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    IPCS INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY
    Health and Safety Guide No. 98

    CHLOROTHALONIL
    HEALTH AND SAFETY GUIDE






    UNITED NATIONS ENVIRONMENT PROGRAMME

    INTERNATIONAL LABOUR ORGANISATION

    WORLD HEALTH ORGANIZATION




    WORLD HEALTH ORGANIZATION, GENEVA 1995

    This is a companion volume to Environmental Health Criteria 183:
    Chlorothalonil

    Published by the World Health Organization for the International
    Programme on Chemical Safety (a collaborative programme of the United
    Nations Environment Programme, the International Labour Organisation,
    and the World Health Organization)

    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

    WHO Library Cataloguing in Publication Data

    Health and safety guide for Chlorothalonil

    (Health and safety guide ; no. 98)

    1.Nitriles - toxicity  2.Fungicides, Industrial
    3.Environmental exposure  4.  I.Series

    ISBN 92 4 151098 6          (NLM Classification: QD 305.N7)
    ISSN 0259-7268

    The World Health Organization welcomes requests for permission to
    reproduce or translate its publications, in part or in full. 
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    (c) World Health Organization 1995

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    The mention of specific companies or of certain manufacturers'
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    proprietary products are distinguished by initial capital letters.

    CONTENTS

    INTRODUCTION

    1. PRODUCT IDENTITY
         1.1. Identity
         1.2. Physical and chemical properties

    2. SUMMARY AND EVALUATION
         2.1. Summary
               2.1.1. Identity, physical and chemical properties, and
                       analytical methods
               2.1.2. Sources of human and environmental exposure
               2.1.3. Environmental transport, distribution, and
                       transformation
               2.1.4. Environmental levels and human exposure
               2.1.5. Kinetics and metabolism in laboratory animals
               2.1.6. Effects on experimental mammals, and in vitro test
                       systems
               2.1.7. Effects on humans
               2.1.8. Effects on non-target organisms in the laboratory
                       and field
         2.2. Evaluation
               2.2.1. Toxicological assessment
               2.2.2. Environmental assessment
                       2.2.2.1   Transport, distribution, and
                                 transformation
                       2.2.2.2   Aquatic organisms
                       2.2.2.3   Terrestrial organisms
               2.2.3. Toxicological criteria for setting guideline values

    3. CONCLUSIONS AND RECOMMENDATIONS

    4. HUMAN HEALTH HAZARDS, PREVENTION AND PROTECTION, EMERGENCY ACTION
         4.1. Main human health hazards, prevention and protection,
               first aid
               4.1.1. Prevention and protection
               4.1.2. First aid
         4.2. Advice to physicians
         4.3. Explosion and fire hazards
         4.4. Storage and transport
         4.5. Spillage and disposal
               4.5.1. Spillage
               4.5.2. Waste disposal

    5. HAZARDS FOR THE ENVIRONMENT AND THEIR PREVENTION

    6. CURRENT REGULATIONS, GUIDELINES, AND STANDARDS
         6.1. Previous evaluations by international bodies
         6.2. Exposure limit values
         6.3. Specific restrictions
         6.4. Labelling, packaging, and transport

    BIBLIOGRAPHY

    

    INTRODUCTION

    The Environmental Health Criteria (EHC) monographs produced by the
    International Programme on Chemical Safety include an assessment of
    the effects on the environment and on human health of exposure to a
    chemical or combination of chemicals, or physical or biological
    agents. They also provide guidelines for setting exposure limits.

    The purpose of a Health and Safety Guide is to facilitate the
    application of these guidelines in national chemical safety
    programmes. The first three sections of a Health and Safety Guide
    highlight the relevant technical information in the corresponding EHC.
    Section 4 includes advice on preventive and protective measures and
    emergency action; health workers should be thoroughly familiar with
    the medical information to ensure that they can act efficiently in an
    emergency. Within the Guide is a Summary of Chemical Safety
    Information which should be readily available, and should be clearly
    explained, to all who could come into contact with the chemical. The
    section on regulatory information has been extracted from the legal
    file of the International Register of Potentially Toxic Chemicals
    (IRPTC) and from other United Nations sources.

    The target readership includes occupational health services, those in
    ministries, governmental agencies, industry, and trade unions who are
    involved in the safe use of chemicals and the avoidance of
    environmental health hazards, and those wanting more information on
    this topic. An attempt has been made to use only terms that will be
    familiar to the intended user. However, sections 1 and 2 inevitably
    contain some technical terms. A bibliography has been included for
    readers who require further background information.

    Revision of the information in this Guide will take place in due
    course, and the eventual aim is to use standardized terminology.
    Comments on any difficulties encountered in using the Guide would be
    very helpful and should be addressed to:

    The Director
    International Programme on Chemical Safety
    World Health Organization
    1211 Geneva 27
    Switzerland

    THE INFORMATION IN THIS GUIDE SHOULD BE CONSIDERED AS A STARTING POINT
    TO A COMPREHENSIVE HEALTH AND SAFETY PROGRAMME

    1.  PRODUCT IDENTITY AND USES

    1.1  Identity

    Chemical structure

                                CHEMICAL STRUCTURE

    Molecular formula:          C8Cl4N2

    Relative molecular mass:    265.9

    CAS chemical name:          2,4,5,6,-tetrachloro-1,3-
                                benzenedicarbonitrile

    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-cyanobenzonitrile

    Trade names:                Bravo (ISK Biotech) (manufacturers &
                                suppliers); Daconil (ISK Biotech); Faber
                                (Tripart Farm Chemicals); Repulse (ICI);
                                Exotherm (Alto Elite); Nopocide (a
                                preservative in paints and adhesives)

    Technical product purity:   >97%

    Technical product
    impurities (%):             Tetrachlorophthalonitrile (<0.1);
                                Tetrachloroterephthalonitrile (0.1-1.6);
                                Pentachlorobenzonitrile (0.5-2.5);
                                Partially chlorinated dicyanobenzenes
                                (0.2-1.0); Unchlorinated dicyanobenzenes
                                (0.1-1.6); Insoluble in xylene (0.1-1.0)
                                HCB (0.03); xylene insolubles (0.35) 

    1.2  Physical and Chemical Properties

    The physical properties of chlorothalonil are listed in Table 1.

    Table 1. 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 25C             5.72  10-7
    Relative density                    1.8
    Octanol-water partition             2.88-3.86
    coefficient (Log Kow)
    Solubility in water (mg/litre)      0.6-1.2
      at 25C
    Solubility in organic               acetone 20, dimethylformamide 30,
    solvents (g/litre)                  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 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 25C. 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. Chlorothalonil is not corrosive.

    2.  SUMMARY AND EVALUATION

    2.1  Summary

    2.1.1  Identity, physical and chemical properties, and analytical
           methods

    Chlorothalonil is a colourless, odourless, crystalline solid with a
    melting point of 250C and a vapour pressure of 7.63  10-5 Pa (5.72 
    10-7 mmHg) at 25C. It is poorly soluble in water (0.6-1.2 mg/litre at
    25C) with an octanol/water partition coefficient (log Kow) of
    2.882. It is slowly hydrolysed in water at pH 9, but is stable at pH 7
    or below (at 25C).

    The most prevalent analytical method, after sample extraction and
    clean-up, is gas-liquid chromatography using an electron-capture
    detector.

    2.1.2  Sources of human and environmental exposure

    Chlorothalonil has been produced commercially since 1969 by the
    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 diluted readily
    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
    the preparation and application of the products, and from ingestion of
    crop residues in foodstuffs (see section 2.1.4).

    2.1.3  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 involving enzyme processes may occur
    in natural waters. 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 in 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.

    2.1.4  Environmental levels and human exposure

    In a potato crop study, a small stream was oversprayed with
    chlorothalonil. Subsequent sampling/analysis of downstream water
    demonstrated rapid disappearance of chlorothalonil (i.e., 450 g/litre
    30 min after spraying to 2-6 g/litre 12 h after spraying). The
    routine spraying of irrigated field crops, such as potatoes and
    barley, gave rise to low concentrations of chlorothalonil (0.04-
    3.6 g/litre) in tile drain water on a small number of sampling
    occasions.

    Crop residues are composed mainly of chlorothalonil itself. Residue
    levels depend on the applied rate, the 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 throughout the world and have been 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 residues in milk and only very low levels in tissues.

    Total diet and individual food analyses in several countries have
    shown low or undetectable concentrations of chlorothalonil in sampling
    surveys. Residue levels on foodstuffs are further reduced by
    preparation processes, such as washing, peeling, and cooking.

    2.1.5  Kinetics and metabolism in laboratory animals

    About 30% of an oral dose of chlorothalonil was absorbed after 48 h in
    rats administered doses of up to 50 mg/kg body weight. At higher
    doses, absorption was lower, indicating a saturation process. When 
    14C-chlorothalonil was given orally the radioactivity was distributed
    into blood and tissues within 2 h. The greatest concentration was
    found in the kidney, followed by the liver and blood. The kidneys
    contained 0.3% of a dose of 5 mg/kg body weight after 24 h.

    Most of an oral dose of chlorothalonil in rats was found in the faeces
    (>82% within 48-72 h, regardless of dose). Biliary excretion was
    rapid, peaking within 2 h after an oral dose of 5 mg/kg body weight,
    and was saturated at doses of 50 mg/kg body weight and above. Urinary
    excretion accounted for 5-10% of the dose in rats.

    Faecal elimination is the main route in dogs and monkeys, but urinary
    excretion (<4%) is less than in rats.

    Metabolic studies on 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 -lyase to thiol analogues that are excreted in the urine.
    When germ-free rats were dosed with chlorothalonil, the thiol
    metabolites appeared in the urine in much smaller amounts than in
    normal rats, indicating the involvement of intestinal microflora in
    the metabolism of chlorothalonil. Dogs or monkeys dosed orally with
    chlorothalonil excreted little, or no, thiol derivatives in the 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 the faeces and 6% in the urine within 120 h.

    2.1.6  Effects on laboratory mammals, and in vitro test systems

    The acute oral and dermal toxicities of chlorothalonil in rats and
    rabbits are low (acute oral and dermal LD50s of >10 000 mg/kg body
    weight). Hammer-milled technical chlorothalonil (MMAD 5-8 m)
    exhibited high toxicity in rats in an inhalation study with a 4-h
    LC50 of 0.1 mg/litre.

    Chlorothalonil was 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 were on the stomach
    and kidney. Groups of 25 rats/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, 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 on 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 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. On the basis of these changes, the NOEL was
    15 mg chlorothalonil/kg diet, equivalent to 3 mg/kg body weight per
    day.

    A 16-week study on dogs receiving dietary levels of chlorothalonil 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 of chlorothalonil were
    characterized histologically as an increase in both the incidence and
    severity of hyperplasia, hyperkeratosis and ulcers and erosions of the
    squamous mucosa of the forestomach, and epithelial hyperplasia of the
    kidney proximal convoluted tubules at doses of 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 increased incidence in kidney
    tumours in males at 15 mg/kg and for stomach tumours at 3.8 and
    15 mg/kg in both males and females. The NOEL for neoplastic effects
    was, therefore, 1.8 mg/kg body weight per day, on the basis of 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 chlorothalonil/kg diet),
    an increased incidence of renal tubular hyperplasia occurred at doses
    of 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 on
    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 diet), no effects
    attributable to chlorothalonil were found. The NOEL was, therefore,
    120 mg/kg diet (equivalent to 3 mg/kg body weight per day).

    Chlorothalonil was not mutagenic in several  in vitro and  in vivo
    tests, though 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 of 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 of up to 1500 mg/kg diet in a
    two-generation study on 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.

    2.1.7  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.

    2.1.8  Effects on non-target organisms in the laboratory and field

    Chlorothalonil was highly toxic for fish and aquatic invertebrates in
    laboratory studies, with similar LC50s below 0.5 mg/litre. The
    maximum acceptable toxicant concentration (MATC) in a two-generation
    reproduction study on  Daphnia magna was 35 g/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.

    The toxicity of chlorothalonil for birds is low, with a reported acute
    oral LD50 of 4640 mg/kg diet in the mallard duck. No significant
    reproductive effects were reported.

    The results of a field study on aquatic organisms, exposed following
    chlorothalonil application, suggest that the toxicity is less than
    that predicted from laboratory studies; this is again consistent with
    the physical and chemical properties of the compound. While deaths
    were seen in some species exposed experimentally in the field, there
    have been no reported incidents of kills in the environment. Although
    the residence time of chlorothalonil in environmental media is short,
    kills would be expected to occur. However, linking kills to the
    compound would be difficult because residues would not persist long
    enough for chlorothalonil to be identified.

    2.2  Evaluation

    2.2.1  Toxicological assessment

    A review of the toxicological data for chlorothalonil revealed that
    the most important studies for human risk estimation were the
    long-term studies on 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 representatives 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 that act
    directly upon the kidney was seen to be a major factor. In the kidney,
    glutathione conjugates are converted by -lyase to chlorothalonil
    thiol derivatives. Chlorothalonil is thought to be conjugated with
    glutathione (GSH) mainly in the gastrointestinal tract prior to
    absorption, though 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 -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 was 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. In studies on dogs and monkeys,
    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 -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 effects of
    chlorothalonil in humans and that the dog was a more representative
    species for this purpose. The NOEL of 120 mg/kg diet in the 2-year
    study on dogs, equivalent to 3 mg/kg body weight per day, should,
    therefore, be used for the purposes of human risk estimation.

    2.2.2  Environmental assessment

    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.

    Acute toxicity tests in the laboratory showed chlorothalonil to be
    very highly toxic for many aquatic animals including fish and  Daphnia,
    but that molluscs appeared to be insensitive. The LC50 concentrations
    for a range of fish and invertebrates were similar and were below
    0.5 mg/litre.

    A single study indicated reproductive effects in fish following
    continuous exposure to chlorothalonil for 35 days. Since the compound
    both adsorbs on suspended material and is degraded rapidly, the
    significance of this finding was considered to be questionable.

    The results of a field study on aquatic organisms exposed following
    chlorothalonil application suggest that the toxicity is less than that
    predicted from laboratory studies; this is again consistent with the
    physical and chemical properties of the compound. Deaths were seen in
    some species exposed experimentally in the field, but there have been
    no reported incidents of kills in the environment. Despite the short
    residence time of chlorothalonil in environmental media, kills would
    be expected to occur immediately after application. However, linking
    kills to the compound would be difficult as residues would not persist
    long enough for chlorothalonil to be identified.

    With minor exceptions, chlorothalonil is not phytotoxic.

    Several studies have shown that chlorothalonil at recommended
    application rates was not toxic for earthworms. At an exposure of five
    times the maximum recommended rate, the compound severely reduced worm
    reproduction.

    Chlorothalonil is classified as "relatively non-toxic" for honey-bees.
    Earwigs exposed to residues topically and via food showed some
    mortality (20-55%), but there was no other evidence of insecticidal
    action.

    In acute or dietary tests the toxicity of chlorothalonil for birds was
    low. The low acute toxicity of chlorothalonil for laboratory mammals
    tempered with its short persistence in the environment suggests
    minimal hazards for wild mammal species.

    2.2.2.1  Transport, distribution, and transformation

    Chlorothalonil adsorbs strongly on 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 on to
    suspended material and to a lesser extent on 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 the dissipation of this metabolite from
    non-sterile soils ranged 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 following termination of exposure.
    Chlorothalonil is metabolized in fish through glutathione conjugation
    and the conjugates are excreted through the bile.

    2.2.2.2  Aquatic organisms

    The results were available of a single field study in which
    concentrations of chlorothalonil in water were measured following
    overspraying of the water; corresponding data on concentrations of
    chlorothalonil in suspended and bottom sediment were unreliable.
    Output from the EXAMS II fate model using the same application
    scenario produced estimated water concentrations that closely
    corresponded to the measured ones. Little or no chlorothalonil was
    predicted in bottom sediment.

    On the basis of 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.

    2.2.2.3  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 2 contains a summary of risk quotients for avian and fish risk
    categories.

        Table 2.  Toxicity-exposure ratios for birds and fish based on application rates
              of 2.5 kg a.i./ha of chlorothalonil to soybeans (worst case)
                                                                                                  

    Risk category             LC50 as         Estimated exposurea,b     Toxicity/exposure
                              mg/litre or     as mg/litre               ratio (TER)c
                              mg/kg diet      or mg/kg diet
                                                                                                  

    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 STEAM model based on a single
       application and estimated runoff 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.
    
    2.2.3  Toxicological criteria for setting guideline values

    The toxicological studies on chlorothalonil of relevance for setting
    guideline values are displayed in Table 3. The study results and their
    significance are described briefly, and gaps in test requirements are
    indicated.

        Table 3.  Toxicological criteria for setting guideline 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, rat      High toxicity in 4-h study with
                                                    hammer-milled technical
                                                    chlorothalonil (MMAD 5-8 m);
                                                    not relevant for most human
                                                    exposure situations
    Medium-term     Repeat dermal, rabbit           21-day study; irritant at
    (1-26 weeks)                                    2.5 mg/kg body weight per day
                                                    and above; no systemic effects
                                                    at 50 mg/kg body weight per day
                    Repeat oral, mice and rats      13-22 week studies; NOEL=
                                                    3 mg/kg 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
                                                                                             
    
    3.  CONCLUSIONS AND RECOMMENDATIONS

    Considering the toxicological characteristics of chlorothalonil, both
    qualitatively and quantitatively, the CAG concluded, using the NOEL of
    3 mg/kg body weight per day 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.

    4.  HUMAN HEALTH HAZARDS, PREVENTION AND PROTECTION, EMERGENCY ACTION

    4.1  Human Health Hazards, Prevention and Protection, First Aid

    The acute oral toxicity of technical chlorothalonil for human beings
    is low. The compound may cause irritation of the respiratory tract,
    the skin, and the eyes. It may act as a sensitizer.

    In view of its irritating properties, exposure of humans beings should
    be kept to a minimum.

    4.1.1  Prevention and protection

    The following precautions should be observed during the handling and
    use of chlorothalonil, in order to reduce the risk of accidental
    contamination.

    *    Avoid contact with the skin and eyes by using protective clothing
         and goggles or a face-shield.

    *    Do not smoke, drink, or eat in the workplace. Wash hands and any
         exposed skin before eating, drinking, or smoking, and after work.

    *    Avoid raising a dust cloud when handling wettable powder
         formulations.

    *    Avoid breathing the dust from powder products.

    *    When unloading and handling containers, wear protective PVC or
         neoprene gloves.

    *    When handling leaking containers, or when dealing with leaks and
         spills, wear overalls, PVC or neoprene gloves, boots, and
         eye/face protection. Avoid creating a dust. If overalls become
         contaminated, change and wash them thoroughly before re-use.

    *    Store products in closed original containers, out of reach of
         children and unauthorized persons, and away from food, drink, and
         animal feed.

    4.1.2  First aid

    Acute poisoning by chlorothalonil is unlikely, unless large amounts
    are ingested. In cases of over-exposure, apply routine first aid
    measures. If the compound has been spilled on the skin, immediately
    remove the victim from the source of contamination, remove all

    contaminated clothing, and wash affected areas with soap and running
    water. If the material is in the eyes, flush with clean water for at
    least 15 min. In case of ingestion of significant quantities, if the
    victim is conscious, give several glasses of water or a slurry of
    activated charcoal in water. Do not induce vomiting. In serious cases,
    medical attention should be sought.

    4.2 Advice to Physicians

    The acute oral toxicity of chlorothalonil for human beings is low.
    There is no specific antidote. Treat symptomatically, paying special
    attention to respiratory and dermal symptoms when necessary. In cases
    of ingestion of large amounts, gastric lavage may be indicated.

    4.3  Explosion and Fire Hazards

    Chlorothalonil is not flammable but, on heating, may produce toxic
    fumes, such as nitrogen oxides, hydrochloric acid, and phosgene.

    Extinguish small fires with carbon dioxide, dry powder, or
    alcohol-resistant foam. Water spray can be used for larger fires and
    for the cooling of unaffected stock, but avoid the accumulation of
    polluted run-off from the site. Fire service personnel should be
    advised that self-contained breathing apparatus may be required,
    because of the generation of noxious fumes.

    4.4  Storage and Transport

    All products should be stored in secure buildings, out of reach of
    children and animals, and local regulations should be complied with.
    Containers should be sound and adequately labelled.

    4.5  Spillage and Disposal

    4.5.1  Spillage

    Avoid contact with the solid or dust. Keep spectators away from any
    leakage. This pesticide is highly toxic for fish and other aquatic
    organisms. Prevent contamination of other goods or cargo, and of
    nearby vegetation and waterways.

    Absorb spilled liquid products with earth or sand. If available,
    sawdust, peat, moss, or straw are also suitable absorbents; sweep up
    and place in a separate container. Empty any product remaining in
    damaged or leaking containers into a clean, empty container, which
    should be suitably labelled. Sweep up any spilled powder with damp
    sawdust, taking care not to raise a dust cloud (use a vacuum cleaner).
    Remove trapped material with suction hoses. Place in a separate
    container for subsequent disposal. Use mechanical dredges or lifts to
    remove immobilized masses of pollutants and precipitates.

    4.5.2  Waste disposal

    Chlorothalonil can be incinerated in units operating at 850C fitted
    with effluent-gas scrubbing equipment.

    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, 1985b; GIFAP, 1987). However,
    chlorothalonil is most difficult to remove, even by 3 rinsings with
    water (Braun et al., 1983).

    5.  HAZARDS FOR THE ENVIRONMENT AND THEIR PREVENTION

    Chlorothalonil is readily degraded in soil and adsorbed on suspended
    matter in water. It may bioaccumulate. It is toxic for aquatic
    organisms. It is moderately toxic for honey-bees, and its toxicity for
    birds is low.

    Avoid contamination of soil, water, and the atmosphere by proper
    methods of use, storage, transport, handling, and waste disposal. In
    case of spillage, use the methods advised in section 4.5.1.

    6.  CURRENT REGULATIONS, GUIDELINES AND STANDARDS

    The information in this section has been extracted from the
    International Register of Potentially Toxic Chemicals (IRPTC) legal
    file and other UN sources. It is a representative but non-exhaustive
    overview of current regulations, guidelines, and standards.

    The reader should be aware that regulatory decisions about chemicals
    taken in a certain country can only be fully understood in the
    framework of the legislation of that country. Furthermore, the
    regulations and guidelines of all countries are subject to change and
    should always be verified with the appropriate regulatory authorities
    before application.

    6.1  Previous Evaluations by International Bodies

    The Joint FAO/WHO Meeting on Pesticide Residues (JMPR) discussed and
    evaluated chlorothalonil at its meetings in 1974, 1977, 1978, 1979,
    1981, 1983, 1985, 1987, and 1990. In 1990, an acceptable daily intake
    (ADI) of 0-0.03 mg/kg body weight was established. This ADI was
    confirmed in 1992, on the basis of the no-observed-adverse-effect
    level (NOAEL) of 3 mg/kg body weight per day, established in the
    two-year dog study.

    Temporary maximum residue limits (MRLs) have been recommended for
    various crops at the above evaluations (see Table 4).

    WHO has classified chlorothalonil as a technical product unlikely to
    present an acute hazard in normal use (WHO, 1992).

    On the basis of data available at the time, IARC evaluated
    chlorothalonil as showing limited evidence of carcinogenicity in
    animal studies and categorized it as an agent not classifiable as to
    its carcinogenicity to humans (IARC, 1987).

    6.2  Exposure Limit Values

    Some exposure limit values are given in Table 4.

    For preharvest intervals, check with the competent National Authority.

    6.3  Specific Restrictions

    Chlorothalonil is approved as a pesticide in many countries. Specific
    uses, limitations, and precautions are listed in national regulatory
    documents.

    6.4  Labelling, Packaging, and Transport

    Neither the United Nations Committee of Experts on the Transportation
    of Dangerous Goods nor the European Economic Community Legislation
    give specific labelling requirements for chlorothalonil.

    Table 4.  Codex MRLs for chlorothalonila
                                                                         

    Commodity                                        MRL in mg/kg product
                                                                         

    Peanuts (kernels), potatoes                             0.1
    Lima beans (without pod), peanuts (whole)               0.5
    Carrots, sugar beets, sweet corn                        1
    Beans (green in the pod), broccoli,
    brussel sprouts, cabbage, cauliflower,
    citrus fruit, cranberries, cucumbers, melons,
    onions, pumpkins, squash, tomatoes                       5
    Blackberries, cherries, chicory sprouts,
    collards, endive, kale, lettuce (head),
    peppers, raspberries                                    10
    Celery                                                  15
    Currants (red, black, white), peaches                   25
                                                                         

    a  From: FAO/WHO (1986).

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    See Also:
       Toxicological Abbreviations
       Chlorothalonil (EHC 183, 1996)
       Chlorothalonil (ICSC)
       Chlorothalonil (WHO Pesticide Residues Series 4)
       Chlorothalonil (Pesticide residues in food: 1977 evaluations)
       Chlorothalonil (Pesticide residues in food: 1981 evaluations)
       Chlorothalonil (Pesticide residues in food: 1983 evaluations)
       Chlorothalonil (Pesticide residues in food: 1985 evaluations Part II Toxicology)
       Chlorothalonil (Pesticide residues in food: 1987 evaluations Part II Toxicology)
       Chlorothalonil (Pesticide residues in food: 1990 evaluations Toxicology)
       Chlorothalonil (Pesticide residues in food: 1992 evaluations Part II Toxicology)
       Chlorothalonil  (IARC Summary & Evaluation, Volume 30, 1983)
       Chlorothalonil  (IARC Summary & Evaluation, Volume 73, 1999)