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    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY



    ENVIRONMENTAL HEALTH CRITERIA 121



    ALDICARB









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

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

    First draft prepared by Dr. J. Risher and Dr. H. Choudhury,
    US Environmental Protection Agency,
    Cincinnati, Ohio, USA

    World Health Orgnization
    Geneva, 1991


         The International Programme on Chemical Safety (IPCS) is a
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    development of know-how for coping with chemical accidents,
    coordination of laboratory testing and epidemiological studies, and
    promotion of research on the mechanisms of the biological action of
    chemicals.

    WHO Library Cataloguing in Publication Data

    Aldicarb.

        (Environmental health criteria ; 121)

        1.Aldicarb - adverse effects 2.Aldicarb - toxicity 3.Environmental
        exposure 4.Environmental pollutants       I.Series

        ISBN 92 4 157121 7        (NLM Classification: WA 240)
        ISSN 0250-863X

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    CONTENTS

    ENVIRONMENTAL HEALTH CRITERIA FOR ALDICARB

    1. SUMMARY

         1.1. Identity, properties, and analytical methods
         1.2. Uses, sources, and levels of exposure
         1.3. Kinetics and metabolism
         1.4. Studies on experimental animals
         1.5. Effects on humans

     2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, AND ANALYTICAL
         METHODS

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

    3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

         3.1. Natural occurrence
         3.2. Anthropogenic sources
              3.2.1. Production levels, processes, and uses
                        3.2.1.1World production figures
                        3.2.1.2Manufacturing processes

    4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

         4.1. Transport and distribution between media
              4.1.1. Air
              4.1.2. Water and soil
              4.1.3. Vegetation and wildlife
         4.2. Biotransformation
         4.3. Interaction with other physical, chemical or biological
              factors
              4.3.1. Soil microorganisms

    5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

         5.1. Environmental levels
              5.1.1. Air
              5.1.2. Water
              5.1.3. Food and feed
         5.2. General population exposure
         5.3. Occupational exposure during manufacture, formulation
              or use

    6. KINETICS AND METABOLISM

         6.1. Absorption
         6.2. Distribution
         6.3. Metabolic transformation
         6.4. Elimination and excretion in expired air, faeces, and
              urine

    7. EFFECTS ON LABORATORY MAMMALS AND  IN VITRO TEST SYSTEMS

         7.1. Single exposure
         7.2. Short-term exposure
         7.3. Skin and eye irritation; sensitization
         7.4. Long-term exposure
         7.5. Reproduction, embryotoxicity, and teratogenicity
         7.6. Mutagenicity and related end-points
         7.7. Carcinogenicity
         7.8. Other special studies
         7.9. Factors modifying toxicity; toxicity of metabolites
         7.10. Mechanisms of toxicity - mode of action

    8. EFFECTS ON HUMANS

         8.1. General population exposure
              8.1.1. Acute toxicity; poisoning incidents
              8.1.2. Human studies
              8.1.3. Epidemiological studies
         8.2. Occupational exposure
              8.2.1. Acute toxicity; poisoning incidents
              8.2.2. Effects of short- and long-term exposure;
                        epidemiological studies

    9. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

         9.1. Microorganisms
         9.2. Aquatic organisms
         9.3. Terrestrial organisms
         9.4. Population and ecosystem effects

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

         10.1. Evaluation of human health risks
              10.1.1. Exposure levels
                        10.1.1.1  General population
                        10.1.1.2  Occupational exposure
              10.1.2. Toxic effects
              10.1.3. Risk evaluation
         10.2. Evaluation of effects on the environment

    11. CONCLUSIONS AND RECOMMENDATIONS

         11.1. Conclusions
              11.1.1. General population
              11.1.2. Occupational exposure
              11.1.3. Environmental effects
         11.2. Recommendations

    12. FURTHER RESEARCH

    13. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

         REFERENCES

         RESUME

         EVALUATION DES RISQUES POUR LA SANTE HUMAINE ET DES EFFETS
         SUR L'ENVIRONNEMENT

         CONCLUSIONS ET RECOMMENDATIONS

         RECHERCHES A EFFECTUER

         RESUMEN

         EVALUACION DE LOS RIESGOS PARA LA SALUD HUMANA Y DE LOS
         EFFECTOS EN EL MEDIO AMBIENTE

         CONCLUSIONES Y RECOMENDACIONES

         OTRAS INVESTIGACIONES

    WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR ALDICARB

     Members 

    Dr I. Boyer, The Mitre Corporation, McLean, Virginia, USA

    Dr G. Burin, Health Effects Division, Office of Pesticide
         Programs, US Environmental Protection Agency, Washington, DC, USA
          (Joint Rapporteur)

    Dr S. Dobson, Institute of Terrestrial Ecology, Monks Wood
         Experimental Station, Abbots Ripton, Huntingdon, United Kingdom
          (Vice Chairman)

    Professor W. J. Hayes, Jr., School of Medicine, Vanderbilt
         University, Nashville, Tennessee, USA  (Chairman)

    Professor F. Kaloyanova, Institute of Hygiene and
         Occupational Health, Medical Academy, Sofia, Bulgaria

    Dr S. K. Kashyap, National Institute of Occupational
         Health, Indian Council of Medical Research, Meghani Nagar,
         Ahmedabad, India

    Dr H. P. Misra, University Center for Toxicology, Virginia
         Polytechnic Institute and State University, Blacksburg, Virginia,
         USA

    Mr D. Renshaw, Department of Health, Hannibal House,
         London, United Kingdom

    Dr J. Withey, Environmental & Occupational Toxicology
         Division, Environmental Health Center, Tunney's Pasture, Ottawa,
         Ontario, Canada

    Dr Shou-zheng Xue, School of Public Health, Shanghai
         Medical University, Shanghai, China

     Representatives of other organizations

    Dr L. Hodges, International Group of National Associations
         of Manufacturers of Agrochemical Products (GIFAP), Brussels,
         Belgium

    Dr J. M. Charles, International Group of National
         Associations of Manufacturers of Agrochemical Products (GIFAP),
         Brussels, Belgium

     Secretariat

    Dr B. H. Chen, International Programme on Chemical Safety,
         World Health Organization, Geneva, Switzerland  (Secretary)

    Dr H. Choudhury, Environmental Criteria and Assessment
         Office, US Environmental Protection Agency, Cincinnati, Ohio, USA
          (Joint Rapporteur)

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

    NOTE TO READERS OF THE CRITERIA MONOGRAPHS

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

                                   *  *  *

         A detailed data profile and a legal file can be obtained from the
    International Register of Potentially Toxic Chemicals, Palais des
    Nations, 1211 Geneva 10, Switzerland (Telephone No. 7988400 or
    7985850).

    ENVIRONMENTAL HEALTH CRITERIA FOR ALDICARB

         A WHO Task Group on Environmental Health Criteria for Aldicarb
    met in Cincinnati, USA, from 6 to 10 August 1990. Dr C. DeRosa opened
    the meeting on behalf of the US Environmental Protection Agency. Dr
    B.H. Chen of the International Programme on Chemical Safety (IPCS)
    welcomed the participants on behalf of the Manager, IPCS, and the
    three IPCS cooperating organizations (UNEP/ILO/ WHO). The Task Group
    reviewed and revised the draft criteria monograph and made an
    evaluation of the risks for human health and the environment from
    exposure to aldicarb.

         The first draft of this monograph was prepared by Dr J. Risher
    and Dr H. Choudhury of the US Environmental Protection Agency. The
    second draft was prepared by Dr H. Choudhury incorporating comments
    received following the circulation of the first draft to the IPCS
    Contact Points for Environmental Health Criteria documents. During the
    Task Group meeting all the participants contributed to review the
    large amount of information submitted by Rhne-Poulenc, and undertook
    a substantial revision of the second draft. Dr B.H. Chen 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 document are gratefully acknowledged. The Secretariat wishes to
    thank Dr S. Dobson and Dr G. Burin for the significant contributions
    and revisions of the draft document during the meeting.

         Financial support for the meeting was provided by the US
    Environmental Protection Agency, Cincinnati, USA.

    ABBREVIATIONS


         ADI       acceptable daily intake

         ai        active ingredient

         CHO       Chinese hamster ovary

         FAD       flavin adenine dinucleotide

         FPD       flame photometric detector

         GC        gas chromatography

         GPC       gel permeation chromatography

         HPLC      high-performance liquid chromatography

         LC        liquid chromatography

         MATC      maximum acceptable toxic concentration

         MS        mass spectroscopy

         NADPH     reduced nicotinamide adenine dinucleotide phosphate

         NOEL      no-observed-effect level

         TLC       thin-layer chromatography

         UV        ultraviolet

    1.  SUMMARY

    1.1  Identity, properties, and analytical methods

         Aldicarb is a carbamate ester. It is a white crystal-line solid,
    moderately soluble in water, and susceptible to oxidation and
    hydrolytic reactions.

         Several different analytical methods, including thin-layer
    chromatography, gas chromatography (electron capture, flame
    ionization, etc.), and liquid chromatography, are available. The
    currently preferred method for analysing aldicarb and its major
    decomposition products is high-performance liquid chromatography with
    post-column derivatization and fluorescence detectors.

    1.2  Uses, sources, and levels of exposure

         Aldicarb is a systemic pesticide that is applied to the soil to
    control certain insects, mites, and nematodes.  The soil application
    includes a wide range of crops, such as bananas, cotton, coffee,
    maize, onions, citrus fruits, beans (dried), pecans, potatoes,
    peanuts, soybeans, sugar beets, sugar cane, sweet potatoes, sorghum,
    tobacco, as well as ornamental plants and tree nurseries. Exposure of
    the general population to aldicarb and its toxic metabolites (the
    sulfoxide and sulfone) occurs mainly through food. The ingestion of
    contaminated food has led to poisoning incidents from aldicarb and its
    toxic metabolites (the sulfoxide and sulfone).

         Due to the high acute toxicity of aldicarb, both inhalation and
    skin contact under occupational exposure conditions may be dangerous
    for workers if preventive measures are inadequate. There have been a
    few incidents of accidental exposure of workers due to improper use or
    lack of protective measures.

         Aldicarb is oxidized fairly rapidly to the sulfoxide, 48%
    conversion of parent compound to sulfoxide occurring within 7 days
    after application to certain types of soils. It is oxidized much more
    slowly to the sulfone. Hydrolysis of the carbamate ester group, which
    inactivates the pesticide, is ph dependent, half-lives in distilled
    water varying from a few minutes at a pH of > 12 to 560 days at a pH
    of 6.0. Half-lives in surface soils are approximately 0.5 to 3 months
    and in the saturated zone from 0.4 to 36 months Aldicarb hydrolyses
    somewhat more slowly than either the sulfoxide or the sulfone.
    Laboratory measurement of the biotic and abiotic breakdown of aldicarb
    have yielded very variable results and have led to extrapolations
    radically different from field observation. Field data on the
    breakdown products of aldicarb furnish more reliable estimates of its
    fate.

         Sandy soils with low organic matter content allow the greatest
    leaching, particularly where the water table is high. Drainage
    aquifers and local shallow wells have been contaminated with aldicarb
    sulfoxide and sulfone; levels have generally ranged between 1 and
    50g/litre, although an occasional level of approximately 500 g/litre
    has been recorded.

         As aldicarb is systemic in plants, residues may occur in foods.
    Residue levels greater than 1 mg/kg have been reported in raw
    potatoes. In the USA, where the tolerance limit for potatoes is 1
    mg/kg, residue levels of up to 0.82 mg/kg have been reported from
    controlled field trials using application rates recommended by the
    manufacturer. An upper 95th percentile level of 0.43 mg/kg has been
    estimated from field trial data, and upper 95th percentile levels of
    up to 0.0677 mg/kg in raw potatoes have been determined from a
    market-basket survey.

    1.3  Kinetics and metabolism

         Aldicarb is efficiently absorbed from the gastrointestinal tract
    and, to a lesser extent, through the skin. It could be readily
    absorbed by the respiratory tract if dust were present. It distributes
    to all tissues, including those of the developing rat fetus. It is
    metabolically transformed to the sulfoxide and the sulfone (both of
    which are toxic), and is detoxified by hydrolysis to oximes and
    nitriles. The excretion of aldicarb and its metabolites is rapid and
    primarily via the urine. A minor part is also subject to biliary
    elimination and, consequently, to enterohepatic recycling. Aldicarb
    does not accumulate in the body as a result of long-term exposure. The
    inhibition of cholinesterase activity  in vitro by aldicarb is
    spontaneously reversible, the half-life being 30-40 min.

    1.4  Studies on experimental animals

         Aldicarb is a potent inhibitor of cholinesterases and has a high
    acute toxicity. Recovery from its cholinergic effects is spontaneous
    and complete within 6 h, unless death intervenes. There is no
    substantial evidence to indicate that aldicarb is teratogenic,
    mutagenic, carcinogenic, or immunotoxic.

         Birds and small mammals have been killed as a result of ingesting
    aldicarb granules not fully incorporated into the soil as recommended.
    In laboratory tests, aldicarb is acutely toxic to aquatic organisms.
    There is no indication, however, that effects would occur in the
    field.

    1.5  Effects on humans

         The inhibition of acetylcholinesterase at the nervous synapse and
    myoneural junction is the only recognized effect of aldicarb in humans
    and is similar to the action of organophosphates. The carbamyolated
    enzyme is unstable, and spontaneous reactivation is relatively rapid
    compared with that of a phosphorylated enzyme. Non-fatal poisoning in
    man is rapidly reversible. Recovery is aided by the administration of
    atropine.

    2.  IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, AND ANALYTICAL METHODS

    2.1  Identity

         Common name:   Aldicarb

         Chemical structure:

                          CH3           O
                          '             "
                   CH3S - C - CH = N - OCNHCH3
                          '
                          CH3

         Molecular formula:  C7H14N2O2S

         Synonyms and        Aldicarb (English); Aldicarbe (French);
         common trade        Carbanolate; ENT 27 093; 2-methyl-2-
         names:              (methylthio)propanal
                              O-[(methylamino)-carbonyl]oxime (C.A.);
                             2-methyl-2-(methylthio)propionaldehyde
                              O-methyl-carbamoyloxime (IUPAC);
                             NCI-CO8640; OMS-771; Propanal,
                             2-methyl-2-(methylthio)-,
                              O-((methylamino)carbonyl)oxime; Temic;
                             Temik; Temik G; Temik M; Temik LD; Sentry;
                             Temik 5G; Temik 10G; Temik 15G; Temik 150G;
                             Union Carbide UC 21 149.

         CAS registry
         number              116-06-3

         RTECS no.           UE2275000.

    2.2  Physical and chemical properties

         Some physical and chemical properties of aldicarb are given in
    Table 1.

         Aldicarb, for which the IUPAC name is
    2-methyl-2-(methylthio)propionaldehyde  O-methylcarbamoyloxime, is an
    oxime carbamate insecticide that was introduced in 1965 by the Union
    Carbide Corporation under the code number UC 21 149 and the trade name
    Temik (Worthing & Walker, 1987).

         Takusagawa & Jacobson (1977) reported that the molecular
    structure of the aldicarb crystal, as determined by single-crystal
    X-ray diffraction techniques, consists of an orthorhombic unit cell
    with eight molecules per cell. The C-O single bond length in the
    carbamate group was reported to be significantly greater than in
    carboxylic acid esters. This supports the theory that interaction with
    acetylcholinesterase involves disruption of this bond.

         Aldicarb has two geometrical isomers as shown below:

    CHEMICAL STRUCTURE

         The commercial product is a mixture of these two isomers. It is
    not certain which isomer is the more active.

    2.3  Conversion factors

    In air at 25 C and 101.3 kPa (760 mmHg): 

                   1 ppm (v/v) = 7.78 mg/m3

                   1 mg/m3 = 0.129 ppm (v/v).

    2.4  Analytical methods

         The methods for analysing aldicarb include thin-layer
    chromatography (Knaak et al., 1966a,b; Metcalf et al., 1966), liquid
    chromatography (LC) (Wright et al., 1982), ultraviolet detection
    (Sparacino et al., 1973), post-column derivatization and fluorometric
    detection (Moye et al., 1977; Krause, 1979), and gas chromatography
    (GC) with various detectors. These include the Hall detector (Galoux
    et al., 1979), mass spectrometry (Muszkat & Aharonson, 1983), flame
    ionization detection (Knaak et al., 1966a,b), and esterification and
    electron capture detection (Moye, 1975). A multiple residue method
    exists for detecting  N-methylcarbamate insecticide in grapes and
    potatoes. It involves separation by reverse phase liquid
    chromatography and detection by a post-column fluorometric technique
    (AOAC, 1990).

        Table 1. Some physical and chemical properties of aldicarba
                                                                                  
    Relative molecular mass:           190.3

    Form:                              colourless crystals (odourless or slight
                                       sulfurous smell)

    Melting point:                     100 C

    Boiling point:                     unknown; decomposes above 100 C

    Vapour pressure (25 C):           13 mPa (1 x 10-4 mmHg)

    Relative density (25 C):          1.195

    Solubility (20 C):                6 g/litre of water; 40% in acetone;
                                       35% in chloroform; 10% in toluene

    Properties:                        heat sensitive, relatively unstable
                                       chemical; stable in acidic media but 
                                       decomposes rapidly in alkaline media;
                                       non-corrosive to metal; non-flammable;
                                       oxidizing agents rapidly convert it to
                                       the sulfoxide and slowly to the sulfone

    Impurities                         dimethylamine; 2-methyl-2-(methylthio)
                                       propionitrile; 2-methyl-2-(2-methyl-
                                       thiopropylenaminoxy) propinaldehyde
                                        O-  (methylcarbamoyl) oxime;
                                       2-methyl-2-(methylthio) propionaldehyde
                                       oxime

    Log octanol/water partition        1.359
    coefficient
                                                                                  

    a  From: Kuhr & Dorough (1976), Worthing & Walker (1987), and FAO/WHO (1980).
    
         Because of aldicarb's thermal lability, it degrades rapidly in
    the injection port or on the column during GC analysis. Thus, short
    columns have been used to facilitate more rapid analyses and prevent
    thermal degradation (Riva & Carisano, 1969). A major drawback to using
    GC methods is that aldicarb degrades to aldicarb nitrile during GC;
    this degradation may also occur in the environment (US EPA, 1984).
    During GC analysis by conventional-length columns, aldicarb nitrile
    interferes with aldicarb analysis, thus necessitating a time-consuming
    clean-up procedure. Furthermore, aldicarb nitrile cannot be detected
    by LC with UV detection since absorption does not occur in the UV
    range (US EPA, 1984). The post-column fluorometric technique used in
    LC requires hydrolysis of the analyte, with the formation of
    methylamine, which reacts with  o-phthalaldehyde to form a
    fluorophore. Since aldicarb nitrile does not hydrolyse to form
    methylamine, it cannot be detected (Krause, 1985a).

         US EPA (1984) reported that high-performance liquid
    chromatography (HPLC) can be used to determine
     N-methyl-carbamoyloximes and  N-methylcarbamates in drinking-water.
    With this method, the water sample is filtered and a 400-l aliquot is
    injected into a reverse-phase HPLC column. Compounds are separated by
    using gradient elution chromatography. After elution from the column,
    the compounds are hydrolysed with sodium hydroxide. The methylamine
    formed during hydrolysis reacts with  o-phthalaldehyde (OPA) to form
    a fluorescent derivative, which is detected with a fluorescence
    detector. The estimated detection limit for this method is 1.3 g
    aldicarb/litre.

         Reding (1987) suggested that samples be kept chilled, acidified
    with hydrochloric acid to pH 3, and dechlorinated with sodium
    thiosulfate. Other procedures used were the same as those described in
    the previous paragraph.

         In a collaborative study, Krause (1985a,b) reported an LC
    multi-residue method for determining the residues of
     N-methylcarbamate insecticides in crops. The average recovery for 11
    carbamates (which included aldicarb and aldicarb sulfone) from 14
    crops was 99%, with a coefficient of variation of 8% (fortification
    levels of 0.03-1.8 mg/kg), and for aldicarb sulfoxide, a very polar
    metabolite, was 55% and 57% at levels of 0.95 and 1.0 mg/kg,
    respectively. Methanol and a mechanical ultrasonic homogenizer were
    used to extract the carbamates. Water-soluble plant co-extractives and
    non-polar plant lipid materials were removed from the carbamate
    residues by liquid-liquid partitioning. Additional crop co-extractives
    (carotenes, chlorophylls) were removed with a Nuchar S-N-silanized
    Celite column. The carbamate residues were then separated on a
    reverse-phase LC column, using acetonitrile-water gradient mobile
    phase. Eluted residues were detected by an in-line post-column
    fluorometric detection technique. Six laboratories participated in

    this collaborative study.  Each laboratory determined all the
    carbamates at two levels (0.05 and 0.5 mg/kg) in blind duplicate
    samples of grapes and potatoes. Repeatability coefficients of
    variation and reproducibility coefficients of variation for all
    carbamates in the two crops averaged 4.7 and 8.7%, respectively. The
    estimated limit of quantification was 0.01 mg/kg.

         Ting & Kho (1986) discussed a rapid analytical method using HPLC.
    They modified their previous method (Ting et al., 1984) by using a
    25-cm CH-Cyclohexyl column instead of the 15-cm C-18 column. This
    modification resulted in the separation of the interference peak found
    in watermelon co-extractives. The separation of the interference peak
    and the aldicarb sulfoxide peak was made possible by the additional 10
    cm in the length of the column and the higher polarity of the
    CH-Cyclohexyl. Acetonitrile and methanol were used in the extraction
    and derivatization procedure before the HPLC determination. Water
    melons fortified with aldicarb sulfoxide at 0.1, 0.2, and 0.4 mg/kg
    showed a mean recovery of 74-76%.

         Chaput (1988) described a simplified method for determining seven
     N-methylcarbamates (aldicarb, carbaryl, carbofuran, methiocarb,
    methomyl, oxamyl, and propoxur) and three related metabolites
    (aldicarb sulfoxide, aldicarb sulfone, and 3-hydroxy-carbofuran) in
    fruits and vegetables. Residues are extracted from crops with
    methanol, and co-extractives are then separated by gel permeation
    chromatography (GPC) or GPC with on-line Nuchar-Celite clean-up for
    crops with high chlorophyll and/or carotene content (e.g., cabbage and
    broccoli). Carbamates are separated on a reverse-phase liquid
    chromatography column, using a methanol-water gradient mobile phase.
    Separation is followed by post-column hydrolysis to yield methylamine
    and by the formation of a flurophore with  o-phthalaldehyde and
    2-mercaptoethanol prior to fluorescence detection. Recovery data were
    obtained by fortifying five different crops (apples, broccoli,
    cabbages, cauliflower, and potatoes) at 0.05 and 0.5 mg/kg. Recoveries
    averaged 93% at both fortification levels, except in the case of the
    very polar aldicarb sulfoxide for which recoveries averaged around 52%
    at both levels. The coefficient of variation of the method at both
    levels was < 5% and the limit of detection, defined as five times the
    baseline noise, varied between 5 and 10 g/kg, depending on the
    compound.

         The International Register of Potentially Toxic Chemicals (IRPTC,
    1989) reported a GLC-FPD method for aldicarb analysis in foodstuffs.
    The limit of quantification was 0.01-0.03 mg/kg with a recovery rate
    of 76-125%. In this method, the acetone/dichloromethane-extracted
    sample is evaporated to dryness and the residue is dissolved in a
    buffered solution of potassium permanganate in water in order to
    oxidize the thioether pesticide and its sulfoxide metabolite to the
    corresponding sulfone. Aldicarb sulfone is then extracted with
    dichloromethane and the extract is evaporated to dryness. The residue
    is dissolved in acetone and the solution is analysed by GC-FPD using
    a pyrex column filled with 5% ov-225 on chromosorb W-HP, 150-180 U
    (the column temperature is 175 C and the carrier gas is nitrogen with
    a flow rate of 60 ml/min).

    3.  SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

    3.1  Natural occurrence

         Aldicarb is a synthetic insecticide; there are no natural sources
    of this ester.

    3.2  Anthropogenic sources

    3.2.1  Production levels, processes, and uses

         Aldicarb is a systemic pesticide used to control certain insects,
    mites, and nematodes. It is applied below the soil surface (either
    placed directly into the seed furrow or banded in the row) to be
    absorbed by the plant roots. Owing to the potential for dermal
    absorption of carbamate insecticides (Maibach et al., 1971), aldicarb
    is produced only in a granular form. The commercial formulation,
    Temik, is available as Temik 5G, Temik 10G, and Temik 15G, which
    contain 50, 100, and 150 g aldicarb/kg dry weight, respectively. The
    metabolite aldicarb sulfone is also used as a pesticide under the
    common name aldoxycarb. Aldicarb is usually applied to the soil in the
    form of Temik 5G, 10G, or 15G granules at rates of 0.56-5.6 kg ai/ha.
    Soil moisture is essential for its release from the granules, and
    uptake by plants is rapid. Plant protection can last up to 12 weeks
    (Worthing & Walker, 1987), but actual insecticidal activity may vary
    from 2 to 15 weeks, depending on the organism involved and on the
    application method (Hopkins & Taft, 1965; Cowan et al., 1966; Davis et
    al., 1966; Ridgway et al., 1966). The effective life of this
    insecticide will vary, depending on the type of soil, the soil
    moisture, the soil temperature, the rainfall and irrigation
    conditions, and the presence of soil micro-organisms.

         Aldicarb is approved for use on a variety of crops, which include
    bananas, cotton plants, citrus fruits, coffee, maize, onions, sugar
    beet, sugar cane, potatoes, sweet potatoes, peanuts, pecans, beans
    (dried), soybeans, and ornamental plants (FAO/WHO 1980; Berg, 1981).
    Its use in the home and garden has been proscribed by the
    manufacturer.

         Since aldicarb is used in a granular form, this reduces the
    handling hazards, as water is necessary for the active ingredient to
    be released. Respirators and protective clothing should, however, be
    used in certain field application settings (Lee & Ransdell, 1984).

    3.2.1.1  World production figures

         In the USA, a total of 725 tonnes was sold domestically for
    commercial use in 1974 (SRI, 1984).

         The US EPA (1985) estimated that aldicarb production from 1979 to
    1981 ranged from 1360 to 2130 tonnes/year. In 1988, the US EPA
    estimated that between 2359 and 2586 tonnes of aldicarb were applied
    annually in the USA (US EPA, 1988a). More recent world production
    figures are not available.

    3.2.1.2  Manufacturing processes

         Aldicarb is produced in solution by the reaction of methyl
    isocyanate with 2-methyl-2-(methylthio)propanal-doxime (Payne et al.,
    1966). During normal production, loss to the environment is not
    significant.

    4.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

    4.1  Transport and distribution between media

         The fate and transport of aldicarb and its decomposition products
    in various types of soil have been studied extensively under
    laboratory and field conditions. Owing to the physical properties of
    aldicarb such as its low vapour pressure, its commercial granular
    form, and its application beneath the surface of the soil, the vapour
    hazard of aldicarb is low. Thus the fate of aldicarb in the atmosphere
    has not received much attention. Similarly, its fate in surface water
    has not been extensively studied. However, the rates and mechanisms of
    the hydrolysis of aldicarb have been studied in the laboratory in some
    detail.

    4.1.1  Air

         No studies on the stability or migration of aldicarb in the air
    over or near treated fields have been reported.  Laboratory migration
    studies with radiolabelled aldicarb in various soil types showed a
    loss of the applied substrate. This loss could not be explained unless
    aldicarb or its decomposition products had been transferred to the
    vapour phase (Coppedge et al., 1977). When 34 mg of 14C-aldicarb
    granules was applied 38 mm below the surface of a column of soil
    contained in a 63 x 128 mm poly-propylene tube, about 43% of the
    radiolabel was collected in the atmosphere above the column.
    Additional experiments showed that the transfer of radioactivity to
    the surrounding atmosphere was inversely proportional to the depth of
    application in the soil.  When 14C- and 35S-labelled aldicarb were
    used separately in similar experiments, only the experiments in which
    the 14C-labelled compound was used led to a transfer of
    radioactivity to the surrounding atmosphere, thus showing that the
    volatile compound was a carbon-containing breakdown product rather
    than aldicarb  per se.

         In a subsequent study with aldicarb using 14C at the
     S-methyl,  N-methyl, and tertiary carbon, Richey et al. (1977)
    reported that 83% of the radiolabel was recovered as carbon dioxide
    from a column of soil. The rate of degradation depended on the
    characteristics of the soil, e.g., pH and humidity.

         Supak et al. (1977) reported that when aldicarb (1 mg/g) was
    applied to clay soil and placed in a volatilizer, its volatilization
    was very limited. The authors stated that the possibility of aldicarb
    causing an air contamination hazard when it is applied in the field is
    negligible since it is applied at a rate of only 1.1-3.4 kg/ha and is
    inserted to 5-10 cm below the soil surface.

    4.1.2  Water and soil

         There have been numerous studies on aldicarb, under field and
    laboratory conditions, to investigate its movement through soil and
    water, persistence, and degradation. While earlier studies suggested
    that aldicarb degraded readily in soil and did not leach, later
    identification of residues in wells indicated that persistence could
    be longer than predicted and that mobility was greater. Laboratory
    studies have given variable results and the only totally reliable data
    are from full-scale field studies.

         In one of the few studies conducted with natural water (Quraishi,
    1972), rain overflow and seepage water were collected from ditches
    near untreated fields, filtered, and then treated with aldicarb at a
    concentration of 100 mg/litre. Solutions were stored in ambient
    lighting at temperatures ranging from 16 to 20 C. It took 46 weeks
    for the aldicarb concentration to decrease to 0.37 mg/litre.

         Following an extensive study under laboratory-controlled
    conditions, Given & Dierberg (1985) reported that the hydrolysis of
    aldicarb was dependent on pH. They found that the apparent first-order
    hydrolysis rate over the pH range 6-8 and at 20 C was relatively slow
    (Table 2). Above pH 8 the increase in the hydrolysis rate showed a
    first-order dependence on hydroxide ion concentration. The authors
    stated that these studies probably represented a "worst-case"
    situation with respect to the persistence of aldicarb in water, since
    other means of aldicarb removal or decomposition (e.g.,
    volatilization, adsorption, leaching, and plant and microbial uptake)
    had been prevented.

         Hansen & Spiegel (1983) showed that aldicarb hydrolyses at much
    slower rates than aldicarb sulfoxide and aldicarb sulfone. Since
    aldicarb oxidizes fairly rapidly to the sulfoxide and at a slower rate
    to the sulfone, and subsequent hydrolysis of the oxidation products
    usually occurs, aldicarb does not persist in the aerobic environment.

         In his review, de Haan (1988) discussed leaching of aldicarb to
    surface water in the Netherlands. Some of the factors favourable to
    leaching are weak soil binding, high rainfall, irrigation practices,
    and low transformation rates of the oxidation products of aldicarb.

         Aharonson et al. (1987) reported that hydrolysis of aldicarb is
    one of the abiotic chemical reactions that is linked to the detection
    of the pesticide in the ground water. The hydrolysis half-life at pH
    7 and 15 C has been estimated by these authors to be as long as
    50-500 weeks.

        Table 2. Apparent first-order rate constant (k), half-life (t), and
    coefficient of variation of the regression line (r2) for aldicarb
    hydrolysis at 20 C in pH-buffered distilled watera
                                                                         

    pH          Period     k (day-1)b          tb               r2
                (days)                         (days)
                                                                         

    3.95        89         5.3 x 10-3            131           0.86

    6.02        89         1.2 x 10-3            559           0.90

    7.96        89         2.1 x 10-3            324           0.62

    8.85        89         1.3 x 10-3             55           0.98

    9.85        15         1.2 x 10-1              6           1.00
                                                                          

    a  Adapted from Given & Dierberg (1985).
    b  Rates and resulting half-life values for pH 6-8 represent
       only estimates since the slopes of the log percentage
       remaining versus time regression lines were probably not
       significantly different from zero.

             The products of aldicarb hydrolysis at 15 C under alkaline
    conditions (pH 12.9 and 13.4) are aldicarb oxime, methylamine, and
    carbonate (Lemley & Zhong, 1983). The half-lives of hydrolysis at
    these two pHs are 4.0 and 1.3 min, respectively. Other hydrolysis
    data, determined at pH 8.5 and 8.2, yielded rates with half-lives of
    43 and 69 days, respectively (Hansen & Spiegel, 1983; Krause, 1985a).
    Lemley et al. (1988) reported that at pH values of 5-8 the sorption of
    aldicarb, aldicarb sulfoxide, and aldicarb sulfone decreases as the
    temperature increases from 15 to 35 C.

         Andrawes et al. (1967) applied the pesticide at the recommended
    rate of 3.4 kg/ha to potato fields and found that < 0.5% of the
    original dose remained at the end of a 90-day period. In fallow soil,
    decomposition of aldicarb to its sulfoxide and sulfone was rapid, >
    50% of the administered compound dissipating within 7 days after
    application. Peak concentrations of the aldicarb sulfoxide (8.24
    mg/kg) and aldicarb sulfone (0.8 mg/kg) were reached at day 14 after
    the application.

         Ou et al. (1986) investigated the degradation and metabolism of
    14C-aldicarb in soils under aerobic and anaerobic conditions. They
    found that under aerobic conditions, aldicarb rapidly disappeared and
    aldicarb sulfoxide was rapidly formed; the latter in turn was slowly
    oxidized to aldicarb sulfone. The sulfoxide was the principal
    metabolite in soils under strictly aerobic conditions. Although the

    parent compound aldicarb persisted considerably longer in anaerobic
    soils, anaerobic half-lives for total toxic residue (aldicarb,
    aldicarb sulfoxide, and aldicarb sulfone) in subsurface soils were
    significantly shorter than under aerobic conditions.

         A number of factors, including soil texture and type, soil
    organic content, soil moisture levels, time, and temperature, affect
    the rate of aldicarb degradations (Coppedge et al., 1967; Bull, 1968;
    Bull et al., 1970; Andrawes et al., 1971a; Suspak et al., 1977). Bull
    et al.  (1970) reported that soil pH had no significant effect on the
    breakdown of aldicarb, but Supak et al. (1977) noted an increase in
    the rate of degradation when the pH was lowered.

         Lightfoot & Thorne (1987) investigated the degradation of
    aldicarb, aldicarb sulfoxide, and aldicarb sulfone in the laboratory
    using distilled water, water extracted from soil, and water with soil
    particles (Table 3). Degradation of all three compounds was greatest
    in the uppermost "plough" layer of the soil profile and much higher in
    the presence of soil particulates. Even after sterilization of the
    soil, degradation was fast in this layer, indicating that the effect
    of particulate matter is not entirely microbial. Degradation continued
    in the saturated zone (ground water) at a slower rate (particularly
    for the sulfoxide and sulfone). A further series of experiments
    investigated the degradation of mixtures of aldicarb sulfoxide and
    sulfone in soil and water from the saturated zone of two soil types
    (Table 4). The half-life was longer in the acidic Harrellsville soil
    than the alkaline Livingston soil. As in the case of laboratory
    experiments, the presence of particulates considerably increased the
    rate of degradation of the carbamates. Investigation of many variables
    in the laboratory led the authors to conclude that pH, temperature,
    redox potential, and perhaps the presence of trace substances can all
    affect degradation rates. They believed that laboratory
    experimentation could not provide definitive results without the
    identification of critical variables and that field observation was a
    more reliable indicator of aldicarb degradation

        Table 3.  Degradation rates for aldicarb, aldicarb sulfoxide,
              and aldicarb sulfonea
                                                                                   
                                                  Half-life at 25 C (days)b

                                       Aldicarb                 Total carbamatesc
                                                                                   

    Plough-layer soil
         sterilized                   2.5 (2.3-2.6)              10 (7-16)
         unsterilized                 1.0 (0.9-1.1)              44 (39-50)

    Soil water
         sterilized                  1679 (1056-4064)          1924 (1133-6370)
         unsterilized                 156 (143-176)             175 (158-195)

    Distilled water (no buffers)      671 (507-994)             697 (518-1064)

    Saturated zone soil and water
         sterilized                    15 (14-16)                16 (15-18)
         unsterilized                  37 (33-42)               123 (115-132)
                                                                                   

    a    From: Lightfoot & Thorne (1987).
    b    Values in parentheses represent 95% confidence intervals.
    c    Aldicarb, aldicarb sulfoxide, and aldicarb sulfone.
    pH measurements
         sterilized soil water: 6.6-7.0 for 238 days;
         4.8-5.0 at day 368 unsterilized soil water: 6.6-6.7 for 56
         days; 4.2-4.4 at day 238, 3.2 at day 368 distilled water:
         7.3-7.5 for 238 days, 6.2-6.8 at day 368 saturated zone soil
         and water: 4.1-4.5 throughout entire study.
    
         Coppedge et al. (1977) studied the movement and persistence of
    aldicarb in four different types of soil in laboratory and field
    settings using a radiolabelled substrate. Samples of clay, loam,
    "muck" (soil with high organic content), and sand were packed in
    polypropylene columns (63 x 128 mm), saturated with water, and
    maintained at 25 C throughout the study. Radiolabelled aldicarb
    granules (34 mg) were applied to each column at a point 38 mm below
    the soil surface. Water was then applied to each soil column at a rate
    of 2.5 cm/week for the next 7 weeks. The water eluted through the
    columns was collected and analysed for radiolabel. At the end of the
    7-week period, the soil was removed in layers 25 mm thick and analysed
    for residual radiolabel. The results of this study are shown in Tables
    5 and 6. The radiolabel (< 1%) in the loam and clay soils remained in
    the upper layers of the column, close to where it had been applied. In
    the sand, the residual radiolabel (2-3%) passed through to the lower

    parts of the column. A much higher percentage (5-6%)  of the
    radiolabel was retained in the muck soil column and was evenly
    distributed along the column. The radiolabel leached into the water
    eluted from the sand was 8-10 times greater than that from the other
    soil types. The nature of the decomposition products (ultimately shown
    to be carbon dioxide) resulted in some loss to the atmosphere
    surrounding the soils. The data in Table 6 indicate that most of the
    radioactivity retained in clay and loam soils represented aldicarb,
    sulfoxide whereas that in sand largely represented the parent
    compound. Greater leaching through sand decreased loss to the
    atmosphere by degradation to carbon dioxide.

         Coppedge et al. (1977) also studied the persistence  of aldicarb
    using field lysimeters. Aldicarb (34 mg), labelled with 35S, was
    added to columns (63 x 128 mm) containing Lufkin fine sandy loam soil
    at a point 76 mm below the surface. The contents were moistened with
    water and then buried in the same type of soil at a depth where the
    insecticide granules were 152 mm below the surface.  The experiment
    lasted for 7 weeks and rain was the only other source of moisture. The
    column recovered 3 days after the application yielded 71% of the
    radiolabel, while the column recovered at the end of 7 weeks yielded
    only 0.9%. This suggested an approximate half-life for the aldicarb of
    < 1 week, and the label distribution suggested an upward movement
    through volatilization of the decomposition products. The authors
    therefore concluded that there was little danger that aldicarb would
    move into the underground water supply in this type of soil.

         Bowman (1988) studied the mobility and persistence of aldicarb
    using field lysimeters containing cores (diameter, 15 cm; length, 70
    cm) of Plainfield sand. Half of the cores received only rainfall,
    while the remainder received rainfall plus simulated rainfall (50.8
    mm) on the second and eighth days after treatment, followed by
    simulated irrigation for the duration of the study. The results of
    this study indicated that under normal rainfall about 9% of the
    applied aldicarb leached out of the soil cores as sulfoxide or
    sulfone, whereas, in cores receiving supplementary watering, up to 64%
    of applied aldicarb appeared in the effluent principally as sulfoxide
    or sulfone.


        Table 4.  Degradation rates for aldicarb sulfoxide and aldicarb sulfone mixtures in groundwater degradation mechanism studiesa
                                                                                                                               
                                                      Sterilized (25 C)                         Unsterilized (25 C)
    Soil type and medium
                                               Half-lifeb                pHc              Half-lifeb                   pHc
                                                                                                                               

    Harrellsville, NC
         saturated zone soil and water                                                    137 (117-165)                5

    Harrellsville, NC (first set)
         saturated zone soil and water          378 (287-550)           4.3              1910 (1170-5180)              4.2
         coarse-filtered water                 1100 (760-1970)          4.6            > 2000                          4.6
         fine-filtered water                 > 2000                     4.6            > 2000                          4.2

    Livingston, CA (original data)
         saturated zone soil and water                                                    8 (7-10)                     7

    Livingston, CA
         saturated zone soil and water          1.3 (1.2-1.4)           9.0               7.5 (6.9-8.1)                8.4
         coarse-filtered water                 19 (17-22)               7.7               6.0 (5.7-6.3)                8.3
                                                                                                                               

    a    From: Lightfoot & Thorne (1987).
    b    Half-life (days) for carbamate residues.  Values in parentheses represent 95% confidence intervals.  Since the experiments
         were conducted for only 1 year, half-life estimates greater than about 600 days are not as reliable as other estimates. 
         Half-lives longer than about 2000 days could not be determined.
    c    Approximate average value during experiment.

    Table 5.  Distribution and persistence of 14C-aldicarb equivalents in soil columnsa,b

                                                                                                                                        

                                  Percentage of total dose in the various layers                        Percentage of total dose

    Soil type                                                           Total    Unextractable  In leached
                      0-25 c    25-50      50-75     75-100   100-128  extracted  residue from     water d      Recovered        Lost
                                                                      from soil     soil
                                                                                                                                        

    Houston clay       0.4       0.1       0.1        T         T        0.6       2.5           12.5           15.6           84.4

    Lufkin loam        1.2       0.3       0.1       0.1        T        1.7       3.0            3.9            8.6           91.4

    Coarse sand         T         T        0.2       0.5       2.0       2.7       0.2           84.0           86.9           13.1

    Muck               8.7       5.3       8.5       5.6       4.8      32.9       7.1            3.5           43.5           56.5

                                                                                                                                   

    a    From: Coppedge et al. (1977).
    b    Results are the average from triplicate samples. Trace amounts (T) = < 0.1% of total dose.
    c    Layers are indicated by the distance (in mm) from the surface.
    d    Water that passed through the columns after the weekly addition of moisture.

    Table 6. 14C-labelled aldicarb and metabolites in water eluted through soil columnsa,b
                                                                                                                                    

                                                Percentage of total dose recovered at indicated days after treatment

    Soil type and compounds       3         10        16        23        29        35        41        47        53

                                                                                                                                    

    Clay
         aldicarb                                    0.5       0.2                 T         0
         sulfoxide                                   3.2       1.9                 0.4       0.2
     sulfone                                         0         T                   T         0
     other metabolites                               0.7       0.6                 0.3       0.2

    Total                       0        3.2        4.4       2.7       0.8       0.7       0.4       0.3       0
    Accumulative total       0        3.2        7.6      10.3      11.1      11.8      12.2      12.5      12.5

    Sand
         aldicarb                                    7.3      31.5                 5.0       5.4       2.3
         sulfoxide                                   0.9       2.6                 1.6       2.0       2.1
         sulfone                                     0         0                   0         0         0
          other metabolites                          0.2       1.9                 0.4       0.5       1.1

    Total                       0        3.5        8.4      36.0       9.2       7.0       7.9       5.5       6.7
    Accumulative total       0        3.5       11.9      47.9      57.1      64.1      72.0      77.5      84.0
                                                                                                                                    

    Table 6 (contd). 14C-labelled aldicarb and metabolites in water eluted through soil columnsa,b
                                                                                                                                    

                                                Percentage of total dose recovered at indicated days after treatment

    Soil type and compounds       3         10        16        23        29        35        41        47        53

                                                                                                                                    
    Loam
         aldicarb                                    T                   T                   T         0
         sulfoxide                                   0.9       0.3       0.2       0.3       0.2       0.3
         sulfone                                     0         0                   T         T
         other metabolites                           0.2       T         0.2       T         0.1       0.2

    Total                        0        0.7       1.1       0.3       0.4       0.3       0.3       0.5       0.3
    Accumulative total        0        0.7       1.8       2.1       2.5       2.8       3.1       3.6       3.9

    Muck
         aldicarb                                              T
         sulfoxide                                             0.1
         sulfone                                               0
         other metabolites                                     0.2

    Total                        0        0.2       0.6       0.9       0.9       0.3       0.1       0.3       0.3
    Accumulative total        0        0.2       0.8       1.7       2.6       2.9       3.0       3.3       3.6
                                                                                                                                    

    a    From: Coppedge et al. (1977).
    b    Results are the average from triplicate samples. Trace amounts (T) = < 0.1% of total dose.  Where a "total" value is given
          without values for each component, the volume of samples was insufficient for individual analyses.
    
         Andrawes et al. (1971a) studied the fate of radio-labelled
    aldicarb ( S-methyl-14C-Temik) in potato fields. The initial soil
    concentration was 13.1 mg/kg, which fell to 25.6 and 9.5% of the
    applied amount after 7 and 90 days, respectively. Samples taken as
    early as 30 min after the application showed that 12.7% of the
    aldicarb had already been converted to aldicarb sufoxide. By day 7 it
    had increased to 48%. In fallow soil, aldicarb was applied as an
    acetone/water solution at the same level as that used in the planted
    field. The dissipation of 14C residues occurred at a relatively slow
    rate for the first 2 weeks and then at a faster rate. The breakdown
    products in both the fallow and planted fields were essentially the
    same.

         LaFrance et al. (1988) studied the adsorption characteristics of
    aldicarb on loamy sand and its mobility through a water-saturated
    column in the presence of dissolved organic matter. The results of
    these studies suggested that aldicarb does not undergo appreciable
    complexation with dissolved humic materials found in the interstitial
    water of the unsaturated zones. Thus the presence of dissolved humic
    substances in the soil interstitial water should not markedly affect
    the transport of the pesticide towards the water table.

         Woodham et al. (1973a) studied the lateral movement of aldicarb
    in sandy loam soil. They applied the granular commercial formulation
    of the pesticide (Temik 10G) to irrigated and non-irrigated fields at
    a rate of 16.8 kg/ha and placed it 15-20 cm to the side of cotton
    seedlings and 12.5-15 cm deep. Soil samples were collected throughout
    the growing season from a depth of 15 cm, from the bottom of a creek
    adjacent to a treated field, and from sites 0.40 and 1.61 km
    downstream. The aldicarb used in this study was found to have a short
    residence time. Levels in the treated field fell to 15% within one
    month. Only 8% remained after 47 days. No residues were found after 4
    months and no aldicarb was detected either between rows or in the bed
    of the creek that collected water drainage.  The authors concluded
    that aldicarb was translocated into crop plants and weeds but that
    there would be no carry-over of aldicarb or its metabolites from one
    growing season to another (Woodham et al., 1973b). The results of
    studies by Andrawes et al. (1971a) and Maitlen & Powell (1982) agree
    with the observations of Woodham and his colleagues. Gonzalez & Weaver
    (1986) failed to detect aldicarb or its breakdown products in run-off
    water from a field treated with aldicarb in California, USA.

         The method and timing of application can also affect the
    migration and degradation of aldicarb (Jones et al., 1986). Aldicarb
    was applied in-furrow during the planting of potatoes and as a
    top-dressing at crop emergence. At the end of the growing season the
    residues from the first application were found primarily in the top
    0.6 m of soil, and the residues from the emergence application were
    found primarily in the top 0.3 m of soil.

         In a three-year Wisconsin potato field study (sandy plain),
    Fathulla et al. (1988) monitored aldicarb residues in the saturated
    zone ground water under fluctuating conditions of temperature, pH, and
    total hardness. Soils were well drained sands, loamy sands or sandy
    loams (with 1 to 2% organic matter). The water table was high with a
    depth to the saturated zone of between 1.3 and 4.6 m. Sampling wells
    were bored to a maximum of 7.5 m for groundwater sampling. Rothschild
    et al. (1982) had found all residues of aldicarb (and its breakdown
    products) within the upper 1.5 m of the ground water in the same area
    in an earlier study. This is consistent with the views of both groups
    of authors that movement of aldicarb will occur in these aquifers. The
    report of Fathulla et al. (1988) indicated that detection and
    persistence of aldicarb in the ground water were dependent on
    alkalinity and temperature. Movement of aldicarb was lateral as well
    as vertical and the authors emphasized the importance of seasonal
    changes in water table depth and precipitation as factors influencing
    movement. Degradation by microorganisms in the upper layers of the
    soil and ground water was noted and identified as a major factor in
    the short-term fate of the aldicarb. Hegg et al. (1988) measured the
    movement and degradation of aldicarb in a loamy sand soil in South
    Carolina, USA, and found that it degraded at a rate corresponding to
    a half-life of 9 days with essentially no residues present 4 months
    after application. This was a faster loss of aldicarb from the soil
    than in comparable studies in neighbouring areas. Using the
    unsaturated plant root zone model (PRZM) with rainfall records from 15
    years, aldicarb residues were predicted to be limited to the upper 1.5
    m, regardless of year-to-year variations in rainfall.

         Pacenka et al. (1987) sampled both soil cores and ground water
    from sites on Long Island (New York, USA), where earlier surveys had
    suggested contamination of wells with aldicarb and its breakdown
    products (the sulfone and sulfoxide). Three study areas were chosen
    with shallow (3 m), medium (10 m), and deep (30 m) water tables. All
    were overlain with sandy soils. Soil cores, driven to the depth of the
    water table, were taken from a field where aldicarb had been applied
    to potatoes and from surrounding areas. Ground water was sampled from
    188 wells of varying depth and at different distances from the
    aldicarb source.  Results indicated that the residence time of
    aldicarb (including the sulfone and sulfoxide) in the soil depended on
    the depth of the water table and, hence, the overlying unsaturated
    zone. In the shallow and medium depth water table sites, all aldicarb
    residues had disappeared within 3 years of the last use of the
    compound. In deeper unsaturated layers, aldicarb residues were present
    at increasing concentrations in soil water from 10 m down to the water
    table at 30 m. The uppermost 10 m was free of residues. Analysis of
    the groundwater samples showed lateral movement of residues extending
    from 120 m to 270 m "downstream" of the source in a single year. It
    was calculated that the relatively shallow aquifer in the area (which
    lay over a deeper aquifer capped by an impervious layer of clay) would

    flush residues from the area completely within 100 years and lead to
    concentrations below the drinking-water guideline level (New York) of
    7 g/litre being attained between 1987 and 2010 (depending on
    assumptions for dispersion and degradation). Pacenka et al. (1987)
    revised this figure downwards on the basis of their more extensive
    field observations, although no firm figure could be advanced.

         Studies in other geographical areas of the USA, including those
    showing some residues of aldicarb or the sulfoxide and sulfone in
    wells, have demonstrated a shorter residence time and more rapid
    degradation than in the Long Island study (Jones et al., 1986; Wyman
    et al., 1987; Jones, 1986, 1987). In these studies there was little
    lateral movement of the ground water in the saturated zone. Water
    table levels in these areas were generally high and much of the
    sampling of the ground water was in the top 4-5 m of the saturated
    zone. Much greater lateral movement of ground water in the Florida
    Ridge area at a shallower depth than similar movement in Long Island
    also shifted the aldicarb residues away from the treated area.
    However, degradation was sufficiently fast in these soils to reduce
    the chance of contamination of wells used for drinking-water. An
    impervious layer 6 m down would prevent deeper contamination in this
    area (Jones et al., 1987a).

         A review of well and groundwater monitoring of aldicarb residues
    throughout the USA has been published by Lorber et al. (1989, 1990),
    which indicates geographical areas at greatest risk of water
    contamination and local restrictions on the use of aldicarb.

    4.1.3  Vegetation and wildlife

         The uptake of aldicarb and its residues by food crops and plants
    has been reported in several studies (Andrawes et al., 1974; Maitlen
    & Powell, 1982). Residue levels in plants and crops grown in
    aldicarb-treated soil are given in Table 7. Of the many varieties and
    species of birds and mammals studied, only the oriole had aldicarb
    residues (0.07 mg aldicarb equivalents per kg) in its tissues (Woodham
    et al., 1973b).

         In a study by Iwata et al. (1977), aldicarb was applied to the
    soil in orange groves at rates of 2.8, 5.6, 11.2, and 22.4 kg ai/ha.
    Residues found on day 118 after application in the soil were 0.03,
    0.16, 0.20, and 0.42 mg/kg, respectively. On day 193, samples were
    taken from the pulp of oranges grown in soil that had been given the
    highest amount (22.4 kg ai/ha) of aldicarb. The residues in these
    samples ranged from 0.02-0.03 mg/kg.

         After aldicarb was applied to the leaves of young cotton plants
    under field conditions, it was not translocated to other parts of the
    plant to any great extent (Bull, 1968). Two weeks after application, 

    93% of the recovered radiolabel was found at the application site. The
    remainder was spread evenly throughout the plant, including the roots
    and fruit.

    4.2  Biotransformation

         In plants, aldicarb is metabolized by processes involving
    oxidation to the sulfoxide and sulfone, as well as by hydrolysis to
    the corresponding oximes and, ultimately, to the nitrile.

         There have been several studies on the metabolism of aldicarb by
    the cotton plant. Metcalf et al. (1966) found that aldicarb was
    completely converted within 4-9 days to the sulfoxide, which was then
    hydrolysed to the oxime. The subsequent oxidation of the sulfoxide to
    the sulfone occurred more slowly and was found to lead to
    bioaccumulation in aged residues (Coppedge et al., 1967).

         When aldicarb (10 l of an aqueous solution containing 10g
    aldicarb) was applied to the leaves of cotton plants, 7.1% of the
    administered dose was converted to the sulfoxide within 15 min. Two
    days later there was no residual aldicarb in or on the plant tissues,
    and the principal metabolite (78.4% of the initial dose) was the
    sulfoxide. After 8 days, 7.4% of the initial dose was found as the
    sulfone while the nitrile sulfoxide and an unidentified metabolite
    were the final products of decomposition (Bull, 1968).

    4.3  Interaction with other physical, chemical or biological factors

    4.3.1  Soil microorganisms

         Kuseske et al. (1974) studied the degradation of aldicarb under
    aerobic and anaerobic conditions and found that degradation was much
    slower under anaerobic conditions. Jones (1976) studied the metabolism
    of aldicarb by five common soil fungi. The potential for aldicarb
    detoxification by these fungi (in decreasing order) was as follows:
     Gliocladium catenulatum > Penicillium multicolor = Cunninghamella
     elegans > Rhizoctonia sp. > Trichoderma harzianum . The major
    organosoluble metabolites were identified as aldicarb sulfoxide, the
    oxime sulfoxide, the nitrile sulfoxide, and smaller amounts of the
    corresponding sulfones, indicating that the metabolic pathways were
    similar to those found in higher plants and animals.

         Spurr & Sousa (1966, 1974) tested the effects of aldicarb and its
    metabolites on pathogenic and saprophytic microorganisms and found
    that some of the microorganisms appeared to use aldicarb as a carbon
    source. The various bacteria and fungi used in these tests showed no
    growth inhibition when aldicarb was added at levels up to 20 times
    those usually used in field conditions.


        Table 7. Residues (in mg/kg) of aldicarb and its sulfoxide and sulfone metabolites found in various
    crops grown in aldicarb-treated soila,b
                                                                                                                                   

    Replicate           Potato         Potato         Alfalfa        Alfalfa        Mint      Mustard        Radish    Radish
    no.                 leavesc        leaves         (transplanted) (seeded)       foliage   greens         tops      roots
                        (70)d          (408)          (456)          (456)          (408)     (408)          (408)     (408)
                                                                                                                                    

    3.4 kg ai/ha application

         1               7.65           0.52           0.14           0.16          0.02       ND             0.08     ND
         2               7.93           0.15           ND             0.04          0.01       O.03           0.07     ND
         3               8.11           1.34           0.09           0.05          0.05       0.08           0.05     ND
         4               8.74           1.27           0.24           0.14          0.10
         5               9.60           1.03           0.13           0.24          0.06

    Average              8.41           0.66           0.12           0.13          0.05       0.04           0.07     ND

    15.0 kg ai/ha application

         1              19.30           0.69           0.89           0.89          0.64       ND             0.27      0.04
         2              14.90           1.10           0.34           1.47          0.92       0.26           0.27      0.05
         3              20.80           1.12           0.43           0.26          0.37       0.40           0.18      0.03
         4              19.40           0.50           0.76           0.61          0.23
         5              22.60           1.96           1.37           8.37          1.55

    Average             19.40           1.07           0.76           2.32          0.74       0.22           0.24      0.04
                                                                                                                                    

    a    From: Maitlen & Powell (1982).
    b    Residues in this table were determined by oxidizing the aldicarb, aldicarb sufoxide, and aldicarb sulfone and then
          determining them as one combined compound, aldicarb sulfone.  ND = none detected; the lower limit of reliable detection for
          these samples was < 5.0 ng/aliquot analysed or < 0.02 mg/kg.
    c    These samples are from the crop of 1979.  All others are from the crop of 1980.
    d    Figures in parentheses are the interval in days between treatment of soil and sampling of plants.
    

    5.  ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

    5.1  Environmental levels

    5.1.1  Air

         Since aldicarb is applied in granular form to the soil surface,
    it reaches the atmosphere only by upward migration and by
    volatilization. Thus, it is not transported to the atmosphere to any
    great extent and so is not expected to contribute a significant health
    threat from this source. In a volatilization study (Supak et al.,
    1977), a special apparatus was designed to determine the volatility of
    aldicarb from the soil. The air eluted from the apparatus after it had
    passed over soil samples containing dispersed aldicarb was analysed by
    the method of Maitlen et al. (1970). This method allowed the
    quantitative analysis of aldicarb and its two oxidation products, the
    sulfoxide and sulfone, both of which are toxic. Nontoxic decomposition
    products, such as the sulfoxide and sulfone oximes, both of which
    interfere with the determination of aldicarb sulfone by this method,
    were removed by LC.  When aldicarb was mixed with soil to a
    concentration of 1 mg/kg, only 2g of aldicarb volatilized over the
    first 9 days of the experiment and subsequent losses increased to a
    steady-state rate of approximately 1g/day. According to the authors,
    this rate of volatilization was almost negligible and not high enough
    to cause a potential health hazard.

    5.1.2  Water

         Run-off to surface water and leaching to aquifers used as sources
    of water for human consumption have been investigated. Aldicarb
    residues have been found in drinking-water wells in New York
    (Wilkinson et al., 1983; Varma et al., 1983), Wisconsin (Rothschild et
    al., 1982), and Florida (Miller et al., 1985). The US EPA groundwater
    team reported that they had found groundwater residues in 22 states
    (US EPA, 1988b). In Canada, water samples taken from private wells
    showed contamination with aldicarb up to 6.0 g/litre; ground water
    from Quebec (maximum of 28 g/litre) and Ontario (maximum of 1.1
    g/litre) also contained detectable levels (Hiebsch, 1988).

         Prince Edward Island, Canada, is wholly dependent upon ground
    water from a highly permeable sandstone aquifer for domestic,
    agricultural, and industrial use. Priddle et al.  (1989) reported that
    12% of monitored wells exceeded the Canadian drinking-water guideline
    of 9g/litre for aldicarb. The maximum level detected was 15 g/litre.

         Following extensive agricultural use of aldicarb and as a result
    of a combination of environmental and hydro-logical conditions on
    eastern Long Island, New York, in 1978 the insecticide

    and its metabolites had leached into groundwater aquifers that
    constitute the major source of drinking-water for local inhabitants.
    In December 1978, detectable levels of aldicarb were found in 20 of 31
    water sources; similar results were obtained in the following June.
    When both private and community wells located near potato farms were
    sampled in August 1979, analyses revealed detectable levels of
    aldicarb in potable water.  In March 1980, the Department of Health
    Services in Suffolk County, New York, undertook an extensive sampling
    programme that included nearly 8000 wells. Union Carbide performed the
    analyses, with the New York Department of Health serving as the
    quality control arm. Levels of aldicarb ranging from trace amounts to
    > 400 g/litre were detected in 27% of the wells sampled. Baier &
    Moran (1981)  reported that of 7802 wells sampled, 5745 (73.6%) did
    not have detectable concentrations of aldicarb, 1025 (13.1%) had
    concentrations in excess of the 7 g/litre guideline of the New York
    State Department of Health, and the remaining 1032 (13.3%) had trace
    amounts of this insecticide.

         Aldicarb has been found at levels of 1-50 g/litre in the ground
    water of the USA (Cohen et al., 1986; de Hann, 1988).

         The contamination of the Long Island (New York) aquifer by
    aldicarb at levels of up to 500 g/litre (in one well) was attributed
    by Marshall (1985) to a combination of circumstances (high rainfall,
    coarse sandy soil, low soil temperatures, and a shallow water table)
    that favoured leaching. There have been some predictions that this
    undesirable situation would persist for only a year or two, but also
    some suggestions that wells could remain contaminated for up to a
    century. Marshall (1985) also voiced concern that under anaerobic
    conditions in cool climates, such as those in northern regions, the
    breakdown of aldicarb and its residues would be a much slower process.
    Contamination would also be favoured by heavy usage of Temik.

         During 1982, aldicarb was identified in several wells in the
    state of Florida (Miller et al., 1985). The state Commission of
    Agriculture and Consumer Services subsequently banned the use of Temik
    on citrus crops in 1983. A University of Florida task force was
    appointed to sample the 10 largest drinking-water systems that
    obtained water from groundwater sources in 35 counties. Neither
    aldicarb nor its oxidative sulfoxide or sulfone metabolites were
    detected in any of the almost 400 samples collected.

         During the application season of 1984 (January to April), 2040
    tonnes of aldicarb was used on citrus fruits at a rate of 5.6 kg ai/ha
    in more than 30 counties in Florida. No residues were detected in
    samples taken from community water systems, but trace amounts of
    aldicarb, aldicarb sulfoxide, and aldicarb sulfone were found in the

    Calloosahatchee River from which Lee County draws its drinking-water.
    (However, no residues were found in finished drinking-water in Lee
    County). The authors stated that the persistence of aldicarb and its
    metabolites in shallow ground water may also contaminate
    drinking-water. The results of a monitoring study by the Union Carbide
    Corporation (UCC) showed that in shallow ground water aldicarb can
    move further from its application point than originally predicted.

    5.1.3  Food and feed

         Residues have been detected on a variety of crops for which
    aldicarb is used (see section 3.2.1). In the USA, aldicarb
    intoxication from eating contaminated watermelons has been reported in
    California (Jackson et al., 1986) and in Oregon (Green et al., 1987),
    and two episodes of poisoning from eating aldicarb-contaminated
    cucumbers have been reported in Nebraska (Goes et al., 1980).
    Store-bought cucumbers, grown hydroponically, were found to contain
    between 7 and 10 mg aldicarb/kg (Aaronson et al., 1980). It should be
    noted that aldicarb is not approved for use on these crops.

         Laski & Vannelli (1984) reported the results of a survey of
    potatoes grown in New York State in 1982. Fifty samples, each
    consisting of 9 kg, were collected after harvest from four areas. In
    each of these areas, except one (Long Island), aldicarb was applied at
    rates of 14 to 22 kg/ha at planting stage. Samples were analysed for
    aldicarb, aldicarb sulfoxide, and aldicarb sulfone by the method of
    Krause (1980). Over 50% (23 out of 43) of potato samples obtained from
    areas where aldicarb was applied were positive for aldicarb sulfoxide
    (trace to 0.48 mg/kg)  and/or sulfone (trace to 0.20 mg/kg), but
    aldicarb itself was not detected. No residues were found in any of the
    7 samples from Long Island. The maximum concentrations were detected
    in samples from the North Eastern location, where there is sandy soil.
    Potatoes with the maximum concentration (0.48 mg/kg) were found to
    contain two and a half times higher concentrations (1.2 mg/kg) when
    reanalysed by a more sensitive method (Union Carbide, 1983). The
    investigators suggested that soil type and climatic conditions
    influenced residues in the crops.

         When Krause (1985b) analysed aldicarb and its oxidative
    metabolites in "market basket" potatoes, he detected levels of
    aldicarb sulfone ranging from < 0.01 to 0.18 mg/kg and of aldicarb
    sulfoxide from < 0.01 to 0.61 mg/kg.  All 39 samples collected
    between 1980 and 1983 contained residues of aldicarb or its
    metabolites.

         Potato samples collected from farms in the north-central part of
    New York, where soil is of the wet muck type, contained lower aldicarb
    residues than did the rocky-sandy soil type found in the north-eastern
    part of the state, even though application rates were the same in both
    areas. These lower residue levels were the result of aldicarb
    decomposition associated with moisture. Cairns et al. (1984) described
    the persistence of aldicarb in fresh potatoes.

         Peterson & Gregorio (1988) reported upper 95 percentile residue
    levels of 0.0677 mg/kg in raw potatoes (tolerance = 1 mg/kg), 0.0658
    mg/kg in fresh bananas (tolerance = 0.3 mg/kg), and 0.0212 mg/kg in
    grapefruit (tolerance = 0.3 mg/kg) in a market basket survey conducted
    in the USA (national food survey). These authors also reported a
    maximum residue level of 0.82 mg/kg in raw potatoes obtained in
    controlled field trials, as well as upper 95 percentile residue levels
    as high as 0.43 mg/kg in raw potatoes, 0.12 mg/kg in bananas, and 0.17
    mg/kg in citrus products, estimated from the distribution of residue
    levels obtained in field trials.

    5.2  General population exposure

         The general population may be exposed to aldicarb and its
    residues primarily through the ingestion of food containing aldicarb
    and from contaminated water, as discussed in sections 5.1.2, 5.1.3.,
    and section 8. The largest documented episode of foodborne pesticide
    poisoning in North American history occurred in July 1985. This
    resulted from the consumption of Californian watermelons contaminated
    with up to 3.3 mg/kg of aldicarb sulfoxide (Ting & Kho, 1986).

         Hirsch et al. (1987) reported 140 cases of poisoning incidences
    in the Vancouver area of British Columbia, Canada. A review of the
    onset of symptoms and food consumed suggested illness associated with
    eating cucumbers contaminated with aldicarb. Analytical investigations
    confirmed that the cucumbers from one producer contained residues of
    total aldicarb up to 26 mg/kg.

         Petersen & Gregorio (1988) reported the results of a
    comprehensive analysis of aldicarb data from controlled field residue
    studies and provided estimates of the upper 95 percentile of residues
    in foods in the USA. The analysis showed that daily exposure at the
    upper 95 percentile consumption rate for aldicarb-treated commodities
    containing the estimated upper 95 percentile aldicarb residue levels
    would be approximately one-quarter of the daily exposure calculated by
    assuming that all of the aldicarb-treated commodities contained
    residues at the tolerance levels (e.g., 1.77 g/kg per day versus 6.38
    g/kg per day for the USA population). In addition, Petersen &
    Gregorio (1988) presented the results of a statistically designed 

    national food survey on the five commodities that were estimated to 
    be responsible for more than 90% of the dietary exposure to aldicarb 
    residues in the USA (bananas, white potatoes, sweet potatoes, oranges, 
    and grapefruit). Daily exposure to aldicarb at the 95 percentile 
    consumption rate for aldicarb-treated commodities containing the 
    95 percentile aldicarb residue levels, as estimated from the national 
    food survey, would be approximately 6% of the daily exposure calculated 
    by assuming aldicarb residue levels at the tolerance levels 
    (e.g. 0.40 g/kg body weight per day versus 6.38 g/kg per day for the 
    USA population).

         The highest daily exposure estimated from the results of the
    national food survey was 0.89 g/kg per day for non-nursing infants
    and children (1-6 years of age).

         A US EPA survey indicated that the vast majority of wells
    contained levels of aldicarb residues less than 10 g/litre and noted
    that heat treatment of water used in cooking would result in aldicarb
    residues no higher than 5 g/litre (Cohen et al., 1986).

         Accidental leaks of several gases at a plant producing aldicarb
    in Institute, West Virginia, USA, required 135 people to be the
    hospitalized (Marshall, 1985).

    5.3  Occupational exposure during manufacture, formulation or use

         The dangers of inadequate safety precautions and improper dress
    and handling procedures are discussed in section 8. People involved in
    the manufacture and field application of aldicarb are potentially at
    higher risk than the general population (Doull et al., 1980) and
    should always take proper safety precautions.

    6.  KINETICS AND METABOLISM

    6.1  Absorption

         A number of studies on various mammalian and non-mammalian
    species have shown that aldicarb, as well as its sulfoxide and sulfone
    metabolites, is absorbed readily and almost completely from the
    gastrointestinal tract (Knaak et al., 1966a,b; Andrawes et al., 1967;
    Dorough & Ivie, 1968; Dorough et al., 1970; Hicks et al., 1972; Cambon
    et al., 1979). Andrawes et al. (1967) reported that the uptake of
    aldicarb and aldicarb sulfoxide from the gastro-intestinal tract of
    the rat was rapid and efficient. They recovered 80-90% of the
    radiolabel in the urine during the first 24 h after administration.
    Their observation was substantiated by Knaak et al. (1966a,b), who
    also recovered > 90% of the administered oral dose in rats.

         Cambon et al. (1979) reported the rapid uptake of aldicarb in
    pregnant rats. The rats showed overt signs of depression of
    cholinesterase activity < 5 min after they were given single oral
    doses of aldicarb ranging from 0.001 to 0.10 mg/kg. At all dose
    levels, acetylcholin-esterase activity was significantly decreased in
    fetal blood, brain, and liver 1 h after dosing.

         Dorough et al. (1970) recovered 92% of the doses (0.006-0.52
    mg/kg per day) of aldicarb and aldicarb sulfone in the urine of
    lactating Holstein cows dosed during a 14-day period. Dorough & Ivie
    (1968) found that > 90% of a single dose of 0.1 mg/kg administered
    orally to lactating Jersey cows was absorbed and excreted in the
    urine. In laying hens, oral doses of aldicarb and aldicarb sulfone
    were administered in a 21-day short-term feeding study and in a single
    capsule dose study, respectively. In the short-term feeding study,
    80-85% of each daily dose was excreted in the faeces during the
    following 24 h, while 90% of the total dose consumed was excreted
    within one week after the cessation of aldicarb intake. In the single
    dose study, 90% of the single oral dose was excreted within 10 days
    (Hicks et al., 1972).

         Feldman & Maibach (1970) reported the relatively efficient dermal
    uptake of carbamate insecticides in man (73.9% of a dermally applied
    dose of carbaryl was absorbed over a period of 5 days compared with
    10% for five other representative pesticides). The percutaneous uptake
    of aldicarb in water or in toluene has also been demonstrated
    qualitatively in rabbits (Kuhr & Dorough, 1976; Martin & Worthing,
    1977) and in rats (Gaines, 1969).

    6.2  Distribution

         The rapid depression of acetylcholinesterase activity in fetal
    and maternal blood and tissues observed after the oral administration
    of aldicarb to pregnant rats demonstrated that aldicarb or its toxic
    metabolites (the sulfoxide and sulfone) are distributed to the tissues
    by the systemic circulation (Cambon et al., 1979, 1980). The
    quantitative distribution of radiolabelled aldicarb and its
    metabolites in the tissues of female rats, given a single oral dose of
    0.4 mg aldicarb/kg, is shown in Table 8 (Andrawes et al., 1967).
    Aldicarb and its residues appeared to be distributed among the various
    tissues examined with no tendency to be sequestered or accumulated in
    any one tissue, since animals killed from 5 to 11 days after dosing
    had no detectable radiolabelled residues.

         Aldicarb and its metabolites were found to be concentrated in the
    livers of cows fed 0.12, 0.6, or 1.2 mg aldicarb/kg diet for up to 14
    days (Dorough et al., 1970).  Levels of the radiolabel in muscle, fat,
    and bone were low or below the detection levels. In a previous study,
    Dorough & Ivie (1968) found that 3% of the radiolabel was excreted in
    the milk of a lactating cow after a single oral dose of 0.1 mg/kg.

         Hicks et al. (1972) conducted a study in which single oral doses
    (0.7 mg/kg) of aldicarb or a 1:1 molar ratio of aldicarb and aldicarb
    sulfone were administered to laying hens. The radiolabel equivalents
    were greatest in the liver and kidneys for the first 24 h, much lower
    levels being found in fat and muscle. In a second study,
    aldicarb/aldicarb sulfone was administered at 0.1, 1.0, or 20 mg/kg
    diet for 21 days. Distribution to the tissues after this multiple
    dosing regimen was similar to that after the single dose, the highest
    residue levels appearing in the liver and kidneys.

        Table 8. Total aldicarb equivalents (mg/kg) in tissues of rats treated
             orally with 35  S-aldicarba
                                                                                                 

                                      Time period (days after dosing)b

                                Day 1              Day 2              Day 3             Day 4
                             W        D         W         D        W         D       W        D
                                                                                                 
    Heart                   0.12     0.44      0.09      0.32    0.08       0.29    0.11     0.38

    Kidneys                 0.16     0.56      0.08      0.25    0.06       0.16    0.07     0.21

    Brain                   0.11     0.35      0.02      0.08    0.08       0.25    0.05     0.19

    Lungs                   0.15     0.60      0.02      0.48    0.04       0.14    0.06     1.19

    Spleen                  0.27     1.08      0.04      0.12    0.10       0.37    0.05     0.17

    Liver                   0.16     0.28      0.07      0.22    0.07       0.21    0.05     0.14

    Leg muscle              0.16     0.61      0.02      0.07    0.05       0.20    0.04     0.12

    Fat                     0.23     0.72      0.11      0.12    0.09       0.11    0.03     0.04

    Bone                    0.11     0.15      0.09      0.13    0.06       0.08    0.02     0.04

    Stomach                 0.19     0.64      0.07      0.26    0.08       0.29    0.06     0.19

    Stomach contents        0.18     0.94      0.14      1.05    0.10       0.65    0.03     0.09

    Small intestine         0.18     0.74      0.13      0.45    0.10       0.30    0.06     0.16

    Small intestine         0.25     1.20      0.19      1.03    0.08       0.49    0.06     0.24
         contents
                                                                                                  

    Table 8 cont'd. Total aldicarb equivalents (mg/kg) in tissues of rats treated
            orally with 35  S-aldicarba
                                                                                                 
                                      Time period (days after dosing)b

                              Day 1               Day 2             Day 3             Day 4
                          W          D         W        D        W         D       W        D
                                                                                                 

    Large intestine       0.15       0.66      0.12     0.54    0.08       0.27    0.13     0.30

    Large intestine       0.18       0.67      0.05     0.24    0.09       0.39    0.04     0.16
         contents

    Blood                 0.16       0.74      0.14     0.18    0.08       0.21    0.05     0.17
                                                                                                 

    a     From: Andrawes et al. (1967).
    b     W = wet weight; D = dry weight.
    

    6.3  Metabolic transformation

         Carbamates undergo a limited number of  in vivo reactions:
    oxidation, reduction, hydrolysis, and conjugation (Ryan, 1971). In
    animals, the enzymes involved in these processes are found in the
    microsomal fraction of the liver homogenate. In the case of aldicarb,
    both oxidation of the sulfur to the sulfoxide and sulfone and
    hydrolysis of the carbamate ester group are involved (Andrawes et al.,
    1967). Although the hydrolysis reaction destroys insecticidal
    activity, both the sulfoxide and sulfone are active anticholinesterase
    agents (Andrawes et al., 1967; Bull et al., 1967; NAS, 1977). The
    metabolic pathways for aldicarb in the rat are shown in Fig. 1
    (Wilkinson et al., 1983). The metabolism of aldicarb in animals
    usually results in the formation of the sulfoxide, sulfone, oxime
    sulfoxide, oxime sulfone, nitrile sulfoxide, nitrile sulfone, and at
    least five other metabolites (Knaak et al., 1966a,b; Dorough et al.,
    1970). Aldicarb metabolites formed by incubation with liver microsomal
    enzymes are similar to the metabolites formed in plants and insects
    (Oonnithan & Casida, 1967). The rapid conversion to the sulfoxide and
    sulfone has been demonstrated in plants (Metcalf et al., 1966;
    Coppedge et al., 1967) and animals (Andrawes et al., 1967; Dorough &
    Ivie, 1968).

          In vitro studies by Oonnithan & Casida (1967) showed that the
    first stage in the metabolism of aldicarb involves the microsomal
    reduced nicotinamide adenine dinucleotide phosphate (NADPH) system to
    form the sulfoxide, but that the subsequent oxidation to the sulfone
    derivative occurs only to a small extent. Andrawes et al. (1967)
    confirmed these findings and showed that in the presence of the NADPH
    cofactor the production of metabolites increases by a factor of 15.
    The same authors also demonstrated that the principal urinary
    metabolites in the rat consist of hydrolytic products with only a
    small amount of carbamate. In studies with pig liver enzymes, Hajjar
    & Hodgson (1982) concluded that, under aerobic conditions and in the
    presence of NADPH, the FAD-dependent monooxygenase is responsible for
    the observed oxidation of the thio-ether in the primary metabolic
    step. The same authors found that sulfoxidation is enhanced rather
    than inhibited by  n-octylamine, a known inhibitor of cyto-chrome
    P-450-dependent oxygenation.

    6.4  Elimination and excretion in expired air, faeces, and urine

         Most studies on the elimination and excretion of aldicarb and its
    metabolites have used the radiolabelled compound. No kinetic
    coefficients have been reported, although studies in which rats (Knaak
    et al., 1966a,b; Andrawes et al., 1967; Dorough & Ivie, 1968; Marshall
    & Dorough, 1979), cows (Dorough & Ivie, 1968; Dorough et al., 1970),
    and chickens (Hicks et al., 1972) were used gave some information
    about the clearance rates, mechanisms, and routes of excretion. In all
    species, the principal excretion route for aldicarb and its

    metabolites (> 90%) is via the urine. A small amount of aldicarb and
    its metabolic products is excreted via the faeces (which is in part
    due to biliary excretion), or is exhaled as carbon dioxide.

         The total excretion of  S-methyl-C14-,  tert-butyl-C14-,
    and  N-methyl-C14-labelled aldicarb by rats after oral dosing was
    investigated by Knaak et al. (1966a). Within 24 h, the total excretion
    of the  S-methyl,  tert-butyl, and  N-methyl labels was
    approximately 90, 90, and 60%, respectively. For the  S-methyl- and
     tert-butyl-labelled compounds, > 90% was excreted via the urine and
    only 1.1% of the radiolabel was excreted as carbon dioxide. In a study
    on rats dosed orally with aldicarb (labelled in a different position
    and with different radioisotopes), Andrawes et al. (1967) showed that
    > 80% of the applied dose (labelled with 14C) was excreted over 24
    days, while 6.6% was excreted in the faeces within 4 days.

         The biliary excretion of aldicarb and its metabolites was studied
    by Marshall & Dorough (1979) in rats with cannulated bile ducts. A
    single oral dose of 14C-thiomethyl aldicarb (0.1 mg/kg) in 0.2 ml of
    vegetable oil was given by intubation, and urine, bile, and faeces
    were collected over the next 72 h. Biliary excretion accounted for
    2.6, 9.5, 22.9, 28.1, and 28.6% of the administered dose at 3, 6, 12,
    24, and 48 h after dosing, respectively. More than 64% was excreted in
    the urine over the 48-h period, and < 1% was recovered from the
    faeces.

         In a study by Dorough & Ivie (1968), 83% of an oral dose of 0.1
    mg/kg given to a lactating cow was recovered in the urine within 24 h,
    this increasing to 90% over 22.5 days. Only 2.85% of the radiolabel
    was recovered in the faeces within 8 days after dosing. All samples of
    milk taken from 3 h to 22.5 days after dosing contained the radiolabel
    and accounted for 3.02% of the administered dose.

         Hicks et al. (1972) dosed laying hens with 35S-aldicarb or with
    a 1:1 molar ratio of 14C-aldicarb and 14C-aldicarb sulfone. The
    dose (0.7 mg/kg) was administered orally in a gelatin capsule. In both
    cases, the label was excreted rapidly; 75% of the radiolabel was
    recovered in the faeces within 24 h and > 80% was recovered within 48
    h. Repeated dosing, twice a day for 21 days, resulted in a similar
    pattern of excretion, 80-85% of the daily dose being excreted in the
    faeces within 24 h after the administration of each dose.

         

    FIGURE 1

    7.  EFFECTS ON LABORATORY MAMMALS AND  IN VITRO TEST SYSTEMS

    7.1  Single exposure

         The acute oral and dermal toxicity of aldicarb has been studied
    in several species (Table 9). Oral LD50 values appear to be fairly
    consistent (0.3-0.9 mg/kg body weight in the rat) and not dependent on
    the carrier vehicle. Oral administration of the granular formulation
    of aldicarb gives LD50 values proportional to the active ingredient
    content (Carpenter & Smyth, 1965). The oral LD50 values for aldicarb
    sulfoxide and sulfone in rats are 0.88 mg/kg body weight and 25.0
    mg/kg body weight, respectively (Weil, 1968). Dermal LD50 values
    vary with the mode of application and the carrier vehicle used.
    Several acute dermal toxicity studies using different carrier vehicles
    have been reported. The dermal 24-h LD50 in rabbits for a single
    application of aldicarb in water was 32 mg/kg body weight (West &
    Carpenter, 1966).  However, when aldicarb was tested in propylene
    glycol, the observed dermal LD50 was 5 mg/kg body weight (Striegel
    & Carpenter, 1962). A dermal LD50 of 141 mg/kg body weight was
    reported in a 4-h exposure study on rabbits using dry Temik 10G
    formulation. On the basis of results of acute oral and dermal toxicity
    studies, aldicarb should be labelled as extremely hazardous (WHO,
    1990b).

         Carpenter & Smyth (1965) reported 100% mortality within 5 min
    when rats, mice, and guinea-pigs were exposed to aldicarb dust at a
    concentration of 200 mg/m3. The rats and mice were more sensitive
    than the guinea-pigs. Rats survived a dust concentration of 6.7
    mg/m3 for 15 min, but five out of six died after 30 min. All rats
    survived for 8 h when exposed to a saturated vapour concentration.
    Rats were also less sensitive to aerosol concentrations than to
    similar concentrations of the dust. Two of six rats survived an 8-h
    exposure to an aerosol concentration of 7.6 mg/m3. Weil & Carpenter
    (1970)  determined an LD50 of 0.44 mg/kg body weight in rats by the
    intraperitoneal route.


        Table 9.  Acute toxicity of aldicarb and its formulation products
                                                                                                          

    Compound       Route of       Vehicle             Species  LD50                  Reference
                   adminis                                     (mg/kg body
                   tration                                     weight)a
                                                                                                          
    Technical      oral                               rat           0.93           Martin & Worthing
    aldicarb                                                                       (1977)

                   oral           peanut oil          rat        M: 0.8            Gaines (1969)
                                                                 F: 0.65

                   oral           corn oil            rat        M: 0.09           Carpenter & Smyth
                                                                                   (1965)

                   oral           corn oil            rat        F: 1.0            Weiden et al. (1965)

                   oral           not specified       mouse         0.3            Black et al. (1973)

                   skin           xylene              rat        M: 3.0            Gaines (1969)
                                                                 F: 2.5

                   skin           not specified       rabbit        5.0            Weiden et al. (1965)

                   skin           propylene glycol    rabbit        5.0            Striegel & Carpenter
                                  (5%)                                             (1962)

    Temik 10G      oral           not specified       rat           7.7            Weil (1973)

                   dermal         water               rat         400              Carpenter & Smyth
                   (4 h)                                                           (1965)

                   dermal         none                rat         200              Carpenter & Smyth
                                                                                   (1965)

                                                                                                          

    Table 9 cont'd.  Acute toxicity of aldicarb and its formulation products
                                                                                                          

    Compound       Route of ad-      Vehicle             Species  LD50               Reference
                   ministration                                   (mg/kg body
                                                                  weight)a
                                                                                                          

                   dermal            none                rat         850            Weil (1973)

                   dermal            water (50%)         rabbit       32            West & Carpenter
                                                                                    (1966)

                   dermal            dimethyl            rabbit       12.5          West & Carpenter
                   (4 h)             phthalate                                      (1966)

                   dermal            toluene (5%)        rabbit        3.5          West & Carpenter
                   (4 h)                                                            (1966)
                                                                                                          

    a    M = male; F = female.
    

         Trutter (1989a) investigated the clinical effects and the effect
    on plasma cholinesterase and erythrocyte acetylcholinesterase of a
    single feeding of aldicarb residues (about 83.4% sulfoxide and 16.6%
    sulfone). These residues were contained in a watermelon grown under
    experimental conditions, aldicarb having been applied to the soil at
    intervals beginning at the time of planting. Water-melon with a
    residue concentration of 4.9 mg/kg was fed to three male and three
    female cynomolgus monkeys at a dosage that provided a residue intake
    of 0.005 mg/kg body weight. Additional groups of three male and three
    female monkeys received untreated water-melon (20 g/kg body weight).
    The test monkeys received supplemental untreated water-melon so that
    their total intake of the fruit was the same as that of the controls.
    Cholinesterase activity was measured 16, 9, and 3 days before and
    immediately before the test. Peak inhibition of plasma cholinesterase
    (31-46%) occurred 1 h after treatment. It was only slightly less at 2
    h but was absent at 4 h after feeding. Observations continued at
    intervals for 24 h. No inhibition of erythrocyte cholinesterase and no
    clinical effects occurred (Trutter, 1989a).

         A similar study with identical numbers of cynomolgus monkeys was
    conducted using treated bananas. The total residue level (0.25-0.29
    mg/kg) in six bananas was less than that in the water-melon, and the
    average distribution of metabolites was different (91.8% sulfoxide and
    8.2% sulfone). The dosage of aldicarb metabolites for the test monkeys
    was 0.005 mg/kg body weight and the banana intake for both test and
    control animals was 20 g/kg body weight. Inhibition of cholinesterase
    was similar in male and female test monkeys, averaging 23% one hour
    after dosing, increasing to 33% by the second hour, and decreasing to
    24% by the fourth hour. No inhibition of erythrocyte cholinesterase
    and no clinical effects occurred (Trutter, 1989b).

    7.2  Short-term exposure

         Short-term studies have been conducted in several species with
    aldicarb and its principal metabolites (the sulfoxide and sulfone)
    both alone and in combination.

         In studies by Weil & Carpenter (1968b,c), male and female rats
    were fed daily doses of aldicarb sulfoxide (0, 0.125, 0.25, 0.5, and
    1.0 mg/kg body weight) or aldicarb sulfone (0, 0.2, 0.6, 1.8, 5.4, and
    16.2 mg/kg body weight) in the diet for 3 and 6 months.
    Acetylcholinesterase activities were depressed at the three highest
    levels of each compound, and this was accompanied by some growth
    retardation. No mortality or pathological effects (gross or
    microscopic) were observed. In an earlier study, Weil & Carpenter
    (1963) fed male and female rats daily with 0, 0.02, 0.10, or 0.50 mg
    aldicarb/kg for 93 days. Plasma cholinesterase activity was depressed
    in both males and females but erythrocyte cholinesterase activity was
    depressed only in males. Male and female rats fed doses of either 

    aldicarb sulfoxide or the sulfone (0.4, 1.0, 2.5, or 5.0 mg/kg body
    weight per day) for 7 days tolerated the lowest dose level of the
    sulfoxide with no effects on body or organ weight (Nycum & Carpenter,
    1970). There was no evidence of plasma, erythrocyte or brain
    cholinesterase inhibition at that dose level. However, these
    parameters were significantly affected at all higher dose levels. 
    Aldicarb sulfone caused a significant decrease in brain, plasma, and
    erythrocyte cholinesterase activity at the highest dose level in rats
    of both sexes. Reduction in brain cholinesterase activity also
    occurred at the two intermediate dose levels for the sulfone in female
    rats only.

         In a 13-week feeding study (NCI, 1979), there was 100% mortality
    in rats exposed to 100 or 320 mg aldicarb/kg and body weight loss at
    80 mg/kg in male rats.

         DePass et al. (1985) exposed 8-week-old male and female Wistar
    rats (10 of each sex per group) to a 1:1 mixture of aldicarb sulfoxide
    and aldicarb sulfone in their drinking-water for 29 days. Their study
    was based on a report by Wilkinson et al. (1983) that residues of
    aldicarb in drinking-water consist essentially of a 1:1 mixture of the
    sulfoxide and sulfone. The drinking-water levels were 0, 0.075, 0.30,
    1.20, 4.80, and 19.20 mg/litre (0-1.67 mg/kg body weight per day for
    males and 0-1.94 mg/kg body weight per day for females). The authors
    concluded that 4.8 mg/litre (470g/kg body weight per day) was the
    no-observed-effect level (NOEL), based on erythrocyte
    acetylcholinesterase and plasma cholinesterase inhibition observed at
    the highest dose level.

         Short-term dermal studies were conducted in which Temik 10G (with
    10% ai) was applied with wetted gauze to the abraded skin of male
    albino rabbits for 6 h/day for 15 days (Carpenter & Smyth, 1966). Dose
    levels of 0.05, 0.10, and 0.20 g/kg body weight were applied daily,
    and weight gain, food consumption, organ weights, cholinesterase
    activity, and the histopathology of several tissues were examined.
    Only plasma cholinesterase activity levels and weight gain at dose
    levels of 0.1 and 0.2 g/kg per day were significantly altered.

         In a 2-year study on beagle dogs, aldicarb was administered in
    the diet at dose levels of 0, 0.025, 0.05, and 0.10 mg/kg body weight
    per day (Weil & Carpenter, 1966).  The same parameters as those
    monitored in the rat study conducted by these authors were
    investigated in this study, but none were significantly different from
    controls. The authors concluded that the NOEL for rats and dogs was at
    least 0.10 mg/kg body weight per day, since this was the highest level
    tested.

         In a study by Hamada (1988), male and female beagle dogs were fed
    for one year a diet containing 0, 1, 2, 5 or 10 mg technical aldicarb
    per kg to provide approximately 0, 0.025, 0.05, 0.13, or 0.25 mg/kg
    body weight per day. No dogs died during the study, and there were no

    effects on body weight, food and water consumption, organ weights, or
    on haematological, ophthalmological, histopathological, and gross
    pathological parameters. However, statistically significant increases,
    compared to controls, in the combined incidence of soft stools, mucoid
    stools, and diarrhoea were found in all groups treated with 0.05 mg/kg
    per day or more, as well as in females treated with 0.025 mg/kg per
    day. No statistically significant decrease in erythrocyte or brain
    cholinesterase was found in groups treated with 0.025 or 0.05 mg/kg
    body weight per day.  However, plasma cholinesterase was inhibited in
    male dogs treated with 0.05 mg/kg body weight per day or more
    throughout the observation period of this study (weeks  5-52). In
    addition, plasma cholinesterase was inhibited at the conclusion of the
    study (week 52) in male dogs treated with 0.025 mg/kg body weight per
    day. The author noted that plasma cholinesterase activity in the male
    dogs treated with 0.025 mg/kg body weight per day was subsequently
    determined to be within historical control values, and that the
    statistically significant increase in soft stools and related effects
    in females treated with 0.025 mg/kg body weight per day could be
    attributable to an unusually high incidence of mucoid stools in one
    dog during the last half of the experiment. The author concluded that
    the NOEL in this study was 1 mg/kg (0.025 mg/kg body weight per day).

         In a short-term study, Dorough et al. (1970) dosed lactating
    Holstein cows with Temik (10% ai) at 0.042 mg ai/kg body weight per
    day in their diet for 10 days and, in a second experiment, with a
    mixture of aldicarb and aldicarb sulfone (Temik equivalents of 0.006,
    0.027, and 0.052 mg/kg body weight per day) for a period of 14 days.
    Although no alteration in blood cholinesterase activity levels or
    other clinical effects were noted, aldicarb sulfoxide and sulfone were
    detected in tissues. Milk production, feed consumption, and amount of
    excreta were unaltered.

    7.3  Skin and eye irritation; sensitization

         Pozzani & Carpenter (1968) observed that aldicarb (0.7 mg/kg body
    weight) in saline injected intradermally into male guinea-pigs had no
    sensitizing properties.

         In male albino rabbits, application of aldicarb as a solution in
    propylene glycol on covered clipped skin did not produce any
    irritation. Instillation of 0.1 ml of a 25% suspension of aldicarb in
    propylene glycol or 1 mg of dry compound did not cause corneal
    irritation (Striegel & Carpenter, 1962).

         The administration of 25 mg of aldicarb (Temik 5G)  into the
    conjunctival sac of rabbits resulted in conjunctival irritation, which
    lasted for 24 h, in all the six test albino rabbits (Myers et al.,
    1983).

         In a study by Myers et al. (1982), the application of 500 mg
    Temik 5G, moistened in saline solution, did not produce primary skin
    irritation in rabbits. Similarly percutaneous administration to
    abraded skin did not cause focal skin irritation.

         Separate tests using aldicarb (75% wettable powder)  and
    technical aldicarb in saline resulted in no sensitization response in
    male albino guinea-pigs following intradermal injections (Pozzani &
    Carpenter, 1968).

    7.4  Long-term exposure

         In a study by Weil & Carpenter (1972), male and female rats were
    fed aldicarb (0.3 mg/kg body weight per day), aldicarb sulfoxide (0.3
    or 0.6 mg/kg body weight per day), aldicarb sulfone (0.6 or 2.4 mg/kg
    body weight/day), or a 1:1 mixture of the sulfoxide plus sulfone (0.6
    or 1.2 mg/kg body weight per day) for 2 years. No effects were
    observed at the low dose level with any of the treatments. At the high
    dose level (except in the case of the sulfone), there was increased
    mortality within the first 30 days and a reduction in plasma
    cholinesterase activity, as well as decreased weight gain in the
    males. The NOEL values determined for aldicarb, aldicarb sulfoxide,
    aldicarb sulfone, and a 1:1 aldicarb sulfoxide/aldicarb sulfone
    mixture were 0.3, 0.3, 2.4, and 0.6 mg/kg body weight per day,
    respectively.

         When male and female rats were fed diets containing aldicarb
    (0.005, 0.025, 0.05, or 0.1 mg/kg body weight per day) for 2 years,
    there were no effects on food consumption, mortality, lifespan,
    incidence of infection, liver and kidney weight, haematocrit,
    incidence of neoplasms and pathological lesions, or on plasma, brain,
    and erythrocyte cholinesterase levels (Weil & Carpenter, 1965).

    7.5  Reproduction, embryotoxicity, and teratogenicity

         Proctor et al. (1976) studied the effects of several methyl
    carbamate and organophosphate insecticides on teratogenicity and
    chicken embryo nicotinamide adenine dinucleotide (NAD) levels. Fertile
    White Leghorn eggs (45-55 g) were used for the test. After the eggs
    were incubated at 37 C and 73% relative humidity for 4 or 5 days, 1
    mg of aldicarb in a 30-l methoxytriglycol solution was injected into
    the yolk and the injection hole on the shell was then sealed with
    paraffin wax. On day 12 after injection, some of the embryos were
    removed and the NAD levels were examined. On day 19 after injection,
    the remaining embryos (at least 10) were examined. NAD levels were
    similar to those of controls. There were no terato-genic effects
    (straight legs, abnormal feathers, or wry neck) in any of the embryos
    exposed to aldicarb.

         In a study by Weil & Carpenter (1964), pregnant rats were fed
    with doses of 0, 0.04, 0.20, and 1.0 mg aldicarb per kg body weight
    per day. One group was fed throughout the pregnancy and until the pups
    were weaned, a second group was fed from the day of appearance of the
    vaginal plug until the 7th day of gestation, and a third group
    received aldicarb between days 5 and 15 of gestation.  Although the
    highest dose administered was near the reported LD50 for rats, no
    significant effects on fertility, viability of offspring, lactation or
    other parameters were observed.

         In a teratology study, Harlan-Wistar rats were fed aldicarb
    sulfone in their diets at dosages of 0.6, 2.4 or 9.6 mg/kg body weight
    per day, administered either during the first 20 days of gestation,
    during day 6 to day 15 of gestation, or during day 7 to day 9 of
    gestation. No treatment-related teratogenicity occurred as a result of
    any of the treatment regimes at any of the levels of exposure to the
    sulfone (Woodside et al., 1977).

         Groups of 16 pregnant Dutch Belted rabbits were given doses of 0,
    0.1, 0.25 or 0.50 mg aldicarb/kg body weight per day by gavage on days
    7-27 of gestation (IRDC, 1983). Fetuses were then removed by Caesarean
    section. One spontaneous abortion was reported in each group given
    0.25 or 0.50 mg/kg body weight per day. Although the number of viable
    fetuses and total implantation values were lower in all treatment
    groups than those in controls, they fell within historical control
    ranges and no significant differences were recorded.

         Developmental toxicity of aldicarb has been evaluated by Tyl &
    Neeper-Bradley (1988). Four groups of pregnant CD Sprague-Dawley rats,
    25 in each group, were administered aldicarb (0.125, 0.25 or 0.5 mg/kg
    body weight per day) in water solution by gavage from gestation days
    6 to 15. There were three treatment-related maternal deaths in the
    high-dose group on day 7 of gestation (second day of administration).
    Maternal toxicity at that dose level was indicated by reduced body
    weight and food consumption and cholinergic signs. Body weight and
    food consumption were also reduced in the rats given 0.25 mg/kg body
    weight per day. The NOEL for maternal toxicity was 0.125 mg/kg body
    weight per day. Litter weight was significantly reduced at 0.5 mg/kg
    body weight per day. Fetotoxicity was indicated by body weight
    reduction, increased skeletal variation, retarded ossification, and
    ecchymosis on the trunk. No embryotoxicity was observed. An increased
    incidence of dilation of the cerebral lateral ventricle was observed
    at the highest dose level. However, due to the very high baseline
    control value for such changes found in pooled historical review, this
    increase was not considered to be significant.

         In a 3-generation reproductive study on rats conducted by Weil &
    Carpenter (1964), aldicarb was incorporat