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    UNITED NATIONS ENVIRONMENT PROGRAMME
    INTERNATIONAL LABOUR ORGANISATION
    WORLD HEALTH ORGANIZATION


    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY



    ENVIRONMENTAL HEALTH CRITERIA 198





    Diazinon







    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.


    Environmental Health Criteria 198

    First draft prepared by Dr K. Barabás, Albert Szent-Gyorgyi University
    Medical School, Szeged, Hungary

    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, 1998

         The International Programme on Chemical Safety (IPCS) is a joint
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    WHO Library Cataloguing in Publication Data

    Diazinon

    (Environmental health criteria ; 198)

    1.Diazinon - toxicity                2.Diazinon - adverse effects
    3.Environmental exposure             4.Occupational exposure
    I.International Programme on Chemical Safety   II.Series

    ISBN 92 4 157198 5                 (NLM Classification: WA 240)
    ISSN 0250-863X

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    CONTENTS

    ENVIRONMENTAL HEALTH CRITERIA FOR DIAZINON

    PREAMBLE

    ABBREVIATIONS

    1. SUMMARY

         1.1. Identity, physical and chemical properties, analytical
               methods
         1.2. Production, uses and sources of human and environmental
               exposure
         1.3. Environmental transport, distribution and transformation
         1.4. Environmental levels and human exposure
         1.5. Kinetics and metabolism
         1.6. Effects on experimental animals and  in vitro test systems
         1.7. Effects on humans
         1.8. Effects on other organisms in the laboratory and field

    2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS

         2.1. Identity
               2.1.1. Primary constituent
               2.1.2. Technical product
         2.2. Physical and chemical properties
         2.3. Analytical methods

    3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

         3.1. Natural occurrence
         3.2. Man-made sources
               3.2.1. Production levels and processes
                       3.2.1.1   Manufacturing process
               3.2.2. Uses
               3.2.3. Formulations

    4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION

         4.1. Transport and distribution between media
               4.1.1. Volatilization
               4.1.2. Movement in soil
         4.2. Degradation
               4.2.1. Degradation in soil
               4.2.2. Degradation in water
               4.2.3. Bioconcentration
                       4.2.3.1   Fish and aquatic invertebrates

    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. Fruit, vegetables and food
               5.1.5. Milk
               5.1.6. Meat and fat
         5.2. General population exposure
         5.3. Occupational exposure

    6. KINETICS AND METABOLISM

         6.1. Absorption, distribution and excretion
               6.1.1. Oral administration
                       6.1.1.1   Rats
                       6.1.1.2   Guinea-pigs
                       6.1.1.3   Dogs
                       6.1.1.4   Goats
                       6.1.1.5   Cow
                       6.1.1.6   Hens
               6.1.2. Dermal application
                       6.1.2.1   Rats
                       6.1.2.2   Sheep
                       6.1.2.3   Humans
               6.1.3. Other routes
                       6.1.3.1   Intraperitoneal administration
                       6.1.3.2   Subcutaneous administration
                       6.1.3.3   Intravenous administration
         6.2. Metabolism
               6.2.1.  In vivo metabolic transformations
                       6.2.1.1   Mice
                       6.2.1.2   Rats
                       6.2.1.3   Dogs
                       6.2.1.4   Sheep
                       6.2.1.5   Goats
                       6.2.1.6   Hens
               6.2.2.  In vitro metabolic transformations
         6.3. Metabolic aspects of diazinon toxicity

    7. EFFECTS ON LABORATORY MAMMALS AND  IN VITRO TEST SYSTEMS

         7.1. Single exposure
               7.1.1. Oral
               7.1.2. Dermal
               7.1.3. Inhalation
               7.1.4. Intraperitoneal

         7.2. Short-term exposure
               7.2.1. Oral
                       7.2.1.1   Rats
                       7.2.1.2   Dogs
                       7.2.1.3   Pigs
               7.2.2. Inhalation
               7.2.3. Dermal
                       7.2.3.1   Rabbits
         7.3. Long-term exposure
               7.3.1. Rats
               7.3.2. Dogs
               7.3.3. Rhesus monkeys
         7.4. Skin and eye irritation; sensitization
               7.4.1. Primary skin irritation
               7.4.2. Primary eye irritation
               7.4.3. Skin sensitization
         7.5. Reproduction, embryotoxicity and teratogenicity
               7.5.1. Reproduction
                       7.5.1.1   Rat
                       7.5.1.2   Cattle
               7.5.2. Embryotoxicity and teratogenicity
                       7.5.2.1   Mice
                       7.5.2.2   Rats
                       7.5.2.3   Hamsters
                       7.5.2.4   Rabbits
                       7.5.2.5   Chicken
         7.6. Mutagenicity and related end-points
         7.7. Carcinogenicity
               7.7.1. Mice
               7.7.2. Rats
         7.8. Special studies
               7.8.1. Neurotoxicity
               7.8.2. Effects on enzymes and transmitters
               7.8.3. Effects on the immune system
               7.8.4. Effect on pancreas
         7.9. Factors that modify toxicity; toxicity of metabolites
               7.9.1. Metabolic enzymes
               7.9.2. Antidotes
               7.9.3. Potentiation

    8. EFFECTS ON HUMANS

         8.1. Exposure of the general population
               8.1.1. Acute toxicity, poisoning incidents
                       8.1.1.1   Acute pancreatitis
                       8.1.1.2   Intermediate syndrome
                       8.1.1.3   Unusual case reports
               8.1.2. Controlled human studies

         8.2. Occupational exposure
               8.2.1. Acute poisoning
               8.2.2. Effect of short-term and long-term
                       exposure

    9. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

         9.1. Microorganisms
         9.2. Aquatic invertebrates
         9.3. Fish
         9.4. Effects in mesocosms and the field
         9.5. Terrestrial invertebrates
         9.6. Birds
               9.6.1. Field studies

    10. EVALUATION OF HUMAN HEALTH RISK AND EFFECTS ON THE ENVIRONMENT

         10.1. Evaluation of human health risk
         10.2. Evaluation for effects on the environment
               10.2.1. Aquatic organisms
                       10.2.1.1  Acute risk
                       10.2.1.2  Chronic risk
               10.2.2. Terrestrial organisms
                       10.2.2.1  Birds
                       10.2.2.2  Mammals
                       10.2.2.3  Bees
                       10.2.2.4  Earthworms

    11. CONCLUSIONS AND RECOMMENDATIONS FOR PROTECTION OF HUMAN HEALTH
         AND THE ENVIRONMENT

         11.1. Conclusions
         11.2. Recommendations for protection of human health and the
               environment
               11.2.1. Recommendation on regulation of compound
                       11.2.1.1  Transport and storage
                       11.2.1.2  Handling
                       11.2.1.3  Disposal
                       11.2.1.4  Selection, training and medical
                                 supervision of workers
                       11.2.1.5  Labelling
                       11.2.1.6  Residues in food
               11.2.2. Prevention of poisoning in man and emergency aid
                       11.2.2.1  Manufacture and formulation
                       11.2.2.2  Mixers and applicators
                       11.2.2.3  Other associated workers
                       11.2.2.4  Other populations likely to be affected

               11.2.3. Entry into treated areas
               11.2.4. Emergency aid
               11.2.5. Surveillance test

    12. FURTHER RESEARCH

    13. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

    REFERENCES

    RÉSUMÉ ET ÉVALUATIONS

    RESUMEN Y EVALUACIONES
    

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    FIGURE 1

    WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR DIAZINON

     Members

    Dr P.J. Abbott, Australia and New Zealand Food Authority
         (ANZFA), Canberra, Australia

    Dr K. Barabás, Department of Public Health, Albert Szent-Gyorgyi,
         University Medical School, Szeged, Hungary

    Dr A.L. Black, Woden, ACT, Australia

    Professor J.F. Borzelleca, Pharmacology and Toxicology,
         Richmond, Virginia, USA

    Dr P.J. Campbell, Pesticides Safety Directorate, Ministry of
         Agriculture, Fisheries and Food, Kings Pool, York,
         United Kingdom

    Professor L.G. Costa, Department of Environmental Health,
         University of Washington, Seattle, USA

    Dr S. Dobson, Institute of Terrestrial Ecology, Monks Wood,
         Abbots Ripton, Huntingdon, Cambridgeshire, United Kingdom

    Dr I. Dewhurst, Mammalian Toxicology Branch, Pesticides Safety
         Directorate, Ministry of Agriculture, Fisheries and Food,
         Kings Pool, York, United Kingdom

    Dr V. Drevenkar, Institute for Medical Research and Occupational
         Health, Zagreb, Croatia

    Dr W. Erickson, Environmental Fate and Effects Division,
         US Environmental Protection Agency, Washington, D.C., USA

    Dr A. Finizio, Group of Ecotoxicology, Institute of Agricultural
         Entomology, University of Milan, Milan, Italy

    Mr K. Garvey, Office of Pesticide Programs (7501C),
         US Environmental Protection Agency, Washington, D.C., USA

    Dr A.B. Kocialski, Health Effects Division, Office of Pesticide
         Programs, US Environmental Protection Agency,
         Washington, D.C., USA

    Dr A. Moretto, Institute of Occupational Medicine, University
         of Padua, Padua, Italy

    Professor O. Pelkonen, Department of Pharmacology and
         Toxicology, University of Oulu, Oulu, Finland

    Dr D. Ray, Medical Research Council Toxicology Unit, University
         of Leicester, Leicester, United Kingdom

    Dr J.H.M. Temmink, Department of Toxicology, Wageningen
         Agricultural University, Wageningen, The Netherlands

     Observers

    Dr J.W. Adcock, AgrEvo UK Limited, Chesterford Park, Saffron,
         Waldon, Essex, United Kingdom

    Mr D. Arnold, Environmental Sciences, AgrEvo UK Ltd.,
         Chesterford Park, Saffron Waldon, Essex, United Kingdom

    Dr E. Bellet, CCII, Overland Park, Kansas, USA

    Mr Jan Chart, AMVAC Chemical Corporation, Newport Beach,
         California, USA

    Dr H. Egli, Novartis Crop Protection AG, Basel, Switzerland

    Dr P. Harvey, AgrEvo UK Ltd., Chesterford Park, Saffron Walden,
         Essex, United Kingdom

    Dr G. Krinke, Novartis Crop Protection AG, Basel, Switzerland

    Dr A. McReath, DowElanco Limited, Letcombe Regis, Wantage,
         Oxford, United Kingdom

    Dr H. Scheffler, Novartis Crop Protection AG, Basel, Switzerland

    Dr A.E. Smith, Novartis Crop Protection AG, Basel, Switzerland

     Secretariat

    Dr L. Harrison, Health and Safety Executive, Bootle, Merseyside,
         United Kingdom

    Dr J.L. Herrman, International Programme on Chemical Safety,
         World Health Organization, Geneva, Switzerland

    Dr P.G. Jenkins, International Programme on Chemical Safety,
         World Health Organization, Geneva, Switzerland

    Dr D. McGregor, Unit of Carcinogen Identification and Evaluation,
         International Agency for Research on Cancer, Lyon, France

    Dr R. Plestina, International Programme on Chemical Safety,
         World Health Organization, Geneva, Switzerland

    Dr E. Smith, International Programme on Chemical Safety,
         World Health Organization, Geneva, Switzerland

    Dr P. Toft, International Programme on Chemical Safety,
         World Health Organization, Geneva, Switzerland

    ENVIRONMENTAL HEALTH CRITERIA FOR DIAZINON

         The Core Assessment Group (CAG) of the Joint Meeting on
    Pesticides (JMP) met at the Institute for Environment and Health,
    Leicester, United Kingdom, from 3 to 8 March 1997.  Dr L.L. Smith
    welcomed the participants on behalf of the Institute and
    Dr R. Plestina on behalf of the three IPCS cooperating organizations
    (UNEP/ILO/WHO).  The CAG reviewed and revised the draft monograph and
    made an evaluation of the risks for human health and the environment
    from exposure to diazinon.

         The first draft of the monograph was prepared by Dr K. Barabás,
    Albert Szent-Gyorgyi University Medical School, Szeged, Hungary. 
    Extensive scientific comments were received following circulation of
    the first draft to the IPCS contact points for Environmental Health
    Criteria monographs and these comments were incorporated into the
    second draft by the Secretariat.

         Dr R. Plestina and Dr P.G. Jenkins, both members of the IPCS
    Central Unit,  were responsible for the overall scientific content and
    technical editing, respectively.

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

    ABBREVIATIONS

    AChE       acetylcholinesterase

    ai         active ingredient

    ChE        cholinesterase

    CNS        central nervous system

    DETP       diethylthiophosphate

    DT         degradation time

    EDTA       ethylenediaminetetraacetic acid

    fc         field capacity

    GABA       gamma-aminobutyric acid

    ip         intraperitoneal

    MRL        maximum residue limit

    NAD        nicotinamide adenine dinucleotide

    NIOSH      National Institute for Occupational Safety and Health (USA)

    NOAEL      no-observed-adverse-effect level

    NOEC       no-observed-effect concentration

    NOEL       no-observed-effect level

    OSHA       Occupational Safety and Health Administration (USA)

    2-PAM      pralidoxine (2-pyridine aldoxime methyl) chloride

    PEC        predicted environmental concentration

    TEPP       tetraethyl-pyrophosphate

    TER        toxicity-exposure ratio

    TLV        threshold limit value

    1.  SUMMARY

    1.1  Identity, physical and chemical properties, analytical methods

         The chemical name for diazinon is  O, O-diethyl
     O-2-isopropyl-6-methylpyrimidinyl-4-yl phosphorothioate. The pure
    material forms a colourless liquid with a faint ester-like odour. The
    technical active ingredient is a yellow/brown liquid with a slight
    compound-specific odour. The boiling point is 83-84°C at 26.6 mPa and
    the vapour pressure (volatility) is low (9.7 mPa at 20°C). The
    solubility in water at room temperature is 60 mg/litre. Diazinon is
    soluble in most organic solvents and has an octanol/water partition
    coefficient (log Pow) of 3.40. It is stable in neutral media, but is
    slowly hydrolysed in alkaline media and more rapidly in acid media. It
    decomposes at temperatures above 120°C.

         A large number of sampling and analytical methods have been
    developed for the determination of diazinon and its metabolites in
    different media. Sensitive methods, such as gas chromatography,
    high-performance liquid chromatography, mass spectrometry and
    immunoassay methods, are increasingly used.

    1.2  Production, uses and sources of human and environmental exposure

         Diazinon is a contact organophosphorus insecticide with a wide
    range of insecticidal activity. It is effective against adult and
    juvenile forms of flying insects, crawling insects, acarians and
    spiders. It has been used from the early 1950s. Diazinon is mainly
    formulated as wettable powders and emulsifiable concentrates. It is
    also available in mixed formulations with other insecticides.

    1.3  Environmental transport, distribution and transformation

         Volatilization of diazinon from soil is of minor importance.
    Diazinon has a tropospheric half-life of 1.5 h.

         The movement of diazinon through soil is highly influenced by a
    number of factors, particularly by organic matter and calcium
    carbonate content. Diazinon is not expected to bind strongly to soil,
    owing to its KOC value of 500, and is expected to show moderate
    mobility in the soil.

         Biological processes appear to be the main factor in the
    degradation of diazinon in soil. At 20°C and a soil moisture content
    of 60% of field capacity (f.c.) in a silt loam soil, the DT50 was
    5 days. Under sterile conditions at 20°C and 60% f.c., the DT50 was
    118 days, suggesting that biological activity is mainly responsible
    for degradation in soil.

         In natural water diazinon has a half-life of the order of 5-15
    days. Both chemical and biological processes seem to play a role in
    the degradation of diazinon, leading to mineralization within a few
    weeks.

         Uptake of diazinon by aquatic organisms is rapid. Low
    bioconcentration factors have been reported for aquatic organisms,
    ranging from 3 for shrimp to 152 for gudgeon, consistent with rapid
    metabolism and loss. Depuration half-lives for fish have been reported
    to be up to 30 h (muscle).

    1.4  Environmental levels and human exposure

         Environmental levels of diazinon are generally low. The routes of
    exposure for the general population are inhalational and dietary.
    Exposure through water is negligible. Occupational exposure is
    primarily dermal.

         Diazinon uses fall into two major categories: as a pesticide in
    agriculture and as a drug in veterinary medicine. Thus, the major
    source of diazinon residues in edible crops are from its use as an
    agricultural pesticide, while those in meat, offal and other animal
    products arise from its use as a veterinary drug containing active
    ingredient.

         Diazinon residues in vegetables, fruits and animal products are
    very low. The results of total-diet studies suggest that diazinon
    rapidly breaks down in both plant and animal products. Diazinon has
    not been detected in drinking-water samples and its concentrations in
    surface water are at the level of ng/litre.

    1.5  Kinetics and metabolism

         Diazinon may be absorbed from the gastrointestinal tract,
    through the intact skin and following inhalation. Transdermal
    absorption in humans is low. Diazinon is oxidized by the microsomal
    enzymes to cholinesterase-inhibiting metabolites such as diazoxon,
    hydroxydiazoxon, and hydroxydiazinon. Only minimal quantities of
    metabolites are detectable in milk and eggs. Diazinon and its
    metabolites do not accumulate in body tissue; 59-95% of an oral dose
    of diazinon is excreted within 24 h and 95-98% is excreted within
    7 days, mainly in urine.

         The main metabolic pathways of degradation of diazinon are:

    a)   Cleavage of the ester bond leading to the hydroxypyrimidine
         derivatives.

    b)   Transformation of P-S moiety to the P-O derivate.

    c)   Oxidation of isopropyl substituent leading to the corresponding
         tertiary and primary alcohol derivatives.

    d)   Oxidation of the methyl substituent leading to the corresponding
         alcohol.

    e)   Glutathione-mediated cleavage of the ester bond leading to a
         glutathione conjugate.

         The cleavage of the phosphorus ester bond, leading directly, or
    via diazoxon, to the pyrimidyl metabolite plays the major role in the
    metabolism of diazinon. Metabolites maintaining the phosphorus ester
    bond are of transient nature and have been observed only in small
    quantities. Yields and rates of production of metabolites vary greatly
    between species. The production of diazoxon is not generally
    correlated with susceptibility to diazinon poisoning, although it is
    lowest in the least susceptible species, the sheep. The extrahepatic
    metabolism of diazinon, especially the hydrolysis of diazoxon in
    plasma, is more important toxicologically than the metabolism in
    the liver, although the liver is probably the most important site
    of metabolism in avian species. The metabolites formed, i.e.
    diethylphosphoric acid, diethylthiophosphoric acid and the derivates
    of the pyrimidinyl ring, are eliminated mainly via the kidneys.

    1.6  Effects on experimental animals and in vitro test systems

         Improvements in the manufacture of diazinon since 1979 have
    significantly reduced the content of highly toxic impurities, e.g.,
    tetraethyl-pyrophosphate (TEPP). As a result of these progressive
    improvements, the acute oral LD50 of technical grade diazinon has
    increased (e.g., from 250 mg/kg to 1250 mg/kg in the rat).

         The acute oral, dermal and inhalational toxicity is low.
    Short-term and long-term studies in mice, rats, rabbits, dogs and
    monkeys have shown that the only effect of concern is dose-related
    inhibition of acetyl cholinesterase activity.

         Diazinon is slightly irritant to rabbit skin but not to the eye.
    Diazinon is not a dermal sensitizer. Reproductive and developmental
    studies have revealed no evidence of embryotoxic or teratogenic
    potential. There was no effect on reproductive performance at dose
    levels that were not toxic to the parent animals. Mutagenicity studies
    with various end-points  in vivo and  in vitro gave no evidence of a
    mutagenic potential. There is no evidence of carcinogenicity in rats
    or mice. Diazinon does not cause delayed neuropathy in hens. In the
    dog and guinea-pig, diazinon has been reported to cause acute
    pancreatitis; this is considered to be a species-specific effect.

    1.7  Effects on humans

         Several cases of accidental or suicidal poisoning by diazinon
    have been reported, some of which were fatal. In some of these the
    cholinergic syndrome may have been more severe than expected because
    of the presence of highly toxic impurities such as TEPP. In certain
    cases, acute reversible pancreatitis was associated with a severe
    cholinergic syndrome. This occurs also after poisoning with other
    cholinesterase inhibitors. In a number of cases, the intermediate
    syndrome was also observed. No cases of delayed neuropathy have ever
    been reported, as expected from animal data. Reported cases of
    poisoning after occupational exposure have always been associated with
    the presence of impurities such as TEPP, monothio-TEPP or sulfo-TEPP
    in the formulation. These impurities are unlikely to be found in
    currently available formulations.

    1.8  Effects on other organisms in the laboratory and field

         Effects of diazinon on unicellular algae are variable; both
    inhibition and stimulation of growth have been reported for different
    species at concentrations between 0.01 and 5 mg/litre. Generally,
    growth rates are reduced at concentration above 10 mg/litre, although
    in certain cases population size can remain unaltered at 100 mg/litre.
    Fewer and variable data make effects on other microorganisms difficult
    to assess.

         Acute LC50 values for aquatic invertebrates range from
    0.2 µg/litre for  Gammarus fasciatus to 4.0 µg/litre for the shrimp
     Hyallela azteca in 96-h tests. Molluscs are substantially less
    sensitive according to a single test on the snail  Gillia 
     attilis. Sublethal effects on behaviour have been reported at
    concentrations between 0.1 and 0.01 mg/litre.

         Acute LC50 values for fish range from 0.09 mg/litre for rainbow
    trout  (Oncorhynchus mykiss) to 3.1 mg/litre for the catfish
     (Channa punctatus). Growth of early life stages of fish was
    inhibited at concentrations between 0.01 and 0.2 mg/litre. Brain
    acetylcholinesterase activity is suppressed following acute exposure
    to diazinon.

         The LC50 for the earthworm  Eisenia foetida in soil is
    130 mg/kg soil.

         The acute oral toxicity (LD50) in birds ranges from 1.1 mg/kg
    body weight for Japanese quail to 85 mg/kg body weight for cowbirds.
    Dietary LC50 values range from 32 mg/kg diet for mallard to 900 mg/kg
    diet for Japanese quail (repellency was noted at these high dietary
    concentrations). The no-observed-effect concentration in diet for
    reproductive effects on birds in laboratory studies was 20 mg/kg

    diet for mallard and 40 mg/kg diet for bobwhite quail. Brain
    acetylcholinesterase activity is inhibited following ingestion.
    Diazinon may also be taken in via the dermal route. There have been
    reports of substantial field kills of water fowl following application
    of diazinon to turf. Field studies applying liquid formulations to
    turf at 4.8 kg ai/ha resulted in no mortality or reproductive effects
    on song birds. Application of granules caused a small reduction in
    song bird population size compared to that of controls. Ingestion of
    small numbers of granules can be fatal for small birds, as
    demonstrated in laboratory studies.

    2.  IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS

    2.1  Identity

    2.1.1  Primary constituent

    Common name:                  diazinon

    Chemical structure:

    CHEMICAL STRUCTURE 1

    Chemical formula:             C12H21N2O3PS

    Relative molecular mass:      304.35

    IUPAC Chemical names:          O,O-diethyl  O-2-isopropyl-6-methyl-
                                  pyrimidin-4-yl phosphorothioate

    CAS chemical name:             O,O-diethyl  O-[6-methyl-2-
                                  (1-methylethyl)-4-pirimidinyl]
                                  phosphorothioate

    CAS registry number:          333-41-5

    RTECS number:                 TF3325000

    Official number:              OMS 469; ENT 19 507

    Synonyms:                     dimpylate, diazide, G.24480, Basudin,
                                  Kayazinon, Necidol/Nucidol

    2.1.2  Technical product

    Trade names:                  Diazinon (Alpha, Darlingtons Mushroom
                                  Laboratories, Murphy Chemicals and
                                  Rentokil); Basudin (Ciba-Geigy);
                                  Crompest (Cromessel Co. Ltd); Dethlac
                                  (Gerhardt Pharmaceuticals); Isectalac
                                  (Sorex Ltd); Murphy Root Guard (Fisons);
                                  Rentokil Flytrol and Knox out 2FM
                                  (Rentokil); Secto AntSpray and Root
                                  Powder (Secto Ltd); Dazzel, Diagran,
                                  Dianon (Nippon Kayaku); Diazotol
                                  Gardentox, Nipsan (Nippon Kayaku);
                                  Dyzol, Dizion (Nippon Kayaku);
                                  Spectracide (Ciba-Geigy)

    2.2  Physical and chemical properties

         Diazinon is a clear colourless liquid (technical 95% yellow oil)
    with a faint ester-like odour.

    Boiling point:                83-84°C at 26.6 mPa; 125°C at 133 mPa

    Vapour pressure:              9.7 mPa at 20°C

    Density:                      1.11 g/cm3 at 20°C

    Refractive index:             1.4978-1.4981

    Specific gravity:             1.116-1.118 at 20°C

    Stability:                    susceptible to oxidation above 100°C;
                                  stable in neutral media, but slowly
                                  hydrolysed in alkaline media, and more
                                  rapidly in acidic media

    Decomposes:                   above 120°C

    Corrosiveness:                non-corrosive

    Solubility:                   60 mg/litre in water at 20°C;
                                  completely miscible with common organic
                                  solvents, e.g., ethers, acetone,
                                  alcohols, benzene, toluene, cyclohexane,
                                  hexane, dichloromethane, petroleum oils

    2.3  Analytical methods

         Formulated diazinon products are cleaned up by column
    chromatography to remove the basic impurities and analysed by
    titration with perchloric acid in acetic acid. They are also analysed
    by gas-liquid chromatography (Eberle et al., 1974; Allender & Britt,
    1994).

         Residues in soil, water, air, plants, foods, and animal and human
    tissues can be determined using gas chromatography using detectors
    selective for phosphorus-containing compounds, and by other
    chromatographic techniques. Table 1 outlines various methods for
    determination of diazinon in different media.

         Farran et al. (1988a) described a method for the determination of
    organophosphorus insecticides and their hydrolysis products. The
    method involves the analysis of compounds by liquid chromatography in
    combination with UV and thermospray-mass spectrometric detection.

         An automated identification method has been developed for water-
    borne toxicants, including diazinon, using an ion chromatography/
    high-performance liquid chromatography system (Fort et al., 1995).

         A compendium of analytical methods for organophosphorus compounds
    has been issued (NIOSH, 1994).

        Table 1.  Analytical methods for diazinon
                                                                                             

    Medium                  Analytical method                          References
                                                                                             

    Air                     adsorption on XAD-2 resin, gas             NIOSH (1994)
                            chromatography with flame
                            photometric detector

    Soil                    gas chromatography                         Singmaster & Acin-
                                                                       Diaz (1991)

    Water                   extraction with XAD-2 resin, gas           Le Bel et al. (1979)
                            chromatography with nitrogen-
                            phosphorus detector, gas
                            chromatography/mass spectrometry

                            continuous-flow extraction coupled         Farran et al. (1988b)
                            on-line with high-performance liquid
                            chromatography

                            liquid-solid extraction, gas               Johnson et al. (1991)
                            chromatography/mass spectrometry

                            on-line solid-phase extraction,            Lacorte & Barcelo
                            liquid chromatography/thermal spray -      (1995)
                            mass spectrometry

                            on-line solid-phase extraction,            Lacorte & Barcelo
                            liquid chromatography/atmospheric          (1996)
                            pressure chemical ionization mass
                            spectrometry

                            maleic anhydride immunoassay               Winnett (1992)

    Oil solution            gas chromatography                         Koibuchi et al.
                                                                       (1975)

    Fruit and               solvent extraction, gas                    Ferreira & Silva
    vegetables              chromatography with thermionic             Fernandes (1980)
                            detector

    Apples                  solvent extraction, gas                    Asensio et al. (1991)
                            chromatography with thermionic
                            detector
                                                                                             

    Table 1.  (con't)
                                                                                             

    Medium                  Analytical method                          References
                                                                                             

    Oranges                 matrix solid-phase dispersion              Torres et al. (1996)
                            extraction, gas chromatography with
                            electron capture detector

    Rice                    solvent extraction, gas                    Adachi et al. (1984)
                            chromatography with flame ionization
                            detector

    Spinach                 preparative thin-layer                     Gilmore & Cortes
                            chromatography, autoradiography,           (1996)
                            liquid scintillation counting

                            solvent extraction, gas                    Cairns et al. (1985)
                            chromatography with electrolytic
                            conductivity detector, gas
                            chromatography/chemical ionization
                            mass spectrometry

    Milk                    gas chromatography                         Toyoda et al. (1990)

    Human tissue            solvent extraction, thin-layer             Kirkbride (1987)
                            chromatography, gas chromatography
                            with nitrogen-phosphorus detector

    Blood plasma            gas chromatography                         Machin et al. (1975)

                            solvent extraction, gas                    Wu et al. (1994)
                            chromatography with electron capture
                            detector

    Metabolites in urine

    DEP, DEPT               extraction by anion exchange resin,        Lores & Bradway
                            gas chromatography with flame              (1977)
                            photometric detector                       Weisskcp & Seiber
                                                                       (1989)

    GW7 550,                solvent extraction, gas                    Lawrence & Iverson
    GS 31 144               chromatography with electrolytic           (1975)
                            conductivity detector
                                                                                             
    
    3.  SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

    3.1  Natural occurrence

         Diazinon does not occur as a natural product.

    3.2  Man-made sources

    3.2.1  Production levels and processes

    3.2.1.1  Manufacturing process

         Diazinon is the common name for  O, O-diethyl
     O-2-isopropyl-6-methylpyrimidin-4-yl phosphorothioate (IUPAC name),
    an organophosphate insecticide. Its insecticidal properties were first
    described by Gasser (1953) and it was introduced in 1952, by
    J. R. Geigy S.A. under the code number G 24480, trade names Basudin,
    Diazitol, Neocidol and Nucidol, and the protection of BP 713278; USP
    2754243. Meanwhile, improvements in the manufacturing process and the
    stabilization of the technical grade diazinon by epoxidized soybean
    oil have significantly reduced the content and formation of toxic
    by-products and breakdown products and have reduced the acute toxicity
    of diazinon products.

    3.2.2  Uses

         Diazinon is a contact organophosphorus insecticide with a wide
    range of insecticidal activity, having long persistence and relatively
    low mammalian toxicity. Diazinon is effective against adult and
    juvenile forms of insects, but also against acarina. The spectrum of
    activity includes the following arthropod groups:

    *    flying insects: flies and fly maggots, mosquitoes

    *    crawling insects: cockroaches, bedbugs, lice and ants

    *    acarina: dog ticks

    *    arachnideae: spiders

         The main applications are rice, fruit, vineyards, sugar-cane,
    corn, tobacco, potatoes, horticultural crops, animal dips and sprays.

         Diazinon is also used by trained pest control operators in
    households and outbuildings to control cockroaches, ants, silverfish,
    spiders, carpet beetles and scorpions and in insecticidal collars on
    domestic pets.

    3.2.3  Formulations

         The most important diazinon formulations are: ULV concentrates,
    wettable powders 400 g/kg; emulsifiable concentrates 600, 400 and
    250 g/litre; dust 20-40 g/kg; granules 30-140 g/kg; aerosols
    200 g/litre.

         Some typical formulations for agricultural and horticultural use
    include: Basudin 5 (50 g a.i./kg); Basudin 10 (100 g a.i./kg) GR;
    Basudin 40WP (400 g a.i./kg); Basudin 50SD (500 g a.i./kg); Basudin
    60EC (EC 600 g a.i./litre); Diazitol Liquid; Basudin Ulvair 500;
    Basudin 20 Mushroom Aerosol, KN; Knox-out (Pennwalt), flowable
    microcapsules (230 g a.i./litre); Neocidol 60, Nucidol 60,
    EC (600 g a.i./litre) for veterinary use.

    4.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION

    4.1  Transport and distribution between media

    4.1.1  Volatilization

         It has been shown that diazinon is lost from soil through
    volatilization (Harris & Mazurek, 1966), but the rate of loss is
    unknown. Results of earlier studies with 14C-labelled insecticide and
    the use of capped containers for holding treated soils indicated that
    volatility was of minor importance. Under field conditions,
    co-distillation, high temperatures and exposed surface areas probably
    contribute to a greater loss of the insecticide through
    volatilization.

         Rate estimations according to the Atkinson incremental method
    indicate that diazinon is rapidly degraded by hydroxyl radicals in the
    atmosphere. The tropospheric half-life of diazinon lies between 1.3
    and 1.5 h (Stamm, 1994).

    4.1.2  Movement in soil

         A study concerning degradation rate and mobility of diazinon in a
    thatch layer of turf grass and in the underlying soil (2.5 cm) was
    performed by Sears & Chapman (1979). Immediately following the
    pesticide application, 2200 litres of water were applied to the total
    treated area of 80 m2. Fourteen days after the application, less than
    2% of the compound remained in the grass-thatch layer, and less than
    1% in the root zone and in the underlying soil. The authors concluded
    that the compound readily disappeared by degradation and/or
    volatilization. However, it must be considered that only the top
    2.5-cm layer was analysed.

         The movement of diazinon and other organophosphorus compounds in
    the soil was evaluated by means of soil thin-layer chromatography
    (Sharma et al., 1986). The experiment was performed with two types of
    soil (silt loam and sandy loam) showing different percentages of
    organic matter (1.05 and 0.35%, respectively). The authors found a
    generally poorer movement of diazinon in the silt loam soil, probably
    due to the higher organic matter content and higher cation exchange
    capacity. When natural soils were used as adsorbent and distilled
    water as eluent, diazinon showed relatively high mobility. In this
    study, the effects of pH and the presence of leachates of alkaline and
    saline salts were also evaluated. Diazinon showed a slight decrease of
    mobility in both soils at pH 4, whereas at pH 10 there was increase
    mobility in the silt loam and slight decrease in mobility in the sandy
    loam. The effects of leachate salt were not significant, with the
    exception of calcium sulfate, which decreased mobility in the silt
    loam soil.

         The adsorption and mobility of diazinon in 25 Spanish soils and
    the influence of soil properties on both processes were studied
    (Arienzo et al., 1994). Adsorption constants of diazinon in the soils
    were measured using soil thin-layer chromatography and soil column
    leaching. The experiments were conducted with 14C-labelled diazinon.
    Adsorption of diazinon was found to follow the Freundlich adsorption
    equation. The Freundlich adsorption constant (K) ranged from 0.70 to
    25.73. Adsorption was highly significantly correlated (p <0.001) with
    the content of organic matter (OM). The median KOM value was 290
    corresponding to a KOC value of 500. There was also a significant
    correlation (p <0.01) of K and the distribution coefficient Kd with
    the silt-plus-clay content in soils with low organic material content
    (<2%). On the basis of the soil thin-layer chromatography
    experiments, diazinon was found to be slightly mobile in 80% and
    immobile in 20% of the soils studied. In the soil column experiment,
    the pesticide was quite mobile under saturated flow in soils of light
    texture containing little organic matter. Under non-saturated flow
    conditions, which are more similar to natural conditions, diazinon
    should not be easily leached from the studied soils to groundwater.

    4.2  Degradation

    4.2.1  Degradation in soil

         Seyfried (1994) studied the degradation of diazinon in an
    agricultural soil (silt loam, USDA) under various experimental
    conditions. At 20°C and a soil moisture of 60% of the field capacity,
    the DT50 was 5 days and DT90 22 days. The main metabolite,
    2-isopropyl-4-methyl-6-hydroxy pyrimidine, occurred transiently and
    degraded with a DT50 of 20 days. Mineralization accounted for 86% of
    the applied diazinon within the experimental period of 120 days.
    Whereas the application rate did not influence the degradation rate,
    there was a dependence on temperature (DT50 of 12 days at 10°C) and
    soil moisture (DT50 of 8 days at 30% field capacity). Under sterile
    conditions, the DT50 was increased to 118 days at 20°C and 60% field
    capacity. This suggests that the main route of soil degradation is
    microbial.

         Getzin (1968) studied persistence of diazinon in soils and
    measured loss in autoclaved and non-autoclaved soil at several
    temperatures, moisture contents and pH levels under controlled
    laboratory conditions. Microorganisms and non-biological factors
    affected the persistence of diazinon in Sultan silt loam. Diazinon was
    primarily degraded through non-biological pathways. Although diazinon
    was not metabolized to any great extent by microorganisms in Sultan
    silt loam, it is known that soil microflora are capable of degrading
    the insecticide. Gunner et al. (1966) isolated a bacterium from soil
    that utilized diazinon as a source of sulfur, phosphorus, carbon and
    nitrogen, but the importance of this microorganism as a contributor to
    the metabolism of the insecticide in soil was not determined.

         Miles et al. (1978) demonstrated that diazinon can accumulate and
    persist in organic soils for more than a year. It was also shown that
    diazinon can move from its soil-bound form into the aqueous
    environment either via leaching or by direct soil erosion (Miles &
    Harris, 1978a). Morganian & Wall (1972) demonstrated that diazinon
    treatment of a marine salt marsh led to a build-up of diazinon in salt
    marsh sod and mud.

         At pH 6.8, the time required for 50% loss of diazinon is 6 weeks
    in autoclaved soil and 18 weeks in buffered water. Mortland & Raman
    (1967) demonstrated the catalytic hydrolysis of diazinon in CuCl2
    solutions and Cu-montmorillonite suspensions. Catalytic reactions of
    this nature may occur in soil, but attempts to demonstrate this
    phenomenon in Sultan silt loam have so far failed. Moisture variations
    from 50 to 100% of the moisture equivalent did not appreciably alter
    the degradation rates of diazinon. Variations in soil temperature
    between 10 and 30°C resulted in a 4- to 10-fold difference in the time
    required for 50% loss of the insecticides in soil. The non-biological
    degradation of diazinon increased with increased acidity.

         Schoen & Winterlin (1987) have studied the factors affecting the
    rate of diazinon degradation in soil. These are pH, soil type, organic
    amendments, soil moisture and pesticide concentration. Of the soil
    factors investigated, the conditions for diazinon degradation in
    pesticide mixtures were optimum when the pesticides were present at
    low concentrations in moist soil, amended with peat and acidified to
    pH 4. Degradation was least at high pesticide concentration in neutral
    or alkaline mineral soil.

         Utilization of diazinon by an  Arthrobacter species and a
     Streptomyces species has been shown to alter the microbial
    population by stimulating a selective enrichment of these species.
    The  Arthrobacter species previously reported to attack the side
    chain of the molecule was unable to metabolize completely the ring
    portion of the molecule. Similar results demonstrated that the
     Streptomyces species, too, could not by itself convert pyrimidinyl
    carbon to carbon dioxide. When, however, both the  Arthrobacter and
     Streptomyces organisms were incubated together, 15-20% of the 14C
    appeared as labelled BaCO3 after 18 h, suggesting a synergistic
    relationship between these two organisms in attacking the pyrimidinyl
    portion of diazinon (Gunner & Zuckerman, 1968).

         Barik & Munnecke (1982) demonstrated that a bacterial enzyme can
    hydrolyse diazinon in soil. In their research, an enzyme was obtained
    from a  Pseudomonas sp. that could hydrolyse diazinon and several
    other methoxy- or ethoxy-substituted organophosphates. In this
    experiment, diazinon, either in 25% EC formulations or as a technical
    grade chemical, was enzymatically hydrolysed in an agricultural sandy
    soil when present at concentrations up to 1%. The degradation rate was

    approximately proportional to enzyme concentration up to 12 units per
    20 g soil. This indicates that the initial rate of diazinon
    degradation is directly dependent on enzyme activities, and not on
    chemical or physical parameters of the soil-pesticide interactions.
    Although the enzyme was examined only in one soil, it is expected that
    it could also operate on cement or asphalt type surfaces, as well as
    on synthetic polymers such as carpet.

         Al-Attar & Knowles (1982) studied the uptake, metabolism and
    elimination of diazinon in  Panagrellus redivivus, a free-living soil
    nematode, and  Bursaphelenchus xylophilus, a plant parasitic
    nematode. Nematodes were exposed to a solution of diazinon labelled
    with radiocarbon. Both nematode species metabolized diazinon, although
     P. redivivus was more active. Metabolites from  B. xylophilus 
    included  O, O-diethyl  O-(2-isopropyl-4-methyl-6-pyrimidinyl)
    phosphate or diazoxon and pyrimidinol. Radioactivity accumulated to a
    greater extent in  B. xylophilus than in  P. redivivus. Elimination
    of radiocarbon was more rapid with  P. redivivus than with
     B. xylophilus, and this resulted in the presence of high levels
    of the polar pyrimidinol metabolite in the incubation medium of
     P. redivivus.

    4.2.2  Degradation in water

         Keller (1983) investigated the degradation of diazinon in samples
    of pond and river water, each containing 1% of sediment. Diazinon was
    degraded with a DT50 of 7 to 10 days in the pond system and 8 to 15
    days in the river water. Mineralization accounted for >60% of the
    applied material within 7 weeks in both systems.

         In a mesocosm study conducted with 17 treated and 4 untreated
    ponds (0.05 hectare each), diazinon degraded rapidly. The
    disappearance half-lives averaged 5.2 to 12.2 days (Giddings, 1992).

         Kanazawa (1975) found diazinon to be fairly persistent in tap
    water in a glass aquarium, degrading to 27% in 30 days.

         Ferrando et al. (1992) studied the persistence of diazinon in
    natural water from Albufera Lake and in experimental water from their
    laboratory. Degradation was faster in lake water, the half-lives being
    70 and 79 h for lake and laboratory water, respectively. The
    degradation process in both media was comparable until 96 h. The
    authors found 43.5 and 49.4% of the applied diazinon in natural and
    experimental water, respectively, at 96 h.

    4.2.3  Bioconcentration

    4.2.3.1  Fish and aquatic invertebrates

         The bioconcentration factors (BCF) of diazinon over a 7-day
    period were as follows: topmouth gudgeon 152; carp 65; guppy 18;
    crayfish 4.9; red snail 17; pond snail 5.9 (Kanazawa, 1978).

         Seguchi & Asaka (1981) reported the intake and excretion of
    diazinon and its metabolites in freshwater fish, and the relationship
    between the BCF of diazinon and fat content of fish. During exposure
    to continuous-flow water containing 0.02 mg diazinon/litre the
    concentration of diazinon in fish rapidly increased, reaching a
    maximum after 3 days. Thereafter, the diazinon concentration slightly
    decreased and remained at equilibrium. The BCFs for carp, rainbow
    trout, leech and shrimp at equilibrium were 120, 63, 26 and 3,
    respectively. As for the metabolites, pyrimidine analogue was found in
    all fish species, but diazinon and related compounds were found only
    in carp and rainbow trout. The concentration of the metabolites
    reached a maximum after 3-7 days exposure to diazinon. Diazinon was
    metabolized to diazoxon in the channel catfish liver microsomal enzyme
    system, but it was not found in any other fish species. When the fish
    were transferred to clean water, diazinon and its metabolites were
    rapidly lost from the fish. Seven days after being transferred to
    clean water, the diazinon concentration decreased to 0.3-8.0% of the
    equilibrium concentration, and the metabolites decreased below the
    detection limit.

         Similar results have been observed for topmouth gudgeon by
    Kanazawa (1975, 1978). A linear relationship was observed between the
    bioconcentration ratio and fat content in fish. Seguchi & Asaka (1981)
    identified six metabolites of diazinon, and Fujii & Asaka (1982)
    identified another three: hydroxydiazinon, hydroxymethyl diazinon and
    isopropenyl diazoxon.

         The toxicity, accumulation and elimination of diazinon were
    investigated in the European eel  (Anguilla anguilla). Fish exposed
    to sublethal concentration (0.042 mg/litre) accumulated diazinon in
    the liver and muscle tissues. The BCFs for diazinon were 1859 in liver
    and 775 in muscle over the 96-h exposure period. When removed from
    diazinon-containing water, the contaminated fish rapidly eliminated
    diazinon. The excretion rate constants were 0.108 per h for liver and
    0.016 per h for muscle. Diazinon half-lives were 16.6 and 33.2 h for
    liver and muscle, respectively (Sancho et al., 1992).

         The freshwater fish Motsugo  (Pseudorasbora parva) was reared in
    an aquarium tank containing about 1 mg diazinon/litre for 30 days. The
    persistence of the insecticide in water and the uptake and excretion
    of the insecticide by fish were monitored. Diazinon degraded by 72% in

    30 days. The concentration of diazinon in fish reached a maximum level
    of 211 mg/kg after 3 days. Afterwards, the concentration of the
    insecticide decreased gradually due to metabolism and excretion
    (Kanazawa, 1975).

         Bioconcentration and excretion of diazinon were studied in the
    carp ( Cyprinus carpio L.). The average BCF values for diazinon were
    20.9 in muscle, 60.0 in liver, 111.1 in kidney and 32.2 in gall
    bladder over a 168-h exposure period. The excretion rate constants of
    diazinon (ng/g per h) were 0.002-0.024 for muscle, 0.001-0.020 for
    liver, 0.0004-0.004 for kidney and 0.002-0.023 for gall bladder,
    respectively (Tsuda et al., 1990).

    5.  ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

    5.1  Environmental levels

    5.1.1  Air

         The amount of insecticide present in the air of commercial pest
    control buildings, service vehicles and food preparation-serving areas
    following routine commercial insecticide application has been
    measured. Diazinon was measured in the ambient air of storage and
    office rooms in six North Carolina (USA) firms in a 4-h period. In the
    storage rooms the mean value was 284 (85-837) ng/m3 air and in the
    offices 163 (31-572) ng/m3 air. Diazinon was also detected in the
    ambient air of vehicles used in commercial pest control activities.
    Mean diazinon concentrations (ng/m3 air) in 2-h of sampling from six
    vehicles were 88 (7-239) in sedans and 171 (11-543) in vans, the mean
    value being 130 (7-543). The highest level of diazinon detected in the
    ambient air of offices of pest control building was far below the
    allowable limits (TLV : 100 µg/m3) (Wright & Leidy, 1980).

         Wright et al. (1982) studied the amount of diazinon in cabs of
    stationary pick-up trucks used by the pest control service. Additional
    air samples, taken while the same pick-up truck was moving, provided
    data for comparison of insecticide levels in individual pick-up trucks
    when moving and stationary. Diazinon was present in significantly
    greater concentrations than chlorpyrifos. This may be attributable to
    the facts that the service technicians kept diazinon in sprayers
    during the sampling periods and that they used it in servicing
    accounts during the sampling day. It could therefore have contaminated
    their clothing and skin and passed into the air when they were in the
    pick-ups. The maximum diazinon detected was 5.15 µg/m3 for a 2-h
    period or 20.6 µg/m3 for an 8-h period, which is about 1/5 of the
    allowable limit. However, the amount of airborne diazinon to which a
    technician was actually exposed during a working day was even less
    than 20.6 µg/m3, since the maximum time any technician spent in a
    pick-up was 3.8 h.

         Wachs et al. (1983) reported the concentration of diazinon in
    the air of a retail garden store that sold the insecticide. The
    concentration found in the air based on the 14-h period pumping
    through the polyurethane filters was 3.4 µg/m3. All of the diazinon
    was found in the polyurethane plug closest to the air inlet. Diazinon
    was not found in the second plug or unused plugs which were similarly
    Soxhlet-extracted and analysed. It was concluded that the
    concentration of diazinon in air depended on a number of factors,
    including the type of formulation, air temperature, type and condition
    of containers, prior spills and types of floor covering. The
    concentration of diazinon vapour found in this study would not appear
    to constitute a hazard to store personnel or customers.

         Airborne concentrations of diazinon were measured in rooms for
    21 days after crack and crevice application. Residue levels were
    greatest in treated rooms (38 µg/m3) followed by adjacent (1 µg/m3)
    and upper and lower floor rooms (about 0.4 µg/m3). Low levels of
    diazinon were detected in all rooms 21 days after application. Small
    amounts of diazinon (corrected to an 8-min application period) were
    detected on respirator pads (2.6 µg) and waist pads (2.3 µg) worn by
    the applicator (Leidy et al., 1982).

         Airborne and surface concentrations of diazinon were measured at
    intervals up to 10 days after broadcast spray application onto the
    floors of seven offices. Diazinon concentrations peaked 4 h after
    application at 163 and 27 µg/m3 of air sampled, respectively.
    Airborne concentrations of diazinon indicated that building occupants
    should not enter unventilated rooms for at least 2 days after
    spraying. Residues on aluminium plates and furniture were examined at
    intervals of up to 48 h after spraying, and in many cases the surface
    concentrations were higher at 24 or 48 h after spraying than at
    one hour. The peak residue concentration of diazinon was 38 ng/cm2 of
    surface area sampled at 48 h (Currie et al., 1990).

    5.1.2  Water

         Insecticide residues on suspended and bottom sediments of streams
    of Ontario, Canada, have been studied in a tobacco-growing, vegetable
    muck area. Bed load samples contained three to six times higher
    concentrations of insecticides than bottom material (Miles, 1976).

         From 1985 to 1987, a monitoring survey was conducted to determine
    the levels of selected pesticides in farm ditches located in the lower
    mainland of British Columbia, Canada. Diazinon was not detected in
    ditch water (detection limit = 1 µg/litre). In ditch sediments,
    diazinon was sporadically found at concentrations up to 4 µg/kg
    (detection limit = 1 µg/kg) (Wan, 1989).

         During the first half of 1984, diazinon was not detected in raw
    or treated water samples from the Lakeview and Lorne Park Water
    Treatment Plants in Toronto, Ontario (detection limit = 10 ng/litre)
    (MacLaren Plansearch Inc. & FDC Consultants Inc., 1985).

         Detectable concentrations of diazinon occurred in less than 0.1%
    of water samples collected from 11 Southern Ontario agricultural
    watersheds during 1975-1977. The concentration was mainly below
    0.01 µg/litre, the maximum value being 0.15 µg/litre (Frank et al.,
    1982).

         Sampling performed in 1992 by the United Kingdom National Rivers
    Authority showed diazinon at >0.1 µg/litre in 74 out of 2300 fresh
    water samples and at > 0.15 µg/litre in 1 out of 12 seawater samples.

    5.1.3  Soil

         In 1971 hay and soil samples were collected in 9 states in the
    USA to determine the incidence and levels of pesticide residues in
    hayfields. Residues were detected in 8% of the soil samples and 29% of
    the hay samples. Diazinon was detected in four hay samples (Gowen et
    al., 1976).

         In 1976, soil samples from 28 farms located in six vegetable
    growing areas of southwestern Ontario, Canada, contained diazinon
    residues from trace amounts (< 0.02 mg/kg) to 0.29 mg/kg (Miles &
    Harris, 1978b).

    5.1.4  Fruit, vegetables and food

         Results of supervised trials and monitoring of diazinon residues
    in or on food and feed commodities have been comprehensively reviewed
    and summarized (FAO/WHO, 1994a). The following examples indicate that
    diazinon residues are generally low.

         Ward et al. (1972) performed a study to determine the rate of
    decline of diazinon residue on wheat in Texas, USA. There was a steady
    decline in the amount of diazinon remaining on foliage samples after
    application. Only 0.16 mg/kg and 0.31 mg/kg remained 28 days after
    treatment with 0.28 and 0.56 kg a.i./ha, respectively. Harvest samples
    showed that less than 0.05 mg/kg remained in either the foliage or
    grain.

         Between 1978 and 1986, 305 samples of apples were analysed for
    residues of a wide range of pesticides used in their production.
    Residues of diazinon were found occasionally. They were well below the
    maximum residue limit and correlated well with the pattern of use
    (Frank et al., 1989).

         Between 1986 and 1988, 433 composite vegetable samples
    representing 16 commodities, which were treated by various pesticides
    including diazinon, were collected from farm deliveries to the
    marketplace in Ontario, Canada. All samples were analysed for
    insecticides and fungicides. The commodities tested included
    asparagus, beans, carrots, celery, cucumbers, lettuce, onions,
    peppers, potatoes, radishes, rutabagas and tomatoes. In 64% of
    samples, no pesticide residues were identified (the limits of
    detection ranged from 0.005 to 0.05 mg/kg). A further 22% had combined
    insecticide and fungicide residues below 0.1 mg/kg. Only three samples
    (0.7%) had residues that exceeded the Maximum Residue Limit (MRL).
    These involved diazinon on celery. While some commodities had no
    detectable residues, others had measurable residues of up to three
    different pesticides. The highest levels were found on celery, lettuce
    and field tomatoes (Frank et al., 1990).

         Levels of diazinon permitted in the USA on human food range from
    0.1 mg/kg in potatoes to 0.7 mg/kg in most leafy vegetables. During
    the course of pesticide surveillance of vegetables, an unknown
    analytical response in spinach extract was seen, which was
    subsequently identified as diazinon metabolite (2-isopropyl-4-
    methyl-pyrimidin-6-ol). Cairns et al. (1985) described an analytical
    procedure adapted to confirm both diazinon and its metabolite in
    spinach, at very low levels, by methane chemical ionization mass
    spectrometry. The presence of this metabolite at the 1 mg/kg level
    represents an order of magnitude greater than that found for diazinon
    itself.

         In a study of diazinon residues in prepared foods, accidentally
    exposed during and following treatment, the amounts of diazinon
    residues in food left in the room for 30 min after treatment ranged
    from 0.02 to 0.05 mg/kg. No detectable residues of diazinon were found
    in the potatoes or dinners placed in the rooms 4.5 h after treatment
    and removed after 5 h. A person consuming a dinner at the highest
    residue found would have ingested 0.0153 mg of diazinon. For a person
    weighting 70 kg this would amount to 0.218 µg/kg (Jackson & Wright,
    1975).

    5.1.5  Milk

         Insecticides in polyvinyl chloride pellets were included in a
    commercial dairy protein supplement and fed to dairy cows at 1.4, 2.0
    and 2.5 mg of diazinon/kg body mass for 2 weeks. No insecticidal
    residues were found in milk samples collected at 1, 3, 7, 10 or 14
    days. Even 2.5 mg/kg dosage would provide a 5-fold margin of safety
    for PVC formulation-diazinon fed to cattle to control face fly larvae
    in manure (Lloyd & Matthysse, 1971), and diazinon-PVC was found to
    be still a highly effective larvicide if given at the dose of
    0.5 mg insecticide/kg per day (Lloyd & Matthysse, 1966, 1970).

         Derbyshire & Murphy (1962) reported no diazinon residues in milk
    from cows fed 10 mg/kg body weight for 7 days. Robbins et al. (1957)
    found only traces of radioactivity in a cow's milk 6-24 h after a
    single oral dose of 32P-labelled diazinon (20 mg/kg).

    5.1.6  Meat and fat

         Tissue residues were determined and toxicity symptoms were noted
    after lambs were sprinkled and dipped with 0.06% diazinon emulsion or
    sprinkled with 1% diazinon emulsion. The only diazinon residues found
    were 1.45-2.30 mg/kg in fat, 1 day after dipping in 0.06% diazinon,
    with concurrent 44-47% plasma cholinesterase activity depression. Low
    residues were present in blood from these sheep. Most tissues
    contained no detectable diazinon at 15 or 26 days after lambs were
    dipped in 0.06% diazinon, but fat contained up to 0.52 mg/kg at 15
    days and 0.31 mg/kg at 26 days. Sprinkling with 1% diazinon produced

    no residues in most tissues. A maximum of 23 mg/kg was found in fat.
    The only clinical poisoning involved a 3-day-old lamb dipped in 0.12%
    diazinon suspension. Lambs more than 1 week old were not poisoned by
    0.06% diazinon nor were lambs more than 1 month old when treated by
    0.25% diazinon (Matthysse et al., 1968).

         Harrison et al. (1962) found 0.4 mg diazinon/kg in meat of
    unshorn sheep 1 day after dipping in 0.05% diazinon emulsion. This
    decreased to 0.25 mg/kg and 0.16 mg/kg at 4 and 7 days after dipping,
    respectively, and there were negligible amounts 25 days after dipping.

         Claborn et al. (1963) found 0.69 mg/kg in beef fat 1 day after
    the last of 11 weekly spraying with 0.05% diazinon suspension. The
    authors reported a rapid loss of diazinon from beef fat and the amount
    of residues were negligible 14 days after spraying.

         Samples obtained from retail outlets in the United Kingdom during
    1984-1986 generally showed zero or low levels of diazinon residues.
    Diazinon was not detected in samples of beef, imported lamb, pork or
    veal, but low levels were found in United Kingdom lamb in 1984/1985
    (up to 1.7 mg/kg) and 1985/1986 (up to 0.1 mg/kg). Samples of fat
    taken in 1986 were analysed and, out of 274, 19% contained diazinon.
    In 1987, however, out of 280 samples analysed, 7% contained diazinon
    and in four of them residues exceeded the Codex MRL of 0.7 mg/kg fat.
    Diazinon was not detected in butter, milk or cheese (MAFF, 1989).

         Various pesticides and pollutants were examined in poultry meat
    from Israel. The levels of these, which included diazinon in broilers,
    turkeys and geese, were said to be extremely low and below the USA
    tolerance levels (Kathein, 1986)

    5.2  General population exposure

         The primary exposure to the general population will be through
    intermittent dietary exposure and inhalation exposure. Exposure via
    water is negligible. Total-diet studies commenced in the United
    Kingdom in 1966. In the second survey (1970-1971) and in the latest
    survey (1985-1988), diazinon residues were not detected (Egan &
    Weston, 1977; MAFF, 1982, 1986, 1989). Findings similar to those in
    the United Kingdom were also made in the USA. Toddler total diets have
    also been the subject of investigation in the USA. Diets collected in
    ten American cities between 1978 and 1979 were examined. The
    components were drinking-water, whole milk, other dairy products and
    dairy substitutes, meat/fish/poultry, grain cereals, potatoes,
    vegetables, fruit juices, oils and fats, sugars and beverages
    (Gartrell et al., 1985a). A similar exercise in the years 1980-1982
    was conducted in 13 American cities. The results were similar to those
    obtained in 1978-1979, with intake of diazinon being low (Gartrell et
    al., 1985a,b).

         A total-diet study in New Zealand was performed at 3-monthly
    intervals in the period 1974-1975. Of 116 samples analysed, 82 (71%)
    had no detectable residues of diazinon. Intakes were well below the
    Codex MRLs (Dick et al., 1978).

         The overwhelming evidence from residue and total-diet studies
    suggests that residues of diazinon are generally within the acceptable
    levels set by the Codex Alimentarius Commission. The results suggest
    that the compounds are rapidly broken down, whether on plants or in
    animals, further reducing the risks to humans (IPCS, 1986).

         During a 5-year study period (1981-1986), the US Food and Drug
    Administration analysed nearly 20 000 domestic and imported samples of
    food and feed commodities for pesticide residues. The results showed
    that 29 out of 6391 domestic agricultural commodities and 35 out of
    12 044 imported agricultural commodities had diazinon levels greater
    than 0.05 mg/kg (Hundley et al., 1988).

         Diethyl phosphate (DEP), an organophosphate metabolite, was found
    in the urine of symptomatic residents who resided in a household that
    had been sprayed with diazinon 4.5 months earlier. Pre- and
    post-decontamination data with regard to symptoms and to DEP,
    cholinesterase, and surface and air levels underscore the utility of
    alkyl phosphate metabolites for monitoring exposure. The data also
    emphasize the efficacy of clean-up measures when baseline data are not
    available to determine if "within-normal" cholinesterase levels are,
    in fact, depressed (Richter et al., 1992).

    5.3  Occupational exposure

         An occupational exposure study was conducted for a firm employing
    22 pest control operators (PCOs) exposed to three organophosphorus
    insecticides including diazinon. The 8-h exposure levels were less
    than 131.0 µg/m3. Urine samples (24-h) were analysed for alkyl
    phosphates and showed the presence of metabolites for these three
    insecticides. The effect of this exposure was reflected by a
    statistically significant inhibition of plasma cholinesterase activity
    among the PCOs, but physical examinations detected no apparent toxic
    effects (Hayes et al., 1980).

         A behavioural evaluation of pest control workers with short-term
    (mean 39 days) low-level exposure to diazinon was conducted in 1985
    during the course of a pest control program in California (see section
    8.2.2). The diazinon metabolite diethylthiophosphate (DETP) was
    measured in pre- and post-shift urine samples and the full-shift
    exposure to diazinon was quantified for 19 subjects using personal
    air monitoring and passive badges. The median diazinon exposure was
    2.1 mg/day (Maizlish et al., 1987).

         An investigation was conducted to determine worker exposure to
    airborne pesticides during tree and ornamental shrub applications
    using hand-held equipment during an entire work shift. Employee
    exposure data were collected for 3 consecutive years. The sampling was
    performed during the late spring, summer and early autumn when insect
    and disease activity was most prevalent. Sampling was conducted at 23
    locations. Those applying these chemicals sustained low-level exposure
    to acephate, benomyl, carbaryl, chlorothalonil, diazinon and dicofol.
    As pesticide label instructions for mixing and applying pesticides
    were strictly followed, the tree and ornamental shrub applicators were
    able to keep inhalation exposures below the levels recommended by OSHA
    and NIOSH. Of the 74 exposures monitored, 67% were below the detection
    limit (0.001 mg/m3), while others were 0.001-0.040 mg/m3. This
    observation supports the correctness of not including specific
    respiratory protection measures on pesticide label directions for
    mixing, loading and applying these pesticides (Leonard & Yeary 1990).

         Dermal, respiratory and urine measurements were made on workers
    applying granular diazinon pesticide formulation. In all, 15 workers
    and four control subjects were monitored. The workers applied the
    compound in yards and small pastures using hand equipment comparable
    to that used in a home environment. Respiratory air samples, ethanol
    hand rinse samples, clothing patch samples and urine samples were
    collected. The diazinon exposures were correlated with job category,
    application duration, application equipment and protective clothing.
    The best determinants of diazinon exposure were the job categories and
    the use of the belly grinder type of spreader. The rank of exposure
    magnitude, from highest to lowest, was the crew using the belly
    grinder, the crew not using the belly grinder, the crew chief and the
    supervisor. The mean daily dermal and respiratory diazinon exposures
    for these four job categories ranged from 0.6 to 11 mg, 0.1 to 1.8 mg,
    0.1 to 0.25 mg, and 0.03 to 0.07 mg, respectively. The amount of
    urinary diethylthiophosphate increased during the day for all job
    levels, but showed variable recovery (Weisskop et al., 1988).

    6.  KINETICS AND METABOLISM

    6.1  Absorption, distribution and excretion

    6.1.1  Oral administration

    6.1.1.1  Rats

         Four male and 2 female Wistar rats were treated with single
    oral doses of 0.8 mg [pyrimidine-14C]-diazinon (specific activity
    4.0 µCi/mg). An additional group of 4 males received [ethoxy-14C]-
    diazinon (3.2 µCi/mg) at the same dose level. During the observation
    period of 168 h, both labelled parts of the molecule were excreted
    almost completely, 65.4-80.0% of the administered radioactivity being
    detected in urine, 16.0-23.5% in the faeces and, with the ethyl-label,
    5.6% in the expired air (total recovery 90.2-98.3%). No radioactive
    CO2 was detected with the pyrimidine label. The half-life times of
    excretion were 7 h with the ethyl label and 12 h for both sexes
    treated with the pyrimidine-labelled material. Daily oral
    administration of 0.1 mg [pyramidine-14C]-diazinon to male rats for
    10 consecutive days resulted in no accumulation of the radioactivity
    in any organ investigated (oesophagus, stomach, intestines, liver,
    spleen, pancreas, kidneys, lungs, testes, muscles, fat). Six hours
    after the last administration, the highest residues were detected in
    the muscles (0.77% of the totally applied dose), caecum (0.76%) and
    small intestine (0.65%). The residues were below the detectable limit
    48 h after the cessation of the treatment (Mücke et al., 1970).

         Sprague Dawley rats received [pyrimidine-14C]-diazinon at single
    oral doses of 10 mg/kg (specific activity 30.3 µCi/mg) or 100 mg/kg
    (specific activity 9.7 µCi/mg). A third group was treated with daily
    oral doses of 10 mg/kg technical diazinon (87.7% pure) for 14
    consecutive days, followed by a single treatment at the same dose
    level with the 14C-labelled compound. The disposition of the
    administered 14C was observed for a 7-day period before the animals
    were killed and the tissues removed for analysis. The average recovery
    of the radioactivity was 99.2%. Elimination of diazinon equivalents
    was rapid. In the low-dose group, males and females eliminated 93 and
    86%, respectively, of the administered radioactivity in the urine
    within 24 h. Faecal elimination amounted to 1.6 and 1.1%,
    respectively, in the same time period. In the high-dose group, the
    respective values were slightly lower and indicated that the
    elimination was more rapid in males (90.8% in urine and 2.2% in
    faeces) than in females (58.2% in urine and 0.87% in faeces). The
    pre-conditioning of the rats had no influence on absorption and
    elimination. Seven days after the administration of the [pyrimidine
    14C]-diazinon, the residual radio-activity was generally low. Among
    the tissues examined (heart, lung, spleen, kidney, liver, fat, testes,
    ovaries, uterus, muscle, brain, blood plasma, blood cells, bone), the
    residual radioactivity amounted to approximately 0.01 mg/kg diazinon

    equivalents in the low-dose group; only fat (0.02 mg/kg), blood cells
    (0.05 mg/kg) and bone (<0.017 mg/kg) contained higher amounts of
    radioactivity. In the high-dose group, the residual radioactivity was
    8-10 times higher. Pretreatment with technical diazinon for 14 days
    led to residues similar to those observed in the low-dose group
    (Craine 1989a,b).

    6.1.1.2  Guinea-pigs

         Male guinea-pigs treated orally with 45 mg/kg [32P]-diazinon
    (specific activity 117-197 cpm/mg) in peanut oil, the tissue
    distribution was determined at 2, 4, 8 and 16 h after treatment and
    the excretion of 32P was investigated over an 8-day period. Following
    oral administration, the compound was rapidly absorbed as shown by a
    sharp decrease of activity in the stomach and low levels found in the
    small intestine. Within 16 h, 46.6% of the administered radioactivity
    was eliminated in the urine and 0.34% appeared in the faeces. The
    caecum showed a gradual increase of radioactivity, 13-36% of the
    administered dose accumulating in the caecum over 16 h after the
    administration. Irrespective of this accumulation, within 48 h after
    dosing, 80% of the administered radioactivity was eliminated in the
    urine while only 8% was eliminated in the faeces (Kaplanis et al.,
    1962).

    6.1.1.3  Dogs

         Two female Beagle dogs were intravenously dosed with 0.2 mg/kg
    [ethoxy-14C]-diazinon (specific activity 3.4 µCi/mg) in 0.7 ml
    ethanol. Blood samples were drawn at times ranging from 5 min to 7 h
    after the injection. The decline of the radioactivity in the blood
    was biphasic with a slower second phase. The half-life of elimination
    from blood for this second phase was calculated to be 363 min.
    Approximately 58% of the administered radioactivity was recovered in
    the urine within 24 h after the administration. Another two female
    beagle dogs were orally dosed by capsule with 4.0 mg/kg [ethoxy-14C]
    diazinon in ethanol. Approximately 85% of the administered
    radioactivity was recovered within 24 h after oral administration,
    with 53% of it occurring in urine (Iverson et al., 1975).

    6.1.1.4  Goats

         Two lactating goats were orally treated with [pyrimidine-14C]-
    diazinon (specific activity 9.7 µCi/mg) in gelatin capsules for four
    consecutive days at a dose level of 4.5 mg/kg per day, corresponding
    to a dietary exposure of 100 mg/kg of feed. During the observation
    period, in average 64.1% of the administered radioactivity was
    excreted with urine, 10.4% with the faeces and 0.31% with the milk.

    A plateau of radioactivity in the milk was reached after 3 days of
    dosing at a mean level of 0.46 mg/kg diazinon equivalent. At
    sacrifice, radioactivity in the blood accounted for 0.2% and the
    tissues examined accumulated 0.92% of the administered dose. The
    highest residual radioactivity was detected in the kidney (2.0 mg/kg)
    and the liver (1.2 mg/kg). The other tissues examined contained
    0.23-0.3 mg/kg diazinon equivalents (Simoneaux 1988a,b; Pickles &
    Seim, 1988).

    6.1.1.5  Cow

         A lactating Hereford cow (body weight 268 kg) was orally treated
    with a gelatin capsule containing 20 mg/kg 32P-diazinon (specific
    activity 518 cpm/µg). Urine and faeces were collected during 36 h
    after treatment and further samples were investigated until the study
    was terminated after 168 h. In addition, milk and blood samples were
    investigated. Within 36 h, approximately 74% of the administered
    radioactivity was excreted with the urine, 6.5% appeared in the faeces
    and 0.08% was found in the milk. A peak concentration of 2.27 mg/kg
    diazinon equivalents was reached 18 h after the administration
    (Robbins et al., 1957).

    6.1.1.6  Hens

         Four laying Leghorn hens were treated with 2-14C-diazinon
    (specific activity 30.3 µCi/mg) in gelatine capsules for seven
    consecutive days at daily doses of 1.7 mg/kg body weight,
    corresponding to a dietary exposure of 25 mg/kg in feed. Excreta and
    eggs were collected and, approximately 24 h after the final dose, the
    animals were killed and tissue samples of liver, kidney, blood, lean
    meat, skin and attached fat, and peritoneal fat were examined.
    Elimination of most of the administered radioactivity occurred via the
    excreta, with 78.6% of the total dose being excreted during the study
    period. Approximately 0.1% of the radioactivity was found in tissues
    and blood, less than 0.01% appeared in the egg yolks and 0.07% was
    detected in the egg whites. The residual radioactivity in the
    tissues amounted to 0.148 mg/kg diazinon equivalents in the kidney,
    0.137 mg/kg in blood, 0.11 mg/kg in the liver and 0.01-0.025 mg/kg in
    the other tissues examined. The residues in the egg yolks ranged from
    0.006 mg/kg diazinon equivalents to 0.065 mg/kg while those in the egg
    whites ranged from 0.038 mg/kg to 0.066 mg/kg. On a whole egg basis, a
    plateau concentration of 0.047 mg/kg was reached on day 4 of treatment
    (Simoneaux 1988c,d; Burgener & Seim, 1988).

    6.1.2  Dermal application

    6.1.2.1  Rats

         The percutaneous absorption of diazinon was investigated in male
    and female Sprague Dawley rats dermally exposed to 1 mg/kg (specific
    activity 25.2 µCi/mg) and 10 mg/kg (specific activity 2.62 µCi/mg) of
    [pyrimidine-14C-diazinon] dissolved in tetrahydrofuran. The dermal
    absorption, excretion and tissue residues were determined after 0, 2,
    8, 24, 48, 72 and 144 h. At each time point, four rats per sex and
    dose group were used. The total recoveries for the balance data
    averaged 96.3-101.5%. Calculated t50 absorption rates (i.e. the
    amount of time required for 50% of the administered dose to be
    absorbed into or penetrate through the skin) in males and females were
    11.8 and 5.2 h, respectively, at the low-dose level of 1 mg/kg. At
    10 mg/kg the respective t50 absorption rates were 10.2 and 5.3 h,
    respectively, indicating that dermal absorption was more rapid in
    females and was dose-dependent. The urine was the major route of
    excretion in both sexes at both dose levels, 65-78% of the radiolabel
    being excreted within 72 h. Times for 50% excretion in males and
    females dosed at 1 mg/kg were 28.1 and 26.8 h, respectively. In the
    high-dose groups the times for 50% excretion were 24.1 and 20.3 h in
    males and females, respectively. The residual radioactivity in tissues
    reached a maximum at 8 h after the administration in both dose groups
    (plasma, red blood cells, fat, brain, muscle, lung, heart, spleen,
    kidney, liver, stomach, small and large intestines, gonads, skin wash
    and dissolved skin were assayed). In the low-dose group of males after
    8 h, highest values were found in stomach (0.36 mg/kg diazinon
    equivalents), small intestines (0.16 mg/kg), kidney (0.15 mg/kg),
    liver (0.1 mg/kg) and skin (3.9 mg/kg in the skin wash and 0.86 mg/kg
    in the dissolved skin). Reflecting their absorption rate, the females
    of the low-dose group showed slightly higher tissue levels and a lower
    residual radioactivity in the skin wash. After 144 h, residues were
    down to the limit of quantification in most tissues, in both dose
    groups and in both sexes (Ballantine, 1984).

    6.1.2.2  Sheep

         Two sheep were dermally treated with [pyrimidine-14C-diazinon]
    (specific activity: 3.7 µCi/mg) dissolved in acetone for three
    consecutive days. In order to mimic an extreme maximum exposure in a
    dermal treatment of 40 mg/kg, 2270 mg 14C-diazinon was applied daily
    to a shaved area of the back that constituted approximately 10% of the
    animal's surface area. The area of application was left uncovered. Six
    hours after the last administration the animals were killed and heart,
    liver, kidney, back fat and leg muscle were analysed. The tissue
    extractability was greater than 90% for all tissues. The highest
    average residues were detected in kidney (9.4 mg/kg diazinon
    equivalents) and back fat (7.3 mg/kg), while levels in heart, liver
    and leg muscle amounted to 4-4.4 mg/kg (Capps, 1990; Pickles, 1990).

    6.1.2.3  Humans

         The dermal absorption of diazinon in humans is much less than in
    rats. Six volunteers were dermally treated with [pyrimidine-14C]-
    diazinon on the ventral forearm or the abdomen. The test material was
    administered in acetone solution (2 µg/cm2) or dissolved in lanoline
    wool grease (1.47 µg/cm2) over a 10-cm2 area of the skin without
    occlusion. After 24 h, the test substance remaining on the site of
    administration was washed off and the renal elimination followed for
    seven days. Independent of the vehicle and the site of administration,
    only 3-4% of the dose applied was percutaneously absorbed (Wester et
    al., 1993).

    6.1.3  Other routes

    6.1.3.1  Intraperitoneal administration

         The tissue distribution of diazinon and the inhibition of
    cholinesterase (ChE) activities in plasma and erythrocytes were
    investigated using male rats that received a single intraperitoneal
    dose of diazinon (100 mg/kg body weight) in olive oil. The blood
    diazinon level was estimated to reach a maximum at 1-2 h after
    intraperitoneal administration. It was demonstrated that the diazinon
    residue levels were highest in the kidney, when comparing the
    distribution of diazinon among liver, kidney and brain in the animals
    after dosing. Erythrocyte and plasma ChE activities were inhibited
    rapidly, but ChE inhibition was greater in the erythrocytes than in
    plasma (Tomokuni & Hasegawa, 1985).

         The tissue distribution of diazinon and the inhibition of ChE
    activities in plasma, erythrocyte and brain was investigated using
    male rats and mice that received a single intraperitoneal (i.p.) dose
    of diazinon (20 or 100 mg/kg body weight) in olive oil. The blood
    diazinon level was estimated to reach a maximum 1-2 h after the i.p.
    administration. It was demonstrated that the diazinon residue levels
    were highest in the kidney, when comparing the distribution of
    diazinon among liver, kidney and brain in the animals after dosing.
    The ChE inhibition by diazinon exposure was greater in the plasma than
    in the erythrocytes for male mice, while its inhibition was greater in
    the erythrocytes for male rats. Brain ChE activity was also inhibited
    markedly in the mice after dosing (Tomokuni et al., 1985).

    6.1.3.2  Subcutaneous administration

         Male guinea-pigs were subcutaneously treated with 45 mg/kg
    32P-labelled diazinon (specific activity -117-197 cpm/µg) in peanut
    oil. The tissue distribution was determined 2, 4, 8 and 16 h after
    treatment, and excretion of 32P was investigated over an 8-day
    period. Following subcutaneous administration, urinary elimination
    amounted to 20% of the administered dose after 16 h. The levels of

    radioactivity found in the gastrointestinal tract were low apart from
    the caecum, which accumulated up to 5.5% of the administered dose over
    16 h. After 48 h, urinary elimination amounted to about 60%, while
    only trace amounts were eliminated with the faeces (Kaplanis et al.,
    1962).

    6.1.3.3  Intravenous administration

         Four female Rhesus monkeys were dosed intravenously with 2.1 µCi
    (31.8 µg) [pyrimidine-14C]-diazinon dissolved in propylene glycol.
    Within 7 days, average values of 56 and 23% of the dose were
    eliminated in urine and faeces, respectively (Wester et al., 1993).

    6.2  Metabolism

         The metabolic fate of diazinon was studied with different modes
    of administration using unlabelled and radiolabelled diazinon in
    various species including rat, mouse, guinea-pig, dog, sheep, goat,
    cow and chicken. Additional  in vitro experiments were conducted
    using tissue slices or cell fractions. A comparative summary of the
    results available was provided by Hagenbuch & Mücke (1985). In all
    species tested, diazinon was rapidly and almost completely absorbed
    from the gastrointestinal tract. It was also absorbed from the skin.

         The main metabolic pathways of degradation of diazinon are:

    a)   Cleavage of the ester bond of diazinon or diazinoxon leading to
         the hydroxypyrimidine derivatives.

    b)   Transformation of P-S moiety to the P-O derivative, leading to
         the active metabolite, diazoxon.

    c)   Oxidation of isopropyl substituent leading to the corresponding
         tertiary and primary alcohol derivatives.

    d)   Oxidation of the methyl substituent leading to the corresponding
         alcohol.

    e)   Glutathione-mediated cleavage of the ester bond leading to a
         glutathione conjugate.

         The hydrolytic and oxidative cleavage of the phosphorus ester
    bond, leading directly or via diazoxon to the pyrimidinyl derivative,
    play the most prominent role in the metabolism of diazinon.
    Glutathione conjugation appears to be of small importance. Metabolites
    maintaining the phosphorus ester bond are of transient nature and are
    only observed in minor quantities.

         The general metabolic pathways of diazinon in mammals are given
    in Fig. 1.

    FIGURE 1

         The metabolites formed, i.e. diethylphosphoric acid,
    diethylthiophosphoric acid and the derivatives of pyrimidinyl ring,
    are eliminated mainly via the kidneys. Only minimal quantities of the
    metabolites were detected in milk and eggs.

    6.2.1  In vivo metabolic transformations

    6.2.1.1  Mice

         When male ICR mice (number not stated) were treated orally with
    diazinon or [pyrimidine14C] diazinon at 50 or 75 mg/kg body weight,
    one half of the high-dose animals died and the rest showed symptoms
    (sweating, crouching) (Miyazaki et al., 1970; Sekine, 1972). At the
    low dose, no signs of toxicity were observed. Metabolism and excretion
    occurred rapidly, and the metabolites diazoxon,  O, O-diethyl-
     O-[2-(alpha-hydroxyisopropyl)-4-methyl)-6-pyrimidinyl]
    phosphorothioate, and  O, O-diethyl- O-(2-(2-propenyl)-4-methyl-6-
    pyrimidinyl) phosphorothioate were found in the urine 1 h after
    treatment. Most of the metabolites were found in urine 6 h after
    treatment, but metabolism was not identical in the two dose groups. In
    the low-dose group  O, O-diethyl- O-(2-isopropyl-4-hydroxymethyl-6-
    pyrimidinyl) phosphorothioate and  O, O-diethyl- O-(2-isopropyl-4-
    formyl-6-pyrimidinyl) phosphorothioate were found, but this was not
    observed in the high-dose group. In the high-dose, but not the low-
    dose group  O, O-diethyl- O-(2-(a-hydroxyethyl)-4-methyl-6-
    pyrimidinyl) phosphorothioate was found.

         The metabolism of [pyrimidine-14C]-diazinon and [ethoxy-14C]-
    diazinon was investigated by Mücke et al. (1970). Four metabolite
    fractions were found in urine and faeces, three metabolites
    representing approximately 70% of the total radioactivity applied.
    Hydrolysis of the ester bond yielded 2-isopropyl-4-methyl-6-
    hydroxypyrimidine (22.5% of the applied radioactivity in urine);
    oxidation at the primary carbon atom produced 9% of the applied
    radioactivity in urine, while oxidation at the tertiary carbon atom of
    the isopropyl side chain produced 22%. In addition, trace amounts of
    unchanged diazinon were detected in faeces. No cleavage of the
    pyrimidine ring with subsequent oxidation of the fragments to CO2
    took place (Mücke et al., 1970).

    6.2.1.2  Rats

         A study by Capps (1989) investigated the diazinon metabolites in
    male and female rats orally treated with single doses of 10 and
    100 mg/kg [pyrimidine 14C]-diazinon and in rats preconditioned with
    14 daily treatments at 10 mg/kg before the final administration of
    radiolabelled compound. The metabolite pattern was similar in the
    urine and faeces of the rats from all dose groups and from both sexes.

    The major urinary metabolites were identified as 2-isopropyl-6-
    methyl-4(1 H)- pyrimidinone (average 38.2% of the totally applied
    dose), 2-(alpha-hydroxyisopropyl)-6-methyl-4(1 H)-pyrimidinone
    (17.3%) and 2-(beta-hydroxyisopropyl-6-methyl-4(1 H)-pyrimidinone
    (9.7%). Six unknown aqueous components accounted for an average of
    14.9% of the administered dose, and trace amounts of unchanged
    diazinon (0.11%), diazoxon (0.14%) and the hydroxy-isopropyl
    derivative of diazinon (0.12%) were also detected. The identity of the
    metabolites was confirmed by gas chromatography and mass spectrometry
    (GC/MS) with synthetic standards.

    6.2.1.3  Dogs

         The urinary metabolites of Beagle dogs were characterized after
    oral administration of 4.0 mg/kg body weight 14C-ring-labelled
    diazinon. The metabolite 2-isopropyl-4-methyl-6-hydroxypyrimidine
    accounted for 10% of the applied radioactivity in the urine and the
    tertiary hydroxy-isopropyl derivative of diazinon represented 23%
    (Iverson et al., 1975).

    6.2.1.4  Sheep

         When two sheep were dermally treated with [pyramidine-14C]-
    diazinon, radiolabelled residues were detected in all tissues examined
    (heart, liver, kidney, back fat and leg muscle). Unmetabolized
    diazinon was the only significant residue in fat, and was a major
    residue in heart and leg muscle. The major metabolites in urine and
    all tissues except fat were 2-isopropyl-6-methyl-4(1 H)-pyrimidinone
    (urine, 10% of the administered radioactivity; liver, 18%; kidney,
    23%) and 2-(alpha- hydroxyisopropyl)-6-methyl-4(1 H)-pyrimidinone
    (urine, 22.7%; liver, 10%; kidney, 28%), which were also present in
    the form of glucuronide conjugates. The identity of the metabolites
    was confirmed by GC/MS with synthetic standards. In addition, several
    unidentified polar (urine, 18.6%) and minor amounts of non-polar
    (urine, 4.0%) metabolites were detected (Capps, 1990).

    6.2.1.5  Goats

         Two lactating goats were orally treated with [pyrimidine-14C]-
    diazinon in gelatin capsules for four consecutive days. Similarly to
    sheep, in urine and faeces the metabolites 2-isopropyl-6-methyl-
    4(1 H)-pyrimidinone (urine, 4.5% of the totally administered radio-
    activity; faeces, 2.6%) and 2-(alpha-hydroxyisopropyl)-6-methyl-
    4(1 H)-pyrimidinone (urine, 12.5%; faeces, 1.7%) were identified.
    Approximately 48.6% of the urinary radioactivity consisted of unknown
    water-soluble compounds. Characterization of selected tissues showed
    the presence of mainly the above-mentioned metabolites. Unchanged
    diazinon, its hydroxy-isopropyl derivative and diazoxon accounted for
    less than 10% of the radioactivity detected in these tissues.
    Metabolites in fat consisted primarily of unchanged diazinon (66%),
    its hydroxy-isopropyl derivative (12.5%) and diazoxon (3%). The major

    metabolites in the milk were 2-isopropyl-6-methyl-4(1 H)-
    pyrimidinone (39.3% of the residual radioactivity) and
    2-(alpha-hydroxyisopropyl)-6-methyl-4(1 H)-pirimidinone (37.3%).
    Substantial portions of the polar metabolites in urine, faeces and
    tissues were glucuronide conjugates. The identity of the metabolites
    was confirmed by GC/MS with synthetic standards (Simoneaux,
    1988a,b,e).

    6.2.1.6  Hens

         Four laying Leghorn hens were treated with [pyrimidine-14C]-
    diazinon in gelatin capsules for seven consecutive days at daily doses
    of 2.75 mg/kg day. The main metabolites detected in the excreta were
    unchanged diazinon (14.9% of the extractable radio-activity),
    2-isopropyl-6-methyl-4(1 H)-pyrimidinone (5.9%), 2-(alpha-hydroxy-
    isopropyl)-6-methyl-4(1 H)-pyrimidinone (10.8%) and 2-(beta-
    hydroxyisopropyl)-6-methyl-4(1 H)-pyrimidinone (7.2%). Approximately
    25% of the radioactivity in the excreta consisted of unknown
    water-soluble compounds. The residues in tissues primarily consisted
    of 2-isopropyl-6-methyl-4(1 H)-pyrimidinone (0.6-2.6% of the residual
    radioactivity), 2-(alpha-hydroxyisopropyl)-6-methyl-4(1 H)-
    pyrimidinone (3.1-6.5%) and 2-(beta-hydroxyisopropyl)-6-methyl-
    4(1 H)- pyrimidinone (2.0-5.7%). Unchanged diazinon was detected
    primarily in the peritoneal fat (2% of residues). In the eggs,
    primarily 2-isopropyl-6-methyl-4(1 H)-pyrimidinone (yolk, 11.1% of
    the residual radioactivity; white, 9.4%), 2-(alpha-hydroxyisopropyl)-
    6-methyl-4(1 H)-pyrimidinone (yolk, 18.6%; white, 33.3%) and
    2-(beta-hydroxyisopropyl)-6-methyl-4(1 H)-pyrimidinone (yolk, 7.0%;
    white, 35.3%) were detected. As in goats, a substantial portion of the
    polar metabolites in tissues, eggs and excreta were glucuronide
    conjugates. The identity of the metabolites was confirmed by GC/MS
    with synthetic standards (Simoneaux, 1988c,e; Simoneaux, 1989).

         More information on kinetics and metabolism in other species is
    given in chapter 9.

    6.2.2  In vitro metabolic transformations

         The metabolism of [ethoxy-14C]-diazinon and diazoxon was studied
     in vitro using rat liver cell fractions. It was shown that the
    degradation by diazinon is catalysed by a microsomal enzyme that
    requires NADPH and oxygen, and is inhibited by carbon monoxide. It is
    presumably the cytochrome P-450 oxidase system. Diazoxon was shown to
    be degraded by enzymes located in the nuclear, mitochondrial,
    microsomal and soluble fractions of the liver. The microsomal enzymes
    were the most active and were not dependent on NADPH. Reduced
    gluthation had little effect. With diazinon, products of the reactions
    were diethylphosphorothioic acid and diethylphosphoric acid. Diazoxon
    was degraded to diethylphosphoric acid (Yang et al., 1969, 1971;

    Nakatsugawa et al., 1969). These results were confirmed by independent
    experiments (Dahm, 1970). The oxidation of diazinon was investigated
    by using microsomal preparations from rat liver. The major metabolic
    products of diazinon were hydroxydiazinon, diazoxon and
    hydroxydiazoxon, which are biologically active, and additional
    inactive products such as diethylphosphorothioic acid,
    diethylphosophoric acid and derivatives of the pyrimidyl moiety. It
    was demonstrated that desulfuration, hydroxylation of the ring alkyl
    side-chain and cleavage of the aryl phosphate bond may occur,
    depending on the presence of NADPH or NADH. EDTA stimulated the
    overall metabolism of diazinon (Shishido et al., 1972a).

         The enzymatic hydrolysis of diazoxon was investigated using rat
    tissue homogenates. The hydrolytic activity of the tissues decreased
    in the order liver>blood>lung>heart>kidney>brain. In the liver,
    the hydrolytic activity was localized in microsomal preparations.
    Diethyl phosphoric acid and 2-isopropyl-4-methyl-6-hydroxypyrimidine
    were identified as the products. The reactions were inhibited by EDTA,
    heavy and rare earth metal ions, and sulfhydryl reagents (L-cysteine,
    2-mercaptoethanol, thioglycolic acid), while calcium ions activated
    the hydrolysis (Shishido & Fukami, 1972).

         Liver homogenates were prepared from male mice (North Carolina
    Department of Health strain) and incubated for 1 h with either
    14C-diazinon or 14C-diazoxon. Inhibition of metabolism was
    studied by co-incubation with piperonyl butoxide, NIA 16824 or
    1-(2-isopropylphenyl) imidazole. Diazoxon formation from diazinon
    (thiophosphate to phosphate conversion) was inhibited by 45 to 60% by
    the inhibitors studied. All the inhibitors also reduced oxidative
    dearylation of diazinon to diethyl phosphoric and diethyl
    phosphorothioic acids (Smith et al., 1974).

         Conjugation with glutathione forms the third enzymatic mechanism
    of the diazinon metabolism in rat tissue preparations (liver, heart,
    brain, lung, kidney and blood were investigated). The highest activity
    (14-89 times as high as in other tissues) for this reaction was
    localized in the cytoplasmatic fractions of the liver. The reaction
    products were identified as diethyl phosphorothioic acid and
    S-(2-isopropyl-4-methyl-6-hydroxypyrimidinyl) glutathione, which were
    formed by conjugation and simultaneous cleavage of the phosphate ester
    bond. The enzymatic activity was increased by the addition of
    glutathione-SH, and was inhibited by various sulfhydryl reagents,
    oxidized glutathione and some chelating agents ( o-phenanthroline,
    8-hydroxyquinoline) (Shishido et al., 1972b).

    6.3  Metabolic aspects of diazinon toxicity

         Diazinon was incubated with liver microsomes and liver slices
    from sheep, cow, pig, guinea-pig, rat, turkey, chicken and ducks.
    Hydroxydiazinon, isohydroxydiazinon, dehydrodiazinon, their oxons

    and diazoxon were identified and determined quantitatively or
    semi-quantitatively. It was shown that yields and rates of production
    of the metabolites varied greatly between the species. The production
    of the oxon was not generally correlated with susceptibility to
    diazinon poisoning, although it was lowest in the least susceptible
    animal, the sheep. The highly susceptible avian species (acute oral
    LD50 of around 2-15 mg/kg) do not produce higher rates of oxons than
    rat or pig (acute oral LD50 around 300-600 mg/kg). However, the
    mammalian blood hydrolyses diazoxon rapidly, whereas the avian species
    have virtually no hydrolytic activity. It was concluded that
    extrahepatic metabolism of diazinon, in particular the hydrolysis of
    diazoxon in the blood, appears to be the main factor affecting
    susceptibility to diazinon poisoning. In mammals the extrahepatic
    metabolism of diazinon is more important toxicologically than the
    metabolism in the liver, while the liver is probably the most
    important site of metabolism in avian species (Machin et al., 1975).

         Recently, the hydrolytic metabolism of diazinon by plasma was
    investigated in 92 individuals of Hispanic origin (Davies et al.,
    1996). Diazoxon is hydrolysed by the enzyme paraoxonase (PON1),
    leading to the formation of 2-isopropyl-4-methyl-6-hydroxypyrimidine
    and diethylphosphate. An important observation of this study was that
    the effect of the PON1 polymorphism for diazoxon hydrolysis relative
    to paraoxon hydrolysis was reversed. Thus, RR individuals (Arg192
    homozygotes) who displayed high paraoxonase activity had lower
    diazonoxonase activity (mean = 7948 U/litre) than QQ homozygotes
    (12 318 U/litre).

    7.  EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS

    7.1  Single exposure

    7.1.1  Oral

         Improvements since 1979 in the manufacturing of diazinon have
    significantly reduced the content of highly toxic by-products, in
    particular tetraethyl-pyrophosphate (TEPP). As a result of these
    stepwise improvements, the acute oral LD50 of technical grade
    diazinon increased to values around 1000 mg/kg (Piccirillo, 1978;
    Bathe & Gfeller, 1980; Schoch & Gfeller, 1985; Kuhn, 1989a). The most
    recent study resulted in an oral LD50 in rats of 1250 mg/kg. The LD50
    values for different species are summarized in Table 2.

         Signs of poisoning after a single dose of diazinon are typical of
    organophosphate intoxication and include decrease of spontaneous
    activity, sedation, dyspnoea, ataxia, tremors, muscle spasms,
    convulsions, lacrimation and diarrhoea. The signs were found to be
    reversible in surviving animals.

         Diazinon (88% purity) was administered by gavage to 15 rats per
    sex and dose at single doses of 0, 2.5, 150, 300 and 600 mg/kg
    (Potrepka, 1994). Three, 9 or 24 h after dosing, five animals of each
    group were bled for determination of serum and red blood cell
    cholinesterase activity and then killed for determination of CNS
    cholinesterase activity. There was no mortality. Signs of cholinergic
    poisoning, e.g., salivation, diarrhoea and muscle fasciculations, were
    observed in animals of both sexes dosed at 300 and 600 mg/kg. Clinical
    signs first appeared 3 h after treatment. Maximum observable toxicity
    was noted 9 h after treatment in males and 24 h after treatment in
    females. Serum cholinesterase activity was significantly decreased at
    all time points in all groups treated with 2.5 mg/kg or more. Maximum
    inhibition was observed 9 h after dosing, and values remained
    depressed at 24 h after dosing. Red blood cell cholinesterase activity
    was significantly inhibited at all time intervals in animals of both
    sexes treated with >150 mg/kg. Again, maximum inhibition was
    observed 9 h after dosing, and activity remained depressed at 24 h
    after dosing. In addition, a significant inhibition of red blood cell
    cholinesterase activity was noted in females dosed with 2.5 mg/kg
    diazinon 9 h after dosing. Cerebellum, cerebral cortex, striatum,
    hippocampus and thoracic spinal cord cholinesterase activities were
    decreased in female rats dosed with >150 mg/kg at all three time
    points. Cerebellum, striatum and hippocampus cholinesterase activities
    were decreased in male rats dosed with >150 mg/kg at all three time
    intervals, whereas cerebral cortex and thoracic spinal cord
    cholinesterase activities were decreased in male rats dosed with
    >150 mg/kg at 9 and 24 h after dosing. The NOAEL for inhibition of
    brain cholinesterase activity was 2.5 mg/kg for both sexes (Potrepka,
    1994).

        Table 2.  Acute toxicity of diazinona
                                                                                               

    Species        Sex        Route of administration    LD50 (mg/kg)     Reference
                                                                                               

    Rat            male             oral                 235              Gasser (1953)
    Rat            male             oral                 435              Shaffer & West (1960)
    Rat            male             oral                 250              Gaines (1969)
    Rat            female           oral                 285              Gaines (1969)
    Rat            both             oral                 300              Piccirillo (1978)
    Rat            both             oral                 422              Bathe & Gfeller (1980)
    Rat            both             oral                 1012             Schoch & Gfeller (1985)
    Rat            both             oral                 1250             Kuhn (1989a)
    Rat            male             dermal               900              Gaines (1960)
    Rat            female           dermal               455              Gaines (1960)
    Rat            both             dermal               >2150            Bathe (1972a)
    Rat            both             inhalation           >2300b           Holbert (1989)
    Mounse         male             oral                 82               Bruce et al. (1955)
    Mounse         both             oral                 96               Gasser (1953)
    Mounse         both             oral                 187              Bathe (1972b)
    Mounse         both             i.p.                 65               Klotzsche (1955)
    Guinea-pig                      oral                 320              Gasser (1953)
    Rabbit                          oral                 130              Gasser (1953)
    Rabbit         both             dermal               >2020            Kuhn (1989b)
    Turkey                          oral                 6.8              FAO/WHO (1965)
    Chicken                         oral                 40.8             FAO/WHO (1965)
    Goose                           oral                 14.7             FAO/WHO (1965)
    Gosling                         oral                 2.8              Egyed et al. (1974)
                                                                                               

    a  It should be noted that progressive improvement in the manufacturing process has reduced
       the acute toxicity of diazinon.
    b  This value is the LC50, the units being mg/m3.
    
         Brain cholinesterase activities were determined for white-footed
    mice  (Peromyscus leucopus) orally dosed with diazinon at 18.8 mg/kg
    body weight (Montz & Kirkpatrick, 1985). Following treatment with
    diazinon, a latent period of approximately 6 h elapsed during which
    time acetylcholinesterase activity was relatively unaffected. After
    the latent phase, ChE activity rapidly declined to a minimum 12 h
    after dosing. After 48 h, ChE activity recovered to a level only
    slightly below that of the controls. The response of both male and
    female mouse brain ChE activities declined rapidly at 6 h and reached
    a minimum 24 h after dosing. ChE activity of treated animals was
    comparable to that of controls 48 h after treatment. Brain ChE
    activities of treated female mice were significantly lower (P <0.05)
    than those of treated males.

         An acute oral toxicity study in rats was conduced in two phases
    to determine a NOEL of the test material (87.9% active ingredient) for
    clinical, behavioural and body weight effects in phase 1 and a NOEL
    for effects on plasma, red blood cell and brain cholinesterase in
    phase 2 after single oral gavage application to rats. In phase 1 each
    test group consisted of 5 rats. The applied dose levels were 25 and
    50 mg/kg body weight for female rats only; levels of 100, 250 and
    500 mg/kg body weight were tested in both sexes. One female given
    500 mg/kg body weight died. Clinical signs such as miosis,
    hypoactivity, absence of pain reflex, red-stained face, yellow-stained
    abdomen/urogenital area, soft stool or few faeces were seen in all
    animals except 100- mg/kg males and 25-mg/kg females. The NOAEL for
    clinical/behavioural/body weight effects was 100 mg/kg body weight in
    males and 25 mg/kg body weight in females. In phase 2 each test group
    consisted of 5 rats. Males were treated with 0.05, 0.50. 1.0, 10.0,
    100 or 500 mg/kg body weight and females with 0.05, 0.12, 0.25, 2.5,
    25 and 250 mg/kg body weight. Clinical signs such as miosis,
    hypoactivity, absence of pain reflexes, staggered gait, excessive
    salivation, red-stained face and yellow-stained and/or wet
    ventral/urogenital area were only observed in males at 500 mg/kg body
    weight (one male at 100 mg/kg body weight showed miosis) and females
    at 250 mg/kg body weight The only findings at necropsy were yellow
    staining of the perineum and red paranasal discharge in animals of
    these dose groups. Plasma cholinesterase activity was significantly
    reduced in males dosed with 10, 100 or 500 mg/kg body weight and in
    females dosed with 2.5, 25 or 250 mg/kg body weight. Red blood cell
    cholinesterase activity was significantly lower in males given 100 or
    500 mg/kg body weight and in females given 25 or 250 mg/kg body
    weight. Brain cholinesterase activity was significantly reduced at the
    highest dose level for both sexes. Brain cholinesterase activity in
    females dosed with 25 mg/kg body weight was inhibited by 37% (without
    reaching statistical significance) (Glaza, 1993).

    7.1.2  Dermal

         Diazinon was dispersed on the shaved back of each of three male
    and three female Tif: RAI rats at a level of 2150 mg/kg and covered
    with aluminium foil for 24 h. None of the animals died. Neither
    clinical signs nor dermal irritation was observed. Autopsy revealed no
    substance-related gross organ changes. The acute dermal LD50 in rats
    was found to be greater than 2150 mg/kg (Bathe, 1972a). Sherman strain
    rats were given one dermal application of diazinon dissolved in
    xylene, and no attempt was made to remove the compound during the
    observation time of 14 days. The LD50 was 900 mg/kg for males and
    455 mg/kg for females (Gaines, 1960).

         Dermal LD50 values for diazinon were determined in mice after
    application of the solution to hind feet. Values were simultaneously
    generated for the ED50 for both cholinesterases (acetylcholinesterase
    and pseudocholinesterase). LD50 values were higher than those
    reported for mice treated on shaved back skin. Diazinon appeared to
    have much more inhibitory potential for blood than for nervous tissue
    cholinesterase (Skinner & Kilgore, 1982).

         Undiluted diazinon was applied to the clipped dorsal trunk of
    each of five male and five female New Zealand White rabbits at a level
    of 2020 mg/kg and kept under semi-occlusive dressing for 24 h. Signs
    were typical of organophosphate intoxication; two out of ten animals
    died. The LD50 was >2020 mg/kg (Kuhn, 1989b,c).

    7.1.3  Inhalation

         Sprague-Dawley rats were exposed (whole body exposure) to
    diazinon for 4 h. The acute inhalation LC50 for diazinon MG 8
    FL880045 was greater than 2330 mg/m3 when it was administered
    undiluted as an aerosol (Holbert, 1989).

         Groups of five male and five female HSD:SD rats were exposed to
    an aerosol generated from undiluted liquid diazinon MG87% (88% purity)
    for 4 h (nose-only exposure). An exposure concentration of 5540 mg/m3
    was obtained, 8.82% of particles being smaller than 1 mm in diameter.
    There was no mortality. Prominent in-life observations included
    activity decrease, piloerection and polyuria, no longer seen by day 6.
    Body weight gain was largely unaffected. Gross necropsy revealed
    discoloration of the lungs in all animals. The acute inhalation LC50
    for diazinon in the rat was greater than 5440 mg/m3 (Holbert, 1994).

    7.1.4  Intraperitoneal

         Mild structural and functional changes were observed in the liver
    and testes of rats after a single intraperitoneal administration of
    diazinon (21.6 mg/kg). Kidney, however, showed no pathological
    lesions. Attempts were made to correlate the pathological changes in

    these organs with the activity of succinic dehydrogenase, adenosine
    triphosphatase and alkaline phosphatase (Dikshith et al., 1975). A
    single intraperitoneal dose of diazinon caused hyperglycaemia in rats,
    which peaked 2 h after intraperitoneal treatment with 40 mg
    diazinon/kg. The brain acetylcholinesterase activity was significantly
    reduced. The blood level of pyruvic acid was unchanged while that of
    lactic acid was significantly increased. In diazinon-treated
    hyperglycaemic animals, the glycogen content of the brain was
    depleted, the activities of glycogen phosphorylase, phosphoglucomutase
    and hexokinase were significantly increased, and the activity of
    glucose-6-phosphatase remained unchanged. Lactate dehydrogenase
    activity was increased by treatment with diazinon. The induced changes
    may have compensated for the energy requirement of stimulatory effects
    caused by the pesticide (Husain & Matin, 1986; Matin & Husain, 1987;
    Matin et al.,1989). Changes in energy metabolism are regarded as
    secondary, following cholinesterase inhibition.

         In an acute intraperitoneal study in rats, an LD50 value of
    260 mg/kg body weight was determined for both sexes. Clinical signs
    were typical of organophosphate poisoning, e.g., sedation, dyspnoea
    and tonic-clonic spasms. Surviving animals had recovered within 3 to 6
    days, and no substance-related gross organ changes were observed
    (Bathe, 1973).

         Diazinon given as an intraperitoneal single dose (40 mg/kg) to
    rats produced tremors and convulsions with lactic acidosis. This was
    accompanied by depletion of glycogen phosphorylase activity in the
    triceps and diaphragm muscles 2 h after the administration (Husain &
    Matin, 1986; Husain & Ansari, 1988).

    7.2  Short-term exposure

    7.2.1  Oral

    7.2.1.1  Rats

         Davies & Holub (1980a,b) found that diazinon (99.2% purity) fed
    to rats for 4 weeks at doses up to 25 mg/kg diet produced no visible
    toxic manifestations such as tremors or hyperexcitability. Feeding
    diazinon 25 mg/kg diet for 30 days produced more significant
    reduction of cholinesterase activity in plasma (by 22-30%) and brain
    (by 5-9%) among treated females than among males. Erythrocyte
    acetylcholinesterase activity was significantly more depressed (by
    13-17%) in treated females than in males at days 21-28 of the feeding
    trial. The greater degree of cholinesterase inhibition in females was
    possibly attributable to the higher amount of diazinon ingested by
    females than by males after day 15 of the study.

         Female Wistar rats were fed a semi-purified diet containing
    either no pesticide or 0.1 to 15 mg/kg diazinon for up to 92 days. At
    specified times, blood samples were taken to measure plasma and
    erythrocyte cholinesterase activity using a radiometric method.
    Additional rats were killed to determine brain cholinesterase
    activity. Measurements included body weight gain and feed consumption
    during the growing period. Feeding diazinon at the stated levels
    produced no visible toxic manifestations. Treated animals showed
    weight gain and feed consumption that was comparable to controls.
    Feeding trials lasting up to 90 days revealed that rats were highly
    sensitive to diazinon after 31 to 35 days exposure, as judged by
    reduction of plasma and erythrocyte cholinesterase activities. Brain
    acetylcholinesterase was found to be practically insensitive to
    dietary intake of diazinon (1.0 to 15 mg/kg), although moderate
    reduction (by 6%) of brain enzyme activity was noted among animals fed
    10 mg/kg diet at day 92. For all feeding trials, plasma cholinesterase
    was a more sensitive indicator of diazinon exposure than erythrocyte
    or brain acetylcholinesterase. The NOAEL of diazinon for the rat was
    estimated to be 0.1 mg/kg diet, which is equivalent to a daily intake
    of 0.009 mg/kg body weight per day (Davies & Holub, 1980a).

         In a feeding study, diazinon (87.7% pure) was administered to
    groups of 15 male and 15 female Sprague Dawley rats for 13 weeks at
    dietary concentrations of 0, 0.5, 5, 250 and 2500 mg/kg, corresponding
    to mean daily doses of 0, 0.03, 0.3, 15 and 168 mg/kg body weight in
    males and 0, 0.04, 0.4, 19 and 212 mg/kg body weight in females,
    respectively. The rats treated at the highest dose level showed
    hypersensitivity to touch and sound and some of the males showed
    apparent aggressiveness, hyperactivity and soft faeces. Body weight
    gain and food consumption were reduced in both sexes. At this dose
    level, the haematological examination revealed a decreased haemoglobin
    level, a lower haematocrit and an increased number of reticulocytes in
    the females. The examination of blood biochemistry revealed a reduced
    activity of serum cholinesterase in both sexes treated with 5 mg/kg
    diet or more. In addition, the low-dose females showed a 17% reduction
    in the erythrocyte cholinesterase activity. At 250 mg/kg diet or more,
    the erythrocyte and brain cholinesterase activities were reduced in
    both sexes. The absolute and relative liver weights were increased in
    both sexes in the highest dose level, and there was microscopic
    evidence of centrilobular hepatocellular hypertrophy (Singh et al.,
    1988). The NOAEL, based on reduction in brain cholinesterase activity,
    was 5 mg/kg diet (equivalent to 0.4 mg/kg body weight per day).

         In a second, similar, study (Pettersen & Morrissey, 1994),
    Sprague Dawley rats were fed diazinon at 0, 0.3, 30, 300 or 3000 mg/kg
    diet for 13 weeks. Serum, erythrocyte and regional brain
    cholinesterase inhibition was measured in groups of five males and
    five females at weeks 4, 8 and 13. Serum and erythrocyte
    cholinesterases were inhibited by 45-86 and 60-75%, respectively, at
    30 mg/kg diet, but not consistently at 0.3 mg/kg diet. Brain regional

    cholinesterase was inhibited by up to 25% in females at 30 mg/kg diet
    and by 55-75% at 300 mg/kg diet. Males were less sensitive, showing no
    effect at 30 mg/kg diet and a fall of 62-77% at 3000 mg/kg diet.
    Observable neuromuscular deficits were seen only at 3000 mg/kg diet.
    Consequently the NOEL and NOAEL for this study was 0.3 mg/kg diet
    (equivalent to 0.019 mg/kg body weight per day), based on the
    reductions in serum, erythrocyte and brain cholinesterase seen at the
    next highest dose of 30 mg/kg diet. However, given the lack of an
    intermediate dietary level of 5 mg/kg, which set the NOAEL in the
    Singh et al. (1988) study, and the modest fall in brain cholinesterase
    seen at 30 mg/kg diet in this second study, it is concluded that the
    previous NOAEL of 5 mg/kg diet (0.4 mg/kg body weight per day) should
    stand.

         The effect of low levels of diazinon treatment on four marker
    enzymes in rat heart and skeletal muscles have been investigated by
    Wilkinson et al. (1986). Typical differences in succinate
    dehydrogenase (SDH), lactate dehydrogenase (LDH), phosphofructokinase
    (PFK) and hexokinase (HK) activities were observed between heart and
    skeletal muscles. Diazinon feeding had no effect on heart, soleus,
    gastrocnemius and plantaris SDH, LDH or PKF enzyme activities after
    28 weeks. HK activity was significantly increased in sham-control
    soleus and plantaris muscle after 28 weeks. Diazinon feeding inhibited
    HK activity in plantaris muscle after 28 weeks treatment. These
    results demonstrate that chronic low levels of diazinon have little
    effect on the glycolytic and oxidative activity in heart and skeletal
    muscles.

         Adult Wistar rats were given diazinon by gavage twice weekly at a
    dose of 0.5 mg/kg body weight for twenty-eight weeks. Selected control
    and experimental animals were killed after 7, 14 and 28 weeks.
    Histological examination of the liver revealed that animals repeatedly
    treated with sublethal doses of diazinon sustain a form of hepatic
    injury characterized by cellular lipid accumulation. The finding of
    increased lipid accumulation in the liver following prolonged
    treatment with diazinon, however, still does not resolve the question
    of whether impaired lipid metabolism and/or storage is the primary
    effect (Anthony et al., 1986).

         Rats were exposed to diazinon-impregnated strips in a
    conventional laboratory animal room. The air in the room was monitored
    for the pesticide. Erythrocyte and plasma cholinesterase activities
    were determined periodically. Air concentration of the pesticide never
    exceeded 1.34 mg/m3. No significant change in enzyme activities were
    observed (Hinkle et al., 1980).

    7.2.1.2  Dogs

         Feeding studies with dogs (Bruce et al., 1955; Williams et al.,
    1959) did not differentiate between the sexes and therefore relevant
    data from male and female animals were pooled. In another study
    (Barnes et al., 1988) diazinon (87% pure) was given to groups of four
    male and four female Beagle dogs for 13 weeks at concentrations of 0,
    0.1, 0.5, 150 and 300 mg/kg diet, corresponding approximately to a
    mean daily intake of 0.0034, 0.02, 5.9 and 10.9 mg/kg body weight
    respectively. Vomiting was observed in groups fed a diet containing
    150 or 300 mg/kg. Serum cholinesterase activity was reduced at
    0.5 mg/kg or more in males and at 150 and 300 mg/kg in females.
    Erythrocyte and brain cholinesterases activity was depressed at 150
    and 300 mg/kg in both sexes. The histopathological examination
    revealed a moderate atrophy of pancreatic acini in one high-dose group
    of male dogs. Body weight gain was decreased in females at 150 mg/kg
    diet and in both sexes at 300 mg/kg diet. The serum calcium level was
    decreased in females at 150 mg/kg diet and in males at 150 and
    300 mg/kg diet. The serum albumin level was decreased in both sexes at
    300 mg/kg diet. As a slight reduction of serum cholinesterase activity
    was the only change observed, 0.5 mg/kg diet, corresponding to a mean
    diazinon intake of 0.02 mg/kg body weight per day, is considered to be
    the dietary concentration causing no toxicological effect (NOAEL),
    based on inhibition of brain and erythrocyte cholinesterase at higher
    doses.

    7.2.1.3  Pigs

         Pigs were orally administered diazinon in capsules at doses of
    0, 1.25, 2.5, 5 and 10 mg/kg body weight daily for periods of up to
    8 months. In pigs, mortality and cholinergic signs of poisoning were
    evident at 2.5 mg/kg body weight per day (FAO/WHO, 1979).

    7.2.2  Inhalation

         Two short-term inhalation studies were conducted in rats. In the
    first study, diazinon (97.1% pure) was administered in an inhalation
    chamber to four groups of nine male and female Tif RAIf rats for 6 h
    per day, 5 days a week, for three weeks, at concentrations of 0, 151,
    245 and 559 mg/m3. Four animals of each sex from the control group
    and from the highest concentration group were kept for a 25-day post-
    treatment observation period, while the others were sacrificed at day
    21 after treatment. No compound-related deaths occurred. Exophthalmus
    and diarrhoea were observed at all dose levels. In addition, the high-
    dose group animals showed salivation, ruffled fur and tonic-clonic
    convulsions during 2 h after each exposure. No toxic signs occurred in
    the 25-day follow-up period. Food consumption was reduced during the
    first three days of exposure in the high-dose group, plasma
    cholinesterase activity was reduced in the intermediate and high-dose

    groups, and brain cholinesterase activity was reduced at all dose
    levels. Erythrocyte cholinesterase activity was reduced in the high-
    dose group. The changes were reversible. There were no macro or
    histopathological findings related to the exposure to diazinon (Zak et
    al., 1973).

         In the second study the main purpose was the definition of a
    NOAEL for cholinesterase inhibition. Groups of ten male and ten female
    Tif RAlf rats were exposed to diazinon 6 h a day for 5 days per week
    for 3 weeks. The effective concentrations at the inhalation site
    were 0, 0.05, 0.46, 1.57 and 11.6 mg/m3 air. There were no
    compound-related signs, and no changes in body weight or food
    consumption. In comparison with the control animals, the number of
    erythrocytes, haemoglobin level and packed cell volume were slightly
    lower in the highest-dose group. A minor decrease of brain
    cholinesterase activity was noted in the highest-dose group of
    females. Plasma glucose levels were significantly reduced among males
    exposed to 1.57 and 11.6 mg/m3 (Hartmann, 1990). As the exposure to
    0.46 mg/m3 inhibited the plasma cholinesterase only, this
    concentration is the NOAEL.

    7.2.3  Dermal

    7.2.3.1  Rabbits

         Diazinon (97.1% pure) was suspended in 50% aqueous polyethylene
    glycol 300 and topically administered under semi-occlusive dressing to
    groups of five male and five female albino rabbits at daily doses of
    0, 1, 5 and 100 mg/kg body weight for 5 days per week for 3 weeks. In
    the highest-dose group, four males treated at 100 mg/kg died during
    the first week of treatment. Consequently, the dose was reduced to
    50 mg/kg. Clinical signs were observed in the highest-dose group and
    included anorexia, ataxia, fasciculations, tremors, diarrhoea,
    hypoactivity, hypotonia and salivation. Most of the signs disappeared
    after the dose was reduced. Mild dermal reactions were noted at site
    of test substance administration. Body weight gain and food
    consumption was similar in all groups, and most laboratory parameters
    remained unaffected by the treatment. Reduced cholinesterase
    activities were found in serum, red blood cells and the brain in
    animals treated at >5 mg/kg. In the highest-dose group, the
    reductions were significant for brain, red blood cells and serum
    cholinesterase activities, while with 5 mg/kg there was a
    statistically significant decrease of activity in the brain
    cholinesterase of females only. In the highest-dose animals, the
    histopathological examination showed a slight hyperkeratosis of the
    skin at the site of treatment (Tai & Katz, 1984). The NOEL was
    considered to be 1 mg/kg, based on inhibition of brain cholinesterase.

    7.3  Long-term exposure

    7.3.1  Rats

         Groups of 30 or 40 Sprague Dawley male and female rats received
    diazinon (87.7% pure) at dietary concentrations of 0, 0.1, 1.5, 125
    and 250 mg/kg (equivalent to a mean daily diazinon intake of 0, 0.004,
    0.06, 5 and 10 mg/kg body weight in males and of 0.005, 0.07, 6 and
    12 mg/kg body weight in females) for 99 weeks. An additional control
    group received 26.5 mg/kg diet epoxidized soybean oil, the stabilizer
    used in technical diazinon, at the concentration corresponding to the
    application to the test group of animals. Eight to ten randomly
    selected animals per sex and dose group were killed after one year of
    treatment, and nine or ten animals from the control group and from the
    highest-dose group were killed after 4 weeks of recovery at week 56.
    There were no compound-related clinical signs. At 250 mg/kg diet, the
    mean body weight and the food consumption were slightly, but
    significantly, increased in both sexes. Serum cholinesterase
    activities were reduced at >1.5 mg/kg diet. Red blood cell and
    brain cholinesterase activities were inhibited in groups fed on a diet
    containing 125 or 250 mg/kg. Cholinesterase inhibition was at least
    partially reversible during the 4-week recovery period after one year
    of treatment. No treatment-related changes were seen during pathology
    or histology examination (Kirchner et al., 1991). A pathological
    re-evaluation of eyes and optic nerves from all control and high-dose
    animals of the above study from interim necropsy (week 52), interim
    recovery necropsy (week 56) and chronic necropsy (week 98/99) was
    conducted. Histopathological lesions like cataracts, inflammatory
    changes of the globe and surface of the eye and several different
    types of retinal atrophy were found in both control and treated
    animals at final sacrifice. None of these findings had an increased
    incidence in treated rats compared to controls and they were not
    regarded as compound-related. As the dietary concentration of
    1.5 mg diazinon/kg, equivalent to a mean intake of 0.06 mg/kg body
    weight per day, inhibited serum cholinesterase only, this dose level
    was considered to be the NOAEL (Mann, 1993).

    7.3.2  Dogs

         Groups of Beagle dogs (four males, four females) received
    diazinon (87.7% pure) for 52 weeks at dietary concentrations of 0,
    0.1, 0.5, 150 and 300 mg/kg (equivalent to a mean daily intake of
    0.0032, 0.015, 4.7 and 7.7 mg/kg body weight for males and 0.0037,
    0.02, 4.5 and 9.1 mg/kg body weight for females). Owing to a general
    lack of body weight gain, the highest dose level was reduced from
    300 mg/kg diet to 225 mg/kg diet after 14 weeks of treatment. One male
    dog from the highest-dose group showed emaciation and dehydration due
    to severely reduced food consumption and weight reduction. In the
    other animals from the highest-dose group (300 mg/kg/diet) the body

    weight gain was also severely depressed during the initial 14 weeks of
    treatment. After the reduction of dose to 225 mg/kg/diet, body weight
    gain remained depressed in two of the males, while the females
    returned to normal. A slightly reduced body weight gain was also noted
    among males at 150 mg/kg diet. Food consumption was reduced in both
    sexes fed on a diet containing >150 mg/kg diazinon. Haematology and
    urine analysis showed no treatment-related changes. Significantly
    decreased cholinesterase activities were noted at >0.5 mg/kg diet.
    Serum cholinesterase activity was inhibited at 150 mg/kg diet at
    all sampling intervals and at several occasions at 0.5 mg/kg diet. Red
    blood cell and brain cholinesterase activities were reduced at
    >150 mg/kg diet. In addition, a slight reduction in the mean serum
    amylase activity was noted in both sexes fed a diet of >150 mg/kg.
    The organ weight analysis showed no treatment-related changes and
    macro- and histopathology were unremarkable (Rudzki et al., 1991). A
    re-evaluation of eyes and optic nerves from all control and high-dose
    animals from the study was conducted. No histopathological findings in
    the eyes were noted (Mann, 1993). The dietary diazinon concentration
    of 0.5 mg/kg, equivalent to a mean daily diazinon intake of
    0.015 mg/kg, inhibited serum cholinesterase activity only, and was
    considered to be the NOAEL, based on inhibition of brain and
    erythrocyte cholinesterase.

    7.3.3  Rhesus monkeys

         This study was conducted with a 50% WP diazinon formulation
    containing an actual concentration of 48.6% diazinon. The dose levels
    given below refer to the active ingredient. Groups of three male and
    three female Rhesus monkeys received initial daily doses of 0, 0.1,
    1.0 and 10.0 mg diazinon/kg body weight, administered by gastric
    intubation. After 34 days the doses were lowered to 0.05, 0.5 and
    5.0 mg/kg and after 106 weeks of treatment the study was terminated.

         Mortality was similar in all dose groups: the death of one animal
    at each dose was of infectious etiology. Clinical signs included
    tremor in the highest-dose group animals and an increased incidence
    of soft stools was noted at 1.0 and 10.0 mg/kg. In comparison to
    the controls, all treated animals gained slightly less weight.
    Treatment-related deviations in the laboratory parameters examined
    were limited to reductions of cholinesterase activities. At the
    0.5 mg/kg dose level, the erythrocyte cholinesterase activity was
    occasionally reduced in some animals and plasma cholinesterase
    activity was consistently depressed. At the highest-dose level, plasma
    and erythrocyte cholinesterase activities were markedly inhibited and
    the brain cholinesterase activity was reduced in one monkey. The
    postmortem examinations revealed no changes of toxicological
    relevance. The daily dose of 0.5 mg diazinon/kg inhibited plasma and
    (occasionally slightly) erythrocyte cholinesterase activity. The

    toxicologically relevant brain cholinesterase activity remained
    unaffected. Therefore, this dose level was considered to be the NOAEL,
    based on inhibition of erythrocyte cholinesterase (Cockrell et al.,
    1966).

    7.4  Skin and eye irritation; sensitization

    7.4.1  Primary skin irritation

         Diazinon (0.5 ml undiluted, technical material) was applied to
    the shaved skin of three male and three female New Zealand white
    rabbits and covered with gauze patches and an impermeable material.
    The dressing was removed after 4 h. Slight erythema and minimal oedema
    were seen in all rabbits, which disappeared within 1 week. In the
    report the compound received the descriptive rating as "slightly
    irritant" to rabbit skin (Kuhn, 1989b,c).

    7.4.2  Primary eye irritation

         Diazinon (0.1 ml undiluted technical material) was instilled into
    the conjunctival sac of three male and three female New Zealand white
    rabbits. In three additional female rabbits, the treated eyes were
    washed for 1´ min after the instillation of diazinon. Diazinon
    produced mildly irritating reactions of the conjunctivae, which
    disappeared within 72 h. It was rated as minimally irritating in
    washed and unwashed eyes of rabbits (Kuhn, 1989d).

    7.4.3  Skin sensitization

         Diazinon was examined for skin sensitizing effects in 10 Hartley
    Albino guinea-pigs. Ten animals were initially treated with 0.5 ml
    undiluted technical diazinon, applied to the shaved skin under
    semi-occlusive dressing for 6 h. After the third treatment one animal
    died, most probably due to intoxication. Therefore, further treatments
    were conducted with a 10% solution of diazinon in ethanol. After 11
    treatments during the 3-week induction period and a 2-week rest phase,
    no sensitization resulted after a single challenge administration
    (Kuhn, 1989e).

    7.5  Reproduction, embryotoxicity and teratogenicity

    7.5.1  Reproduction

    7.5.1.1  Rat

         Diazinon (94.9% pure) was administered in the feed to groups of
    30 male and 30 female Sprague Dawley rats for 10 weeks prior to
    mating, throughout mating of the F0 animals and during two
    generations up to weaning and sacrifice of the F2 pups. The dietary

    concentrations used were 0, 10, 100 and 500 mg/kg. Compound-related
    clinical signs and mortalities were limited to a few parental females
    treated with 500 mg/kg diet. The food consumption was generally
    comparable to, or slightly higher than, control values for females of
    both parental generations in the diazinon-treated groups, while the
    F1 males showed a decreased food consumption during the premating
    period at both 100 and 500 mg/kg diet. The body weight increase was
    reduced at 500 mg/kg in the F0 females and at 100 and 500 mg/kg for
    the F1 animals of both sexes. There were no remarkable gross or
    microscopic findings or effects on organ weights in either the F0 or
    F1 generation. Reproductive parameters including precoital interval,
    gestation duration, mating, fertility and pregnancy indices were
    unaffected by the treatment in both generations at the dose levels of
    10 and 100 mg/kg diet. At 500 mg/kg there was an increase in the
    proportion of dams with prolonged gestation in both generations, and
    in the F1 animals there was a trend toward a decrease in the number
    of pregnancies and viable newborns and adverse effects on fertility
    indices. Mating behaviour was unaffected by treatment. Litter size on
    lactation day 0 was decreased in both the F1 and F2 pups at
    500 mg/kg, whereas pup weight and sex ratio on day 0 were comparable
    to controls for both generations. Decreases in pup survival and
    corresponding decreases in pup weight were observed in both
    generations at 500 mg/kg and in the F1 pups at 100 mg/kg.
    Compound-related clinical and necropsy observations were noted in some
    F1 pups at 500 mg/kg (tremor, no milk in stomach). NOAEL was 10 mg/kg
    diet for pups and parental animals (Giknis, 1989).

    7.5.1.2  Cattle

         As a part of a survey to determine causes of abortion in
    Wisconsin dairy cattle, the possible role of pesticides was examined.
    Of 31 aborted fetuses examined, none contained traces of diazinon. Two
    gravid, non-lactating Holstein Friesian cows were orally treated in
    their feed with diazinon (Diazinon W 50 wettable powder formulation)
    at daily doses of 6.6 mg/kg body weight during their second semester
    of gestation until term. The calves were killed after parturition and
    samples of perirenal fat, liver and kidney were investigated for
    residues of diazinon, as were samples of colostral milk from the cows.
    A histopathological examination of the calves, livers and kidneys was
    conducted. Both cows treated with diazinon vomited and refused feed on
    day 20 of treatment. No abortions occurred and no gross or
    histopathological changes were found in the calves. No diazinon
    residues were detected in the tissues investigated or in the milk
    (Macklin & Ribelin, 1971).

    7.5.2  Embryotoxicity and teratogenicity

    7.5.2.1  Mice

         Groups of 19-22 mated female F2 hybrid mice were orally treated
    with diazinon (admixed to peanut butter, purity not specified) at
    daily doses of 0, 0.18 and 9 mg/kg body weight from the day of mating
    until delivery. The dams were weighed daily. After delivery, the
    physiological and behavioural development of the pups was examined.
    Mothers of all groups gave birth to viable offspring. Litter size and
    the birth weights of the pups were similar in treated and untreated
    groups. In the group receiving the higher dose of diazinon, the body
    weight development of pups was depressed during their first postnatal
    week. According to the authors, the testing of physiological and
    behavioural development revealed subtle deviations from the normal
    development in the offspring from the treated females. After sacrifice
    at 101 days of age, the brains of the offspring of mothers treated at
    the high-dose level showed ambiguous neuropathological changes in the
    forebrains (Spyker & Avery, 1977). This study raises questions that
    cannot be answered from the data presented.

    7.5.2.2  Rats

         Diazinon (purity 95%) was administered orally by gavage to groups
    of 28 to 30 pregnant Sprague-Dawley-derived rats on days 6 to 15 of
    gestation at dose levels of 0, 15, 50 and 100 mg/kg body weight On day
    21 of gestation, all dams were killed and the fetuses delivered by
    cesarean section. The dams of the 100 mg/kg group reacted to the
    treatment by a marked decrease in food consumption and a body weight
    loss in the early administration phase. The dams of the 15 and
    50 mg/kg group showed no reaction. The parameters of reproduction
    (number of corpora lutea, implantations, resorptions, fetal deaths and
    viable fetuses) showed no treatment-related intergroup differences.
    The fetal body weights were similar in all groups and the examination
    of the offspring did not reveal any teratogenic effects of the
    treatment. The NOAEL was 50 mg/kg body weight (Fritz, 1974).

         In rats, doses (95.2 mg/kg body weight on day 9) that increased
    maternal mortality reduced fetal development, as indicated by reduced
    weight of litters and mild "hydronephrosis", but caused no real
    teratogenic effect (Dobbins, 1967). A similar result was reported for
    an intraperitoneal dosage of 100 and 150 mg/kg on day 11 (Kimbrough &
    Gaines, 1968). Repeated administration (40, 50 or 60 mg/kg body weight
    per day) on days 7 to 19 of gestation reduced the growth of the dams
    but had no effect on the number of resorptions or corpora lutea, on
    litter size, or on fetal weight. The cholinesterase activity of the
    fetal brain was reduced. A dosage of 75 mg/kg body weight per day was
    fatal to dams in 4 to 5 days (Hoberman et al., 1979).

         Diazinon (97.4% pure) was administered by gavage to groups of 21
    to 25 pregnant Sprague-Dawley rats from day 6 to 15 of gestation at
    dose levels of 0, 10, 20 and 100 mg/kg body weight. On day 20 of
    gestation, all dams were killed and the fetuses delivered by cesarean
    section. In the highest-dose group of, dams a decreased food
    consumption was noted during days 6-9 of gestation and the animals
    lost weight. The body weight gain of the dams showed some recovery
    thereafter, but the overall body weight gain of the highest-dose group
    remained significantly below that of the untreated controls. The
    numbers of corpora lutea and implantations were similar in all groups.
    Resorptions were significantly increased only in the top-dose group
    and, accordingly, the number of live fetuses was decreased. The fetal
    body weights were higher in the top-dose group than in the untreated
    controls. Three single instances of external malformations were
    observed at the highest-dose level (one fetus with a filamentous tail,
    one fetus with umbilical hernia and one fetus with sublingual
    extraneous soft tissue). Since the malformations were not
    morphologically related, they were considered to be secondary to
    maternal toxicity. An increased incidence of rudimentary 14th ribs was
    noted in the fetuses of the highest-dose group, although it remained
    within the limits of historical controls. The finding was considered
    to be related to fetotoxicity, secondary to severe maternal toxicity.
    Other fetal anomalies were comparable between treated and untreated
    groups. No evidence of teratogenic effect of diazinon was found
    (Infurna & Arthur, 1985).

    7.5.2.3  Hamsters

         In Golden Syrian hamsters diazinon was administered as individual
    oral doses (0.125 and 0.25 mg/kg body weight) during the period of
    organogenesis. Technical grade diazinon diluted with corn oil was
    used. The dose volume was 10 ml/kg body weight. Control animals
    received corn oil on the same days of gestation. The hamsters were
    killed on day 14 of gestation. All fetuses were examined for gross
    defects when delivered by cesarean section. The viability of hamster
    fetuses delivered on day 15 was checked by placing them in a chicken
    hatching incubator for 6 h. All fetuses with enough developmental form
    for determination of structural defects were counted in determining
    the number of fetuses per litter. The total number of fetuses in each
    treatment group was divided by the number of mothers surviving to
    term. Fetuses dying in late embryonic life and resorption sites were
    counted as dead fetuses. No bone defects were seen in four fetuses
    chosen at random from each litter for staining and examination of
    skeleton. Diazinon did not produce any terata when administered to
    hamsters (Robens, 1969).

    7.5.2.4  Rabbits

         Robens (1969) reported that diazinon had not been found to be
    teratogenic in rabbits given 7 or 30 mg/kg body weight, although the
    higher dose of diazinon produced cholinergic signs. Diazinon
    (89.2% pure) was administered orally by gastric intubation to groups
    of 19 to 22 New Zealand white rabbits at daily doses of 7, 25 and
    100 mg/kg body weight from day 6 to 18 of gestation. On day 30 of
    gestation, all dams were killed and the fetuses delivered by cesarean
    section. At the highest-dose level, 9/22 dams died and overt signs of
    toxicity included tremors, convulsions, hypoactivity and anorexia.
    There were no statistically significant differences among the group
    regarding the mean number of implantations and the proportions of
    live, dead or resorbed fetuses. The fetal weights were similar in
    treated and untreated groups, and neither embryotoxicity nor
    teratogenicity was observed (Harris & Holson, 1981).

    7.5.2.5  Chicken

         Several studies have investigated the teratogenic potential of
    diazinon in chick embryos (Khera & Bedok, 1967; Misawa et al., 1981,
    1982; Henderson & Kitos, 1982; Byrne & Kitos, 1983; Wyttenbach &
    Hwang, 1984; Kushaba-Rugaaju & Kitos, 1985). In view of the lack of
    teratogenicity in mammals and the lack of adequate data on
    cholinesterase inhibition  in ovo, these studies are not considered
    relevant in the assessment of mammalian teratogenicity.

    7.6  Mutagenicity and related end-points

         The summary results of mutagenicity studies conducted with
    diazinon are presented in Table 3.

         Diazinon did not induce mutations in either  Salmonella 
     typhimurium or  Escherichia coli, but produced conflicting results
    in mouse lymphoma L5178Y cells at the  tk locus. Unscheduled DNA
    synthesis was not induced in primary cultures of rat hepatocytes. A
    sister chromatid exchange study with human lymphocytes cultured in
    whole blood gave equivocal results, while negative results were
    obtained in three other  in vitro studies and,  in vivo, in bone
    marrow cells of dosed mice.

         Chromosomal aberrations were not induced in cultured human
    lymphocytes. In  Drosophila melanogaster, diazinon did not induce
    either complete or partial chromosome loss.

        Table 3.  Special studies on the mutagenicity of diazinon
                                                                                                                           

    Test system                        Test object                             Results        Reference
                                                                                                                           

    In vitro

    Ames                               Salmonella typhimurium                  negative       Geleick & Arni (1990)
                                       TA98, TA100, TA1535, TA1537,
                                       TA1538; E. coli WP2 uvrA

    Ames                               Salmonella typhimurium                  negative       Marshall et al. (1976)
                                       TA1535, TA1536, TA1537, TA1538

    Mouse lymphoma assay               Mouse lymphoma cells,                   negative       Dollenmeier & Müller (1986)
                                       L5178Y/tk +/-

    Mouse lymphoma assay               Mouse lymphoma cells                    positive       McGregor et al. (1988)
                                       L5178Y/tk +/-

    Sister chromatid exchange study    Chinese hamster cells V79               negative       Chen et al. (1981)

    Sister chromatid exchange study    Human lymphoid cells (LAZ-007)          negative       Sobti et al. (1982)

    Sister chromatid exchange study    Chinese hamster V79 cells               positive       Matsuoka et al. (1979)

    Sister chromatid exchange study    Whole blood human lymphocytes           equivocal      Murli & Haworth (1990a)

    Sister chromatid exchange study    Chinese hamster V79 cells               negative       Kuroda et al. (1992)

    Sister chromatid exchange study    Chinese hamster V79 cells               negative       Nishio & Uyeki (1981)
                                                                                                                           

    Table 3.  (con't)
                                                                                                                           

    Test system                        Test object                             Results        Reference
                                                                                                                           

    Nucleus anomaly                    Chinese hamster V79 cells               negative       Hool & Muller (1981c)

    Chromosomal aberration             Human lymphocytes                       questionable   Lopez & Carrascal (1987)

    Chromosomal aberrations            Human lymphocytes                       negative       Lopez et al. (1986)

    DNA repair test                    Rat hepatocytes                         negative       Hertner & Arni (1990)

    In vivo

    Nucleus anomaly                    Chinese hamster bone marrow cells       negative       Hool & Müller (1981c)

    Micronucleus test                  Mouse bone marrow cells                 negative       Ceresa & Puri (1988)

    Dominant lethal study              Mouse, male                             negative       Fritz (1975)

    Chromosome aberrations             Mouse spermatogonia                     negative       Hool & Müller (1981d)

    Chromosome aberrations             Mouse spermatocytes                     negative       Hool & Müller (1981b)

    Chromosomal loss                   Drosophila melanogaster                 negative       Woodruff et al. (1983)

    Sister chromatid exchange study    Mouse bone marrow cells                 negative       Murli & Haworth (1990b)
                                                                                                                           
             Nuclear anomaly tests in cultured Chinese hamster V79 cells and
    in bone marrow cells of dosed Chinese hamsters gave negative results.
    A micronucleus test in bone marrow polychromatic erythrocytes of mice
    was also negative.

         No chromosomal aberrations were induced in the spermatogonia or
    spermatocytids of dosed mice and a dominant lethal test in dosed male
    mice was negative. It was concluded that diazinon is not genotoxic.

    7.7  Carcinogenicity

    7.7.1  Mice

         Groups of 50 B6C3F1 mice of each sex were treated with diazinon
    (98% pure) at dietary concentrations of 100 and 200 mg/kg diet for
    103 weeks. Two additional groups of 25 males and 25 females each
    served as untreated controls. Hyperactivity was reported for the dosed
    mice but was rare in the control group. The body weight gains for all
    dosed male mice were similar to the control group except for the last
    20 weeks of the study period. The treated females showed slightly
    lower body weights than the controls. The survival at 78 weeks in the
    control 100 and 200 mg/kg groups, respectively, was: males, 21/25
    (84%), 45/50 (90%), 49/50 (98%); females, 24/25 (96%), 50/50 (100%),
    49/50 (98%). Several neoplasms were observed, but apart from lower
    neoplasms in male mice none appeared to be treatment-related or had an
    incidence in treated groups significantly different from that of
    controls. The incidences of hepatocellular carcinomas in the control,
    100 and 200 mg/kg groups, respectively, were: 4/21 (19%), 20/46 (43%)
    and 10/48 (21%). The corresponding incidences of hepatocellular
    carcinomas or adenomas were 5/2 (24%), 20/46 (43%) and 13/48 (27%).
    The Cochrane-Armitage test for trend was significant for carcinomas,
    but not for liver carcinomas and adenomas combined. Fisher's exact
    test for comparison of a dosed group with its matched control groups
    was significant (P=0.046) only for hepatocellular carcinomas alone in
    the 100 mg/kg group of male mice. In view of the lack of a dose-
    related response, the occurrence of liver tumours in male mice could
    not be clearly attributed to diazinon (NCI, 1976).

         A report submitted to the United Kingdom Ministry of Agriculture,
    Fisheries and Food (MAFF, 1991) described a two-year combined chronic
    toxicity/carcinogenicity study conducted with male and female B6C3F1
    mice (60/dose/sex) administered diets containing diazinon at 0, 100,
    200 or 300 mg/kg (males only) or 400 mg/kg (females only). Ten mice of
    each sex per group were killed at 12 months. After 24 months, there
    were reported to be no treatment-related gross or histopathological
    findings. This study provides no evidence for the carcinogenicity of
    diazinon in mice. In particular, it does not confirm the observations
    described in the above-mentioned study on B6C3F1 mice.

    7.7.2  Rats

         Groups of 50 male and 50 female Fischer-344 rats received
    diazinon (98% purity) at dietary concentrations of 400 and 800 mg/kg
    for 103 weeks. All survivors were killed at 105 weeks. An additional
    control group of 25 males and 25 females received an untreated diet.
    There was no significant effect of treatment upon body weight gain.
    Hyperactivity was noted in males and females of the 800 mg/kg group
    and males of the 400 mg/kg group. Urine was discoloured in females of
    the 800 mg/kg group and in dosed females there was vaginal bleeding
    and discharge. Survival at 78 weeks in control, 400 mg/kg and
    800 mg/kg groups, respectively, were: males, 24/25 (96%), 49/50 (98%),
    49/50 (98%); females, 23/25 (92%), 44/50 (88%), 44/50 (88%). Various
    neoplasms were observed, but only the incidence of lymphomas/
    leukaemias in dosed groups of males was significantly different from
    the controls. The incidences in the control, 400 and 800 mg/kg groups,
    respectively, were: males, 5/25 (20%), 25/50 (50%), 12/50 (24%);
    females, 2/25 (8%), 6/50 (12%), 6/50 (12%). The Fisher's exact test
    for comparison with the matched control was significant (P=0.011) only
    in the 400 mg/kg group of males. In view of the lack of a dose-related
    response, the occurrence of lymphomas/leukaemias in male rats could
    not be clearly attributed to diazinon. The frequency of endometrial
    stromal polyps was increased in the dosed groups. This lesion, which
    is commonly observed in Fischer-344 rats, occurred at incidences in
    the control, 400 mg/kg and 800 mg/kg groups, respectively, of 2/23
    (9%), 8/43 (19%) and 11/49 (22%). The carcinogenic status of diazinon
    in this study is unclear (NCI, 1979).

         The chronic toxicity study of Kirchner et al. (1991) described
    earlier (section 7.3.1) included groups of male and female Sprague-
    Dawley rats (approximately 20/dose/sex, progressing for longer than 57
    weeks) administered diets containing diazinon at concentrations 0,
    0.1, 1.5, 125 or 250 mg/kg. No treatment-related increases in
    neoplasms were observed. This study does not provide supportive
    evidence for a carcinogenic effect of diazinon in rats.

         A report submitted to the United Kingdom Ministry of Agriculture,
    Fisheries and Food (MAFF, 1991) described a 120-week combined chronic
    toxicity/carcinogenicity study conducted with male and female F-344
    rats (75/dose/sex) administered diets containing diazinon (0, 0.1, 1.5
    or 22.6 mg/kg body weight per day). Rats of both sexes in the highest-
    dose group that died late in the study (after week 105) showed
    increased ulceration of the forestomach, with associated increased
    incidence of acanthosis, hyperkeratosis, submucosal granulation tissue
    and hyperplasia of the epithelium. Apparently, no neoplastic lesions

    were observed in the study. This study provides no evidence for the
    carcinogenicity of diazinon in rats. In particular, it does not
    confirm the observations described in the above-mentioned study on
    F-344 rats.

         It is concluded that diazinon is not carcinogenic in rats or
    mice.

    7.8  Special studies

    7.8.1  Neurotoxicity

         In a range-finding experiment, groups of four domestic hens (red
    heavy breed) were treated at four dose levels of diazinon (87% pure),
    and an acute oral LD50 of 12.5 mg/kg body weight was determined. A
    schedule was developed to protect the hens from acute cholinergic
    effects. Atropine (10.0 mg/kg intramuscular) was administered prior to
    the treatment with diazinon, and 2-PAM was injected at doses of
    50 mg/kg at the time of the diazinon administration. In addition, the
    hens received post-treatment protection with concurrent doses of
    atropine and 2-PAM after approximately 1 and 5 h and as necessary
    thereafter. In the main neurotoxicity study, diazinon was given as a
    single dose of 28 mg/kg body weight by gastric intubation to a group
    of 18 atropine-pretreated hens. All hens were observed for three weeks
    and again treated with 13 mg diazinon/kg on day 21. The second
    observation period also lasted for three weeks (day 22-42). Additional
    groups, which served as negative controls, were given the vehicle
    (10 hens treated with 1 ml/kg corn oil), and eight hens, treated with
    tri- o-tolyl phosphate (500 mg/kg) served as positive controls. One
    diazinon-treated hen died 5 days after the first dose and another one
    6 h after the second dose. One hen from a negative control group died
    on day 7. There were no neurotoxic signs apparent during either of the
    two observation periods in the negative control group or in the
    treated groups. No histopathological changes in the brain, spinal cord
    or peripheral nerves were detected (Jenkins, 1988).

         In a further test for delayed neuropathy Classen (1996) gave 20
    hens a single oral dose of 100 mg diazinon/kg body weight. Therapeutic
    treatment with physostigmine and atropine for up to 48 h resulted in
    survival of 17 hens, despite a peak inhibition of brain cholinesterase
    by 83%. No ataxia was seen over a 28-day survival period, and no
    inhibition of either brain or spinal cord neuropathy target esterase
    (NTE) was seen at either 24 (n=5) or 48 (n=5) h.

         Diazinon (88% purity) was administered by gavage to 15 rats per
    sex and dose at single doses of 0, 2.5, 150, 300 and 600 mg/kg. A
    negative control group of 15 animals per sex received the vehicle
    (corn oil) only. A group of 10 animals per sex served as positive
    control and was administered a single dose of 150 mg/kg triademefon
    60 min prior to the Functional Observational Battery (FOB). Two males

    and one female dosed at 600 mg/kg died. A transient reduction in body
    weight and body weight gain was observed in males dosed at 300 and
    600 mg/kg during week one. Food consumption was reduced in the same
    males, and in females dosed at >150 mg/kg. These findings decreased
    in incidence and severity with decreasing dose. No treatment-related
    effects were observed in the FOB on study days 8 and 15. In males
    dosed above 150 mg/kg and in females dosed above 2.5 mg/kg, activity
    counts in the figure-8 maze were significantly decreased at the
    estimated time of peak effect only. Serum cholinesterase activity was
    significantly decreased at the time of peak effect in all diazinon-
    treated groups. Full recovery was observed in all groups on study day
    15. Red blood cell cholinesterase activity was significantly inhibited
    on study day 1 in animals of both sexes treated with >150 mg/kg.
    Substantial recovery was observed on study day 15, but significant
    inhibition still remained. No inhibition of brain cholinesterase
    activity was detected on day 15. No neuropathological effects were
    noted for diazinon at necropsy or upon histopathological examination.
    It was concluded that the administration of diazinon resulted in
    reversible neurotoxicity and cholinergic poisoning without
    neuropathological changes. The NOAEL was 2.5 mg/kg body weight for
    both sexes (Chow & Richter, 1994).

    7.8.2  Effects on enzymes and transmitters

         Male rats were treated bi-weekly by gavage with the equivalent of
    0.5 mg/kg per day technical diazinon for up to 28 weeks. The animals
    were killed at specific time intervals (7, 14 and 28 weeks) and
    compared with age-matched controls. Blood and brain tissues were
    analysed for cholinesterase activity and for concentrations of
    catecholamines and amino acids. Only plasma cholinesterase activity
    was significantly reduced. Erythrocyte cholinesterase and brain
    cholinesterase were unchanged while during the same period the levels
    of several putative brain neurotransmitters, aspartate, glutamate
    (excitatory) and taurine as well as GABA (inhibitory) were
    significantly reduced in experimental versus control animals. Blood
    serotonin level was significantly elevated but no other blood or brain
    monoamines were significantly altered. Whilst the authors (Rajendra et
    al., 1986) concluded that oral administration of diazinon exerts
    effects on brain neurotransmitters, even at the low-dose levels
    administered in this study, the biological significance of these
    findings is unclear.

         Intraperitoneal administration of diazinon diminishes formation
    of L-kynurenine by liver slices from 93% at 1 mg/kg dose to 56% at
    40 mg/kg. The ratio of critical intermediates in L-tryptophan
    biosynthetic pathway, L-kynurenine to  N-formyl-L-kynurenine,
    decreases and is reversed with increasing dosage of diazinon (Seifert
    & Cassida, 1979).

         Diazinon altered the formation of several L-tryptophan
    metabolites associated with the L-kynurenine pathway in mice. Liver
    kynurenine formamidase was inhibited almost completely by diazinon
    (10 mg/kg). The enzyme inhibition resulted in reduced L-kynurenine
    biosynthesis in livers and a concomitant accumulation of  N-formyl-L-
    kynurenine. However, in plasma, L-kynurenine level increased up to
    5-fold in diazinon-treated mice. Consequently, the urinary excretion
    of xanthurenic acid and kynurenic acid was raised 5- to 15-fold. The
    revelation of this novel mechanism of diazinon action is an important
    piece of information needed for a better understanding of the non-
    cholinergic toxicity of organophosphorus acid triesters and
    methylcarbamates (Seifert & Pewnim, 1992).

    7.8.3  Effects on the immune system

         Pregnant F2 dihybrid female mice received either a vehicle or 1
    of 2 doses of diazinon (0.18 (n=19) or 9.0 (n=21) mg/kg body weight)
    in the diet, daily throughout gestation. All mothers gave birth to
    viable, overtly normal offspring at term. However, a significant
    number (12%) of pups born to dams who received 9.0 mg/kg died prior to
    weaning on day 28; necropsy findings were consistent with death from
    respiratory infection. There was no significant difference in
    mortality between control and diazinon-treated offspring once they
    reached 28 days of age. Determinations of five different classes of
    serum immunoglobulin (Ig) concentrations (IgG1, IgG2a, IgG2b, IgA,
    IgM) at 101, 400 and 800 days of age indicated transient but
    consistent disturbances of 2 Ig classes in offspring as a result of
    prenatal diazinon exposure. IgG1 concentrations of male offspring
    exposed to 0.18 mg/kg were significantly elevated at 101 days but not
    at 400 or 800 days of age. IgG1 concentrations of female offspring
    exposed to 9.00 mg/kg were significantly depressed at 101 days but not
    different from controls at 400 or 800 days of age. Changes in IgG2b
    levels generally were similar to those recorded for IgG1 but of
    smaller magnitude. There were no significant effects on serum IgG2b or
    IgM concentrations, and only equivocal effects on IgA, as a
    consequence of prenatal exposure to either pesticide. This study
    offers no conclusive information of an effect of diazinon on the
    immune system (Barnett et al., 1980).

    7.8.4  Effect on pancreas

         Diazinon has been reported to cause acute pancreatitis and
    ductal hypertension in dogs, which is due to the absence of
    acetylcholinesterase in pancreatic sphincter, duodenal smooth muscle
    in dogs and a reliance upon the more readily inhibited
    butyrylcholinesterase (Dressel et al., 1980; Frick, 1987).

         Kazacos (1991) examined the toxic effects of diazinon on the
    guinea-pig pancreas. Guinea-pigs were given single intravenous dose of
    diazinon at concentration ranging from 125 to 200 mg/kg body weight.

    Examination of pancreatic tissue from animals killed at various time
    intervals after dosing revealed acinar cell vacuolization after 24 h.
    This cellular injury disappeared within 3 days after the initial toxic
    insult. These are considered to be species-specific effects.

    7.9  Factors that modify toxicity; toxicity of metabolites

    7.9.1  Metabolic enzymes

         Abdelsalam & Ford (1986) found that the toxic effects of diazinon
    were increased by pretreatment with the hepatic microsomal enzyme
    inducers dieldrin and phenobarbitone and that, at the same time, there
    was a rise in the liver carboxylesterase activity. In this experiment,
    the toxicity of diazinon increased when calves were pretreated with
    dieldrin or phenobarbitone despite the increased activity of the liver
    carboxylesterase. Apparently carboxylesterase activity was not
    sufficient to protect against the toxicity of diazinon in the
    pretreated calves. This suggests that either the increased
    carboxylesterase activity had only a minor role in the hydrolytic
    detoxification of diazinon or active metabolites, or that its effect
    might have been overwhelmed by the action of other microsomal oxidase
    activity concurrently induced by dieldrin and phenobarbitone leading
    to a faster rate of activation than degradation of diazinon.

         Abdelsalam & Ford (1987) described the effect of induced liver
    and kidney lesions on the toxicity of levamisole and diazinon, two
    antihelmintics routinely used in ruminant livestock management, and of
    a lung lesion on the toxicity of diazinon in calves. Hepatic or renal
    damage such as may occur naturally as a consequence of infection or of
    the ingestion of poisonous plants or other toxic substances is,
    therefore, likely to affect the metabolism and excretion of drugs
    routinely used in antihelmintic control programmes. Liver damage in
    calves, induced by the oral administration of the flukecide, carbon
    tetrachloride, increased the toxic effect of diazinon but not of
    levamisole, whereas the presence of a renal tubular lesion caused by
    mercuric chloride enhanced the toxicity of both commonly used
    antihelmintic compounds.

    7.9.2  Antidotes

         The effects of atropine/oxime therapy on diazinon-poisoned
    animals was investigated in rats and rabbits. The rats were orally
    treated with 235 mg/kg body weight (0.8 LD50) of diazinon (91.9%
    pure), while rabbits received 1600 mg diazinon/kg body weight by the
    subcutaneous route. In both species, intramuscular administration of
    16 mg/kg atropine (10 min post treatment), and 30 mg/kg of pyridine
    2-aldoxime methochloride (2-PAM Cl) 24 h later, significantly
    increased the reactivation of the diaphragm cholinesterase. The oral
    LD50 for diazinon in the rat was increased by a factor of 1.7 when
    2-PAM Cl was administered intravenously and 3.1 times when 2-PAM Cl

    was given orally. In order to prevent the reappearance of signs the
    authors recommended that 2-PAM Cl be administered intravenously at the
    same time as atropine followed by repeat oral administrations, as
    needed (Harris et al., 1969).

         The antidotal efficacy of pralidoxime iodide and obidoxime
    dichloride was investigated in goslings poisoned by a supralethal dose
    of diazinon. Various doses of both drugs were administered by
    intramuscular injection when the poisoned birds were unable to walk.
    Pralidoxime at 100 mg/kg induced recovery in 4 out of 6 poisoned
    goslings, and 25 mg/kg successfully treated only 1 of 6 birds.
    Obidoxime at 25 mg/kg showed no therapeutic properties, whereas 50
    and 100 mg/kg delayed the death of some birds by several hours. At
    100 mg/kg, all goslings had transient signs of intoxication, which
    precluded the use of this compound as an antidote at higher doses
    (Shlosberg et al., 1976).

    7.9.3  Potentiation

         In a study of the potentiation of the acute toxicity of diazinon
    by several other pesticides (chlordimeform, iodofenphos, profenphos,
    methacrifos), there was no potentiation at equitoxic doses (Sachsse &
    Bathe, 1975, 1976, 1977, 1978).

    8.  EFFECTS ON HUMANS

    8.1  Exposure of the general population

    8.1.1  Acute toxicity, poisoning incidents

         Several cases of intentional (Kabrawala et al., 1965; Banerjee,
    1967; Wadia et al., 1974; Klemmer et al., 1978; Poklis, 1980; Wedin et
    al., 1984; Hodgson & Smith, 1992) and accidental acute poisoning with
    diazinon have been reported. Accidental poisonings were usually due to
    ingestion of improperly stored liquid formulation (Hayes, 1963;
    Zwiener & Ginsburg, 1988; Weizman & Sofer, 1992; Hodgson & Smith,
    1992). Cases of poisoning after cutaneous application of diazinon for
    lice treatment have also been described (Muratore et al., 1960; Hayes,
    1963; Halle & Sloas, 1987). Several accidents involved children (Mizra
    et al., 1972; English et al., 1970; Zwiener & Ginsburg, 1988; Hodgson
    & Smith 1992; Weizman & Sofer, 1992; Wagner & Orwick, 1994).

         Generally, symptoms and signs were typical of AChE inhibition,
    which responded to atropine and oxime treatment. In a case of fatal
    suicidal ingestion of diazinon reported by Poklis et al. (1980),
    diazinon concentrations in postmortem body fluids and tissues were
    found to be 277 mg/litre in blood, 200 mg/litre in the bile and
    15 mg/kg in adipose tissue. In the stomach 44 mg were found. Cases
    with atypical or unusual features are described in section 8.1.1.3. No
    cases of delayed polyneuropathy have been observed, as would be
    expected from the negative animal data. The following sections deal
    with some specific aspects of acute poisoning by diazinon (i.e., the
    acute pancreatitis, the intermediate syndrome, and some unusual case
    reports).

    8.1.1.1  Acute pancreatitis

         Increased levels of serum amylase and glucose have been described
    in some severe cases of diazinon poisoning. In certain cases these
    enzymatic alterations were accompanied by prominent abdominal symptoms
    and signs, including abdominal rigidity. All these were considered
    indicative of acute pancreatitis (Dressel et al., 1979; Dagli et al.,
    1981; Lee, 1989; Weizman & Sofer, 1992). On one occasion a pancreatic
    cyst was observed (Dressel et al., 1979). In all cases, pancreatitis
    was mild and patients fully recovered. Severe poisoning with other
    organophosphates, e.g., parathion (Weizman & Sofer, 1992), coumaphos
    (Lee, 1989) and malathion (Lee, 1989), was also associated with acute
    pancreatitis. Apparently, poisoning with an unknown carbamate was also
    associated with acute pancreatitis (Weizman & Sofer, 1992).

    8.1.1.2  Intermediate syndrome

         Senanayake & Karalliedde (1987) described a syndrome caused by
    organophosphate pesticides and named it "intermediate", because its
    onset was delayed after cholinergic syndrome but appeared earlier than
    polyneuropathy. The syndrome, appeared 24-96 h after poisoning during
    recovery from the cholinergic crisis. It was characterized by
    paralysis of proximal limb muscles, neck flexors, motor cranial nerves
    and respiratory muscles. It was resistant to atropine treatment and,
    in certain patients, required assisted ventilation. It is noteworthy
    that Wadia et al. (1974), reporting the neurological manifestations
    seen in 200 consecutive cases of poisoning, mostly with diazinon,
    described two different types of signs: type I, characteristic of the
    cholinergic syndrome and responsive to atropine, and type II, present
    in about 20% of the cases, which appeared at least 24 h later,
    resembled those of the intermediate syndrome and were not responsive
    to atropine (Wadia et al., 1974).

         Other cases of intermediate syndrome due to diazinon poisoning
    have been described (Hall & Baker, 1989; Samal & Sahu, 1990).

    8.1.1.3  Unusual case reports

         Three-week-old twins were hospitalized because of respiratory
    distress. One was cyanotic on admission, but both had rapid shallow
    breathing, profuse nasal and bronchial secretions, and pinpoint
    pupils; muscle fasciculations were not detectable. At 48 h only the
    sicker twin had slightly reduced pseudocholinesterase activity.
    Treatment was appropriate and recovery uneventful. Investigation
    revealed that the babies lived in one side of a two-story house that
    had been divided into two apartments by partitions. About 10:30 h on
    the previous day the other apartment had been sprayed with 1% diazinon
    for cockroach control using approved spot applications directed mainly
    at cracks. The twins were the only ones who had remained indoors. The
    observed degree of respiratory distress in the presence of little or
    no inhibition of cholinesterase was consistent with exclusively
    respiratory exposure (English et al.1970).

         A 12-week-old infant girl developed persistent hypertonicity of
    the extremities without other signs of intoxication. It was discovered
    that the organophosphate insecticide diazinon was applied in her
    home 5 weeks prior to the onset of signs. Six months after
    application, high levels of diazinon residues were found on the floor
    (230 ng/cm2), in vacuum cleaner dust (1700 mg/kg), and in the air
    (2.8 ng/m3). A diazinon dose of approximately 0.02 mg/kg per day was
    calculated and derived from the infant's urine level of diazinon
    metabolites determined 6 months after application of diazinon in her
    home. Her muscle tone returned to normal shortly after the infant was
    removed from the home (Wagner & Orwick, 1994).

         According to Hata et al. (1986), atypical ocular bobbing resulted
    from an intentional poisoning from diazinon. The authors suggest
    acetylcholine as a neurotransmitter substance within the ocular motor
    pathway.

         A 26-year-old man, who ingested approximately 230 ml of a
    solution of an unknown concentration of diazinon in a suicide attempt,
    developed a severe cholinergic syndrome which was relived by atropine
    and 2-PAM. Diuresis was greatly reduced (22 ml/h) and urine was dark
    and cloudy (specific gravity 1.029). It is possible that significant
    dehydration may have precipitated this reaction (Wedin et al., 1984;
    Albright, 1984).

    8.1.2  Controlled human studies

         A cumulative toxicity study was conducted with human volunteers.
    Four healthy males weighing between 74 and 96 kg and aged between 30
    and 45 years ingested diazinon in gelatin capsules (95.4% pure) at a
    dose of 0.025 mg/kg per day. Two males received 34 consecutive
    treatments (Group B), while the two other volunteers were treated for
    4 days, were left untreated for the next 5 days in order to
    investigate reversibility of the effects and then received the
    capsules again for 32 more days (Group A). The daily dose was split
    into three administrations taken after meals around 9, 13 and 19 h.
    Parameters of haematology, urine analysis and blood biochemistry
    (plasma and erythrocyte cholinesterase, serum alkaline and acidic
    phosphatase activities) were determined at regular intervals. A
    reversible decrease of plasma cholinesterase activity was observed in
    group A during the first 4 days of treatment while the erythrocyte
    cholinesterase activity remained unaffected. During the second
    treatment period of group A and during the entire treatment of group
    B, the cholinesterase activities were similar to those observed at
    pretest. No clinical signs or changes in other parameters were noted.
    It was concluded that the administered daily dose of 0.025 mg/kg
    marginally inhibited the plasma cholinesterase only, and can therefore
    be considered as a NOAEL in humans (Payot, 1966).

    8.2  Occupational exposure

    8.2.1  Acute poisoning

         Poisoning following occupational exposure to diazinon was usually
    associated with improper or prolonged storage of the commercial
    formulations, which, prior to the improvements carried out by the
    manufacturer, tended to give rise to more toxic impurities (mainly
    TEPP).

         Soliman et al. (1982) investigated two spraymen who had a
    cholinergic syndrome (with about 90% red blood cell AChE inhibition)
    after using a commercial formulation of diazinon which was packaged in
    tin-plated cans that had replaced the more expensive aluminium cans.
    Analysis of such commercial formulation revealed the presence of TEPP,
    sulfo-TEPP, monothiono-TEPP and other impurities, but no diazinon.

         Mello et al. (1972) reported an episode where three farmers were
    poisoned when using a commercial formulation of diazinon that was
    transferred from the original container to another container and then
    stored for some time. This formulation contained monothiono-TEPP and
    was about 30 times more toxic to rats than a recently prepared and
    properly stored formulation. On that occasion, 26 of 40 cows died when
    treated against tick infestation with this formulation.

         A fatal case of poisoning by diazinon and malathion, possibly by
    inhalation, was described by Wecker et al. (1985). The 51-year-old man
    was found unconscious in the closed shed where he sprayed three cows
    with the pesticides.

         Two cases of cutaneous hepatic porphyria of toxic origin were
    identified within a short period of time. Both patients were farmers
    and recently handled very intensively, without any precaution, some
    pesticides containing organophosphorus substances (diazinon). The
    symptoms were similar to those of the so-called Turkish porphyria
    (Bopp & Kosminsky, 1975).

    8.2.2  Effect of short-term and long-term exposure

         Neurophysiological investigations and determinations of blood
    cholinesterase activities were carried out on 11 Swedish spraymen
    exposed to bromophos, diazinon, dursbane and malathion. Plasma
    cholinesterase activity was significantly reduced after work, while
    erythrocyte cholinesterase activity was unchanged. In none of the
    workers with a decreased plasma cholinesterase activity after work
    could  any related acute neuromuscular disturbance be detected when
    the men were tested with repetitive nerve stimulation and with single
    fibre electromyography. Signs of subclinical neuropathy were present
    as a slight reduction in sensory conduction velocity and increased
    fibre density in some workers (Stalberg et al., 1978).

         A cohort of 99 workers exposed to diazinon was tested before and
    after the work shift with a neurobehavioural test battery, which
    included a brief examination, a symptom questionnaire and tests of
    concentration, eye-hand coordination, pattern recognition, visual
    memory and finger tapping. The median diazinon exposure level was
    2.1 mg/day and the mean duration of exposure was 39 days (see section
    5.3). There was no correlation between the diethylthiophosphate (DETP)
    concentrations or diazinon exposure and pre- or post-shift

    neurobehavioural function with linear regression models after
    adjusting for age, sex, education and alcohol intake. The study failed
    to demonstrate adverse behavioural effects of repeated, low-level
    diazinon exposure (Maizlish et al., 1987).

         Three groups of agricultural workers with a history of exposure
    to organophosphate pesticides were followed up to evaluate the utility
    of sequential post-exposure cholinesterase analyses to confirm
    organophosphate intoxication in the absence of baseline cholinesterase
    values. Three or more cholinergic symptoms were reported by 50 of the
    72 patients. Pre-exposure red blood cell cholinesterase activities of
    45 workers were above the lower limit of laboratory normal range.
    Follow-up examinations, including blood cholinesterase activity
    analyses, were conducted in 57 subjects. When final post-exposure
    cholinesterase activity determinations were compared with respective
    individual normal baseline values, the plasma and red blood cell
    activities were shown to be inhibited. The data support the use of
    sequential post-exposure blood cholinesterase analyses to confirm the
    diagnosis of organophosphate-induced illness in the absence of
    baseline values (Coye et al., 1987).

         Of 67 described poisoning incidents in California involving 583
    people, nineteen involved a pesticide product containing an
    organophosphate: most often chlorpyriphos (8), diazinon (3) and
    malathion (5). There were also 10 cases that resulted from suicide,
    and two cases involved diazinon (Maddy & Edmiston, 1988).

         In a study of organophosphate-induced contact dermatitis in 202
    patients in Japan, Matsushita et al. (1985) attributed the reactions
    mainly to diaoxabenzafos, fenitrothion, leptophos, cyanophos, diazinon
    and malathion. The areas affected by dermatitis were fingers (62.4%),
    face (39.6%), forearm (31.6%) and neck (29.7%). One quarter of the
    cases with dermatitis had symptoms associated with acute
    organophosphate poisoning.

    9.  EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

    9.1  Microorganisms

         Singh (1973) found that three genera of cyanobacteria (blue-green
    algae) tolerated diazinon at concentrations of 300 and 400 mg/litre.
    Clegg & Koevening (1974) indicated that the population densities of
    three species of freshwater algae were relatively unaltered by a
    concentration of 100 mg/litre. Butler et al. (1975) demonstrated that
    diazinon inhibited growth of numerous species of green algae and
    cyanobacteria at concentrations of 0.01 mg/litre and 0.1 mg/litre.
    Wong & Chang (1988) studied the effects of diazinon on the growth of
    the green alga,  Chlamydomonas reinhardtii. They observed a reduction
    in growth at concentrations of 5 and 10 mg/litre and complete
    inhibition at 20 and 40 mg/litre.

         Doggett & Rhodes (1991) determined the effects of diazinon on
    phytoplankton population dynamics. The objectives of this study were
    to determine the effects of diazinon (1, 5, 10, 20 and 40 mg/litre
    concentration) on the growth rates of three widely distributed species
    of freshwater algae, and to ascertain the effects of this pesticide on
    the diversity of a natural phytoplankton assemblage. Stimulation of
    growth was exhibited by  Selenastrum capricornutum and  Chorella 
    exposed to diazinon at 1 and 5 mg/litre. The higher concentrations of
    10, 20 and 40 mg/litre all inhibited growth. The growth rates of the
    cyanobacteria showed a high degree of tolerance; a suppression of
    growth was observed only at 40 mg/litre. Two genera of green algae
    were stimulated by all concentrations.

         The acute toxicity of diazinon to the freshwater rotifer
     Brachionus calyciflorus was determined after 24 h of exposure; the
    mean LC50 value was 29.2 mg/litre. Based on this result, four
    sublethal concentrations were chosen to determine the median lethal
    time (LT50) at each concentration of diazinon tested. The
    concentrations tested were 1/5, 1/4, ´ and 2/3 of the LC50 (24 h).
    The LT50 values ranged from 6.96 to 2.49 days after diazinon
    exposure, decreasing with increasing exposure concentration
    (Fernandez-Casalderrey et al., 1992).

         Several species of soil-borne fungi invade plant roots forming
    vascular-arbuscular mycorrhizae which aid in growth and nutrient
    element absorption. Pre-plant incorporated treatments at 2 and 4 kg/ha
    of trifluralin and diazinon had no significant effect on growth,
    phosphorus accumulation or root colonization by mycorrhizal fungi in
    soybeans planted in an Andover clay loam. At currently used commercial
    rates, diazinon did not affect mycorrhizal development under the
    conditions of the experiment (Burpee & Cole, 1978).

         Nitrogenase activity of excised soybean nodules was severely
    affected by diazinon following application of 3, 1, 0.5 and 0.25
    multiples of the amounts stated on the label (Hensley, 1991).

    9.2  Aquatic invertebrates

         Acute toxicity of diazinon to aquatic invertebrates is summarized
    in Table 4.

         The effect of diazinon (Basudine, 0.01, 0.1, 1.0 mg/litre) on the
    physical and chemical properties of haemolymph of  Lymnaea stagnalis 
    (L.) and  Planorbius corneus (L.) infected with trematodes was
    studied by Stadnichenko et al. (1987). Haemolymph viscosity and
    density decreased after the treatment.

         Robertson & Mazzella (1989) determined the toxicity of diazinon
    to the freshwater snail  Gillia altilis. Based on nominal
    calculations, the LC50 values for static 4- and 96-h exposures were
    340 mM (93 mg/litre) and 40 mM (11 mg/litre), respectively.

         Experiments were conducted to determine the effects of piperonyl
    butoxide, a synthetic methylenedioxyphenyl inhibitor of cytochrome(s)
    P-450, on the toxicity of organophosphate insecticides to three
    cladoceran test species:  Ceriodaphnia dubia,  Daphnia magna, and
     Daphnia pulex. The acute toxicity of diazinon to three tests species
    was similar, with LC50 values ranging from 0.50 to 0.80 mg/litre.
    Co-administration of piperonyl butoxide effectively reduced the acute
    toxicity of metabolically activated diazinon, and piperonyl butoxide
    concentrations of 500 or 1000 mg/litre completely blocked the toxicity
    of diazinon at concentrations of up to 16 times the 48-h LC50. In the
    case of  D. pulex, piperonyl butoxide at 500 mg/litre also
    significantly reduced the toxicity of diazinon at concentrations of up
    to 16 times the 48-h LC50 (Ankley et al., 1991).

    9.3  Fish

         The acute toxicity of diazinon to fish is summarized in Table 5.

         The median lethal concentration (LC50) of diazinon was
    determined for  Clarias batrachus; the LC50 for 40 days of exposure
    to diazinon was 2.4 mg/litre (Tripathi, 1992). The acute toxicities
    (24, 48, 72 and 96 h) of eight pesticides to  Anguilla anguilla were
    determined. The 24- to 96-h LC50 values for diazinon ranged from 0.16
    to 0.08 mg/litre (Ferrando et al., 1991).

         Bresch (1991) studied the effects of diazinon on early
    life-stages in zebrafish. Zebrafish kept at diazinon concentrations of
    0.2, 0.04 and 0.008 mg/litre grew alike, and no differences among the
    groups were observed. Survival rates of animals of different groups
    did not differ either. In no groups were abnormal fish seen.

        Table 4.  Acute toxicity (LC50) to aquatic invertebrates
                                                                                                                             
    Species                                   Duration (h)   Concentration (mg/litre)              Reference
                                                                                                                             

    Snail (Gillia altilis)                        96         11                                    Robertson & Mazzella (1989)

    Cladocerans                                   48         0.0005-0.0008                         Ankley et al. (1991)

    Cladoceran (Daphnia pulex)                    48         0.001 (0.0006-0.0011)                 Mayer & Ellersieck (1986)

    Cladoceran (Simocephalus serrulatus)          48         0.0014 (0.0012-0.0016) at 21°C        Mayer & Ellersieck (1986)
                                                             0.0018 (0.0014-0.0022) at 15°C

    Scud (Gammarus fasciatus)                     96         0.0002 (0.00015-0.00028)              Mayer & Ellersieck (1986)

    Shrimp (Hyallela azteca)                      96         0.004-0.006                           Collyard et al. (1994)

    Desmocaris trispimosa                         96         0.0208 (0.0192-0.0224)                Ebere & Akintonwa (1992)

    Shrimp (Palaemonetes africanus)               96         0.0179 (0.0147-0.020)                 Ebere & Akintonwa (1992)

    Insect larva (Pteronarcys californica)        96         0.025 (0.020-0.030)                   Mayer & Ellersieck (1986)
                                                                                                                             

    Table 5.  Acute toxicity (LC50) to fish
                                                                                                                                     

    Species                                      Duration (h)        Concentration (mg/litre)           Reference
                                                                                                                                     

    Bluegill sunfish (Lepomis macrocharis)           96              0.17 (0.012-0.22)                  Mayer & Ellersieck (1986)

    Rainbow trout (Oncorynchus mykiss)               96              0.09                               Mayer & Ellersieck (1986)

    Cutthroat trout (Salmo clarkii)                  96              2.76 (2.28-3.33) in soft water     Mayer & Ellersieck (1986)
                                                                     1.7 (1.39-2.09) in hard water

    Walking catfish (Clarias batrachus)                              2.41                               Tripathi (1992)

    Eel (Anguilla anguilla)                          96              0.08 (0.06-0.10)                   Ferrando et al. (1991)

    Channel catfish (Channa punctatus)               96              3.1                                Sastry & Malik (1982a)

    Goby (Gobius) sp.                                96              0.25 (0.23-0.28)                   Ebere & Akintonwa (1992)

    Lake trout (Salvelinus namaycush)                96              0.6 (0.4-0.9)                      Mayer & Ellersieck (1986)
                                                                                                                                     
        Table 6.  Summary of brain acetylcholinesterase activity inhibition by
              diazinon in aquatic organisms
                                                                        

    Organism          Exposure       Duration   Inhibition   Reference
                      concentration    (h)         (%)
                      (mg/litre)
                                                                        

    Bluegill              0.1           6          95       Weiss (1961)

    Fathead minnow        0.1          18          70       Weiss (1961)

    Goldfish              0.1          18          43       Weiss (1961)

    Golden shiner         0.1          18          40       Weiss (1961)

    Sheepshead minnow     6.5          24          71       Goodman
                                                            et al.
                                                            (1979)
                                                                        

         Whereas growth and survival of fathead minnows were not
    influenced at concentrations below 0.2 mg/litre in a test described by
    Allison & Hermanutz (1977), the minnows responded more sensitively in
    a similar test by another laboratory: effects were observed below
    0.08 mg/litre (Jarvinen & Tanner, 1982). Allison (1977) found reduced
    larval growth of the flagfish if reared in water containing diazinon
    at a concentration of 0.014 mg/litre.

         Brain acetylcholinesterase (AchE) activity and changes in
    optomotor behaviour were determined in bluegill sunfish,  Lepomis 
     macrochirus, exposed to graded concentrations (0, 15, 30, 5, 60 and
    75 µg/litre) of diazinon for a period of 24 h (Dutta et al., 1992). A
    significant decrease of AchE activity was observed at and above an
    exposure concentration of 45 µg/litre, whereas a decline in the scores
    of the "following" responses of the fish was observed at an exposure
    concentration of 30 µg/litre.

         Weiss (1961) was the first to investigate  in vivo brain AChE
    activity of fish exposed to organophosphates. He found that the extent
    of enzyme inhibition was proportional to the concentration of the
    substance and extent of exposure, and suggested that fish brain AChE
    activity could be used to detect the presence of anticholinesterases
    in the aquatic environment.

         Goodman et al. (1979) reported a dose-dependent inhibition of
    brain AChE activity in sheepshead minnows for diazinon. For the same
    sublethal exposure (6.5 mg/litre), inhibition was independent of the
    exposure duration, being 68 and 78% on days 4 and 108, respectively.

    The authors found that the brain AChE activity of sheepshead minnows
    exposed to diazinon varied and was susceptible to exposure
    concentration. AChE was depressed long after no measurable diazinon
    was found in exposed sheepshead minnows.

         The effect of acute exposure to diazinon (3.1 mg/litre for 96 h)
    and chronic exposure to a sublethal concentration (0.31 mg/litre) of
    diazinon has been studied in the liver, stomach, intestine and pyloric
    caeca of a freshwater teleost fish,  Channa punctatus. In acute
    exposure, succinate dehydrogenase activity was elevated in intestine
    and pyloric caeca. No alteration was noted in lactate dehydrogenase
    activity but pyruvate dehydrogenase activity was inhibited in pyloric
    caeca. Chronic exposure resulted in inhibition of the activities of
    the three dehydrogenases in all four organs at both intervals (Sastry
    & Malik, 1982a).

         Exposure to diazinon at different concentrations induced
    pathological changes in muscle cell organelles of  Tilapia nilotica. 
    The earliest changes in muscles of fish exposed to 10 mg/litre
    consisted of swelling of sarcoplasmatic reticulum in many fibres and
    the appearance of many cytoplasmatic vacuoles of different sizes. In
    muscle of fishes exposed to the LC50 (20 mg/kg) of diazinon,
    fragmentation of the myofibrils occurred over the entire length of the
    sarcomere with involvement of both the thick myosin filament of the
    A-band and the thinner actin filaments of the I-band. It was
    speculated that these effects may be attributed to the
    anti-cholinesterase activity of these insecticides. (Sakr & Gabr,
    1992).

         Acute effect of diazinon on the intramembranous particles
    (IMPs) of microvilli of the intestinal epithelial cells of  Tilapia 
     nilotica fish was studied using the freeze-fracture technique.
    Exposing fish to different repeated concentrations of diazinon
    (´ LC50) cause a significant decrease in the population density of
    IMPs in P and E faces. IMPs of microvilli found in intestinal
    epithelial cells are thought to represent many kinds of protein
    including enzymes. It was suggested that diazinon induced a reduction
    in enzymatic content of the membrane, which was accompanied by a
    decrease in the IMP density of the microvilli (Sakr et al., 1991).
    El-Elaimy et al. (1990) reported that exposure of  Tilapia nilotica 
    to increasing concentrations of diazinon induced ultrastructural
    alterations in the intestine.

         Four-month old adult siblings of zebrafish  (Brachydanio rerio) 
    were exposed to four concentrations of diazinon for up to 168 h. DNA,
    RNA, protein and total free amino acid content were measured in the
    liver. The DNA, RNA and protein contents were significantly reduced,
    whereas the amino acid content was significantly enhanced. All these
    changes showed a dose-dependent as well as a time-dependent response
    (Ansari & Kumar, 1988).

         Anees (1978) presented the results of sub-lethal exposure to
    diazinon of an adult freshwater teleost. The concentrations of
    insecticide used in the study were given as 0.37 mg/litre per 24 h and
    0.28 mg/litre per 96 h. This was a study on the evaluation of
    histopathology as a possible indicator of aquatic pollution by
    insecticides. Hepatocytes were considerably vacuolated and reduced in
    size after 24 h of exposure. However, 96 h of exposure produced less
    vacuolization but the liver showed a foamy appearance. Damage to the
    hepatic blood supply and the appearance of dark, granular cytoplasmic
    inclusions resulted from a 14-day exposure. The same concentrations of
    pesticide have already been observed to cause many tissue changes in
    the intestine of  Channa punctatus and disturbances in the
    distribution of serum proteins.

         The effect of exposure to the LC50 (12 mg/litre) for 96 h
    and to a sublethal concentration (3.3 mg/litre) for 15 and 30 days
    was studied in the digestive system of the catfish  Heteropneustes 
     fossilis. The most conspicuous pathological changes in the liver
    were vacuolization of the cytoplasm of hepatocytes, enlargement of
    nuclei, rupture of cell membrane, liver cord disarray, and damage of
    connective tissue. Intercellular spaces were widened. In stomach the
    mucosa was eroded. In intestine the nuclei of the columnar epithelial
    cells were reduced in volume and the cytoplasm was highly degenerated.
    In both acute and chronic exposure alkaline phosphatase and
    glucose-6-phosphatase activities were inhibited significantly in the
    different portions of the digestive system. Acid phosphatase activity
    was elevated in all the portions and in both stages of exposure. In
    acute exposure insignificant elevation was observed in the activities
    of amylase and maltase, while lactase activity was inhibited. An
    inhibition in maltase activity was significant only in the liver.
    Lipase activity showed a decrease in all stages of exposures, while
    there was no marked alteration in activities of pepsin and trypsin
    (Sastry & Malik, 1982b).

    9.4  Effects in mesocosms and the field

         A mesocosm study was performed with 17 treated and 4 untreated
    ponds (each 0.1 acre in surface area and 2.2 metres deep). The ponds
    received multiple applications of diazinon with single applications
    ranging from 2 to 25 µg/litre and corresponding to total application
    rates of 5.7, 11.4, 22.9, 45.8 and 91.5 µg/litre. The following
    effects on sediment-dwelling organisms were observed: Trichoptera was
    the most sensitive order, with significant reductions at all treatment
    levels throughout most of the treatment period. Trichoptera was a
    minor component of the macroinvertebrate communities in the mesocosms.
    Diptera and Ephermeroptera were intermediate in sensitivity; both were
    reduced at 22.9 and 91.5 µg/litre by the end of the treatment period,
    though both recovered to control levels shortly after treatment
    ended. Odonata was the least sensitive order with effects only at
    91.5 µg/litre. Total insect abundance generally followed the trend

    of the Diptera, which was the most abundant order; increasingly
    severe effects at 22.9 to 91.5 µg/litre during the treatment
    period was followed by recovery. The abundance of crustaceans in
    macroinvertebrate samples generally followed a similar pattern.
    Gastropods were essentially unaffected by diazinon. Though dipterans
    as a whole were affected only at 22.9 µg/litre or more and recovered
    rapidly, some dipteran sub-taxa were more sensitive or were
    significantly reduced in the post-treatment period. Tanypodinae and
    its dominant tribe, Pentaneurini, were the most sensitive. These were
    significantly reduced in all treated ponds at the end of the treatment
    period. Both groups recovered within eight weeks of the last
    treatment. The sub-family Chironominae was the next most sensitive
    among the family Chironomidae, especially the tribes Tanytarsini and
    Chironomini. Tanytarsinids were reduced at 22.9 µg/litre early in the
    treatment period and then recovered. Chironomini followed a similar
    pattern, including recovery, but were again reduced in number at 22.9
    to 91.5 µg/litre. The sub-family Orthocladiinae was the least
    sensitive chironomid group with effects only at 91.5 µg/litre and full
    recovery within two weeks. With the wide range of sensitivity observed
    among the chironomids, the overall impact of diazinon was relatively
    minor; statistically significant reductions were observed twice early
    in the highest treatment. Two less abundant dipteran families,
    Chaoboridae and Ceratopogonidae, were affected at 11.4 µg/litre or
    more. The greatest effect on Chaoboridae occurred two months into
    treatment and that on Ceratopogonidae occurred during the treatment
    period, but sporadic effects persisted beyond (Giddings, 1992).

         The application of diazinon to a small stream at 3 mg/litre
    resulted in increased drift of benthic organisms and changes in the
    composition of benthic fauna. These changes were not persistent,
    however, as the communities were restored to normal within 4 weeks of
    treatment (Miller et al., 1966).

    9.5  Terrestrial invertebrates

         Stevenson (1978) reported LD50 values for bees of 0.22 µg/bee
    (topical) and 0.20 µg/bee (oral).

         When earthworms  (Eisenia foetida) were exposed to technical
    diazinon in soil, the 14-day LC50 was calculated to be 130 mg/kg
    soil. A no-observed-effect concentration of 12.3 mg/kg was reported
    (Vial, 1990).

         In a field experiment in Connecticut, USA, diazinon was
    applied to tobacco fields as a 10% granular formulation at up to
    4.48 kg a.i./ha; granules were raked into the soil. Mortality of
    earthworms  (Lumbricus terrestris) did not differ between treated and
    control plots (Kring, 1969).

    9.6  Birds

         Acute toxicity to birds is summarized in Table 7.

         The use of diazinon for controlling flies in sheds used to house
    ducks led to the death of an estimated 15 600 young birds (Dougherty,
    1957).

         Ingestion of a few granules could be lethal to sparrow-sized
    birds for diazinon 14G (Hill & Camardese, 1984).

         Variability of toxicity among anticholinesterase formulations was
    shown with a single dose of diazinon administered orally as technical
    grade (TG, 99% a.i.) alone or in corn oil, as granular (GR, 14-15%
    a.i.), or as emulsifiable concentrate (EC, 48% a.i.). The rank of the
    formulations tested, from most to least toxic, based on statistically
    separable (p<0.05) LD50s, was EC > GR=TG > control. The difference
    between the least and most toxic form was nearly three-fold (Hill,
    1988).

         The single acute oral and dermal doses of diazinon were
    determined for 8- and 18-week-old broadbreasted white turkeys. The
    hazard to turkeys of exposure to soils treated for control of chiggers
    was evaluated. Diazinon was lethal for 18-week-old turkeys at 2 mg/kg
    orally and toxic at 5 mg/kg dermally. In spite of this high toxicity,
    exposing the turkeys to soil treated with 18 kg diazinon per hectare
    led to no poisoned birds (Radeleff & Kunz, 1972).

         The activity of acetylcholinesterase (AChE) and the density of
    muscarinic receptors were measured in brains from normal Japanese
    quail  (Coturnix coturnix japonica) and from quail after lethal
    intoxication with diazinon. The maximum relative loss of activity due
    to postmortem decomposition alone during 8 days was 13 and 10% for
    AChE and muscarinic receptors, respectively. During postmortem
    decomposition, the ratio of AChE and muscarinic receptor activities
    remained constant at approximately 1.3:1 in normal brains, while it
    was always less than, or equal to, 0.5:1 after intoxication with
    diazinon. Normal AChE activity could be estimated from muscarinic
    receptor density. Parallel measurement of AChE and muscarinic
    receptors may assist in the postmortem diagnosis of death due to acute
    poisoning with anti-cholinesterase pesticide when control specimens
    are not available (Prijono & Leighton, 1991).

         Anticholinesterases do not pass through the mother to the egg in
    significant amounts, but they may be deposited on the egg from the
    parents feathers or during pesticide application. To simulate topical
    exposure, fertile mallard eggs were either immersed for 30 seconds in
    an aqueous emulsion or single dose of an anticholinesterase in a
    non-toxic oil vehicle pipetted on the shell on day 3 of incubation
    which is a critical period with respect to organogenesis in mallards.

        Table 7.  Acute toxicity to birds
                                                                                                                                     

    Species                                           Age/weight                  LD50      LC50        Reference
                                                                                                                                     

    Japanese quail (Coturnix coturnix japonica)       50-60 days (105-195 g)      4                     Sachsse (1973a)
                                                      5 days (10-30 g)            1.1                   Sachsse & Ullmann (1975a)
                                                      50-60 days                            900a        Sachsse (1972)

    Bobwhite quail (Colinus virginianus)              14 days                     5.2                   Fink (1976)
                                                      140-180 g                   4.3                   Sachsse & Ullmann (1975b)

    Peking duck (Anas domesticus)                     2.5-3.5 kg                  2.7                   Sachsse & Ullmann (1976)
                                                      5 days (40-125 g)           1.9                   Sachsse & Ullmann (1975c)

    Domestic hen (Gallus domesticus)                  5 days (40-50 g)            14                    Sachsse & Ullmann (1975d)

    Mallard duck (Anas platyrhynchus)                 19 weeks (843-1357 g)       1.44                  Fletcher & Pedersen (1988a)
                                                      5 days                                202a        Sachsse (1973b)
                                                      9 days (108-120 g)                    32          Fletcher & Pedersen (1988c)

    Brown-headed cowbird (Molothrus ater)             35-55 g                     85                    Fletcher & Pedersen (1988b)
                                                                                                                                     

    a  Repellency recorded in all dosage groups.
        Organophosphates were shown to be as much as 18 times more toxic when
    applied to the shell in an oil compared with following water
    immersion. Neither method of egg treatment produced teratogenicity or
    developmental effects at realistic pesticide application rates
    (Hoffman & Eastin, 1981).

         A laboratory reproduction study was conducted with mallard in
    which birds were allowed to build their own nests and incubate eggs
    (Marselas et al., 1989a). Birds were fed diets containing 0, 5, 10 and
    20 mg diazinon/kg diet (20 pairs per dose level). The exposure to 5
    and 10 mg/kg did not result in any overt signs of toxicity or effects
    on reproductive performance. At 20 mg/kg, there was an increase in the
    number of hens that did not incubate and, although egg production was
    not affected, there was some reduction in the number of hatchlings and
    14-day-old survivors. A companion study (Marselas et al., 1989b) with
    bobwhite quail was conducted at dietary concentrations of 10, 20 and
    40 mg/kg. Exposures did not result in effects on reproductive
    performance and no mortalities or overt signs of toxicity were
    observed.

         Henderson et al. (1994) described certain oral and dermal
    toxicity of diazinon to the domestic pigeon. Dose-dependent gross
    symptoms of organophosphorus poisoning usually appear within half an
    hour in pigeons dosed orally. There was a 50% inhibition of brain
    cholinesterase activity, i.e. ID50 of diazinon was about 2 mg/kg body
    weight. Plasma cholinesterase activity in dermally exposed birds was
    almost completely inhibited by 24 h after diazinon treatment. The
    recovery of plasma cholinesterase after dermal exposure of pigeon was
    very slow.

         Johnston et al. (1994) studied the interactive effects of
    combined treatment of red-legged partridge with diazinon and an
    ergosterolbiosynthesis-inhibiting (EBI) fungicide (prochloraz). Birds
    were pre-treated with procloraz at 180 mg/kg and then exposed to
    diazinon at 4.3 mg/kg 24 h later. There was a tendency to increased
    inhibition of cholinesterase in the plasma of treated birds but this
    was not significant. Synergism was significant with other
    organophosphorus compounds tested.

    9.6.1  Field studies

         Nine fairways of a golf course located in Bellingham, Washington,
    USA, were treated with Diazinon AG500 at a target application rate of
    2.2 kg a.i./ha. The chemical application with a boomless sprayer
    resulted in a variable distribution of diazinon residues on the turf
    that ranged from 1.0 to 6.2 kg a.i./ha. The diazinon-treated turf was
    irrigated with 1.3 cm of water immediately following application. The
    post-irrigation diazinon residue levels ranged from 100 to 33 mg/kg
    (mean=209; SD=88; n=8). These residue levels were higher than expected
    based on results of turf studies in other regions of the USA.

    Eighty-five American wigeon died after grazing on one treated fairway
    on the day of application following irrigation. The brains of all 85
    wigeon were analysed for acetylcholinesterase activity. Wigeon that
    died on the study area showed 44 to 87% depression of AChE activity
    when compared to controls. Upper gastrointestinal tract contents of 15
    of the 85 dead wigeons contained 0.96 to 18.1 mg/kg diazinon (Kendall
    et al., 1992).

         In the USA, use of diazinon has been discontinued on golf courses
    since 1988. Waterfowl often congregate near ponds on golf courses and
    were exposed to turf treatments. Since this restriction, deaths of
    grazing waterfowl (Canada geese, brent geese and American wigeon) have
    not occurred. Application rate reduction may also be effective in
    reducing risk to Canada geese, the most common grazing bird on turf.
    Kendall et al. (1993) closely monitored geese exposed to diazinon
    applied twice at 2.2 kg a.i./ha, and found no mortality despite
    extensive feeding on treated turf.

         Hummell et al. (1992a,b,c) conducted an extensive, multi-plot
    assessment of the effects of turf applications of granular and liquid
    formulations (4.8 kg a.i./ha) of diazinon on songbirds.

         Since the introduction of diazinon, sporadic mortality of
    waterfowl feeding on treated turf or on orchard grass has come to
    light in Canada. Frank et al. (1991) reported five incidents that
    took place in Ontario between 1986 and 1988. Fifty-seven Canada
    geese were poisoned by diazinon on turf sites in Ontario 1986-88. It
    was determined that median levels of diazinon in turf sprayed and
    then properly irrigated ranged from 45.4 to 256 mg/kg for a single
    application of 1 kg a.i./ha of the EC formulation. A value of
    390 mg/kg was obtained for a single grass sample following spray at
    approximately 9 kg a.i./ha. Maximum residue levels for grass recovered
    from the oesophagi of geese killed by diazinon on turf, and collected
    while still fresh, ranged from 55 to 79 mg/kg.

         In trials evaluating applications to large turf areas (an average
    of ha), survival, behaviour and reproductive performance were
    monitored. Smaller plots (0.09 ha) that simulated large home yards
    were established for granular formulations, and survival and plasma
    ChE were evaluated. On large plots, the liquid formulation had no
    effect on reproductive performance, survival or cholinesterase levels.
    Granular applications had a minor impact on bird population size (9.6%
    reduction) compared to control plots (4.8% reduction). Reproductive
    performance was not affected, although cholinesterase levels were
    reduced compared to controls. On the smaller (home-sized) turf plots
    there was no apparent effect on bird numbers, and plasma
    cholinesterase activity was not affected in any species.

         Decarie et al. (1993) sprayed ornamental and other deciduous
    trees with diazinon at a rate of 2.2 kg a.i./ha in a suburban area of
    Quebec, Canada, where the compound was used to control fruit tree
    mites. Twelve nests of the American robin were sprayed and 65 nests
    untreated were used as controls. Productivity was compared between
    treated and control nests as was the behaviour of the birds. Mean
    productivity was not significantly different between the two groups.
    Number of feeding flights, number of female feeding flight and number
    of faecal sacs removed did not differ between groups but there was a
    significant increase in the total time spent sitting on the nest in
    diazinon-treated birds. The significance of this is unclear. Plasma
    AChE levels were reduced (993 ± 639 µg/litre in treated birds;
    3585 ± 1531 µg/litre in controls), but brain AChE activity was
    unaffected.

    10.  EVALUATION OF HUMAN HEALTH RISK AND EFFECTS ON THE ENVIRONMENT

    10.1  Evaluation of human health risk

         Diazinon is an organophosphorus pesticide classified by WHO as
    "moderately hazardous" Class II (WHO, 1996). It is absorbed from the
    gastrointestinal tract, through intact skin, and by inhalation. The
    sources of exposure to humans are occupational, accidental or through
    diet. Diazinon is used as a pesticide and veterinary drug to control
    ectoparasites. The major source of diazinon food residues in edible
    crops are from agricultural usage while those in meat, offal and other
    animal products arise from veterinary use

         The results of total diet studies in the USA, United Kingdom and
    New Zealand suggest that levels of exposure are below the recommended
    Acceptable Daily Intake (ADI) of 0.002 mg/kg per day (FAO/WHO, 1994b).
    Diazinon is rapidly broken down, whether on plants or in animals,
    further reducing the risk to humans. Several different application
    techniques are used in applying diazinon outside and inside. Residual
    spraying and space treatment are often used in controlling pests
    indoors. Following recommended use, concentrations of diazinon
    detectable in the indoor air are low and do not present a health
    hazard. Some studies of agricultural workers have shown cases of
    contact dermatitis after exposure to diazinon. Toxicity studies in
    humans have shown that the administered daily dose of 0.025 mg/kg body
    weight marginally inhibits the plasma cholinesterase activity and it
    can be considered as the no-observed-adverse-effect level (NOAEL).
    Diazinon is not genotoxic and exhibits no carcinogenic potential in
    rats or mice. Several episodes of fatal and non-fatal accidental and
    suicidal poisoning have occurred. Acute poisoning causes typical
    cholinergic signs and symptoms. Acute pancreatitis can be associated
    with severe poisoning.

    10.2  Evaluation for effects on the environment

         The information on utilization and application rates that has
    been employed for this risk assessment is derived from the
    agricultural use of diazinon within the European Union. It should be
    possible to extrapolate this assessment to other agricultural uses at
    similar application rates elsewhere in the world. The application
    rates for diazinon can be summarized as follows: arable (tractor-
    mounted/drawn hydraulic spray boom applications), 1.0 kg/ha; top fruit
    (broadcast air-assisted applications), 1.2 kg/ha.

         The following risk assessment is based on the principle of
    calculating toxicity-exposure ratios (TERs) (Fig. 2), which follows
    the European and Mediterranean Plant Protection Organisation and
    Council of Europe (EPPO/CoE) Environmental Risk Assessment Scheme
    model and associated trigger values (EPPO/CoE, 1993a,b).

    FIGURE 2

    10.2.1  Aquatic organisms

         The main risk to aquatic organisms from the use of diazinon is
    from spray drift during either arable applications (1.0 kg/ha) or top
    fruit air-assisted (1.2 kg/ha). For each of these risk scenarios, the
    predicted environmental concentration (PEC) in a 30-cm-deep static
    surface water body, arising from either arable-based spray drift at
    1 m from the edge of the spray boom or from top fruit air-assisted
    spray drift at 3 m from the point of application (both based on
    Ganzelmeier et al., 1995), was calculated as follows:

    PEC           =  max application rate (kg/ha) × A (% spray drift)
    (mg diazinon/                                                   
    litre)                              300

    Where A = 5 for ground-based hydraulic spray application 1 m from edge
              of boom

            = 30 for air-assisted application 3 m from point of
              application

    10.2.1.1  Acute risk

         The acute EC50 value for the most sensitive fish was
    0.09 mg/litre and for the most sensitive aquatic invertebrate
     (Gammarus) 0.0002 mg/litre. For the most sensitive algal
    species the 14-day NOEC was 1 mg/litre.

    (a)   Spray drift from ground-based applications: The acute PEC for
    spray drift (l m from the edge of the spray boom into a 30-cm-deep
    static water body at the maximum application rate (see PEC assumptions
    above) is 0.017 mg/litre. Therefore, the TERs, based on this PEC and
    the above EC50/NOEC toxicity values, are: fish, 5.4; aquatic
    invertebrates, 0.01; and algae, 60. Based on the EPPO/CoE
    risk assessment scheme for aquatic organisms, these TERs (i.e. TERs
    >10 = low risk; TERs <1 = high risk) indicate a low acute risk to
    algae and a high risk to these organisms. The TER for fish was between
    1 and 10, indicating an intermediate risk. In such risk situations the
    use of a "no-spray" restriction zone next to surface waters may reduce
    the risk to such aquatic invertebrates. For example, arable spray
    drift at 5 m from the edge of boom is 0.6% (Ganzelmeier et. al.,
    1995). Based on this 5-m drift data, the PEC is 0.002 mg/litre and
    results in a 5-m TER of 45 for fish. This TER at 5 m indicates that
    the use of a 5-m "no-spray" restriction zone next to surface waters
    would reduce the acute risk to fish.

    (b)   Spray drift from broadcast air assisted top fruit 
     applications: The acute PEC for spray drift (3 m from the point of
    application into a 30-cm-deep static water body at the maximum
    application rate (see PEC assumptions above) is 0.12 mg/litre.

    Therefore, the TERs based on this PEC and the above EC50/NOEC
    toxicity values are: fish, 0.75; aquatic invertebrates, 0.0017; and
    algae, 8.3. Based on the CoE/EPPO risk assessment scheme for aquatic
    organisms, these TERs indicate a high acute risk to fish and
    invertebrates and an intermediate risk to algae. Table 8 below
    summarizes the acute TERs for aquatic organisms at 1 m for arable and
    3 m for broadcast air-assisted applications.

    10.2.1.2  Chronic risk

         There were no chronic toxicity data available.

    10.2.2  Terrestrial organisms

         Vertebrates are likely to be exposed to diazinon from either
    grazing treated vegetation or consuming contaminated insects. For this
    risk assessment, typical application rates of 1 kg/ha are used for
    ground spray application on arable crops and 1.2 kg/ha for application
    by air-assisted spraying for fruit

    10.2.2.1  Birds

         The lowest reported acute oral LD50 for birds is 1.1 mg/kg body
    weight for the Japanese quail. The dietary LC50 for the mallard duck
    is 32 mg/kg diet.

         Indicator birds for use in the risk assessment will be:

    *    Greylag goose  (Anser anser), as a grazing species, with a body
         weight of 3 kg and total daily food consumption of 900 g
         vegetation (dry weight) (Owen, 1975)

    *    Blue tit  (Parus caeruleus), as an insectivorous species, with a
         body weight of 11 g and total daily food consumption of 8.23 g
         (dry weight) (Kenaga, 1973).

    a)    Grazing birds

         Initial residues on short grass or cereal shoots, arising from
    application at 1 kg/ha to arable crops, are estimated to be 112 mg/kg
    dry weight (based on 112 × application rate in kg/ha (EPPO/CoE,
    1993a,b) and at 134.4 mg/kg from application to fruit at a rate of
    1.2 kg/ha. This gives an estimated total oral intake for the goose of
    100.8 and 121.0 mg for the two application rates assuming that the
    goose ate exclusively food contaminated at this level. This is
    equivalent to a daily intake of 33.6 and 40.3 mg/kg body weight,
    respectively. TERs can be calculated as follows:

        Table 8.  Acute toxicity-exposure ratio (TERs) for aquatic organisms at 1 m for arable and 3 m
              for broadcast air-assisted applications
                                                                                                                     

    Species                                 EC50/NOEC      PEC            PEC               TER         TER
                                            (mg/litre)     (mg/litre)     (mg/litre)        (arable)    (air-assisted)
                                                           (arable)       (air-assisted)
                                                                                                                     

    Fish (Oncorhynchus mykiss)              0.09           0.017          0.12              5.4         0.75

    Aquatic invertebrate (Gammarus)         0.0002         0.017          0.12              0.012       0.0017

    Algae (Selenastrum capricornutum)       1.0            0.017          0.12              60.0        8.3
                                                                                                                     
                                                                              

    End-point         LD50/L50         Application   Predicted      TER
                                       rate          concentration
                                       (kg/ha)       in food
                                                     (mg/kg)
                                                                          

    Bird acute oral   1.1 mg/kg        1             112            0.033
                      body weight      (arable)
                      Japanese quail

                                       1.2           134.4          0.027
                                       (fruit)

    Bird short-term   32 mg/kg diet    1             112            0.29
    dietary           mallard duck     (arable)
                                       1.2           134.4          0.24
                                       (fruit)
                                                                          

         The calculated TER values fall well below the EPPO/CoE trigger
    values for concern (TER <10) and indicate a high risk to grazing
    birds. This potential risk has been confirmed in practice with
    reported high incidence of fatalities following application of
    diazinon to golf-course turf. This application is no longer
    recommended for this reason.

    b)    Insectivorous birds

         Initial residues on small insects arising from application at
    1 kg/ha to arable crops are estimated to be 29 mg/kg dry weight (based
    on 29 × application rate in kg/ha) (EPPO/CoE, 1993a,b) and 34.8 mg/kg
    from application to fruit at a rate of 1.2 kg/ha. This gives an
    estimated total oral intake for the blue tit of 0.24 mg and 0.29 mg
    for the two application rates assuming that the blue tit ate
    exclusively food contaminated at this level. This is equivalent to a
    daily intake of 21.7 and 26.0 mg/kg body weight, respectively. TERs
    can be calculated as follows:

         The TERs for acute toxicity to insectivorous birds are
    substantially less then the trigger value of <10, indicating high
    acute risk to these birds. The risk factors exceed the trigger for
    insectivorous birds exposed short-term via the diet.

                                                                          

    End-point           LD50/LC50        Application  Predicted      TER
                                         rate         concentration
                                         (kg/ha)      in food
                                                      (mg/kg)
                                                                          

    Bird acute oral     1.1 mg/kg        1            29             0.05
                        body weight      (arable)
                        Japanese quail

                                         1.2          34.8           0.04
                                         (fruit)

    Bird short-term     32 mg/kg diet    1            29             1.1
    dietary                              (arable)

                                         1.2          34.8           0.92
                                         (fruit)
                                                                          

    10.2.2.2  Mammals

         The lowest reported acute oral LD50 for laboratory mammals is
    82 mg/kg body weight for the mouse.

         Indicator mammals for use in the risk assessment will be:

         *    Rabbit  (Orystolagus cuniculus), as a grazing mammal, with
              a body weight of 1200 g and a total daily food consumption
              of 500 g vegetation (dry weight) (Ross, personal
              communication to the IPCS)

         *    Shrew  (Sorex araneus), as an insectivorous mammal, with a
              body weight of 18 g and a total daily food consumption of
              18 g (Churchfield, 1986)

    a)    Grazing mammals

         Initial residues on short grass or cereal shoots arising from
    application at 1 kg/ha to arable crops are estimated to be 112 mg/kg
    dry weight (based on 112 x application rate in kg/ha) (EPPO/CoE,
    1993a,b) and at 134.4 mg/kg from an application to fruit at a rate of
    1.2 kg/ha. This gives an estimated total oral intake for the rabbit of
    56 and 67.2 mg for the two application rates, assuming that the rabbit
    ate exclusively food contaminated at this level. This is equivalent to
    a daily intake of 46.7 and 56 mg/kg body weight, respectively. TERs
    can be calculated as follows:

                                                                        

    End-point    LD50          Application   Predicted        TER
                               rate          concentration
                               (kg/ha)       in food
                                              (mg/kg)
                                                                        

    Mammal       82 mg/kg      1             56               1.76
    acute oral   body weight   (arable)
                 mouse

                               1.2           67.2             1.46
                               (fruit)
                                                                        

         This indicates a high risk to grazing mammals (trigger <10)
    comparable to that for grazing birds. Again, the removal of
    application to golf-course turf would reduce the likelihood of
    exposure to maximum residues of diazinon. However, grazing mammals
    consuming short cereal shoots could be killed following recommended
    use of the compound.

    b)    Insectivorous mammals

         Initial residues on large insects arising from application at
    1 kg/ha to arable crops are estimated to be 2.7 mg/kg dry weight
    (based on 2.7 × application rate in kg/ha) (EPPO/CoE, 1993a,b) and
    3.24 mg/kg from an application to fruit at a rate of 1.2 kg/ha. This
    gives an estimated total oral intake for the shrew of 0.049 mg and
    0.058 mg for the two application rates, assuming that the shrew ate
    exclusively food contaminated at this level. This is equivalent to a
    daily intake of 2.7 and 3.2 mg/kg body weight, respectively. TERs can
    be calculated as follows:

         These TERs fall outside the trigger for high risk for
    insectivorous mammals but within the range for medium risk, reflecting
    the high acute mammalian toxicity.

                                                                        

    End-point     LD50           Application       Predicted       TER
                                 rate              concentration
                                 (kg/ha)           in food
                                                    (mg/kg)
                                                                        

    Mammal        82 mg/kg       1                 2.7             30.4
    acute oral    body weight    (arable)
                  mouse

                                 1.2               3.24            25.3
                                 (fruit)
                                                                        

    10.2.2.3  Bees

         The reported contact and oral toxicity to bees gives LD50 values
    of 0.22 and 0.2 µg/bee, respectively. Using application rates of 1000
    and 1200 g/ha for cereals and fruit, respectively, hazard quotients
    are calculated to be 4545 and 5455 (application in g/ha). The trigger
    for concern is >50 (EPPO/CoE, 1993a,b) and, therefore, there is
    substantial concern for exposed bees. The compound should not be
    applied to flowering plants and exposure of flying bees should be
    avoided.

    10.2.2.4  Earthworms

         Earthworms are likely to be exposed to the highest concentration
    of diazinon following use of the granular formulation incorporated in
    soil at up to 2000 g/ha. Based on a soil depth of 5 cm and a soil
    density of 1.5 g/cm3, the soil PEC would be 2.67 mg/kg, assuming even
    distribution in the medium. The reported LC50 for earthworms
     (Eisenia foetida) is 130 mg/kg soil, giving a TER of 48.75. As this
    is above the trigger value of 10 (EPPO/CoE, 1993a,b), the acute risk
    to earthworms should be low. Reported concentrations measured in soil
    are at least an order of magnitude lower than the PEC suggesting that
    little risk is posed to worms.

    11.  CONCLUSIONS AND RECOMMENDATIONS FOR PROTECTION OF HUMAN HEALTH
         AND THE ENVIRONMENT

    11.1  Conclusions

         The general population does not face a significant health risk
    from diazinon. It may cause acute poisoning in cases of over-exposure
    following intentional ingestion or careless handling during its
    manufacture and use. The general public is exposed to diazinon in the
    form of its residues in food, but the reported intake of diazinon is
    far below the acceptable daily intake. Following residual spraying and
    space treatment, used to control insects, the general population can
    be exposed to residues in the air and on surfaces. With good work
    practice and hygiene measures, and if safety precautions and medical
    surveillance are enforced, diazinon is unlikely to present a hazard to
    those occupationally exposed.

         Diazinon does not persist in the environment and is not
    accumulated by organisms. It has high acute toxicity to aquatic
    invertebrates, fish, terrestrial birds and mammals, leading to high
    risk factors for many of these organisms. Field kills of waterfowl
    have been reported following use of the compound on amenity turf.
    Precautions should be taken to minimize exposure of non-target
    organisms (e.g., do not spray over water bodies, minimize exposure by
    spray drift and avoid areas where wildfowl are likely to graze).

    11.2  Recommendations for protection of human health and the
          environment

         Certain groups within the population, including agricultural
    workers and employees in the chemical industry, have the potential of
    being exposed to diazinon. Gardeners and householders may also be
    involved.

    11.2.1  Recommendation on regulation of compound

         Formulations have different classification categories: (FAO/WHO,
    1979): liquids over 20% are in category 3; other liquids or solids
    over 50% are in category 4; and all other solids are in category 5.

    11.2.1.1  Transport and storage

         Formulations in categories 3 and 4 should be transported and
    stored in clearly labelled rigid and leak-proof containers, away from
    containers of food and drink. Storage should be under lock and key and
    secure from access by unauthorized people. Formulations in category 5
    should be transported and stored in clearly labelled leak-proof
    containers, out of reach of children and away from food and drink.

    11.2.1.2  Handling

         Protective clothing should be used by all handling of the
    compound. Adequate washing facilities should be available at all times
    during handling and should be close to the site of handling. Eating,
    drinking and smoking should be prohibited during handling and before
    washing the hands after handling.

    11.2.1.3  Disposal

         Containers may be decontaminated as recommended by the WHO Expert
    Committee on Vector Biology and Control on the Safe Use of Pesticides
    (WHO, 1991). Decontaminated containers should not be used for food and
    drink. Containers that are not decontaminated should be burned or
    crushed and buried below topsoil. Care must taken to avoid subsequent
    contamination of water sources.

    11.2.1.4  Selection, training and medical supervision of workers

         Pre-employment medical examination of workers is desirable.
    Workers suffering from active hepatic or renal disease should be
    excluded from contact with diazinon. Pre-employment and periodic
    cholinesterase test for workers is desirable especially for those
    handling concentrates. Training of workers in techniques to avoid
    contact is essential. Pilots and loaders should have special training
    in application methods and early symptoms of poisoning, and must wear
    a suitable respirator. Flagmen, if used, should wear overalls and be
    located well away from the dropping zone.

    11.2.1.5  Labelling

         Diazinon is an organophosphorus compound that inhibits
    cholinesterases. It is poisonous if swallowed. It may be absorbed
    though the skin. It is important to avoid skin contact, wear hand
    protection, clean protective clothing. The material must be kept out
    of reach of children and well away from foodstuffs, animal feed and
    their containers. If poisoning occurs, a physician should be called.

    11.2.1.6  Residues in food

         Maximum residue limits have been recommended for diazinon by the
    Joint FAO/WHO Meeting on Pesticides Residues (FAO/WHO, 1975).

    11.2.2  Prevention of poisoning in man and emergency aid

    11.2.2.1  Manufacture and formulation

         Closed systems and forced ventilation may be required to reduce
    as much as possible the exposure of workers to diazinon.

    11.2.2.2  Mixers and applicators

         When mixing, protective impermeable boots, rubber apron, clean
    overalls and gloves should be worn. When spraying tall crops or during
    aerial application, a face mask should be worn, as well as an
    impermeable hat, clothing, boots and gloves. The applicator should
    avoid working in spray mist and avoid contact with the mouth.
    Particular care is needed when equipment is being washed after use.
    All protective clothing should be washed immediately after use.
    Splashes must be washed immediately from the skin or eyes with large
    quantities of water.

    11.2.2.3  Other associated workers

         People exposed to diazinon and associated with its application
    should wear protective clothing and observe the precautions described
    in section 11.2.2.2.

    11.2.2.4  Other populations likely to be affected

         With good application practice, other people should not be
    exposed to hazardous amounts of diazinon.

    11.2.3  Entry into treated areas

         Unprotected people should abide by re-entry periods stated on
    product labels.

    11.2.4  Emergency aid

         If symptoms appear following exposure, the person should stop
    work immediately, remove contaminated clothing, wash the affected skin
    with soap and water, if available, and flush the area with large
    quantities of water. If diazinon has been swallowed and the person is
    conscious, vomiting should be induced.

         Atropine and oximes are specific antidotes and artificial
    respiration may be needed.

    11.2.5  Surveillance test

         Slight reduction of plasma cholinesterase activity can be
    observed. Periodic blood cholinesterase tests for workers is
    desirable.

    12.  FURTHER RESEARCH

    1.   Studies of exposed worker populations should be continued.

    2.   Diazinon should be manufactured and formulated in accordance with
         international specifications. It should be packed and stored
         under conditions that are not conducive to the formation of
         acutely toxic impurities.

    3.   The safe use of diazinon should follow label directions and
         precautions for handling, application and disposal.

    13.  PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

         Diazinon has been evaluated by the Joint FAO/WHO Meeting on
    Pesticide Residues (JMPR) on a number of occasions since 1965. An
    acceptable daily intake (ADI) of 0.002 mg/kg body weight has been
    established and maximal residues levels have been recommended for
    diazinon in a wide range of food commodities (FAO/WHO, 1994a,b).

         The following NOAELs were established:

    Rat (two-year feeding study):      1.5 mg/kg diet
                                       (0.06 mg/kg body weight per day)

    Dog (one-year feeding study):      0.5 mg/kg diet
                                       (0.015 mg/kg body weight per day)

    Rhesus monkey (two-year study):    0.5 mg/kg body weight per day

    Human volunteers (36-day study):   0.025 mg/kg body weight per day

         Diazinon has not been evaluated by the International Agency for
    research on Cancer (IARC).

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    RÉSUMÉ ET ÉVALUATIONS

    1.  Identité, propriétés physiques et chimiques et méthodes d'analyse

         Le diazinon était connu jusqu'à ces dernières années sous le nom
    chimique de thiophosphate de di- O-méthyle de d 'O-(isopropyl-2
    méthyl-6 pyrimidyl-4). Selon les nouvelles conventions de
    nomenclature, sa dénomination chimique est désormais phosphorothioate
    de  O,O-diéthyle et de  O-2-isopropyl-6-méthylpyrimidiny-4-yle. A
    l'état pur, il se présente sous la forme d'un liquide incolore
    dégageant une légère odeur d'ester. La matière active de qualité
    technique est un liquide jaune à brun doté d'une odeur légère mais
    caractéristique. Son point d'ébullition est de 83-84°C sous une
    pression de 26,6 mPa. Sa tension de vapeur (volatilité) est faible
    (9,7 mPa à 20°C). Sa solubilité dans l'eau à la température ambiante
    est de 60 mg/litre. Le diazinon est soluble dans la plupart des
    solvants organiques et son coefficient de partage entre l'octanol et
    l'eau (log Pow) est de 3,40. Il est stable en milieu neutre, mais il
    s' hydrolyse lentement en milieu alcalin et plus rapidement en milieu
    acide. Il se décompose au-dessus de 120°C.

         Il existe de nombreuses méthode d'échantillonnage et d'analyse
    pour le recherche et le dosage du diazinon et de ses métabolites dans
    différents milieux. On fait de plus en plus appel à des méthodes
    sensibles telles que la chromatographie en phase gazeuse, la
    chromatographie en phase liquide à haute performance, la spectrométrie
    de masse et certaines techniques immunologiques.

    2.  Production, usages et sources d'exposition humaine et
        environnementale

         Le diazinon est un insecticide de contact dont le spectre
    d'activité est très étendu. Il est efficace contre les formes adultes
    et juvéniles d'insectes volants ou rampants, ainsi que contre les
    acariens et les arachnides. On l'utilise depuis le début des années
    cinquante. Il est principalement commercialisé sous la forme de
    concentrés émulsionnables et de poudres mouillables. Il existe
    également en formulations dans lesquelles il est associé à d'autres
    insecticides.

    3.  Transport, distribution et transformation dans l'environnement

         La volatilisation du diazinon à partir du sol n'a qu'une
    importance mineure. Sa demi-vie dans la troposphère est de 1,5 h.

         Le mouvement du diazinon dans le sol dépend d'un certain nombre
    de facteurs, en particulier de la teneur en matières organiques et en
    carbonate de calcium. Le diazinon ne devrait pas être très solide-ment
    fixé aux particules du sol, du fait que son Koc est égal à 500 et il
    devrait être modérément mobile dans le sol.

         La décomposition du diazinon dans le sol s'effectue
    principalement par voie biologique. A une température de 20°C et pour
    une teneur en eau du sol égale à 60% de la capacité totale, on a
    constaté que dans un limon, la DT50 était de 5 jours. Dans des
    conditions stériles, et pour la même teneur en eau et la même
    température, on a obtenu une DT50 de 118 jours, ce qui donne à penser
    que c'est bien l'activité biologique qui est principalement
    responsable de la décomposition du diazinon dans le sol.

         Dans les eaux naturelles, le diazinon a une demi-vie de l'ordre
    de 5 à 15 jours. Des processus chimiques et biologiques semblent
    intervenir dans sa décomposition, qui aboutit à une minéralisation en
    quelques semaines.

         Les organismes aquatiques fixent rapidement le diazinon. On a
    fait état de faibles facteurs de bioconcentration chez ces organismes,
    allant de 3 pour la crevette à 152 pour le goujon, ce qui correspond
    bien à une métabolisation et à une excrétion rapides. Une demi-vie de
    dépuration pouvant atteindre 30 h (tissu musculaire) a été mesurée
    chez des poissons.

    4.  Concentrations dans l'environnement et exposition humaine

         Le diazinon est généralement présent à faible concentration dans
    l'environnement. La population générale peut être exposée par voie
    alimentaire ou respiratoire. L'exposition par l'intermédiaire de l'eau
    est négligeable. En milieu professionnel, elle est principalement
    transcutanée.

         On peut diviser les usages du diazinon en deux grandes
    catégories: comme pesticide en agriculture et comme médicament en
    médecine vétérinaire. Dans ces conditions, les résidus de diazinon
    présents dans les cultures vivrières résultent principalement de
    l'utilisation de ce composé comme pesticide en agriculture, alors que
    ceux qui se retrouvent dans la viande, les abats et autres produits
    d'origine animale proviennent de son usage comme principe actif dans
    certains médicaments vétérinaires.

         Il n'y a que de très petites quantités de résidus dans les
    légumes, les fruits et les produits d'origine animale. Des études de
    rations totales ont montré que le composé subit une dégradation rapide
    dans les produits d'origine animale et végétale. On n'a pas décelé la
    présence de diazinon dans les échantillons d'eau de boisson analysés
    et sa concentration dans les eaux superficielles est de l'ordre du
    nanogramme par litre.

    5.  Cinétique et métabolisme

         Le diazinon peut être résorbé dans les voies digestives, par la
    voie transcutanée ou après inhalation. Chez l'homme, l'absorption
    transcutanée est faible. Sous l'action des enzymes microsomiennes, le
    diazinon est oxydé en métabolites inhibant la cholinestérase comme le
    diazoxon, l'hydroxydiazoxon et l'hydroxydiazinon. On ne les retrouve
    qu'en quantités infimes dans le lait et les oeufs. Le diazinon et ses
    métabolites ne s'accumulent pas dans les tissus de l'organisme: une
    dose de diazinon administrée par voie orale est excrétée à 59-95% dans
    les 24 h et à 95-98% au bout de 7 jours, principalement dans les
    urines.

         Les principales voies de dégradation métaboliques sont les
    suivantes:

    a)   Clivage du groupement ester, conduisant à des dérivés de
         l'hydroxypyrimidine.

    b)   Passage de la liaison P=S à la liaison P=O.

    c)   Oxydation du substituant isopropyl en alcool correspondant

    d)   Oxydation du substituant méthyl en alcool correspondant

    e)   Clivage du groupement ester sous l'action du glutathion,
         conduisant à un conjugué avec le glutathion.

         Le clivage de l'ester phosphorique, qui conduit, directement ou
    par l'intermédiaire du diazoxon, aux métabolites à noyau pyrimidine,
    constitue l'étape principale du métabolisme du diazinon. Les
    métabolites qui conservent le groupement ester phosphorique sont de
    nature transitoire et on ne les observe qu'en petite quantité. Les
    métabolites sont produits en proportion et à des vitesses très
    variables selon les espèces. En règle générale, il n'y a pas de
    corrélation entre la sensibilité à l'intoxication par le diazinon et
    la production de diazoxon, encore qu'elle soit la plus faible chez le
    mouton, qui est précisément l'espèce la moins sensible. Le métabolisme
    extrahé-patique du diazinon, en particulier l'hydrolyse du diazoxon
    dans le plasma, joue un rôle toxicologique plus important que le
    métabolisme intrahépatique, mais il est vrai que chez les oiseaux, le
    foie est sans doute l'organe le plus important de ce point de vue. Les
    métabolites qui se forment, à savoir l'acide diéthylphosphorique,
    l'acide diéthyl-thiophosphorique, et un certain nombre de dérivés
    contenant le noyau de la pyrimidine, sont principalement éliminés par
    la voie rénale.

    6.  Effets sur les animaux de laboratoire et les systèmes d'épreuve
        in vitro

         Les améliorations apportées depuis 1979 au procédé de fabrication
    du diazinon ont permis de réduire sensiblement sa teneur en impuretés
    fortement toxiques, comme le pyrophosphate de tétraéthyle (TEPP).
    Grâce à ces améliorations progressives, la DL50 aiguë par voie orale
    de diazinon technique est passée, pour le rat, de 250 à 1250 mg/kg.

         Quelle que soit la voie d'exposition (orale, transcutanée ou
    respiratoire), la toxicité aiguë du diazinon est faible. Des études à
    court et à long terme effectuées sur des souris, des rats, des lapins,
    des chiens et des singes ont montré que le seul effet préoccupant
    était une inhibition, liée à la dose, de l'activité
    acétylcholinesterasique.

         Le diazinon est légèrement irritant pour la peau chez le lapin
    mais il n'irrite pas la muqueuse de l'oeil. Il ne provoque pas de
    sensibilisation cutanée. Les études toxicologiques consacrées à ses
    effets sur la reproduction et le développement n'ont pas mis en
    évidence d'activité embryotoxique ou tératogène. La capacité de
    reproduction n'a pas été affectée aux doses non toxiques pour les
    animaux de la génération parentale. Des études de mutagénicité
    comportant divers points d'aboutissement  in vivo et  in vitro n'ont
    pas non plus indiqué que le diazinon soit doté d'un quelconque pouvoir
    mutagène. Aucun signe d'activité cancérogène n'a été relevé chez le
    rat et la souris. Le diazinon n'a pas provoqué pas de neuropathie
    retardée chez des poules. Chez des chiens et des cobayes, on a observé
    des cas de pancréatite aiguë ; on estime que cet effet est propre aux
    espèces en cause.

    7.  Effets sur l'Homme

         On a fait état d'un certain nombre d'intoxications accidentelles
    ou consécutives à une tentative de suicide, qui, quelquefois, ont eu
    une issue mortelle. Dans certaines de ces circonstances, les troubles
    de nature cholinergique se sont révélés plus graves que prévu en
    raison de la présence d'impuretés très toxiques, comme le
    pyrophosphate de tétraéthyle (TEPP). On a pu aussi constater, dans
    certains cas, la présence d'une pancréatite aiguë réversible
    accompagnant le syndrome cholinergique. Cet effet s'observe également
    dans les intoxications par d'autres inhibiteurs de la cholinestérase.
    On aussi quelquefois observé un syndrome intermédiaire. Aucun cas de
    neuropathie retardée n'a été signalé, conformément aux données
    obtenues sur l'animal.. Dans tous les cas d'intoxication
    professionnelle dont on a eu connaissance, il y avait présence
    d'impuretés telles que le TEPP, le monothio-TEPP ou le sulfo-TEPP dans
    la formulation utilisée. Il est peu probable que les formulations
    actuelles contiennent encore de ces impuretés.

    8.  Effets sur les autres êtres vivants au laboratoire et dans leur
        milieu naturel

         Le diazinon produit des effets variables sur les algues
    unicellulaires; on a constaté des effets d'inhibition  et de
    stimulation de la croissance chez différentes espèces à des
    concentrations de 0,01 et de 5 mg/litre. En général, il y a réduction
    de la croissance au-delà de 10 mg/litre, mais dans certains cas,
    l'effectif de la population n'a pas été modifié à une concentration de
    100 mg/litre. La rareté et la variabilité des données rendent
    difficile l'évaluation des effets produits sur les autres
    microorganismes.

         Les valeurs de la CL50 à 96 h (effets aigus) pour les
    invertébrés aquatiques vont de 0,2 dans le cas de  Gammarus 
     fasciatus à 4,0 mg/litre pour la crevette  Hyallela azteca. Les
    mollusques sont notablement moins sensibles, d'après une épreuve
    effectuée sur le gastéropode  Gillia attilis. Des effets sublétaux
    ont été observés au niveau du comportement à des concentrations
    comprises entre 0,1 et 0,01 mg/litre.

         Les valeurs de la CL50 (effets aigus) pour les poissons varient
    de 0,09 mg/litre chez la truite arc-en-ciel  (Oncorhynchus mykiss) à
    3,1 mg/litre chez le poisson-chat  (Channa punctatus). Chez les
    stades juvéniles des poissons, il y a inhibition de la croissance aux
    concentrations comprises entre 0,01 et 0,2 mg/litre. Une exposition
    aiguë au diazinon provoque la suppression de l'activité acétyl-
    cholinestérase cérébrale.

         Pour le lombric  Eisenia foetida, la CL50 dans le sol est de
    130 mg/kg de terre.

         Chez les oiseaux, la toxicité aiguë par voie orale (DL50) varie
    de 1,1 mg/kg p.c. pour la caille japonaise à 85 mg/kg p.c. pour le
    molothre des troupeaux. Les valeurs de la CL50 obtenues lors d'études
    d'alimentation, vont de 32 mg/kg de nourriture chez le colvert à
    900 mg/kg de nourriture chez la caille japonaise (on observe un effet
    répulsif à ces doses élevées). Des études de rations alimentaires en
    laboratoire ont montré que la dose sans effet nocif observable sur la
    reproduction des oiseaux était égale à 20 mg/kg de nourriture chez le
    colvert et à 40 mg/kg de nourriture chez le colin de Virginie. Après
    ingestion, il y a inhibition de l'acétylcholinesterase cérébrale. Le
    diazinon peut également pénétrer par voie transcutanée. On a signalé
    une mortalité importante chez du gibier d'eau à la suite de
    pulvérisations de diazinon sur du gazon. Des études de terrain au
    cours desquelles on a épandu du diazinon à raison de 4,8 kg de matière
    active par hectare, ont montré qu'il n'en résultait aucune mortalité
    pour les oiseaux chanteurs. L'épandage de granulés a provoqué une

    légère réduction des populations d'oiseaux chanteurs par rapport aux
    populations témoins. Les études de laboratoire montrent que
    l'ingestion d'un petit nombre de granulés peut être fatale à un oiseau
    de petite taille.

    RESUMEN Y EVALUACIONES

    1.  Identidad, propiedades físicas y químicas y métodos analíticos

         El nombre químico del diazinon es  O,O-dietilo  O-2-isopropil-
    6-metilpirimidinil-4-y1 fosforotioato. La sustancia pura forma un
    líquido incoloro con un ligero olor a éster. El principio activo de
    calidad técnica es un líquido amarillo pardusco con un ligero olor
    característico del compuesto. Su punto de ebullición es de 83-84
    oC a 26,6 mPa y su presión de vapor (volatilidad) es baja (9,7 mPa
    a 20oC). Su solubilidad en agua a temperatura ambiente es de
    60 mg/litro. El diazinon es soluble en la mayoría de los disolventes
    orgánicos y tiene un coeficiente de reparto octanol/agua (log Pow) de
    3,40. Es estable en medios neutros, pero se hidroliza lentamente en
    medios alcalinos y más rápidamente en medios ácidos. Se descompone a
    temperaturas superiores a los 120oC.

         Se ha desarrollado un gran número de métodos de muestreo de
    análisis para la determinación del diazinon y sus metabolitos en
    distintos medios. Cada vez se utilizan más los métodos sensibles,
    tales como la cromatografía de gases, la cromatografía líquida de alta
    resolución, la espectrometría de masas y el inmunoensayo.

    2.  Producción, usos y fuentes de exposición humana y ambiental

         El diazinon es un insecticida organofosforado de contacto, con
    una actividad insecticida de amplio espectro. Es eficaz contra las
    formas adultas y juveniles de insectos, voladores o no, ácaros y
    arañas. Se utiliza desde principios del decenio de 1950. El diazinon
    se prepara principalmente en forma de polvos humectables y
    concentrados emulsionables. También se encuentra en preparaciones
    mixtas combinado con otros insecticidas.

    3.  Transporte, distribución y transformación en el medio ambiente

         La volatilización del diazinon en el suelo es de poca magnitud.
    El diazinon tiene una semivida troposférica de 1,5 horas.

         Su movilidad en el suelo depende en gran medida de una serie de
    factores, en particular de la materia orgánica y del contenido en
    carbonato de calcio. Su Koc de 500 no da lugar a prever una fijación
    fuerte a las partículas del suelo, sino a una movilidad moderada en el
    suelo.

         Los procesos biológicos parecen ser el factor principal en la
    degradación del diazinon en el suelo. A 20 oC y con un contenido de
    humedad del suelo del 60% de la capacidad de campo en un suelo franco
    limoso, el TD50 fue de 5 días. En condiciones de esterilidad a 20 oC
    y con un 60% de capacidad de campo, el TD50 fue de 118 días, lo que
    parece indicar que la actividad geológica es la principal responsable
    de la degradación en el suelo.

         En el agua presente en la naturaleza, el diazinon tiene una
    semivida de 5 a 15 días. Al parecer, en la degradación del diazinon
    intervienen procesos tanto químicos como biológicos que dan lugar a la
    mineralización al cabo de pocas semanas.

         La absorción del diazinon por los organismos acuáticos es rápida.
    Con respecto a los organismos acuáticos, se han señalado factores de
    bioconcentración bajos que oscilan entre 3 en el caso del camarón y
    152 en el caso del gobio, lo que parece indicar un metabolismo y una
    eliminación rápidos. Se han notificado semividas de depuración en los
    peces de hasta 30 horas (mejillón).

    4.  Niveles medioambientales y exposición humana

         Los niveles medioambientales de diazinon son generalmente bajos.
    Las vías de exposición de la población general son la inhalación y la
    alimentación. La exposición a través del agua es mínima. La exposición
    profesional es fundamentalmente cutánea.

         Los usos del diazinon se pueden clasificar en dos categorías
    principales, a saber, como plaguicida en la agricultura y como fármaco
    en la medicina veterinaria. Por consiguiente, la presencia de residuos
    de diazinon en los cultivos comestibles obedece principalmente a su
    utilización como plaguicida agrícola, mientras que su presencia en la
    carne, los despojos y otros productos de origen animal se debe a su
    utilización como fármaco de uso veterinario que contiene el principio
    activo.

         Los residuos de diazinon presentes en verduras, hortalizas,
    frutas y productos de origen animal son muy escasos. Los resultados de
    estudios realizados sobre dietas totales dan a entender que el
    diazinon se degrada rápidamente tanto en los productos de origen
    vegetal como en los de origen animal. No se ha detectado la presencia
    de diazinon en muestras de agua potable y su concentración en aguas de
    superficie se sitúa en niveles de ng/litro.

    5.  Cinética y metabolismo

         El diazinon se puede absorber por el aparato digestivo, a través
    de la piel intacta y tras su inhalación. La absorción transcutánea en
    el ser humano es baja. Las enzimas microsómices oxidan el diazinon
    produciendo metabolitos inhibidores de la colinesterasa, tales como el
    diazoxón, el hidroxidiazoxón y el hidroxidiazinon. Sólo se detectan
    cantidades mínimas de metabolitos en la leche y los huevos. El
    diazinon y sus metabolitos no se acumulan en los tejidos corporales;
    el 59-95% de una dosis oral de diazinon se excreta en un plazo de 24
    horas y el 95-98% se excreta en un plazo de 7 días, principalmente por
    orina.

         Las principales vías metabólicas de degradación del diazinon son
    las siguientes:

    a)   Ruptura del enlace de éster, que da lugar a los derivados de la
         hidroxipirimidina.

    b)   Transformación de la fracción P-S en el derivado P-O.

    c)   Oxidación del sustituyente isopropílico, que da lugar a los
         correspondientes derivados alcohólicos terciarios y primarios.

    d)   Oxidación del sustituyente metílico, que da lugar al alcohol
         correspondiente.

    e)   Ruptura del enlace éster mediada por el glutatión, que da lugar a
         un conjugado de glutatión.

         La ruptura del enlace éster fosfato, que da lugar, directamente o
    por vía del diazoxón, al metabolito pirimidílico, desempeña una
    función determinante en el metabolismo del diazinon. Los metabolitos
    que mantienen el enlace éster fosfato son de carácter transitorio y
    sólo se han detectado en pequeñas cantidades. La cantidad de
    metabolitos y su velocidad de producción varían ampliamente de una
    especie a otra. En general, la producción de diazoxón no está
    relacionada con la sensibilidad a la intoxicación por diazinon, si
    bien es más baja en la especie menos vulnerable, los ovinos. El
    metabolismo extrahepático del diazinon, en especial la hidrólisis del
    diazoxón en el plasma, es toxicológicamente más importante que el
    metabolismo hepático, pero este último probablemente sea el más
    importante en las especies aviarias. Los metabolitos formados, esto
    es, el ácido dietilfosfórico, el ácido dietiltiofosfórico y los
    derivados del anillo pirimidinílico, se eliminan principalmente por
    los riñones.

    6.  Efectos en los animales de experimentación y en sistemas de prueba
        in vitro

         Las mejoras introducidas en la fabricación del diazinon desde
    1979 han reducido significativamente su contenido de impurezas
    sumamente tóxicas, como por ejemplo el pirofosfato de tetraetilo
    (TEPP). Como resultado de estas mejoras progresivas, la DL50 aguda
    por vía oral del diazinon de calidad técnica ha aumentado (por
    ejemplo, de 250 mg/kg a 1250 mg/kg en la rata).

         La toxicidad aguda por vía oral o cutánea o por inhalación es
    baja. Los estudios a corto y largo plazo efectuados en ratones, ratas,
    conejos, perros y monos han puesto de manifiesto que el único efecto
    preocupante es la inhibición de la actividad de la
    acetilcolinesterasa, relacionada con la dosis.

         En el conejo, el diazinon ocasiona una ligera irritación de la
    piel, pero no de los ojos. El diazinon no sensibiliza la piel. Los
    estudios de reproducción y desarrollo no han revelado indicios de
    potencial embriotóxico ni teratogénico. No se detectaron efectos en el
    proceso de reproducción tras la administración de dosis que no eran
    tóxicas para los animales progenitores. Los estudios de mutagenicidad
    con distintas variables de valoración  in vivo y  in vitro no
    revelaron un potencial mutagénico. No hay indicios de carcinogenicidad
    en ratas ni en ratones. El diazinon no causa neuropatía retardada en
    las gallinas. Se ha señalado que el diazinon provoca pancreatitis
    aguda en perros y cobayos; se considera que se trata de un efecto
    específico de determinadas especies.

    7.  Efectos en el ser humano

         Se han señalado varios casos de intoxicación accidental o
    suicida con diazinon, algunos de los cuales fueron mortales. En
    algunos de ellos, el síndrome colinérgico puede haber sido más grave
    de lo previsto debido a la presencia de impurezas sumamente tóxicas,
    tales como el TEPP. En algunos casos se produjeron pancreatitis
    agudas reversibles asociadas a un síndrome colinérgico grave. Eso se
    produce también tras la intoxicación con otros inhibidores de la
    colinesterasa. En varios casos también se detectó el síndrome
    intermedio. No se ha señalado ningún caso de neuropatía retardada,
    como es de prever según los datos dimanantes de estudios realizados en
    animales. Los casos notificados de intoxicación tras una exposición
    profesional siempre han ido asociados a la presencia de impurezas en
    la formulación, tales como el TEPP, el monotio-TEPP o el sulfo-TEPP.
    Es poco probable que se encuentren estas impurezas en las
    formulaciones disponibles en la actualidad.

    8.  Efectos en otros organismos en el laboratorio y en el medio
        ambiente

         Los efectos del diazinon en las algas unicelulares son
    variables; se ha señalado tanto la inhibición como la estimulación
    del crecimiento en distintas especies, con concentraciones de 0,01 a
    5 mg/litro. En términos generales, las tasas de crecimiento disminuyen
    con concentraciones superiores a 10 mg/litro, si bien en algunos casos
    el tamaño de la población puede permanecer invariable con
    concentraciones de 100 mg/litro. La escasez y variabilidad de los
    datos dificulta la evaluación de los efectos sobre otros
    microorganismos.

         En pruebas realizadas a las 96-h, la CL50 aguda para los
    invertebrados acuáticos oscilaba entre 0,2 mg/litro en  Gammarus 
     fasciatus y 4,0 mg/litro en camarones  (Hyallela azteca). Según una
    prueba única a la que se sometió a  Gillia attilis, los moluscos son
    sustancialmente menos sensibles. Se han señalado efectos subletales en
    el comportamiento con concentraciones de 0,1 a 0,01 mg/litro.

         La CL50 aguda para los peces oscila entre 0,09 mg/litro para la
    trucha arco iris  (Oncorhynchus mykiss) y 3,1 mg/litro para el bagre
     (Channa punctatus). El crecimiento durante las primeras fases de
    la vida de los peces se inhibía con concentraciones de 0,01 a
    0,2 mg/litro. La actividad de la acetilcolinesterasa cerebral se
    inhibe tras una fuerte exposición al diazinon.

         La CL50 en el suelo para la lombriz de tierra  (Eisenia 
     foetida) es de 130 mg/kg de suelo.

         La toxicidad aguda por vía oral (DL50) en las aves varía entre
    1,1 mg/kg de peso corporal para la codorniz japonesa y 85 mg/kg de
    peso corporal para aves del género  Molothrus. Los valores de la
    CL50 en la alimentación oscilan entre 32 mg/kg de alimentos en
    el pato silvestre y 900 mg/kg de alimentos en la codorniz japonesa
    (se detectó repelencia con estas altas concentraciones en la
    alimentación). En estudios de laboratorio realizados en aves, la
    concentración de diazinon en la dieta sin efectos observados en la
    reproducción era de 20 mg/kg de alimentos en el pato silvestre y de
    40 mg/kg de alimentos en la codorniz  (Colinus virginianus). La
    actividad de la acetilcolinesterasa cerebral se inhibe tras la
    ingestión. El diazinon también se puede absorber por vía cutánea. Se
    ha notificado una considerable mortandad de las aves acuáticas en la
    naturaleza, tras la aplicación de diazinon al césped. En estudios
    sobre el terreno en que se aplicaron formulaciones líquidas al césped
    con una concentración de 4,8 kg ai/ha no se registró mortalidad ni se
    produjeron efectos sobre la reproducción de las aves canoras. La
    aplicación en forma de gránulos provocó una pequeña reducción en el
    tamaño poblacional de aves canoras, en comparación con el grupo
    testigo. La ingestión de pequeñas cantidades de gránulos puede
    resultar mortal para las aves pequeñas, como se ha demostrado en
    estudios de laboratorio.





    See Also:
       Toxicological Abbreviations
       Diazinon (ICSC)
       Diazinon (PDS)
       Diazinon (FAO Meeting Report PL/1965/10/1)
       Diazinon (FAO/PL:CP/15)
       Diazinon (FAO/PL:1967/M/11/1)
       Diazinon (FAO/PL:1968/M/9/1)
       Diazinon (AGP:1970/M/12/1)
       Diazinon (WHO Pesticide Residues Series 5)
       Diazinon (Pesticide residues in food: 1979 evaluations)
       Diazinon (Pesticide residues in food: 1993 evaluations Part II Toxicology)
       Diazinon (JMPR Evaluations 2001 Part II Toxicological)