UNITED NATIONS ENVIRONMENT PROGRAMME
INTERNATIONAL LABOUR ORGANISATION
WORLD HEALTH ORGANIZATION
INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY
ENVIRONMENTAL HEALTH CRITERIA 183
CHLOROTHALONIL
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.
First draft prepared by Dr. M.H. Litchfield, Arundel, United Kingdom
Published under the joint sponsorship of the United Nations
Environment Programme, the International Labour Organisation, and the
World Health Organization, and produced within the framework of the
Inter-Organization Programme for the Sound Management of Chemicals.
World Health Organization
Geneva, 1996
The issue of this document does not constitute formal publication.
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permission of the Manager, International Programme on Chemical Safety,
WHO, Geneva, Switzerland.
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venture of the United Nations Environment Programme (UNEP), the
International Labour Organisation (ILO), and the World Health
Organization (WHO). The main objective of the IPCS is to carry out and
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and the quality of the environment. Supporting activities include the
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research on the mechanisms of the biological action of chemicals.
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is to promote coordination of the policies and activities pursued by
the Participating Organizations, jointly or separately, to achieve the
sound management of chemicals in relation to human health and the
environment.
WHO Library Cataloguing in Publication Data
Chlorothalonil
(Environmental health criteria ; 183)
1.Fungicides, Industrial 2.Pesticides 3.Agrochemicals
4.Environmental exposure I.Series
ISBN 92 4 157183 7 (NLM Classification: WA 240)
ISSN 0250-863X
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CONTENTS
ENVIRONMENTAL HEALTH CRITERIA FOR CHLOROTHALONIL
Preamble
1. SUMMARY AND EVALUATION; CONCLUSIONS AND RECOMMENDATIONS
1.1. Summary
1.1.1. Identity, physical and chemical properties, and
analytical methods
1.1.2. Sources of human and environmental exposure
1.1.3. Environmental transport, distribution and
transformation
1.1.4. Environmental levels and human exposure
1.1.5. Kinetics and metabolism in laboratory animals
1.1.6. Effects on laboratory mammals and in vitro test
systems
1.1.7. Effects on humans
1.1.8. Effects on other organisms in the laboratory and
field
1.2. Evaluation
1.2.1. Evaluation of human health risks
1.2.2. Evaluation of effects on the environment
1.2.2.1 Transport, distribution and
transformation
1.2.2.2 Aquatic organisms
1.2.2.3 Terrestrial organisms
1.2.3. Toxicological criteria for setting guidance values
1.3. Conclusions and recommendations
2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS
2.1. Identity
2.2. Physical and chemical properties
2.3. Analytical methods
2.3.1. Sample preparation
2.3.2. Analytical determination
3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE
3.1. Natural occurrence
3.2. Production levels and processes
3.3. Uses
4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION
4.1. Transport and distribution between media
4.2. Transformation
4.2.1. Biodegradation
4.2.2. Abiotic degradation
4.2.3. Bioaccumulation
4.3. Waste disposal
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. Food crops
5.1.5. Dairy produce
5.1.6. Animal feed
5.2. General population exposure
5.2.1. Food
5.3. Occupational exposure
6. KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS
6.1. Absorption
6.2. Distribution
6.3. Metabolic transformation
6.3.1. Rat
6.3.2. Dog
6.3.3. Monkey
6.4. Elimination and excretion
6.4.1. Rat
6.4.2. Mouse
6.4.3. Dog
6.4.4. Monkey
6.5. Reaction with body components
7. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS
7.1. Single exposure
7.2. Short-term exposure
7.2.1. Oral
7.2.1.1 Rat
7.2.1.2 Mouse
7.2.1.3 Dog
7.2.2. Dermal: Rabbit
7.3. Long-term exposure
7.3.1. Rat
7.3.2. Mouse
7.3.3. Dog
7.3.4. Summary of key dietary studies
7.4. Skin and eye irritation; sensitization
7.5. Reproductive and developmental toxicity
7.6. Mutagenicity
7.7. Carcinogenicity
7.8. Other special studies
7.9. Toxicity of metabolites
8. EFFECTS ON HUMANS
8.1. General population exposure
8.2. Occupational exposure
9. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD
9.1. Laboratory experiments
9.1.1. Microorganisms
9.1.1.1 Aquatic microorganisms
9.1.1.2 Soil microorganisms
9.1.2. Aquatic organisms
9.1.3. Terrestrial organisms
9.1.3.1 Plants
9.1.3.2 Earthworms
9.1.3.3 Earwigs and honey-bees
9.1.3.4 Birds
9.2. Field observations
9.2.1. Soil microorganisms
9.2.2. Plants
10. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES
REFERENCES
RESUME
RESUMEN
NOTE TO READERS OF THE CRITERIA MONOGRAPHS
Every effort has been made to present information in the criteria
monographs as accurately as possible without unduly delaying their
publication. In the interest of all users of the Environmental Health
Criteria monographs, readers are 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
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A detailed data profile and a legal file can be obtained from the
International Register of Potentially Toxic Chemicals, Case postale
356, 1219 Châtelaine, Geneva, Switzerland (Telephone No. 9799111).
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This publication was made possible by grant number 5 U01 ES02617-
15 from the National Institute of Environmental Health Sciences,
National Institutes of Health, USA, and by financial support from the
European Commission.
Environmental Health Criteria
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WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR CHLOROTHALONIL
Members
Dr T. Bailey, US Environmental Protection Agency, Washington DC, USA
Dr A.L. Black, Department of Human Services and Health, Canberra,
Australia
Mr D.J. Clegg, Carp, Ontario, Canada
Dr S. Dobson, Institute of Terrestrial Ecology, Monks Wood, Abbots
Ripton, Huntingdon, Cambridgeshire, United Kingdom (Vice-
Chairman)
Dr P.E.T. Douben, Her Majesty's Inspectorate of Pollution, London,
United Kingdom (EHC Joint Rapporteur)
Dr P. Fenner-Crisp, US Environmental Protection Agency, Washington DC,
USA
Dr R. Hailey, National Institute of Environmental Health Sciences,
National Institutes of Health, Research Triangle Park, USA
Ms K. Hughes, Environmental Health Directorate, Health Canada, Ottawa,
Ontario, Canada (EHC Joint Rapporteur)
Dr D. Kanungo, Central Insecticides Laboratory, Government of India,
Ministry of Agriculture & Cooperation, Directorate of Plant
Protection, Quarantine & Storage, Faridabad, Haryana, India
Dr L. Landner, MFG, European Environmental Research Group Ltd,
Stockholm, Sweden
Dr M.H. Litchfield, Melrose Consultancy, Denmans Lane, Fontwell,
Arundel, West Sussex, United Kingdom (CAG Joint Rapporteur)
Professor M. Lotti, Institute of Occupational Medicine,
University of Padua, Padua, Italy (Chairman)
Professor D.R. Mattison, University of Pittsburgh, Graduate
School of Public Health, Pittsburgh, Pennsylvania, USA
Dr J. Sekizawa, National Institute of Health Sciences, Tokyo, Japan
Dr P. Sinhaseni, Chulalongkorn University, Bangkok, Thailand
Dr S.A. Soliman, King Saud University, Bureidah, Saudi Arabia
Dr M. Tasheva, National Centre of Hygiene, Medical Ecology and
Nutrition, Sofia, Bulgaria (CAG Joint Rapporteur)
Mr J.R. Taylor, Pesticides Safety Directorate, Ministry of
Agriculture, Fisheries and Food, York, United Kingdom
Dr H.M. Temmink, Wageningen Agricultural University, Wageningen, The
Netherlands
Dr M.I. Willems, TNO Nutrition and Food Research Institute, Zeist,
The Netherlands
Representatives of GIFAPa (Groupement International des
Associations Nationales de Fabricants de Produits Agrochimiques)
Dr M. Bliss, Jr., ISK Biosciences Corporation, Mentor, Ohio, USA
Dr A.C. Dykstra, Registration Department BPID, Solvay-Duphar BV, CP
Weesp, The Netherlands
Dr H. Frazier, ISK Biosciences Corporation, Mentor, Ohio, USA
Dr R. Gardiner, GIFAP, Brussels, Belgium
Dr B. Julin, Regulatory Affairs, Du Pont de Nemours (Belgium),
Agricultural Products Department, Mercure Centre, Brussels, Belgium
Dr S.M. Kennedy (Environmental Science), Du Pont de Nemours (Belgium),
Agricultural Products Department, Mercure Centre, Brussels, Belgium
Dr J. Killeen, ISK Biosciences Corporation, Mentor, Ohio, USA
Dr Th. S.M. Koopman, Toxicology Department, Solvay-Duphar BV, CP
Weesp, The Netherlands
Dr R.L. Mull, Du Pont Agricultural Products, Wilmington, Delaware, USA
Dr J.L.G. Thus, Environmental Research Department, Solvay-Duphar BV,
CP Weesp, The Netherlands
Secretariat
Ms A. Sundén Byléhn, International Register of Potentially Toxic
Chemicals, United Nations Environment Programme, Châtelaine,
Switzerland
Dr P. Chamberlain, International Programme on Chemical Safety, World
Health Organization, Geneva, Switzerland
a Participated as required for exchange of information.
Dr J. Herrman, International Programme on Chemical Safety, World
Health Organization, Geneva, Switzerland
Dr K. Jager, International Programme on Chemical Safety, World Health
Organization, Geneva, Switzerland
Dr P. Jenkins, International Programme on Chemical Safety, World
Health Organization, Geneva, Switzerland
Dr W. Kreisel, World Health Organization, Geneva, Switzerland
Dr M. Mercier, International Programme on Chemical Safety, World
Health Organization, Geneva, Switzerland
Dr M.I. Mikheev, Occupational Health, World Health Organization,
Geneva, Switzerland
Dr G. Moy, Food Safety, World Health Organization, Geneva, Switzerland
Mr I. Obadia, International Labour Organisation, Geneva, Switzerland
Dr R. Pleœtina, International Programme on Chemical Safety, World
Health Organization, Geneva, Switzerland
Dr E. Smith, International Programme on Chemical Safety, World Health
Organization, Geneva, Switzerland (EHC Secretary)
Mr J. Wilbourn, International Agency for Research on Cancer, Lyon,
France
ENVIRONMENTAL HEALTH CRITERIA FOR CHLOROTHALONIL
The Core Assessment Group (CAG) of the Joint Meeting on
Pesticides met in Geneva from 25 October to 3 November 1994. Dr W.
Kreisel of the WHO welcomed the participants on behalf of WHO, and
Dr M. Mercier, Director, IPCS, on behalf of the IPCS and its
cooperating organizations (UNEP/ILO/WHO). The Group reviewed and
revised the draft monograph and made an evaluation of the risks for
human health and the environment from exposure to chlorothalonil.
The first draft of the monograph was prepared by Dr M.H.
Litchfield, Arundel, United Kingdom. The second draft, incorporating
comments received following circulation of the first draft to the IPCS
contact points for Environmental Health Criteria monographs, was
prepared by the IPCS Secretariat.
Dr K.W. Jager and Dr P.G. Jenkins, both members of the IPCS
Central Unit, were responsible for the overall scientific content and
technical editing, respectively.
The fact that ISK Biosciences Corporation made available to the
IPCS its proprietary toxicological information on chlorothalonil is
gratefully acknowledged. This allowed the CAG to make its evaluation
on a more complete database.
The efforts of all who helped in the preparation and finalization
of the monograph are gratefully acknowledged.
ABBREVIATIONS
BCF bioconcentration factor
BUN blood urea nitrogen
ECD electron capture detector
EDB 1,2-dibromoethane (ethylene dibromide)
FID flame ionization detector
GC gas chromatography
GSH glutathione
gamma-GT gamma-glutamyltranspeptidase
HECD Hall electron capture detector
LOEL lowest-observed-effect level
MS mass spectrometry
NADPH reduced nicotinamide adenine dinucleotide phosphate
NOEL no-observed-effect level
PIB piperonyl butoxide
SGOT serum glutamic-oxalic transaminase
SGPT serum glutamic-pyruvic transaminase
TEAM total exposure assessment methodology
TWA time-weighted average
UDS unscheduled DNA synthesis
VHH volatile halogenated hydrocarbon
VOC volatile organic carbon compound
1. SUMMARY AND EVALUATION; CONCLUSIONS AND RECOMMENDATIONS
1.1 Summary
1.1.1 Identity, physical and chemical properties, and analytical
methods
Chlorothalonil is a colourless, odourless, crystalline solid with
a melting point of 250°C and a vapour pressure of 7.63 × 10-5 Pa
(5.72 × 10-7 mmHg) at 25°C. It has low water solubility
(0.6-1.2 mg/litre at 25°C) and an octanol/water partition coefficient
(log Kow) of 2.882. It is hydrolysed in water slowly at pH 9 but is
stable at pH 7 or below (at 25°C).
The most prevalent analytical method, after sample extraction and
clean-up, is gas-liquid chromatography using an electron-capture
detector.
1.1.2 Sources of human and environmental exposure
Chlorothalonil has been produced commercially since 1969 by
chlorination of isophthalonitrile or by treatment of
tetrachloroisophthaloyl amide with phosphorus oxychloride. It is a
fungicide with a broad spectrum of activity used mainly in agriculture
but also on turf, lawns and ornamental plants. Crops protected
include pome and stone fruit, citrus, currants, berries, bananas,
tomatoes, green vegetables, coffee, peanuts, potatoes, onions and
cereals. In addition, it is used in wood preservatives and in paints.
The three main formulations are a suspension concentrate, a water
dispersible granule and a wettable powder. They are readily diluted
with water and applied by ground spray systems or by air. Typical
active ingredient rates are 1.2-2.5 kg/ha for crops such as beans,
celery and onions. The main sources of human exposure will be during
preparation and application of the products and from ingestion of crop
residues in foodstuff (see section 1.1.4).
1.1.3 Environmental transport, distribution and transformation
Chlorothalonil is removed from aqueous media by strong adsorption
on suspended matter. Modelled data suggest little or no partition to
bottom sediment. Biodegradation may occur in natural waters with
enzyme processes being involved. Chlorothalonil is rapidly degraded
in soil, and degradation may occur in water with the production of the
4-hydroxy metabolite, 4-hydroxy-2,5,6-trichloroisophthalonitrile.
Half-lives for dissipation of the 4-hydroxy metabolite in soils range
between 6 and 43 days.
Chlorothalonil does not translocate from the site of application
to other parts of a plant. It is metabolized only to a limited extent
on plants and the 4-hydroxy metabolite is usually < 5% of the
residue.
Chlorothalonil is metabolized in fish via glutathione conjugation
to give more polar excretory products. The enzyme glutathione-
S-transferase is involved with this conversion. High concentrations
of radiolabel found in the gall bladder and bile, after exposure of
rainbow trout to 14C-chlorothalonil, are consistent with the
excretion of the compound as glutathione conjugates. The
concentrations of radiolabel accumulating in the gall bladder and
other organs fell rapidly when the fish were placed in clean water.
Chlorothalonil does not bioaccumulate in aquatic organisms.
1.1.4 Environmental levels and human exposure
In a potato crop study, a small stream was oversprayed with
chlorothalonil. Subsequent sampling/analysis of down-stream water
demonstrated rapid disappearance of chlorothalonil (i.e. 450 µg/litre
at 30 min post-spraying to 2-6 µg/litre at 12 h post-spraying). The
routine spraying of irrigated field crops such as potatoes and barley
gave rise to low concentrations of chlorothalonil (0.04-3.6 µg/litre)
in tile drain water on a small number of sampling occasions.
Crop residues are composed mainly of chlorothalonil itself. The
residue levels are dependent upon the applied rate, time interval
between the last application and harvest, and the type of crop.
Residue levels at harvest can be derived from the numerous supervised
trials that have taken place on many crops worldwide and reported to
FAO/WHO. Residues of chlorothalonil in dairy products are expected to
be undetectable or very low. Dairy cows given high concentrations (up
to 250 mg/kg) of chlorothalonil in their feed for 30 days showed no
detectable residue in milk and only very low levels in tissues.
Total diet and individual food analysis in several countries have
shown undetectable or low concentrations of chlorothalonil in sampling
surveys. Residue levels on foodstuffs are further reduced by
preparation processes such as washing, peeling and cooking.
1.1.5 Kinetics and metabolism in laboratory animals
About 30% of an oral dose of chlorothalonil is absorbed within
48 h in rats at doses up to 50 mg/kg body weight. At higher doses,
absorption is lower, indicating a saturation process. When
14C-chlorothalonil is given orally the radioactivity is distributed
into blood and tissues within 2 h. The greatest concentration is
found in the kidney, followed by liver and blood. The kidneys contain
0.3% of a 5 mg/kg body weight dose after 24 h.
Most of an oral dose of chlorothalonil in rats is found in faeces
(> 82% within 48-72 h, regardless of dose). Biliary excretion is
rapid, peaking within 2 h after a 5 mg/kg body weight oral dose, and
is saturated at 50 mg/kg body weight and above. Urinary excretion
accounts for 5-10% of the dose in rats. Faecal excretion is the main
route in dogs and monkeys but urinary excretion (< 4%) is less than
in rats.
Metabolic studies in rats indicate that chlorothalonil is
conjugated with glutathione in the liver as well as in the
gastrointestinal tract. Some of the glutathione conjugates may be
absorbed from the intestine and transported to the kidneys, where they
are converted by cytosolic ß-lyase to thiol analogues that are
excreted in the urine. When germ-free rats are dosed with
chlorothalonil, the thiol metabolites appear in urine in much smaller
amounts than with normal rats, indicating the involvement of
intestinal microflora in the metabolism of chlorothalonil. Dogs or
monkeys dosed orally with chlorothalonil excrete little or no thiol
derivatives in urine.
When 14C-chlorothalonil was applied to rat skin, approximately
28% of the dose was absorbed within 120 h. About 18% of the dose was
found in faeces and 6% in urine within 120 h.
1.1.6 Effects on laboratory mammals and in vitro test systems
Chlorothalonil has low acute oral and dermal toxicity in rats and
rabbits, respectively (acute oral and dermal LD50 values are
> 10 000 mg/kg body weight). Hammer-milled technical chlorothalonil
(MMAD 5-8 µm) exhibited high toxicity in rats in an inhalation study,
with a 4-h LC50 of 0.1 mg/litre.
Chlorothalonil is a skin and eye irritant in the rabbit. Skin
sensitization studies in the guinea-pig were inconclusive.
The main effects of repeated oral dosing in rats are on the
stomach and kidney. Groups of 25 rats of each sex per group were fed
chlorothalonil at 0, 1.5, 3, 10 or 40 mg/kg body weight per day in the
diet for 13 weeks, and this was followed by a 13-week recovery period.
Increased incidences of hyperplasia and hyperkeratosis of the
forestomach occurred at 10 and 40 mg/kg; these reversed when treatment
ceased. At 40 mg/kg, there was an increased incidence of hyperplasia
of kidney proximal tubular epithelium in males at 13 weeks and after
the recovery period. The NOEL was 3 mg/kg body weight per day based
upon lack of forestomach lesions. The onset of the forestomach and
kidney changes was shown to be rapid, with the lesions developing
within 4-7 days in male rats at a dietary level of 175 mg/kg body
weight per day.
In a 13-week study on mice (0, 7.5, 15, 50, 275 or 750 mg/kg in
the diet), increased incidences of hyperplasia and hyperkeratosis of
the squamous epithelial cells of the forestomach occurred in males and
females at 50 mg/kg diet and above. The NOEL, based upon these
changes, was 15 mg/kg chlorothalonil in the diet, equivalent to
3 mg/kg body weight per day.
A 16-week study in dogs with dietary levels of 0, 250, 500 or
750 mg/kg showed no treatment-related changes.
The forestomach and kidney lesions were investigated further in
2-year studies on rats, mice and dogs. In a study on rats (0, 1.8,
3.8, 15 or 175 mg/kg body weight per day), the effects were
characterized histologically as an increase in the incidence and
severity of hyperplasia, hyperkeratosis, and ulcers and erosions of
the squamous mucosa of the forestomach, and as epithelial hyperplasia
of the kidney proximal convoluted tubules at 3.8 mg/kg and above. The
NOEL for non-neoplastic effects was therefore 1.8 mg/kg. The
incidence of renal tumours (adenomas and carcinomas) and forestomach
tumours (papillomas and carcinomas) was markedly increased at
175 mg/kg. There was evidence for an increased incidence of kidney
tumours in males at 15 mg/kg and of stomach tumours at 3.8 and
15 mg/kg in males and females. The NOEL for neoplastic effects was
therefore 1.8 mg/kg body weight per day based upon changes in
forestomach tumour incidence. Supporting evidence for the
carcinogenic potential of chlorothalonil in the kidney and forestomach
of rats was provided by the results from other 2-year studies at
higher dose levels.
In a study on mice (0, 15, 40, 175 or 750 mg/kg in the diet), an
increased incidence of renal tubular hyperplasia occurred at 175 mg/kg
and above and of hyperplasia and hyperkeratosis of the forestomach at
40 mg/kg and above. The incidence of squamous tumours of the
forestomach was slightly increased at 750 mg/kg. The NOELs for
neoplastic and non-neoplastic changes were therefore 175 and 15 mg/kg
in the diet (equivalent to 17.5 and 1.6 mg/kg body weight per day,
respectively). Supporting evidence for these effects in the mouse was
provided in another study at higher dose levels, but a study in
B6C3F1 mice did not show any evidence for carcinogenic potential at
high dose levels.
In a 2-year study on dogs (60 and 120 mg/kg in the diet), no
effects attributable to chlorothalonil were found. The NOEL was
therefore 120 mg/kg in the diet (equivalent to 3 mg/kg body weight per
day).
Chlorothalonil was not mutagenic in several in vitro and in
vivo tests, although it was positive in a small number of assays.
The monothio, dithio, trithio, dicysteine, tricysteine and
monoglutathione derivatives of chlorothalonil, which are potential
nephrotoxicants, were shown to be negative in the Ames assay.
Chlorothalonil was not teratogenic in rats or rabbits at doses up
to 400 and 50 mg/kg body weight per day, respectively. Reproductive
parameters such as mating, fertility and gestation length were not
affected by chlorothalonil at levels up to 1500 mg/kg in the diet in a
two-generation study in rats.
The acute oral toxicity of the 4-hydroxy metabolite is greater
than that of chlorothalonil itself (acute oral LD50 of 332 mg/kg body
weight versus > 10 000 mg/kg body weight). Several studies have been
undertaken to characterize the toxicological profile of this
metabolite and to establish NOELs.
1.1.7 Effects on humans
Contact dermatitis has been reported for personnel working in
chlorothalonil manufacturing and in farmers and horticultural workers.
Workers in the manufacture of wood products have also developed
contact dermatitis on the hands and face when wood preservatives
containing chlorothalonil were used.
1.1.8 Effects on other organisms in the laboratory and field
Chlorothalonil is highly toxic to fish and aquatic invertebrates
in laboratory studies, the LC50 values being below 0.5 mg/litre. The
maximum acceptable toxicant concentration (MATC) in a two-generation
reproduction study in Daphnia magna was 35 µg/litre.
With minor exceptions, chlorothalonil is not phytotoxic.
The LC50 of a suspension concentrate formulation (500 g
chlorothalonil/litre) in artificial soil for earthworms was
> 1000 mg/kg soil (14 days). Earwigs suffered increased mortality
when in contact with chlorothalonil residues on peanut foliage or
ingesting it as a food source in laboratory tests; there was no other
indication of insecticidal action.
Chlorothalonil is of low toxicity to birds with a reported acute
oral LD50 of 4640 mg/kg diet in the mallard duck. No significant
reproductive effects were reported.
A field study of aquatic organisms exposed following
chlorothalonil application suggests that the toxicity is less than
that predicted from laboratory studies; this is again consistent with
the physicochemical properties of the compound. Deaths were seen in
some species exposed experimentally in the field. There have been no
reported incidents of kills in the environment. However, despite the
short residence time of chlorothalonil in environmental media, kills
would be expected to occur. Linking kills to the compound would be
difficult given that residues would not persist long enough for
chlorothalonil to be identified.
1.2 Evaluation
1.2.1 Evaluation of human health risks
The review of the toxicological data for chlorothalonil revealed
that the most important studies for human risk estimation were the
long-term studies in rodents and dogs.
In the rodent studies, chlorothalonil caused lesions in the
forestomach and kidney. The lesions in the forestomach were
characterized as hyperplasia and hyperkeratosis of the squamous
epithelial cells. These occurred soon after dosing and were shown to
be reversible after dosing ceased. Long-term administration led to
the formation of tumours (papilloma and carcinoma). The renal lesions
in rodents were of rapid onset and characterized as hyperplasia of the
proximal tubular epithelium. On longer-term administration, renal
tumours (adenoma and carcinoma) occurred in the rat and in one study
on mice.
In order to interpret the significance of these findings, the
results of the mutagenic studies were taken into account.
Chlorothalonil gave negative results in in vitro and in vivo
mutagenic assays in which a variety of end-points were studied. Thiol
derivatives of chlorothalonil were negative in the Ames test, and
14C-chlorothalonil did not bind to rat kidney DNA in vivo. The
compound does not appear to have genotoxic potential on this basis,
indicating that it probably exerts its carcinogenic effect in rodents
via a non-genotoxic mechanism. The initial forestomach lesions in
rodents were attributed to the irritant action of chlorothalonil, and,
where this does not occur, a NOEL can be attained. The irritant action
on rodent forestomach in conjunction with the relatively long
residence time of the compound in this organ were seen to be factors
presenting the opportunity for the initiation of the lesions and
leading to carcinogenic action on prolonged administration. It was
concluded that, since humans do not possess a comparable organ,
rodents are probably not representative of the action of this compound
in man in this respect. This reasoning is also supported by the fact
that another animal species, the dog, is not affected by the compound
at similar or higher doses.
In the assessment of the relevance of the rodent renal lesions,
the metabolic conversion of chlorothalonil to metabolites which act
directly upon the kidney was seen to be a major factor. In the kidney
glutathione conjugates are converted by ß-lyase to chlorothalonil
thiol derivatives. Chlorothalonil is thought to be conjugated with
glutathione (GSH) mostly in the gastrointestinal tract prior to
absorption, although there is evidence of glutathione conjugation at
other sites. After absorption the conjugates pass to the kidney where
they are converted to chlorothalonil thiol derivatives following the
action of ß-lyase. It has been shown in vitro that the di- and
trithiol metabolites inhibit the function of renal cortical
mitochondria. Therefore, a cycle of cell death and regenerative renal
hyperplasia may be initiated.
In adducing the relevance of these findings for humans, the
species differences in the metabolic pathway for chlorothalonil were
taken into account. It was noted that the formation of the thiol
metabolites, as determined by urinary excretion, was considerably
diminished when chlorothalonil was fed to germ-free rats. This
indicates that the type and/or quantity of gut microflora has a
determining role in the production of the thiol derivatives. Studies
in dogs and monkeys showed that the excretion of the thiol derivatives
was barely detectable after oral administration of chlorothalonil.
This suggests that the rat is rather different from other species in
this respect. Furthermore there is some evidence that ß-lyase
activity in the kidney varies among species, being an order of
magnitude lower in humans than in rats.
For all the reasons stated above it was concluded that the rodent
was not the most relevant species for evaluating the long-term effect
of chlorothalonil in humans and that the dog was a more representative
species for this purpose. The NOEL of 120 mg/kg in the diet in the
2-year study on dogs, equivalent to 3 mg/kg body weight per day,
should therefore be used for the purpose of human risk estimation.
1.2.2 Evaluation of effects on the environment
Chlorothalonil is algicidal for a number of algal species. The
fungicide does not inhibit bacterial growth except at very high
concentrations in laboratory culture. Field and laboratory evidence
shows no effects on nitrogen fixation or nitrification at recommended
application rates and minimal effects at higher application rates in
temperate soils. There was insufficient information to assess effects
on the nitrogen cycle in tropical soils.
Laboratory acute toxicity tests show chlorothalonil to be very
highly toxic to many aquatic animals including fish and Daphnia,
although molluscs appear to be insensitive. The LC50 concentrations
for a range of fish and invertebrates are similar and below
0.5 mg/litre.
A single study indicated reproductive effects in fish following
continuous exposure for 35 days. Since the compound both adsorbs to
suspended material and is degraded rapidly, the significance of this
finding was considered to be questionable.
A field study of aquatic organisms exposed following
chlorothalonil application suggests that the toxicity is less than
that predicted from laboratory studies; this is again consistent with
the physicochemical properties of the compound. Deaths were seen in
some species exposed experimentally in the field. There have been no
reported incidents of kills in the environment. However, despite the
short residence time of chlorothalonil in environmental media, kills
would be expected to occur immediately after application. Linking
kills to the compound would be difficult given that residues would not
persist long enough for chlorothalonil to be identified.
With minor exceptions, chlorothalonil is not phytotoxic.
Several studies have shown no toxicity of chlorothalonil to
earthworms at recommended application rates. At an exposure of five
times the maximum recommended rate, the compound severely reduced worm
reproduction.
Chlorothalonil is classified as "relatively non-toxic" to
honey-bees. Earwigs exposed to residues topically and via food showed
some mortality (20-55%), but there is no other evidence of
insecticidal action.
Chlorothalonil has low toxicity to birds in acute or dietary
tests. The low acute toxicity of chlorothalonil to laboratory mammals
tempered with its short persistence in the environment suggests
minimal hazard to wild mammal species.
1.2.2.1 Transport, distribution and transformation
Chlorothalonil adsorbs strongly to organic matter in soil and
suspended material in water. It is not, therefore, leached from soil
to groundwater. It is removed rapidly from surface water to suspended
material and to a lesser extent to bottom sediment. Chlorothalonil is
not translocated in plants from the site of application.
Abiotic degradation of chlorothalonil in water through photolysis
does not occur. Some hydrolysis does take place at higher pH.
Microbial degradation is the major cause of dissipation in soil
and may take place to some extent in water; this involves several
parallel processes, one of which leads to formation of the 4-hydroxy
metabolite. Half-lives for dissipation of this metabolite from non-
sterile soils range between 6 and 43 days. Biodegradation on plants
is limited and the 4-hydroxy metabolite comprises less than 5% of the
total residues.
During exposure, fish bioconcentrate chlorothalonil, but almost
total degradation occurs within 2 weeks after termination of exposure.
Chlorothalonil is metabolized in fish through glutathione conjugation
and the conjugates are excreted through the bile.
1.2.2.2 Aquatic organisms
The results of a single field study measuring concentrations of
chlorothalonil in water following overspray of the water were
available; corresponding data on concentrations in suspended and
bottom sediment were unreliable. Output from the EXAMS II fate model
using the same application scenario produced estimated water
concentrations which closely corresponded to the measured ones.
Little or no chlorothalonil was predicted in bottom sediment.
Based on this combination of measured and modelled data, the
ratio between a "toxic" concentration (the rainbow trout LC50) and
expected concentration is less than 1 for up to 5 h after overspray
and increases rapidly thereafter. Similar results were obtained for
daphnids. Therefore, despite its rapid removal from water and
degradation, the high toxicity of chlorothalonil is expected to cause
deaths of aquatic organisms in the period immediately after spraying.
This is the worst case situation of direct water overspray.
There were no data to extend this quantitative evaluation to
other field situations or climates.
1.2.2.3 Terrestrial organisms
A calculated maximum soil concentration, based on application of
chlorothalonil at 2.5 kg a.i./ha and complete bioavailability, is 3
orders of magnitude higher than the lowest estimate of LC50 for
earthworms.
For grazing birds (ducks and geese) total daily intake is at
least a factor of 100 below the NOEL for oral toxicity. For rabbits,
total daily intake is also at least 2 orders of magnitude lower than
the reported NOEL. This is based on a maximum recommended application
rate of 2.5 kg a.i./ha, an estimated worst case value for residues on
grass, no degradation of the compound, consumption of the total daily
intake at a single time and no choice but to eat contaminated food.
Table 1 contains a summary of risk quotients for birds, fish and
aquatic invertebrates.
Table 1. Toxicity/exposure ratios for birds, fish and aquatic invertebrates based
on application rates of 2.5 kg a.i./ha of chlorothalonil to soybeans
(worst case)
Risk category LC50 (mg/litre Estimated exposure Toxicity/exposure
or mg/kg diet) (mg/litre or ratio (TER)c
mg/kg diet)a,b
Acute bird 4640 73.7-535.7 63.0-8.7
Acute fish (stream) 0.01 0.009-0.04 1.1-0.25
Acute fish (pond) 0.01 0.01 1.0
Acute aquatic
invertebrate (stream) 0.07 0.009-0.04 7.8-1.8
Acute aquatic
invertebrate (pond) 0.07 0.01 7.0
a Estimated environmental concentration in the terrestrial environment (for bird exposure)
is based on the stated application rate and the assumption of deposition on short grass
using the US EPA nomogram.
b Aquatic exposure concentrations were taken from the STREAM model based on a single
application and estimated run-off into water; no direct overspray is included.
c TER is the toxicity (as LC50) divided by the exposure; values at or below 1.0 indicate
likely exposure to toxic concentrations by organisms in the different risk categories.
1.2.3 Toxicological criteria for setting guidance values
The toxicological studies on chlorothalonil of relevance for
setting guidance values are displayed in Table 2. The study results
and their significance are described briefly and gaps in test
requirements are indicated.
Table 2. Toxicological criteria for setting guidance values for chlorothalonil
Exposure Relevant route/effect/ Result/remarks
scenario species
Short-term skin, irritation, rabbit irritant
(1-7 days)
eye, irritation, rabbit irritant
skin, sensitization, tests were inconclusive
guinea-pig
evidence in humans of contact
dermatitis
inhalation, lethality, high toxicity in 4-h study with
rat hammermilled technical chlorothalonil
(MMAD 5-8 µm); not relevant for most
human exposure situations
Medium-term repeat dermal, rabbit 21-day study; irritant at 2.5 mg/kg
(1-26 weeks) body weight per day and above; no
systemic effects at 50 mg/kg body
weight per day
repeat oral, mice and 13-22 week studies; NOEL = 3 mg/kg
rats body weight per day in rats and mice
maternal, oral, rabbit teratology study; maternal toxicity
NOEL = 10 mg/kg body weight per day
by gavage; no fetotoxic or teratogenic
effect
Long-term repeat oral, dog 2-year study; NOEL = 3 mg/kg body
weight per day
1.3 Conclusions and recommendations
Considering the toxicological characteristics of chlorothalonil,
both qualitatively and quantitatively, it was concluded, on the basis
of the NOEL of 3 mg/kg body weight per day derived in the 2-year study
on dogs and applying a 100-fold uncertainty factor, that 0.03 mg/kg
body weight per day will probably not cause adverse effects in humans
by any route of exposure.
A study to assess the skin irritation potential is needed.
2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS
2.1 Identity
Chemical structure
Molecular formula C8Cl4N2
Relative molecular mass 265.9
CAS chemical name 2,4,5,6,-tetrachloro-1,3-benzenedi
carbonitrile
CAS registry number 1897-45-6
RTECS registry number NT2600000
Common name chlorothalonil
IUPAC name tetrachloroisophthalonitrile
Synonyms m-TCPN; 2,4,5,6-tetrachloro-3-cyano
benzonitrile
Trade names Bravo (ISK Biotech)
(manufacturers & Daconil (ISK Biotech)
suppliers) Faber (Tripart Farm Chemicals)
Repulse (ICI); Exotherm (Alto Elite)
Nopocide (a preservative in paints and
adhesives)
Technical product > 97%
purity
Technical product tetrachlorophthalonitrile (< 0.1),
impurities (%) tetrachloroterephthalonitrile (0.1-1.6),
pentachlorobenzonitrile (0.5-2.5),
partially chlorinated dicyanobenzenes
(0.2-1.0), unchlorinated dicyano
benzenes (0.1-1.6), HCB (0.03),
insoluble in xylene (0.1-1.0)
2.2 Physical and chemical properties
The physical properties of chlorothalonil are listed in Table 3.
Table 3. Physical properties of chlorothalonil
Physical state crystalline solid
Colour colourless
Odour odourless
Melting point (°C) 250-251
Boiling point (°C) 350 (760 mmHg)
Vapour pressure at 25°C 5.72 × 10-7
Relative density 1.8
Octanol-water partition coefficient 2.88-3.86
(log Kow)
Solubility in water (mg/litre) at 25°C 0.6-1.2
Solubility in organic solvents (g/litre) acetone 20, dimethylformamide 30,
dimethylsulfoxide 20, xylene 80, readily
soluble in benzene
Chlorothalonil is non-flammable and non-explosive. It is
thermally stable under normal storage conditions and to UV radiation,
and it is chemically stable in neutral or acidic aqueous solutions.
It breaks down at pH 9, the rate following first-order kinetics at
1.8% per day (at 25°C) (Szalkowski & Stallard, 1977). It has been
shown that chlorothalonil is unstable to light when dissolved in
benzene and that 2,3,5-trichloro-4,6-dicyanobiphenyl is a condensation
product (Kawamura et al., 1978). Chlorothalonil is not corrosive.
2.3 Analytical methods
Analytical methods for determining chlorothalonil in
formulations, fruit, vegetables, soil and water are summarized in
Table 4. In general, the methods also detect the principal metabolite
4-hydroxy-2,5,6-trichloroisophthalonitrile.
2.3.1 Sample preparation
Samples are extracted initially with an organic solvent such as
acetone. For samples where interference with the analytical method is
expected, e.g., plant material, further partitioning with organic
solvents is required, followed by clean-up on alumina or Florisil
columns if necessary. The sample extracts are submitted for
analytical determination.
2.3.2 Analytical determination
In most cases the cleaned-up sample extracts are analysed by
gas-liquid chromatography using an electron capture detector. This
provides sufficient sensitivity for the analysis of trace quantities
of chlorothalonil residues at detection limits down to 0.01 mg/kg in
many cases.
Where less sensitive determination is required, e.g., for
formulation analysis, a flame ionization detector gives sufficient
sensitivity. A method for formulation analysis using infrared
spectroscopy after dichloromethane extraction has been reported (US
EPA, 1976).
The Joint FAO/WHO Codex Alimentarius Commission has given
recommendations for the methods of analysis to be used for the
determination of chlorothalonil residues (FAO/WHO, 1989).
Table 4. Methods for the determination of chlorothalonil
Sample type Sample preparation Analytical Limit of detection Reference
extraction/clean-up methoda (µg/kg or µg/litre)
Formulation extract (1,4-dioxane or methylethylketone/ GC/TCD or - Ballee et al. (1976)
carbon disulfide/1,2-dimethoxyethane) GC/FID -
Fruit & vegetable Strip (dichloromethane) GC/ECD 10 Ballee et al. (1976)
surfaces evaporate, dilute (benzene)
Green leafy extract (acidified acetone), evaporate, GC/ECD 10 Ballee et al. (1976)
vegetables dissolve (aqueous NaHCO3), adjust pH,
extract (diisopropyl ether), evaporate,
dilute (benzene), chromatograph (alumina)
Fruit and extract (acetone), evaporate, acidify GC/ECD 20 Burchfield & Storrs
vegetables and extract (ether), evaporate, chromatograph (1977)
(Florisil), elute (acetone/dichloromethane)
Non-fatty products extract (toluene/isopropanol), aqueous GC/ECD 10-50 Holmes & Wood
especially with separation, evaporate, chromatograph (1972)
S interference, (alumina/AgNO3), elute (hexane)
onion, cabbage,
celery
Potatoes extract (acidified acetone), chromatograph GC/ECD 10 Markus & Puma
(Florisil) derivatize (diazomethane) GC/MCD 20 (1973)
Table 4. (Cont'd)
Sample type Sample preparation Analytical Limit of detection Reference
extraction/clean-up methoda (µg/kg or µg/litre)
Apples rinse (acidified acetone), adjust pH, partition GC/ECD 50 Suzuki & Oda (1977)
(hexane), extract tissue (acidified acetone),
concentrate, partition (hexane), acidify
aqueous fraction, partition (diisopropyl ether)
Cranberries extract (acetone), filter, (Celite 545), adsorb GC/ECD not quoted Camoni et al. (1991)
(Extrelut-20), elute (petroleum ether),
evaporate, dissolve (benzene)
Fresh fruit extract (acetone), partition (petroleum ether HPLC/UV (232 nm) < 50 Gidvydis & Walters
and methylene chloride), concentrate and HPLC/ (1988)
photoconductivity
detection (PC)
Soil extract (acidified acetone), extract GC/ECD 10 Ballee et al. (1976)
(acetonitrile/hexane), partition (aqueous
layer) extract (diisopropyl ether) concentrate,
dilute (benzene) chromatograph (alumina)
extract (acetone: sulfuric acid), partition GC/ECD 10 Kenyon & Wiedmann
(petroleum ether), evaporate, redissolve in (1992b)
hexane/methylene chloride, elute, concentrate
Table 4. (Cont'd)
Sample type Sample preparation Analytical Limit of detection Reference
extraction/clean-up methoda (µg/kg or µg/litre)
Water adjust pH to 4.5, extract (diisopropyl ether), GC/ECD 10 Ballee et al. (1976)
concentrate, dilute (benzene)
adjust pH, extract (petroleum ether), add GC/ECD 0.05 Kenyon & Wiedmann
keeper, concentrate, redissolve (hexane/ (1992a)
methylene chloride), elute (methylene
chloride/hexane/acetonitrile)
Air samples, extraction (methional 2-propanol, n-hexane) HPLC with UV 0.5 Jongen et al. (1991)
dislodgeable detection at 254
residues or 325 nm
a GC = gas chromatography; ECD = electron capture detector; FID = flame ionization detector; HPLC = high performance liquid
chromatography; MCD = microcoulometric detection; TCD = thermal conductivity detection
3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE
3.1 Natural occurrence
Chlorothalonil does not occur naturally in the environment.
3.2 Production levels and processes
Chlorothalonil is produced by the chlorination of
isophthalonitrile or by treatment of tetrachloroisophthaloyl amide
with phosphorus oxychloride. It has been produced commercially in the
USA since 1969. No data on production are available but it has been
estimated at 5000 tonnes annually (IARC, 1983). The annual production
in Japan has been estimated to be 3000 tonnes (IARC, 1983).
Imports into the USA were 1650 tonnes in 1976 and 175 tonnes in
1980 (IARC, 1983).
No data are available on possible releases to the environment
from production processes or transportation.
3.3 Uses
Chlorothalonil is a fungicide with a broad spectrum of activity
used mainly in agriculture but also on turf, lawns and ornamental
plants. It protects plants against a variety of fungal infections
such as rusts, downy mildew, leaf spot, scabs, blossom blight and
black pod. Crops protected include pome fruit, stone fruit, citrus,
currants, cranberries, strawberries, bananas, vines, hops, tomatoes,
green vegetables, tobacco, coffee, tea, soya bean, groundnuts,
potatoes, onions, cereals and sugar beet. In addition, it is used in
wood preservatives, fish net coatings and anti-fouling paints.
Global estimates of chlorothalonil use for these purposes are not
available. The extent of use in various countries on an annual basis
is shown in Table 5.
Chlorothalonil is used in agriculture in formulated products.
The three main formulations are a suspension concentrate containing
500 g chlorothalonil/litre, a water dispersible granule and a wettable
powder containing 75% chlorothalonil. The formulations mix readily
with water and are diluted to give a spray mixture which can be
applied by ground spray systems or by air, and as dilute or
concentrated sprays.
The dose rates recommended for crop protection have been derived
from efficacy studies conducted in a variety of climatic conditions in
various parts of the world. The label recommendations are designed to
give satisfactory fungal disease control and to keep residues within
national and international limits. Typical active ingredient rates
are 1.25-2.5 kg/ha for crops such as beans, celery and onions. Rates
Table 5. Quantities of chlorothalonil used in various countries
Country Year Consumption Usage Reference
(tonnes)
Canada 1982 5.1 potatoes O'Neill (1991)
(New Brunswick)
Colombia 1980 14.5 fruit, flowers, ornamentals IRPTC (1989)
1981 22.2 fruit, flowers, ornamentals IRPTC (1989)
1982 12.5 fruit, flowers, ornamentals IRPTC (1989)
Mexico 1983 250 broccoli, potatoes, etc. IRPTC (1989)
Sweden 1981 30 agricultural crops IRPTC (1989)
3 paint, wood
Thailand 1976 6 agriculture IRPTC (1989)
1982 10.4
United Republic 1981-2 640 coffee beans, tomatoes IRPTC (1989)
of Tanzania
USA 1976 2000 by farmers on major crops IARC (1983)
1978 300 mildewcide in paint IARC (1983)
1980 5000 53% peanuts, 31% vegetables, IARC (1983)
12% turf, 5% potatoes
of use for a variety of purposes are shown in Table 6. Spray volumes
usually range from about 200 to 400 litres/ha for dilute sprays and 45
to 95 litres/ha for concentrated sprays. Applications should commence
when weather conditions favour disease, e.g., high humidity, and prior
to initial infection. Repeat applications may be needed as directed
on the label for the country concerned. Examples of crops, diseases
controlled, agronomic importance, application rates, timing of
treatment and pre-harvest intervals on a variety of crops in the
Netherlands have been given by FAO (1982). A summary of approved uses
for grapes, including formulation used, application rates, number of
treatments and pre-harvest interval for a variety of countries, has
been given by FAO/WHO (1986a).
Chlorothalonil formulations are compatible in use with many other
fungicides and insecticides and combined formulations are registered
and available for use in many countries.
Table 6. Ranges of application rates for chlorothalonil
Application rate
(kg active ingredient per ha)
Agronomic crops:
Corn, lentils, peanuts, potatoes, 0.875-2.0
soybeans, wheat, barley, rice
Tree fruit crops:
Stone, citrus, nut, pome 1.25-3.5
Small fruit:
Cranberry, blackberry, grape 1.25-5.85
Vegetable crops 0.875-2.5
Ornamentals 1.25-2.5
Turf 4.5-25.0
4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION
4.1 Transport and distribution between media
The sorptive characteristics of chlorothalonil have been
investigated to estimate its potential for contamination of aquifers
after application to a cranberry bog (Reduker et al., 1988). The soil
studied was mainly sandy in character. The studies included a kinetic
and an absorption equilibrium assessment, the soil being shaken with
chlorothalonil in water for periods up to 48 h, and a soil column
study with 2.8 mg chlorothalonil/100 ml at a flow rate of 642 ml/day
for 64 days. A linear adsorption relationship was established with a
partition coefficient for chlorothalonil of 74.4 ml/g for this soil.
Very little (< 22%) of the adsorbed chemical was recovered. The soil
column study produced a dispersion coefficient of 100 cm2/day. Only
a small proportion (less than 2.8%) of chlorothalonil appeared in the
effluent or was extracted from the soil, indicating either
irreversible adsorption, degradation, or both.
The movement of chlorothalonil in a sandy soil was observed on a
commercial farm with a high water table and a tile drain system in
Manitoba, Canada. Chlorothalonil was routinely sprayed on irrigated
crops such as potatoes and barley. In one season it was detected in
the tile drain water on 4 out of 66 sampling days at concentrations of
0.04-3.66 µg/litre. In the same period chlorothalonil was also found
in groundwater from a well on the site at levels of 10-272 µg/litre.
There was some evidence of a small amount of carry-over into the
following season (Krawchuk & Webster, 1987). They also reported
serious background contamination problems due to the autosampler.
When these problems were corrected (i.e., 1983), the residue levels in
the well ranged from 0.9 to 8.6 µg/litre. In this report, the authors
interpreted their data to demonstrate both leaching and potential
carry-over. However, it should be noted that an initial tile water
outflow sample, taken in 1981, showed no detectable chlorothalonil
(i.e., < 0.02 µg/litre), although chlorothalonil was applied to the
site that year.
Water/sediment measurements were made after aerial spraying of a
potato crop in Canada (O'Neill, 1991). The area oversprayed included
a small water course with a pond. The results showed a rapidly
decreasing chlorothalonil content in the water phase after
overspraying, little or no compound being found in the sediment
(63-91% sand). The author indicated that sediments with greater clay
or silt content would play a greater role in chlorothalonil transport.
Analysis of stream water samples containing chlorothalonil showed
significant binding to suspended material, with an average log
partition coefficient (log PSm/w) of 5.695 and an average of 81%
chlorothalonil being bound to the suspended matter. Algal growths on
stream pebbles played a dominant role in chlorothalonil removal by
absorption and biodegradation. It was also shown that Galaxias
auratus enhanced chlorothalonil loss in fish tanks by a factor of 25
times (Davies, 1988).
Chlorothalonil does not translocate from the site of
application to other parts of a plant. For example, ring-labelled
14C-chlorothalonil does not translocate when applied topically to
cucumber, bean or tomato leaves. It was not translocated into the
aerial parts of corn or tomato plants when they were cultivated for 23
days in soil treated with 14C-chlorothalonil. There was no movement
or translocation of radioactivity within the root systems of sweet
corn, cucumber or tomato grown in soil treated with ring-labelled
chlorothalonil. This also indicated that the major 4-hydroxy
metabolite in soil was not translocated (Kunkel, 1967a,b).
Chlorothalonil residues remaining on food crops at harvest may
enter the human food chain. Residues in foodstuffs may be further
reduced by processing and cooking (see sections 5.1 and 5.2).
4.2 Transformation
4.2.1 Biodegradation
Studies with river water from two sources in Tasmania showed that
loss of chlorothalonil was slow in still water. Comparison of loss
rates at 5 and 15°C indicated involvement of enzymic processes.
Uptake by algal growths also indicated biodegradation with the
appearance of polar metabolites. However, biodegradation is unlikely
to play a major role in the fate of chlorothalonil in moderate to fast
flowing streams, where volatilization and adsorption are liable to be
dominant factors (Davies, 1988).
Chlorothalonil is rapidly degraded in soil under both laboratory
and field conditions. In laboratory experiments its half-life ranged
from 4 to 40 days in various types of soil. The rate increased with
increasing organic matter content, moisture and temperature. It
appeared that little was lost due to volatilization. On turf plots at
three locations in the USA, the half-life of chlorothalonil ranged
from 26 to 45 days after treatments (Stallard & Wolfe, 1967). The
major soil degradation product is the 4-hydroxy metabolite,
4-hydroxy-2,5,6-trichloroisophthalonitrile. Laboratory studies in
five soils showed half-lives for the 4-hydroxy metabolite of 36 days
in a sandy loam and up to 220 days in clay type soil (Wolfe &
Stallard, 1968). It has been shown that bacteria isolated from soil
are capable of metabolizing chlorothalonil in culture media. It can
be deduced that soil microorganisms play a role in the rapid
degradation of chlorothalonil in soil (Duane, 1970).
Degradation of chlorothalonil in soil involves a series of
parallel processes, one of which involves formation and dissipation of
4-hydroxy-2,5,6-trichloroisophthalonitrile (SDS-3701). Chlorothalonil
dissipation data were re-analysed to obtain half-life estimates for
SDS-3701 soil dissipation. Assuming first order kinetics, non-linear
least-squares regression modelling was used to estimate the values of
the model parameters. For SDS-3701, half-lives between 6 and 43 days
were determined for the various non-sterile soils. An alternative
method of data analysis, utilizing a transformation and a linearizing
approximation, was also used and gave a similar range of half-lives
(Jacobson & Schollenberger, 1992).
The dissipation of chlorothalonil in soils was suppressed by the
repeated applications of this fungicide to the soils. The dissipation
was due to microbial action, since chlorothalonil disappeared in a
nonsterile soil but not in an autoclaved soil. The amendments of the
soil with easily decomposable organic materials recovered the
suppressed dissipation ability of the soil. The results suggested
that easily decomposable organic materials play an important role in
the microbial degradation of chlorothalonil in soil (Katayama, et al.,
1991).
Fig. 1 lists the structure and identification code of the five
soil metabolites that have been identified in aerobic soil studies
involving 14C-chlorothalonil in the laboratory. Identifications were
based on independent synthesis of authentic standard and GLC or
HPLC/MS confirmations. It should be noted that the scheme is a
suggested pathway (Frazier, 1993). There is no direct evidence that
any of the five soil metabolites are converted directly to "bound"
residue. Typical dissipation curves (Figs. 2, 3, 4) show the
dissipation of chlorothalonil and the formation/dissipation of the
4-hydroxy-metabolite (SDS-3701); note that the scale for time is not
linear. These same dissipation curves show the formation of bound
residue. Attempts to liberate and characterize this bound residue have
produced limited characterization data and no definitive structure
identifications.
A complete picture of all of the known transformations which
occur with chlorothalonil under various environmental conditions is
given in Fig. 5 (ISK Biosciences, 1995).
On plants, chlorothalonil is metabolized only to a limited extent
to the 4-hydroxy metabolite. The majority of the residue remains as
the parent compound. Generally less than 5% of the total residue is
present as the 4-hydroxy metabolite. A review of plant residues
worldwide showed that the 4-hydroxy metabolite level was < 0.1 mg/kg
in most of the crops analysed. It accounted for approximately 10% of
the total residue in lima beans, 5% in cantaloupes, 2% in peaches and
onions, 1% in celery and 0.1% in peanuts (FAO/WHO, 1985). The decline
of chlorothalonil residues and the appearance and decline of the
4-hydroxy metabolite on onions is shown in Table 7 (personal
communication to the IPCS by the Government of Canada, 1979). The
chlorothalonil residue decayed with a half-life of about 3 days.
Studies with corn silage showed that 90% of chlorothalonil
degraded within 18 days (30 to 3 mg/kg). The half-life was
approximately 4 days. In a second experiment, the 4-hydroxy
metabolite formation was very low in the bound materials (which were
converted to an extractable form), representing only about 2% of the
chlorothalonil on the first day of ensiling (FAO/WHO, 1978).
After chlorothalonil was applied to growing peanut foliage at
1.26 kg/ha its half-life was 13.6 days (range 7-19 days) under the
field conditions of use (Elliott & Spurr, 1993).
In the excretion of 14C-chlorothalonil metabolites from rainbow
trout (Salmo gairdneri), the almost complete absence of
chlorothalonil itself and the accumulation of 14C entities in the
bile indicated the possibility of glutathione conjugation as the first
step in chlorothalonil metabolism (Davies & White, 1985). Further
studies showed the existence of mono- and diglutathione conjugates of
chlorothalonil in the bile of rainbow trout exposed to
14C-chlorothalonil (Davies, 1985a).
Studies with liver cytosol from five fish species showed that the
enzyme glutathione- S-transferase (GST) is involved in the conversion
of chlorothalonil to polar conjugates. Comparisons of GST activity in
rainbow trout organs revealed that the potential for chlorothalonil
transformation was in the order liver » kidney > spleen, with no
activity in bile. Low concentrations of chlorothalonil in water
induced fish GST activity for its biotransformation. Hepatic
glutathione (GSH) and GST activity for chlorothalonil transformation
were compared in three species of fish (Oncorhynchus mykiss,
Galaxias maculatus and Galaxias auratus). The order of their
asymptotic LC50 values agreed with that of their hepatic GST
activities for chlorothalonil transformation and was consistent with a
detoxification role for GSH-chlorothalonil conjugation (Davies,
1985b). A study involving co-exposure to zinc and chlorothalonil
indicated that metallothionein does not play a significant role in
chlorothalonil detoxification in fish at sublethal exposures (Davies,
1985c).
Small amounts of the 4-hydroxy metabolite were found in the milk
and kidney of a cow fed 250 mg chlorothalonil/kg in its feed. Only
0.2% of the ingested chlorothalonil was eliminated in the milk as the
4-hydroxy metabolite (Ladd et al., 1971).
4.2.2 Abiotic degradation
Chlorothalonil does not break down in aqueous solution
(0.5 mg/litre) in the dark at pH 5 or 7. It is hydrolysed at pH 9,
over 50% disappearing in 49 days, with the formation of 4-hydroxy-
2,5,6-trichloroisophthalonitrile and 3-cyano-2,4,5,6-tetrachloro-
benzamide (Szalkowski & Stallard, 1977).
Chlorothalonil degrades very slowly under aqueous photolytic
conditions to the 4-hydroxy metabolite. The half-life was found to be
approximately 65 days (ISK Biotech proprietary information).
4.2.3 Bioaccumulation
In a study of the uptake and elimination of 14C-chlorothalonil
in rainbow trout, two groups of fish were exposed to 10 µg/litre of
the compound in flow-through tanks for 96 h (Davies & White, 1985).
After exposure was discontinued, the depuration rate was followed for
96 h. There was a very high uptake in the gall bladder and bile
(concentration factors up to 4.4 × 105). Uptake was also high in the
hind gut, liver, fat and kidney with concentration factors of
2-11 × 103. After 96 h of exposure, the concentration factor in
muscle was 940 and 740, respectively, for the two groups of fish, a
level which may give an indication of the magnitude of the whole body
bioconcentration factor (BCF) for rainbow trout (not measured).
After transfer to clean water, gall bladder levels dropped
rapidly, and so did gill and blood levels. In one group of fish,
concentrations in both liver and kidney doubled until 24 h after
transfer and thereafter dropped to the levels in the other group.
Concentrations in the spleen in both groups continued to increase
throughout the depuration period. Muscle levels dropped only slowly
and remained around 1 µg/g. The high concentrations found in the gall
bladder and bile are consistent with the fact that chlorothalonil is
excreted from fish as glutathione conjugates (Davies & White, 1985).
Bluegill sunfish exposed to 8 µg 14C-chlorothalonil/litre in a
flow-through system for 30 days showed a plateau of 14C uptake within
14 days. The residues in whole fish at 30 days were 264 times the
water concentration. When the fish were placed in clean water, 80% of
the radioactive residues were lost within 14 days. Bioaccumulation in
catfish, in a static system, showed a 16-fold concentration at 26
days. In this case 90% of the 14C residues were depurated in 14 days
after removal from the treated water. The 4-hydroxy metabolite did
not bioaccumulate in fish (SDS Biotech Corporation, 1972).
In tanks containing stream water with chlorothalonil at
20 µg/litre, uptake of the compound occurred in algal growths attached
to bottom pebbles. Analysis of the algal growths showed a
concentration factor for chlorothalonil of 270 times after 14 days of
static exposure. Since this represented only 9.5% of the initial dose
it seems that the removal of chlorothalonil from the water is enhanced
by its conversion to polar metabolites in addition to bioconcentration
(Davies, 1988).
4.3 Waste disposal
Chlorothalonil can be incinerated in units operating at 850°C
fitted with off-gas scrubbing equipment (Lawless et al., 1975).
The disposal methods for waste pesticides and containers
advocated by FAO and GIFAP should be applied to unused chlorothalonil
products and their empty packages (FAO, 1985; GIFAP, 1987).
5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE
5.1 Environmental levels
5.1.1 Air
Chlorothalonil was detected (amongst other pesticides) in 3 out
of 9 outdoor and indoor samples and 1 out of 9 personal monitoring
samples in 9 homes in Jacksonville, Florida, USA. No actual figures
were reported (Lewis et al., 1988).
Average exposures to chlorothalonil of 173 persons in
Jacksonville, Florida and Springfield, Massachusetts, USA were
0.7 ng/m3 (personal exposure) and 0.5 ng/m3 (outdoor air
concentrations) (Wallace, 1991).
Chlorothalonil was not detected in 51 samples in an Environmental
Survey of Chemicals in Japan in 1991 (personal communication by the
Office of Health Studies Environment Agency, Tokyo, 1992).
5.1.2 Water
O'Neil (1991) studied concentrations of chlorothalonil in water
and sediment following overspraying of a pond (0.2 ha and 0.5 m deep)
at 875 g a.i./ha (Ernst, 1991). Water and sediment were monitored in
a stream flowing out of the pond at the outlet and 30 m downstream.
The stream was approximately 1 m wide and 0.5 m deep and ran at
0.033 m3/sec for the first overspray and at 0.015 m3/sec for the
repeat spray. Whole water samples were filtered for separate
measurement of chlorothalonil in water and sediment. Following the
first spraying, samples were taken at the downstream site at 30 min
intervals up to 6 h after spraying and further samples were collected
10 and 24 h after spraying. Initial water concentrations of up to
60 µg/litre fell rapidly to around 15 µg/litre 2 h after spraying.
The water concentration was 1.9 µg/litre 10 h after spraying, and at
24 h there was no measurable chlorothalonil. In the second spraying
at the lower stream flow rate, whole water samples were taken more
frequently over the 2 h following application. Concentrations peaked
at 350 to 450 µg/litre at the pond outlet and 30 m downstream,
respectively, 20 to 30 min after application, falling to between 50
and 100 µg/litre at 2 h. A concentration of 6.3 µg/litre was found
12 h after spraying. Total chlorothalonil mass was measured on
suspended sediment following the first spraying and showed 10 µg
persisting for 1.5 h after spraying and thereafter falling to
approximately 0.01 µg at 10 and 24 h. The report did not make clear
the volume of water filtered, which appears, however, to have been
1 litre. Environmental conditions such as total organic carbon (TOC),
pH, temperature and water hardness were not reported; consequently
their impacts on degradation could not be evaluated.
Chlorothalonil was detected on occasions at concentrations up to
3.6 µg/litre in a tile drainage system from a farm in Manitoba,
Canada, where the fungicide was sprayed routinely. It was detected on
one occasion (0.06 µg/litre) in the sump well outflow draining to a
municipal ditch (Krawchuk & Webster, 1987).
Over a 5-year period (1986-1990), water was sampled and analysed
from 1300 community water systems and rural domestic wells for 101
pesticides, including chlorothalonil. Chlorothalonil was not detected
in any of these samples although the reporting limit was 0.12
µg/litre, which represented the minimum quantification limits for this
particular pesticide in the study (US EPA, 1990).
Chlorothalonil was not detected in 57 water samples, 30 sediment
samples and 30 fish samples in an Environmental Survey of Chemicals in
Japan in 1991 (personal communication by the Office of Health Studies,
Environment Agency, Tokyo, 1992).
5.1.3 Soil
Levels of chlorothalonil and its metabolite SDS-3701 (see section
4.2.1) in soil were reported after three annual treatments (Kenyon &
Ballee, 1990; King et al., 1991, 1992). Four plots were established
of bare untreated and treated, winter wheat treated and untreated at
two different sites, Osterwede and Rohlstof (Germany). Treatment
consisted of an annual chlorothalonil application of 2.2 kg a.i./ha.
Soil samples were taken before and after each treatment. No
chlorothalonil was detected in any of the untreated samples.
Consistently there was no carry over from one year to another. Levels
in soil were highest 2 or 3 days after the treatment (sampling
depended on the sites), with mean levels in the bare plots around 0.40
mg/kg and in those with wheat around 0.34 mg/kg (values ranging
between 0.07 and 0.64 mg/kg). Between 52 and 60 days after each
treatment, levels were 0.02-0.03 mg/kg in plots with wheat while in
bare plots they were generally below the detection limit of 0.01
mg/kg. Before each treatment in the previously treated plots the
level of metabolite SDS-3701 ranged from the limit of detection (0.01)
to 0.03 mg/kg, which was the same as the level 2 or 3 days after
treatment. However, between 52 and 60 days after treatment (depending
on the site) levels rose at the Osterwede site to 0.07 mg/kg for the
bare treated plot. One year after the last treatment, levels of
SDS-3701 ranged from the detection limit to 0.03 mg/kg.
5.1.4 Food crops
Chlorothalonil is used as a broad spectrum fungicide on
vegetables, fruit trees, small fruit bushes and other agricultural and
horticultural food crops. Its use is intended to protect crops up to
harvesting, hence small residues will be present at that time. The
residue levels expected in crops at harvest can be derived from the
numerous supervized trials that have taken place on many crops in
countries all over the world (FAO/WHO, 1975, 1978, 1979, 1980, 1982,
1985a, 1986a, 1990a).
The amount of residue at harvest depends upon factors such as the
application rate, time interval between the last application and
harvest, and the type of crop. Residues are composed mainly of
chlorothalonil, and only negligible amounts of the metabolite
4-hydroxy-2,5,6-trichloroisophthalonitrile (SDS-3701) are present (see
Table 7 for example).
The decline of chlorothalonil residues on food crops after
application is shown by the field treatment of apples and pears
against Botryris cynerea by spraying with a chlorothalonil flowable
formulation and then harvesting at intervals after treatment (Camoni
et al., 1991). The results are shown in Table 8.
Table 8. Decline of chlorothalonil residues
Days after treatment Pears Apples
(mg/kg) (mg/kg)
0 3.85 2.35
7 2.48 1.73
14 2.00 0.92
28 1.35 0.98
From: Camoni et al. (1991)
Similar examples of the decline of chlorothalonil residues have
been given for grapes in Australia, Germany and South Africa (FAO/WHO,
1985a). The decline of residues in onions is shown in Table 7. The
distribution of the residues on this plant showed that the levels in
the older outer leaves were about 5 times above those in the younger
leaves (2.4 and 0.51 mg/kg, respectively).
Pre-harvest intervals are set on the basis of supervized trials,
e.g., 7 days for apricots, and cherries in Australia, 7-14 days for
grapes in Australia and 7 days for onions in the Netherlands (FAO/WHO,
1990a).
One of two samples of currants from growers in the United Kingdom
had a residue level of 7.5 mg/kg 54 days after the last of three
treatments at half the recommended rate of application. The residue
level on the second sample was < 0.5 mg/kg 76 days after two
applications at the maximum rate (UK, 1985).
5.1.5 Dairy produce
There have been no reports of chlorothalonil residues in dairy
produce. However, some indication can be gained from studies on dairy
cattle fed high levels of the compound. In one cow fed 250 mg
chlorothalonil/kg feed for 44 days, no chlorothalonil was detected in
the milk and only 0.2% of the dose appeared as the 4-hydroxy
metabolite. Neither compound could be detected in muscle or fat and
only a low level of the 4-hydroxy metabolite (0.7 mg/kg) was found in
the kidney (Ladd et al., 1971; Wolfe & Stallard, 1971). In another
study, groups of four cows were fed chlorothalonil combined with the
4-hydroxy metabolite at levels up to 250 and 0.6 mg/kg, respectively,
for 30 days. At the end of the period half the cows were sacrificed
and half continued for a 32-day recovery period. No chlorothalonil
(< 0.02 mg/kg) was found in milk. Small residues of chlorothalonil
and the 4-hydroxy metabolite were detected in muscle, fat, liver and
kidney after 30 days administration but none were detected in these
organs after the 32-day recovery period (FAO/WHO, 1975). No
chlorothalonil (< 0.03 mg/kg) was detected in milk from a cow fed the
compound at 5 mg/kg in its rations for 4 days (Gutenmann & Lisk,
1966).
5.1.6 Animal feed
Dry cannery waste (tomato pommace), sometimes used for animal
feed, contained < 1 mg/kg chlorothalonil plus its 4-hydroxy
metabolite (in the ratio 6:1) as a residue (FAO/WHO, 1978).
5.2 General population exposure
5.2.1 Food
In a study of imported fruit and vegetables in Finland, chlorothalonil
levels of 0.02-0.15 mg/kg in strawberries, 0.01-0.86 mg/kg in Chinese
lettuce and 0.12-1.2 mg/kg in peaches were found (personal
communication to the IPCS by the Government of Finland, 1979).
No chlorothalonil (< 0.01 mg/kg) was detected in a US Food and
Drug Administration (FDA) total diet study in the USA in 1976 or 1977
(personal communication to the IPCS by J.R. Wessel, 1979). In a
Canadian total diet survey, chlorothalonil was detected in one out of
six composite samples of garden fruits at the detection level (0.02
mg/kg). On the basis of this one sample, a dietary intake of 0.04 µg
per person per day was estimated (McLeod et al., 1980).
Chlorothalonil was detected (0.001-1.35 mg/kg) in most samples of
apples, peaches and other fruit and vegetables marketed in Tokyo
(Koseki et al., 1980).
No chlorothalonil (< 0.005 mg/kg) was detected in samples of
potatoes in Sweden in 1979. During 1981-1983, 1070 out of 1085
samples of domestic and imported commodities in Sweden had
chlorothalonil residues below 0.21 mg/kg. Samples having higher
residues included one of cauliflowers (out of 165) at 0.41 mg/kg, one
of cucumbers (out of 580) at 0.23 mg/kg and two of strawberries (out
of 143) at 2.9 mg/kg (personal communication: data submitted to the
IPCS by the Government of Sweden and entitled "Chlorothalonil residues
in imported and domestic commodities - 1981 to 1983").
In 1982, analysis at the point of retail in the United Kingdom
showed chlorothalonil residues below 0.5 mg/kg in 41 samples of
strawberries, 15 of gooseberries, 13 of currants and 9 of berries.
Other analyses during 1981-3 showed that only one out of 30 samples of
imported strawberries, 2 out of 15 samples of domestic celery and 5
out of 40 of gooseberries had chlorothalonil residues above 0.1 mg/kg
(UK, 1985).
In the United Kingdom, chlorothalonil residues in bananas
(imported), chinese cabbage (all origins) and parsnips (United Kingdom
origin) were below the reporting levels of 0.2, 1.0 and 0.01 mg/kg,
respectively, in 1988-1989. During the same period, one sample out of
ten of imported strawberries contained 0.1 mg/kg (UK MAFF & HSE,
1990).
Residues of chlorothalonil in foodstuffs are decreased by
processes such as washing. For example, it was shown that 94% of the
residue could be removed by washing tomatoes and that there was no
detectable residue in canned tomato pulp, paste or juice. Peaches
washed in water followed by a caustic rinse showed a 97% removal of
field residues. No chlorothalonil was detected in canned peach puree
(FAO/WHO, 1978).
In a Honduran study, unwashed bananas had a maximum residue level
of 0.17 mg/kg and a mean of 0.08 mg/kg. This was reduced to 0.02
mg/kg after washing. No chlorothalonil was found in the edible pulp
(< 0.01 mg/kg). Similar results were obtained in the Philippines
(FAO/WHO, 1980).
Trimming and peeling also removes a large proportion of residues
from some foodstuffs. For example there are significant reductions
after trimming the outer leaves from cabbages and lettuces. Most of
the residue is removed when cucumbers, melons, peanuts and potatoes
are peeled (Diamond Shamrock, 1974).
As much as 85-98% of chlorothalonil added to tomatoes or green
beans was lost during cooking in open vessels. Only 2.4% was
converted to the 4-hydroxy metabolite, which was stable to cooking
(SDS Biotech Corporation, 1983a).
5.3 Occupational exposure
The exposure of a tractor driver applying chlorothalonil to
ornamental plants in Florida, USA, was assessed. Total-body exposure
rates, estimated from external exposure pads and air sampling, were
low (approximately 5 mg a.i./h) (Stamper et al., 1989a). In the case
of a greenhouse drencher, this exposure was approximately 100 mg
a.i./h (Stamper et al., 1989b).
Occupational exposure to four insecticides and two fungicides was
measured for 151 commercial tree and shrub applicators in the USA who
used hand-held equipment when spraying pesticides. The study was
conducted for 3 consecutive years: 1985, 1986 and 1987. Worker
exposure was determined by collecting full-shift, breathing zone air
samples. Sampling was conducted with battery-operated constant-flow
air-sampling devices. Chlorothalonil was detected in only one out of
14 samples at 0.011 mg/m3 (Leonard & Yeary, 1990).
Spencer et al. (1991) estimated the dermal exposure of workers on
mechanical tomato harvesters to residues of chlorothalonil. An
average of 499.6 µg/h was obtained by gauze pad dosimeters placed
outside the workers' clothing, whereas 43.4 µg/h was obtained by
undershirt dosimetry. The results showed that regular work clothing
provides an excellent protection (90% reduction in dermal exposure)
against chlorothalonil. Air concentrations in the field were also
determined and averaged 0.002 to 0.02 µg/litre, which contributed 8 to
28% to the total exposure.
The exposure of 11 pesticide operators mixing, loading or
applying chlorothalonil fungicide formulations by aerial or ground
applicators has been assessed. The highest exposure was on the hands
(1.7 mg/m2 per h) (Diamond Shamrock, 1980).
6. KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS
6.1 Absorption
Biliary excretion of radioactivity was studied in groups of six
male Sprague-Dawley rats administered a single oral dose of 1.5, 5, 50
or 200 mg/kg body weight 14C-chlorothalonil (98% radiochemically
pure), uniformly labelled in the aromatic ring, as a suspension with a
mean particle size of 3.6 to 5.0 µm in 0.75% methylcellulose in water.
The bile duct was cannulated and bile was collected in 1-h fractions
for 48 h after dosing. Blood, urine and faeces were also collected at
various times after dosing and at termination. During the 48 h after
a single dose of 1.5, 5, 50 and 200 mg/kg body weight, biliary
excretion was 22.5, 16.4, 16.3, and 7.7% of the administered dose,
respectively. Profiles of radioactivity excretion after the two low
doses were quantitatively different from those obtained after the two
high doses. The authors interpreted these results as indicative of a
change in metabolism occurring between 5 and 50 mg/kg body weight,
possibly due to saturation of biliary excretion. Mean urinary
excretion during the 48 h after dosing was 8.0, 8.2 and 7.6% of the
administered dose at 1.5, 5 and 50 mg/kg body weight, respectively,
and only 4.7% at the high dose level of 200 mg/kg body weight.
Excretion of radioactivity in the urine within 6 h after dosing was
inversely related to the dose administered. Total recovery of
radioactivity in this study was 89-99% in the three low-dose groups
and 74% in the high-dose group. After doses of 1.5, 5, 50 and
200 mg/kg body weight, rats absorbed 32, 25.7, 25.9 and 15.5% of the
administered dose, respectively. It was concluded by the authors that
enterohepatic circulation or reabsorption of biliary metabolites from
the gastrointestinal tract did not contribute significantly to the
amount of radiolabel in the kidney. Based on a one-compartment model
for chlorothalonil absorption and excretion and using several
assumptions, it was calculated that the rate of absorption of the
200 mg/kg body weight dose was only twice as fast as that of the
50 mg/kg body weight dose (Marciniszyn et al., 1986).
In a study by Chin et al. (1981), absorption was compared by the
oral, dermal and endotracheal routes with a 1 mg/kg body weight dose
of 14C-chlorothalonil in male Sprague-Dawley rats. The comparisons
were made on the basis of blood levels and urine excretion. In each
case, absorption was highest by endotracheal administration and lowest
by the dermal route. Less than 6% of the administered dose was
recovered in blood and urine within 48 h after dosing.
When 14C-chlorothalonil was introduced into sacs formed from the
upper section of rat small intestine, no unchanged substance passed
through the mucosa and was transferred to the serosal side of the sac.
These data suggest that chlorothalonil is very rapidly conjugated,
since in vivo studies have not identified chlorothalonil itself in
body fluids or tissues after oral administration to rats (Savides et
al., 1986e).
14C-chlorothalonil was applied to the skin of male rats at an
averaged dose of 1167 µg/rat (= 5 mg/kg) on an area of 25 cm2. The
amount absorbed was deduced from the amount remaining on the treated
skin area and the amount of radioactivity found at each time interval
in urine, faeces and carcass. Approximately 28% of the applied dose
was absorbed over the experimental exposure period of 120 h. The
absorption appeared to be time-dependent, about 6.3% of the applied
dose being absorbed during each 24 h period. Radioactivity appeared
quickly in blood and rose steadily up to 72 h, when it reached a
plateau (Marciniszyn et al., 1984a).
In a study by Magee et al. (1990), four monkeys were treated
dermally with 5 mg/kg body weight of 14C-chlorothalonil under a
non-occlusive patch. After 48 h the patch was taken off and the skin
was washed. About 90% of the dose was recovered from the surface and
about 2.26% was completely absorbed through the skin. The urine
contained 1% of the dose, but methylated mono-, di- and trithiols were
not detectable in the urine.
6.2 Distribution
Groups of male and female rats were administered
14C-chlorothalonil orally, in microparticulate suspension, as single
doses of 5, 50 or 200 mg/kg, and tissue activity was determined after
2, 9, 24, 96 and 168 h (Marciniszyn et al., 1984b, 1985a). With the
exception of gastrointestinal tract tissues the greatest concentration
of radioactivity was found in the kidneys, at each dose level,
followed by those in liver and whole blood. The peak concentrations
in kidney occurred at 2 h after 5 mg/kg, 9 h after 50 mg/kg and 24 h
after 200 mg/kg. Similar shifts in peak time with dose occurred in
the liver and blood. In terms of the original dose, kidneys, liver
and blood each contained 0.7% of the label 2 h after 5 mg/kg and 0.3%
(kidney), 0.14% (liver) and 0.23% (blood) after 24 h in female rats.
Distribution of radioactivity was also studied after repeated
oral administration of 14C-chlorothalonil to male rats. Five doses
were given at 24 h intervals at concentrations of 1.5, 5, 50 or
160 mg/kg. The rats were killed 2, 9, 24, 96 and 168 h after the last
dose. The distribution of activity showed a similar profile to that
after single dosing, i.e. the highest concentrations occurred in
kidneys, followed by liver and blood, at all doses and times. At all
dose levels, the concentrations peaked 2 h after the last dose. The
percentage of the dose found in the kidney at this time was 0.28% and
0.20% at the 1.5 and 5 mg/kg dose levels, which was significantly
higher than that found at the higher doses (about 0.09%). At dose
levels up to 50 mg/kg there was significant depletion of radioactivity
from the blood during the 24 h between doses. In the kidney there was
a trend to slower overall depletion with increase in dose (Savides et
al., 1986a).
A study in mice showed that the distribution of activity in
non-gastrointestinal tract tissues was similar to that in rats after a
single oral dose of 14C-chlorothalonil. The kidney had the highest
concentration of radioactivity after doses of 1.5, 15 or 105 mg/kg
(Ribovich et al., 1983).
6.3 Metabolic transformation
6.3.1 Rat
Male Sprague-Dawley rats were administered, via oral gavage,
14C-chlorothalonil (purity 99.7%) at a dose level of 200 mg/kg in
order to isolate and identify the urinary metabolites. Urine was
collected 17, 24 and 48 h after dosing. Urinary metabolites accounted
for 2.4% of the administered dose and, except for 30% of the
radiolabel which was non-extractable from the urine, were found to be
trimethylthiomonochloro-isophthalonitrile and dimethylthiodichloro-
isophthalonitrile. These thiols were excreted in urine both as free
thiols and as their methylated derivatives. The authors suggested a
metabolic pathway such that hepatic metabolism proceeds through
conjugation with GSH followed by enzymatic degradation. The smaller
conjugates are then transported via the bloodstream to the kidney,
where they are converted to thiol metabolites and excreted in the
urine (Marciniszyn et al., 1985b).
A study was also carried out in rats given five daily oral doses
of 14C-chlorothalonil (1.5, 5, 50 or 160 mg/kg per day). Urine
samples, acidified and extracted with ethyl acetate, showed decreasing
extractability of radioactivity with increasing dose. GC/MS analysis
identified methylated or partly methylated dithiol and trithiol
derivatives of chlorothalonil from the first dose onwards. The
percentage of the trithiol derivative excreted was constant with
increasing dose while the dithiol increased with dose. Multiple
dosing resulted in a decreasing daily excretion of total thiol
derivatives. These results emphasize the probable involvement of
glutathione in the metabolic pathway for chlorothalonil (Savides et
al., 1986b).
A group of three rats, pretreated with the gamma-glutamyl
transpeptidase inhibitor AT-125, were dosed with 50 mg/kg
14C-chlorothalonil, while three other rats were given chlorothalonil
only. Urine samples were acidified and extracted with ethyl acetate.
The group of rats pre-treated with AT-125 showed only 15% of
radioactivity extractable after 12 h, while the other group showed 75%
extractability. The non-extractable fraction from the
inhibitor-treated rats contained glutathione conjugates of
chlorothalonil. The kidneys contained 2-3 times more radioactivity
than those of the untreated rats. These results gave further support
to the hypothesis that glutathione is involved with chlorothalonil
metabolism (Marciniszyn et al., 1988).
The production of metabolites was also studied in groups of rats
following dermal administration. 14C-chlorothalonil (4.6 mg/kg) was
applied to a shaved area of the dorsal region. The area was covered
and exposure continued for 48 h. Urine samples collected at 24 and
48 h were acidified and extracted with ethyl acetate. The extracts
were submitted to reverse-phase HPLC/LSC followed by methylation and
further clean-up. The trithiol derivative of chlorothalonil was the
major metabolite in all samples. The excretion of total thiol
metabolites was at least 20-fold less than that resulting from oral
dosing at the same dose level (Savides et al., 1987a).
The radiolabelled monoglutathione derivative of chlorothalonil
was administered to male rats (115 mg/kg) as a single oral or
intraperitoneal dose. Six hours after intraperitoneal dosing the
blood level was 10 times higher than after oral dosing. The
proportion of the administered intraperitoneal dose in the kidney was
16 times higher than after oral dosing. Urine from the orally dosed
rats contained 9% trithiol derivative and 5% dithiol, while
intraperitoneally dosed rats showed < 1% dithiol derivative and none
of the trithiol in urine. This indicates that the orally administered
monoglutathione conjugate is further conjugated with glutathione in
the gastrointestinal tract prior to absorption (Savides et al.,
1986f).
Nine germ-free male rats each received approximately 56 µCi
14C-chlorothalonil in a single oral dose of 50 mg/kg. Urine and
faeces were collected over a 96-h period, and the urine was processed
to identify and quantify thiol derivatives of chlorothalonil. These
derivatives were detected in only three of the nine rats and
represented < 0.03% of the dose. This is fifty times less than that
obtained for normal rats. There is therefore strong evidence that
intestinal microflora make a significant contribution to the
metabolism of chlorothalonil after oral administration in the rat
(Savides et al., 1990a).
The HPLC analysis of faecal extracts from rats dosed with 200 mg
chlorothalonil/kg showed that 28% was excreted unchanged and 5% was
converted to 4-hydroxy 2,3,5-trichloroisophthalonitrile. The amounts
after a dose of 5 mg/kg were 1.6 and 6.2%, respectively (Ignatoski et
al., 1983).
The HPLC analysis of faeces from rats given 14C-chlorothalonil
orally at 5, 50 and 200 mg/kg showed the presence of at least seven
radioactive components. Two of the peaks had the same retention times
as chlorothalonil and its 4-hydroxy metabolite. A higher proportion
of the metabolite was present after the 5 mg/kg dose than after the
higher doses. The majority of the activity was unextractable and was
therefore bound to faecal components (Lee et al., 1982).
6.3.2 Dog
Male beagle dogs were given 14C-chlorothalonil at a dose level
of 50 mg/kg either by gelatin capsule or by gavage. In each case the
urinary excretion of radioactivity was very small and none of the
methylated thiol derivatives of chlorothalonil were detected (Savides
et al., 1989, 1990b).
6.3.3 Monkey
Four male Chinese rhesus monkeys were dosed with
14C-chlorothalonil by gavage at 50 mg/kg body weight suspended in
0.75% aqueous methylcellulose. Extraction of urine, collected over
48 h, with acidified ethyl acetate showed that 32-65% of the
radioactivity was extractable. The total amount of chlorothalonil
thiol derivatives excreted was 0.001-0.01% of the administered dose,
mainly as the trimethylthiol entity. This was more than 100 times
less than that excreted from the rat (Savides et al., 1990c).