajo.

         -    A pesar de su gran toxicidad para otros artrópodos que no se
              pretende destruir, el triclorfón se ha utilizado con escasos
              o nulos efectos adversos para las poblaciones de organismos
              del medio ambiente.

    3.  Recomendaciones

         -    Para proteger la salud de los trabajadores y de la población
              general, la manipulación y la aplicación del triclorfón
              deben encomendarse solamente a operarios bien supervisados
              y adiestrados, que observarán medidas adecuadas de seguridad
              y utilizarán el insecticida siguiendo prácticas correctas.

         -    La fabricación, la formulación, el uso agrícola y la
              evacuación del triclorfón deben sujetarse a una gestión
              cuidadosa para reducir al mínimo la contaminación del medio,
              en particular las aguas de superficie.

         -    Las poblaciones de trabajadores y de personas regularmente
              expuestos deben someterse a exámenes médicos periódicos.

         -    Las tasas de aplicación del triclorfón deben limitarse a fin
              de evitar efectos sobre artrópodos que no se pretende
              combatir. Este insecticida nunca debe rociarse sobre masas
              ni corrientes de agua.

    See Also:
       Toxicological Abbreviations
       Trichlorfon (HSG 66, 1991)
       Trichlorfon (JECFA Food Additives Series 51)
       Trichlorfon (WHO Food Additives Series 45)
       TRICHLORFON (JECFA Evaluation)
       Trichlorfon (WHO Pesticide Residues Series 1)
       Trichlorfon (WHO Pesticide Residues Series 5)
       Trichlorfon (Pesticide residues in food: 1978 evaluations)
       Trichlorfon (IARC Summary & Evaluation, Volume 30, 1983)