INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY
ENVIRONMENTAL HEALTH CRITERIA 132
TRICHLORFON
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
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chemicals.
WHO Library Cataloguing in Publication Data
Trichlorfon.
(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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CONTENTS
ENVIRONMENTAL HEALTH CRITERIA FOR TRICHLORFON
INTRODUCTION
1. SUMMARY AND EVALUATION, CONCLUSIONS, AND RECOMMENDATIONS
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. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES,
ANALYTICAL METHODS
2.1 Identity
2.2 Physical and chemical properties
2.3 Conversion factors
2.4 Analytical methods
3. SOURCES OF HUMAN AND
ENVIRONMENTAL EXPOSURE
3.1 Natural occurrence
3.2 Industrial production
3.3 Uses
4. ENVIRONMENTAL TRANSPORT,
DISTRIBUTION, AND TRANSFORMATION
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. ENVIRONMENTAL LEVELS AND
HUMAN EXPOSURE
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. KINETICS AND METABOLISM
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. EFFECTS ON ORGANISMS IN THE ENVIRONMENT
7.1 Microorganisms
7.2 Invertebrates
7.3 Aquatic vertebrates
7.4 Terrestrial vertebrates
7.5 Ecosystems
8. EFFECTS ON EXPERIMENTAL ANIMALS
AND IN VITRO TEST SYSTEMS
8.1 Acute toxicity
8.2 Short-term exposure
8.3 Skin and eye irritation;
sensitization
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
8.4.1.1 Mouse
8.4.1.2 Rat
8.4.1.3 Dog
8.4.1.4 Monkey
8.4.2 Intraperitoneal administration
8.4.2.1 Mouse
8.4.2.2 Rat
8.4.2.3 Hamster
8.4.3 Dermal administration
8.4.3.1 Mouse
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. EFFECTS ON HUMAN BEINGS
9.1 Acute poisoning -
poisoning incidents
9.2 Therapeutic use of
trichlorfon
9.3 Occupational exposures
9.4 Treatment of acute trichlorfon poisoning
10. PREVIOUS EVALUATIONS BY
INTERNATIONAL BODIES
REFERENCES
ANNEX I. Treatment of organophosphate
insecticide poisoning in man
ANNEX II. No-observed-effect levels (NOELs)
in animals treated with
trichlorfon
RESUME ET EVALUATION, CONCLUSIONS,
RECOMMANDATIONS
RESUMEN Y EVALUACION, CONCLUSIONES,
RECOMENDACIONES
WHO TASK GROUP ON ENVIRONMENTAL HEALTH
CRITERIA FOR TRICHLORFON AND FENITROTHION
Members
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,
India
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
Observers
Dr M. Matsuo, Biochemistry and Toxicology Laboratory, Sumitomo
Chemical Co. Ltd, Osaka-shi, Japan (representing GIFAP)
Secretariat
Dr J. Sekizawa, National Institute of Hygienic Sciences, Tokyo, Japan
(Joint Rapporteur)
Dr K.W. Jager, IPCS, World Health Organization, Geneva, Switzerland
(Secretary)
NOTE TO READERS OF THE CRITERIA DOCUMENTS
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 -
7985850).
ENVIRONMENTAL HEALTH CRITERIA FOR TRICHLORFON AND
FENITROTHION
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.
INTRODUCTION
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,
1986).
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,
1983).
1. SUMMARY AND EVALUATION, CONCLUSIONS, AND RECOMMENDATIONS
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
hydrolysis.
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
endings.
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
result.
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
symptoms.
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
practices.
- The manufacture, formulation, agricultural use, and disposal
of trichlorfon should be carefully managed to minimize
contamination of the environment, particularly surface
waters.
- 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. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL
METHODS
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:
O
"
Cl3CCHP(OCH3)2
'
OH
Chemical formula: C4H8Cl3O4P
Relative molecular mass: 257.44
Common name: trichlorfon (ISO)
Chemical name: dimethyl 2,2,2-trichloro-1-
hydroxyethylphosphonate
Synonyms: chlorofos, DEP, DETF, dipterex,
dimethyl 1-hydroxy- 2,2,2-trichloro
ethanephosphonate, O, O-dimethyl
(2,2,2-trichloro-1-hydroxyethyl)
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-
trichloro-1-hydroxyethylphospho
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
20
Density 1.73
4
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
(octanol/water)
Corrosiveness corrosive to metals
a From: Giang et al. (1954); FAO/WHO (1972); Dedek (1981); IARC
(1983).
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)
powder
formulation
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
extraction
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
(0.05-1.0)
animal
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)
acetate
extraction
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
n-hexane
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
calibration
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.,
1954).
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
interference.
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. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE
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
thiabendazole.
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
(tonne)
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,
olives
Czechoslovakiac - 1983
Swedenc 5.7 1982 agriculture, hygiene
Japan 279.7 1987 potatoes, other
vegetables
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,
vegetables
1.8 1987 alfalfa
Mexico 133.1 1987 maize, cotton,
tobacco, tomatoes,
sugar cane, soybeans
Brazil 145.3 soybeans, cotton,
wheat
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).
4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION
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,
1980).
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.,
1971).
[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.
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. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE
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,
1989).
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.,
1981).
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
Day
no. kg/ha formulationb
0 1/3 4/6 7/9 10/12 13/15 17/19 21
Cabbage
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)
[30]
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
Lettuce
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
Day
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)
Parsley
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
Day
no. kg/ha formulationb
0 1/3 4/6 7/9 10/12 13/15 17/19 21
Brussel
sprouts
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
Kale
Netherlands 1 1.0 WP-80 0.33-0.12 Anon. (1978c)
Kohlrabi
Netherlands 1 1.0 WP-80 0.02-0.01 Anon. (1978c)
Spinach
Netherlands 1 1.0 WP-80 5.3-3.4 FAO/WHO (1976)
1 1.0 6.2-2.1
Spinach
(greenhouse)
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
Spinach
(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
Spinach
(outdoor)
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
Day
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)
[44]
Chinese radish
Japan
(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
Day
no. kg/ha formulationb
0 1/3 4/6 7/9 10/12 13/15 17/19 21
Chinese radish
Japan
(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
Onion
USSR 4 2.0 EC 2.7-3.1 0.90-1.2 0.02-0.77 nd-0.04 nd [30] Baida (1975)
Potato
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)
[16]
Tomato
(glasshouse)
Netherlands 1 1.2 WP-50 0.03-nd FAO/WHO (1976)
1 1.2 0.13-nd Abbasov (1972)
Apple
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
Day
no. kg/ha formulationb
0 1/3 4/6 7/9 10/12 13/15 17/19 21
Grape
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
Lemon
USA 1 4.5 WP-80 nd Iwata at el. (1979)
[52-59]
Orange
USA 1 4.5 WP-80 nd Iwata et el. (1979)
[52-59]
Mandarin
orange
Japan 5 3.0 EC-50 nd FAO/WHO (1979)
[27-29]
Kski
persimmon
Japan 3 3g/tree EC-50 0.57-0.53 0.36 0.3-0.25 FAO/WHO (1979)
Raspberry
Finland 2 0.8g/ not stated 5.6 Anon. (1978b)
linear
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
Day
no. kg/ha formulationb
0 1/3 4/6 7/9 10/12 13/15 17/19 21
Strawberry
Japan 3 2.0 EC-50 1.4 0.31 FAO/WHO (1979)
[18-21]
5 2.0 4.6 0.75
3 3.0 2.12 0.46
[18-21]
5 3.0 3.31 1.06
1 1.6-2.4 0.02
[18-21]
3 2-3 not stated 2.1-1.4 0.46-0.33
[20-21]
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]
Rye-grass
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
Day
no. kg/ha formulationb
0 1/3 4/6 7/9 10/12 13/15 17/19 21
Cotton
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)
[48]
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
application
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
(1971)
Dermal 36 0.1-0.2 0.05 Mollhoff
(1971)
Dermal 100 0.1-0.2 0.05-0.1 0.01 Mollhoff
(1971)
Dermal 100 0.05-0.1 0.05 Mollhoff
(1971)
Oral 3 0.033 0.091 0.080 0.052 0.003 0.001 Nakahara
et al.
(1972)
Oral 30 0.56 0.33 0.25 0.16 0.007 0.001 Nakahara
et al.
(1972)
Oral 1a 0.034 0.029 0.021 0.009 0.001 Nakahara
et al.
(1972)
Intramuscularb 25 2.4 1.3 0.7 0.5 0.25 0.1 Dedek &
Schwarz
(1966)
Table 6. (continued)
Method of Residues (mg/kg) in milk after application Reference
application
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
(1979)
Pour-one 20 0.2 0.3 0.35 0.35 0.2 0.1 FAO/WHOc
(1979)
Pour-onf 30 0.45 0.05 0.01 Dedek &
Schwarz
(1966)
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
(1970)
Pig subcu- 25 mg/kg 6 5 3-4 2-3 1 0.1 0.01 Dedek &
taneous Schwarz
(1970)
Sheep spray 4 g/m3 2.3 0.8 0.6 trace NDa Nepoklonov&
Bukshtynov
(1971)
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. KINETICS AND METABOLISM
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,
1986).
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
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
milking.
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).
I