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    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY


    ENVIRONMENTAL HEALTH CRITERIA 90


      

    DIMETHOATE

    
    
    







    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

    World Health Orgnization
    Geneva, 1989


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CONTENTS

ENVIRONMENTAL HEALTH CRITERIA FOR DIMETHOATE

1. SUMMARY

    1.1. Identity, uses and analytical methods
    1.2. Environmental concentrations and exposure
    1.3. Effects on the environment
    1.4. Kinetics and metabolism
    1.5. Effects on experimental animals
    1.6. Effects on man

2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS

    2.1. Identity
    2.2. Physical and chemical properties
    2.3. Analytical methods

3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE
    3.1. Natural occurrence
    3.2. Man-made sources    
          3.2.1. Industrial production
          3.2.2. World production figures
          3.2.3. Uses

4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

    4.1. Transport and distribution between media
          4.1.1. Air
          4.1.2. Water
          4.1.3. Soil
          4.1.4. Plants
          4.1.5. Disposal of wastes

5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

    5.1. Environmental levels
          5.1.1. Air, water, and soil
          5.1.2. Food
    5.2. Occupational exposure

6. KINETICS AND METABOLISM

    6.1. Absorption and distribution
    6.2. Metabolic transformation
    6.3. Elimination and excretion
          6.3.1. Animal studies
          6.3.2. Human studies

7. EFFECTS ON ORGANISMS IN THE ENVIRONMENT

    7.1. Microorganisms
    7.2. Aquatic organisms

    7.3. Terrestrial organisms
          7.3.1. Honey-bees
          7.3.2. Birds
          7.3.3. Farm animals

8. EFFECTS ON EXPERIMENTAL ANIMALS AND  IN VITRO TEST SYSTEMS

    8.1. Single exposures
    8.2. Skin and eye irritation
    8.3. Repeated exposures
    8.4. Reproduction studies
    8.5. Teratogenicity
    8.6. Mutagenicity
    8.7. Carcinogenicity
    8.8. Special studies
    8.9. Factors modifying toxicity
    8.10. Mechanisms of toxicity; mode of action

9. EFFECTS ON MAN

    9.1. General population exposure
          9.1.1. Poisoning incidents
          9.1.2. Controlled human studies
    9.2. Occupational exposure
          9.2.1. Poisoning incidents
    9.3. Early symptoms and treatment of poisoning

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

    10.1. Toxicity of dimethoate
    10.2. Human exposure
    10.3. Evaluation of effects on the environment
    10.4. Conclusions

11. RECOMMENDATIONS

12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

REFERENCES

ANNEX I

WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR DIMETHOATE

 Members

Dr L.  Badaeva,  All  Union  Scientific  Research  Institute  of
   Hygiene  and Toxicology of Pesticides, Polymers and Plastics,
   Kiev, USSR
Dr J. Huff, National Institute of Environmental Health Sciences,
   Research Triangle Park, North Carolina, USA
Dr S.K.  Kashyap,  National  Institute of  Occupational  Health,
   Ahmedabad, India  (Chairman)
Dr J.  Liesivuori,  Institute  of  Occupational  Health,  Kuopio
   Regional Institute of Occupational Health, Kuopio, Finland
Dr I.   Ritter,   Pesticides   Division,  Environmental   Health
   Directorate,  Department  of  National  Health  and  Welfare,
   Tunney's Pasture, Ottawa, Ontario, Canada
Dr A.  Takanaka, Division of Pharmacology, National Institute of
   Hygienic Sciences, Tokyo, Japan  (Vice-Chairman)
Dr M.  Tasheva,  Institute  of Hygiene  &  Occupational  Health,
   Medical Academy, Sofia, Bulgaria  (Rapporteur)
Dr E.M. den Tonkelaar, National Institute of Public  Health  and
   Environment, Bilthoven, Netherlands  (Rapporteur)

 Secretariat

Dr K.W. Jager, International Programme on Chemical Safety, World
   Health Organization, Geneva, Switzerland  (Secretary)
Ms F. Ouane, United Nations Environment Programme, International
   Register  of Potentially Toxic Chemicals, Palais des Nations,
   Geneva, Switzerland

NOTE TO READERS OF THE CRITERIA DOCUMENTS


    Every  effort has been  made to present  information in  the
criteria  documents  as  accurately as  possible  without unduly
delaying their publication.  In the interest of all users of the
environmental  health  criteria  documents, readers  are  kindly
requested  to communicate any errors  that may have occurred  to
the 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 - 7985850).

ENVIRONMENTAL HEALTH CRITERIA FOR DIMETHOATE


    A  WHO  Task  Group  on  Environmental  Health  Criteria for
Dimethoate  met in Geneva  from 11-15 May  1987.  Dr K.W.  Jager
opened  the meeting and welcomed  the participants on behalf  of
the  Manager  of the  IPCS and the  heads of the  three IPCS co-
operating  organizations (UNEP/ILO/WHO).  The Group reviewed and
revised  the draft criteria document  and made an evaluation  of
the  risks for human health and the environment from exposure to
dimethoate.

    The  first  draft  of this  document  and  the second  draft
incorporating   comments received from  the IPCS contact  points
for   Environmental  Health Criteria Documents  were prepared by
Dr  M. TASHEVA, Institute  of Hygiene and  Occupational  Health,
Medical Academy, Sofia, Bulgaria.

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



                           *   *   *



    Partial  financial  support  for  the  publication  of  this
criteria  document  was kindly  provided  by the  United  States
Department of Health and Human Services, through a contract from
the   National  Institute  of  Environmental   Health  Sciences,
Research  Triangle Park,  North Carolina,  USA -  a WHO  Collab-
orating  Centre  for  Environmental Health  Effects.  The United
Kingdom  Department  of  Health and  Social  Security generously
supported the cost of printing.

1.  SUMMARY

1.1.  Identity, Uses and Analytical Methods

    Dimethoate is an organophosphorus insecticide with a contact
and  systemic action.  It was introduced in 1956 and is produced
in  many countries for use  against a broad range  of insects in
agriculture and also for the control of the housefly.

    Dimethoxon,  an  oxygen  analogue metabolite  of dimethoate,
appears  to play a dominant role in its toxicity for insects and
mammals.   Dimethoxon  itself is  also  used as  an insecticide,
known as omethoate.

    Dimethoate  is fairly soluble in water and highly soluble in
most  organic solvents.  It is  fairly stable in water  and acid
solution, and unstable in alkaline solution.

    The analytical method of choice for its determination is gas
chromatography with flame photometric detection.

1.2.  Environmental Concentrations and Exposure

    Hydrolytic  degradation is the main  inactivating pathway of
dimethoate  in the environment.   In moist air,  it is  degraded
photochemically to hydrolytic and oxidation products.  The half-
life  of dimethoate in different plants is between 2 and 5 days.
Degradation in soil is dependent on the type of  soil,  tempera-
ture, moisture, and pH level.

    The general population is not normally exposed to dimethoate
from  air or water.  Levels of residues in food are mainly below
1  mg/kg.   Dimethoate was  only  detected infrequently  in  the
latest reported total-diet studies (1982).

    Occupational  exposure to dimethoate, which may occur during
manufacture,  formulation, and use, is mainly through inhalation
and  dermal  absorption.   Higher occupational  exposure  may be
observed  in  case  of accident  or  as  a result  of  incorrect
handling.

1.3.  Effects on the Environment

    Dimethoate  is  not  persistent  in  the  environment.   Its
toxicity for aquatic organisms and birds has been reported to be
moderate to high.  However, it is very toxic for honey-bees.

1.4.  Kinetics and Metabolism

    Dimethoate  is absorbed following ingestion, inhalation, and
skin  contact.  It has been  detected in the blood  30 min after
oral administration.  Accumulation in the tissues is not likely.
The main metabolic pathways of dimethoate are oxidative desulfu-
ration  and hydrolysis.  Hydrolytic metabolism predominates over
oxidation in mammals, whereas the opposite is true  in  insects.

Dimethoxon  (omethoate), which has been  demonstrated in plants,
insects, and mammals, seems to be the metabolite responsible for
the  toxic action of dimethoate.  Dimethoate is degraded rapidly
in  the rat liver, but  very little degradation occurs  in other
tissues.  It is eliminated predominantly in the form  of  hydro-
lytic urinary products.

1.5.  Effects on Experimental Animals

    Dimethoate  is  moderately toxic;  most  oral LD50s  in rats
ranged from 150 to 400 mg/kg body weight.  Signs of intoxication
in  the rat were observed 0.5-2 h after administration, and were
typical of exposure to organophosphorus pesticides.  Rat and dog
erythrocyte-acetyl   cholinesterase  activity  (AChE)   is  more
susceptible  to  inhibition  than  plasma-cholinesterase  (ChE).
When  rats were  exposed to  dimethoate at  a  concentration  of
10 mg/m3 for 4 h, 40% inhibition of ChE activity was reported.

    The acute dermal LD50 for dimethoate in rats is greater than
600 mg/kg.  It is not irritating to the skin and  only  slightly
irritating  to  the  eye.   No  dermal  sensitization  data  are
available on dimethoate.

    A  dietary level of 5 mg dimethoate/kg is considered to be a
no-observed-adverse-effect  level  in the  rat  on the  basis of
erythrocyte-cholinesterase depression.  No effects were reported
in  rats exposed through inhalation to 0.01 mg dimethoate/m3 for
14 h/day for 3 months.

    Dimethoate   administered   at  60 mg/litre   drinking-water
affected mating in 5 generations of mice tested.

    Dimethoate  did not appear to be teratogenic in experimental
animals.

    However, dimethoate was found to be mutagenic in  a  variety
of  in vitro and  in vivo test systems.a

    Long-term  studies have been conducted  on dimethoate admin-
istered orally to rats and mice and by  intramuscular  injection
in rats.  However, the available data are considered to be inad-
equate to assess the carcinogenic potential of the compound.b

----------------------------------------------------------------
a   On  the basis of the  results of new and  published studies,
    the  FAO/WHO Joint Meeting on Pesticide Residues (JMPR) have
    concluded  that dimethoate is mutagenic  in bacterial tests,
    but negative in mammalian cells and  in vivo tests.

b   Since  the Task  Group met,  the results  of  new  long-term
    carcinogenicity studies on rats and mice have been submitted
    to  the  FAO/WHO Joint  Meeting  on Pesticide  Residues.  No
    indication of carcinogenicity was found.

1.6.  Effects on Man

    Several  cases  of  suicidal  and  accidental  poisoning  by
dimethoate  have  been  reported.  Some  cases  of  occupational
poisoning   that  have  been  reported have been  the result  of
accidents  or neglect of  safety precautions.  The  lethal  oral
dose for human beings has been estimated to be in the  range  of
50-500 mg/kg body weight.

    In human volunteers, an oral dose of 0.2 mg/kg  body  weight
per day, for 39 days, did not produce any effects on whole-blood
cholinesterase values.  No skin irritation or ChE inhibition was
observed after a 2-h dermal exposure to 2.5 ml of a  32%  liquid
formulation of dimethoate.  There have been rare reports of skin
sensitization to dimethoate.

    Minimum  safe  re-entry  periods after  the  application  of
dimethoate have been reported.

2.  IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS

2.1.  Identity

Chemical structure:
    
Chemical Structure

Molecular formula:       C5H12NO3PS2

Common name:             dimethoate   (accepted  by  BSI,  ISO,
                         ANSI,  and  JMAF);  fosfamid (used  in
                         USSR)

Common trade names:      Bi  58;  Cygon; Dimethoate;  Fosfamid;
                         Fostion    MM,   Rogor;   Perfekthion;
                         Roxion

IUPAC name:               O,O-dimethyl      S-methyl-carbamoyl-
                         methyl phosphorodithioate

CAS chemical name:       Phosphorodithioic acid,  O,O-dimethyl
                          S-[2-(methylamino)-2-oxoethyl]   ester
                         (9CI)

CAS registry number:     60-51-5

RTECS registry number:   TE1750000

    Technical  dimethoate  is  about  93-95%  pure.   The  major
impurities  are  O,O-dimethyl    S-methylphosphorodithioate    and
 O-O-S-trimethyl phosphorodithioate.

2.2.  Physical and Chemical Properties

    Pure  dimethoate is a  colourless crystalline solid  with an
odour  of  mercaptan.   Technical dimethoate  (about  93%  pure)
varies  from  off-white  crystals  to  a  grey  semi-crystalline
material.   Some physical and chemical  properties of dimethoate
are given in Table 1.

    Dimethoate   is  highly  soluble  in  chloroform,  methylene
chloride,  benzene,  toluene,  alcohols,  esters,  and  ketones,
slightly  soluble in xylene, carbon tetrachloride, and aliphatic
hydrocarbons, and fairly soluble in water.

    Dimethoate is fairly stable in water and acid  solution,  at
room temperature, and unstable in alkaline solution  (Table  1).
Heating converts it to the  O,S-dimethyl phosphorodithioate.

Table 1.  Some physical and chemical properties of dimethoate
-------------------------------------------------------------

Relative molecular mass        229.2

Odour threshold                0.010 mg/m3

Melting point                  45-52.5 °C

Boiling point                  107 °C at 0.05 mmHg
                                86 °C at 0.01 mmHg

Vapour pressure (25 °C)        8.5 x 10-6 mmHg

Volatility                     1.107 mg/m3

Specific gravity               1.281
(compared to water)

Partition coefficient  n-octanol/water 5.959

Solubility in water (21 °C)    up to 39 g/litre

Half-life: in aqueous media    at pH 2-7, relatively stable
                               at pH 9, 50% loss in l2 days
-------------------------------------------------------------

2.3.  Analytical Methods

    A  review of the detection methods for dimethoate in treated
crop  plants  has been  presented  by De Pietri-Tonelli  et  al.
(1965).   The  procedures  reported are  based  on  colorimetry,
column,  paper,  and  thin-layer chromatography,  paper electro-
phoresis,  gas  chromatography, and  radiometry.  Bioassay tech-
niques  and  autoradiographic  procedures can  also  be applied.
High-performance  thin-layer chromatography has been proposed by
Hauck  & Amadori (1980) as a new potential for the determination
of dimethoate.

    The  Codex  Committee  on  Pesticide  Residues  has   listed
recommended methods for the determination of dimethoate residues
(FAO/WHO  1986) and various methods used in the determination of
dimethoate are summarized in Table 2.

    A  personal air sampler to  measure vapours and aerosols  of
dimethoate  at low concentrations has  been described by Hill  &
Arnold (1979).


Table 2.  Methods for the determination of dimethoate
---------------------------------------------------------------------------------------------------------
Sample type       Method of detection    Comments                    Detection limit   Reference
---------------------------------------------------------------------------------------------------------
Soil              gas-liquid chromato-                               1-20 ng           Getzin & Rosefield
                  graphy/phosphorus                                                    (1968)
                  detection              
                                         
Soil              thin-layer chromato-   50-mg soil samples; ex-     0.1 mg/kg;        Akoronko & Girenko
                  graphy; gas-liquid     traction with chloroform    0.05 mg/kg        (1977)
                  chromatography/therm-
                  ionic detection

Water             thin-layer chromato-   200-ml sample; extraction   0.5 µg;           Girenko et al.       
                  graphy; gas-liquid     with chloroform             5 ng              (1978)
                  chromatography/therm-
                  ionic detection or
                  electron capture
                  detection

Wheat plants      gas chromatography/    suitable for determina-     0.02 mg/kg        Lee & Westcott
                  flame photometric      tion of dimethoate and                        (1981)
                  detection              dimethoxon (omethoate)
                                         residues in field wheat
                                         plants

Plants            colorimetry            enzymatic pig liver         1 µg dimethoate   Nanda Kumar & 
                                         powder used as                                Udaya Bhaskar 
                                         ChE source; more sensi-                       (1980)
                                         tive by converting into     50 ng omethoate   Udaya Bhaskar & 
                                         oxidation product                             Nanda Kumar (1980)

Fruits and        gas-liquid chromato-   extraction with methyl      0.02 mg/kg        Girenko & Klisenko
vegetables        graphy/thermionic      chloride                                      (1977)
                  detection

Fruits and        colorimetry            250 g of sample; extrac-    5 µg (0.1 mg/kg)  Chilwell & Beecham
vegetables                               tion with chloroform                          (1960)

Asparagus         gas chromatography     extraction with             0.002 mg/kg       Szeto et al. 
                  nitrogen/phosphorus/   ethyl acetate               (fresh weight)    (1985)
                  detection
---------------------------------------------------------------------------------------------------------

Table 2.  (contd).
---------------------------------------------------------------------------------------------------------
Sample type       Method of detection    Comments                    Detection limit   Reference
---------------------------------------------------------------------------------------------------------

Vegetables        gas chromatography/    25 g of sample; extrac-     0.008 mg/kg       Van Middelem & 
(snap bean)       electron affinity      tion with methylene                           Waites (1964)
                  detection              chloride; oxygen analogue
                                         could not be detected
                                         at a 1:1 ratio; detectable
                                         at 10 parts oxygen to 1
                                         part dimethoate

Food stuffs       high-performance       suitable for pesticide      0.3 mg/kg         Cabras et al., 
                  liquid                 mixtures; the method can                      (1979)
                  chromatography         also be used for air
                                         samples

Honey             thin-layer chromato-   extraction with hexane      0.1 mg/kg         Petukhov (1975)
                  graphy                 and chloroform

Honey, nectar,    gas chromatography/    extraction with benzene     0.1 ng in nectar; Barker et al. 
and pollen        flame photometric                                  0.5 ng in pollen  (1980)
samples           detection

Milk              gas chromatography/    samples heated at 60 °C     0.001 mg/kg       Beck et al. 
                  flame photometric      in water bath for 20 min                      (1968)
                  detection              to facilitate precipi-
                                         tation; extraction with
                                         methylene chloride

Animal tissues    thin-layer chromato-   dimethoate and dimethoxon                     Sidimanov (1971)
                  graphy                 (omethoate) can be detected
                                         25 days after death of the
                                         animal

Skin and respir-  gas chromatography/    suitable for field          0.01 µg/sample    Copplestone 
ator pads         flame photometric      studies; pads placed in                       et al. (1976)
                  detection              individual 30-ml glass
                                         bottles, each contain-
                                         ing 10 ml benzene

Technical         gas-liquid chromato-             -                        -          WHO (1986c)
material and      graphy/flame ionization
formalizations    detection
---------------------------------------------------------------------------------------------------------
3.  SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

3.1.  Natural Occurrence

    Dimethoate does not occur as a natural product.

3.2.  Man-made Sources

3.2.1.  Industrial production

    Dimethoate was first described by Hoegberg & Cassaday (1951)
and was introduced on the market in 1956.

3.2.2.  World production figures

    Dimethoate  is manufactured in  many countries, but  data on
the world production of dimethoate are not available.

3.2.3.  Uses

    Dimethoate  formulations  are  widely used  as  contact  and
systemic insecticides against a broad range of insects and mites
and  is applied at  0.3-0.7 kg active ingredient/ha  on numerous
crops:  fruits  (apples,  citrus, bananas,  mangoes), vegetables
(beans,   broccoli,  cabbage,  cauliflower,   pepper,  potatoes,
spinach,    tomatoes),   wheat,   alfalfa,    cotton,   tobacco,
ornamentals,  olives, sunflower, and others  (Worthing & Walker,
1983).

    Dimethoate  is also used  for the indoor  control of  house-
flies.   For residual treatment, 10-25 g/litre  formulations are
used  (0.046-0.5 g active ingredient/m2) (WHO,  1984).  The dose
of   dimethoate  for  outdoor   fly  control  is   224 g  active
ingredient/ha (WHO, 1984).

    Dimethoate  is also applied  as a systemic  insecticide  for
control of cattle grubs (Worthing & Walker, 1983).

    The  oxygen analogue of dimethoate, dimethoxon, is also used
as insecticide and is known under the common name of omethoate.

    Formulations  of  dimethoate  include  emulsifiable  concen-
trates,  wettable powders, and granules.  There is also a formu-
lation for ultra low volume application.

4.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

4.1.  Transport and Distribution Between Media

4.1.1.  Air

    Air  concentrations  of  dimethoate were  measured under hot
climatic   conditions  at  a distance  of 300 m  from a  sprayed
area.   Concentrations   on  the  day  of spraying  ranged  from
0.061  to 0.142 mg/m3, but decreased  during the next 4  days to
0.004-0.014 mg/m3.   At a distance of 1500 m, dimethoate was not
detected  on either the day of treatment or during the days that
followed (Madzhidov, 1970).

    Dimethoate is an intermediate product in the  hydrolysis  of
the  pesticide formothion (Melnikov  et al., 1977;  Bolotnyi  et
al., 1978).  After use, formothion is found in the air  the  day
of spraying and dimethoate during the following days up  to  the
10th day.

    In  moist  air,  dimethoate is  degraded  photochemically to
hydrolytic and oxidation products (Melnikov et al., 1977).

4.1.2.  Water

    Aqueous  solutions  of  dimethoate are  fairly  stable.  The
compound  is rapidly hydrolysed in alkali (pH 11):  about 50-57%
of  dimethoate degrades to water-soluble material in ´ h, 68% in
1 h,  and 87% in  2 h.  The predominant  degradation product  is
desmethyl dimethoate (49.3%) (Brady & Arthur, 1963).  Hydrolysis
is  catalyzed by heavy metal ions, such as Cu++, Fe+++, and Mn++
(Sanderson & Edson, 1964).

    The  degradation  pathways of  dimethoate  in air  and water
under environmental conditions are presented in Fig. 1.

4.1.3.  Soil

    The  half-life of dimethoate  after application at  approxi-
mately  1  kg/ha in  sandy loam soil,  was approximately 4  days
during drought conditions and 2.5 days after  moderate  rainfall
(Bohn,  1964).   Following  3 applications,  dimethoate  did not
leach more than 7.5 cm below the surface of the soil.

    Getzin  &  Rosefield  (1968)  studied  the  persistence   of
dimethoate  in  non-sterile,  autoclaved,  and  gamma-radiation-
sterilized  Orissa  soils.   Two weeks  after  application,  the
degradation of dimethoate was 18% in the autoclaved soil, 20% in
irradiated  soil, and 77% in non-sterile soil.  The half-life of
dimethoate  ranged from approximately  9 to 11  days under  non-
sterile  conditions  and  from  16  to  18  days  under  sterile
conditions (Sahu & Pattanaik, 1980).

FIGURE 1

    Different  factors  may  affect the  accumulation and degra-
dation of dimethoate in soil, such as the soil type, the numbers
and  type of microorganisms  present in soil,  the environmental
temperature,  the pH level, the amount of pesticide applied, and
the  degree of evaporation (El Beit et al., 1977a,b, 1978).  The
persistence  of dimethoate was  greater in heavy  than in  light
soil.  At pH 4.2, the pesticide was stable for nearly  19  days;
at  pH 11, it degraded within 20 h.  The amount of dimethoate in
soil increased when higher concentrations were applied.  El Beit
et al. (1977a) reported that soil microorganisms  played  little
part in the degradation of dimethoate.

4.1.4.  Plants

    When  applied to plants, dimethoate was rapidly absorbed and
decomposed,  both  on  the surface  and  within  the  plant,  by
hydrolysis  and oxidation (Menzie, 1969; Melnikov et al., 1977).
The  half-life  of dimethoate  in  the different  plants  varied
between 2-5 days (Melnikov et al., 1977).  Dimethoate completely
disappeared after 15-30 days, depending on the plant species and
the  climatic  conditions.   Decomposition  in  plants  and  the
hydrolysis  of  dimethoate increased  with temperature (Atabaev,
1972).

    The  dissipation of dislodgeable  residues of dimethoate  is
best  characterized by two  first-order kinetic processes.   The
half-life values were 2.2 days in the 1 to 10-day period and 7.0
days in the 10 to 49-day period (Hadjidemetriou et al., 1985).

4.1.5.  Disposal of wastes

    Hydrolytic  decomposition  is  the main  way  to  inactivate
dimethoate.  By adding lime (1-2 kg calcium oxide/m3  water)  to
waste  waters  from  agricultural centres,  dimethoate was fully
inactivated in 45 min (Winkler & Muller, 1979).

    During  pyrolysis,  approximately  50% decomposition  of di-
methoate  occurred at 500 °C with the formation of  O,O-dimethyl-
 S,S-dithionpyrophosphate; decomposition was complete at 1100 °C
(Rosvaga, 1983).

5.  ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

5.1.  Environmental Levels

5.1.1.  Air, water, and soil

    No  studies have been reported  on levels in air,  water, or
soil  under actual conditions  of use and  various environmental
conditions.

5.1.2.  Food

    When  a combination of dimethoate and omethoate (dimethoxon)
was  given to cows in  dosages of 1 and  0.1 mg/kg body  weight,
respectively,  for  14 days,  only  residues of  the  metabolite
omethoate  were observed in the milk (0.004-0.125 mg/kg).  Three
days  after the application, neither compound could be detected.
When  dosages of 0.5 mg  dimethoate/kg and 0.05  mg omethoate/kg
were  given for 14  days or when  corn silage containing  1-7 mg
dimethoate/kg  (resulting  in  dosages of  0.06-0.36  mg/kg body
weight) was given for 28 or 42 days, no residues  were  detected
in the milk (Beck et al., 1968).

    Harvest  residues  found  in  many  crops  1-3  weeks  after
spraying  with dimethoate, during the first years of application
in  the United Kingdom (1957-58), were below 2 mg/kg (Chilwell &
Beecham, 1960).

    The  dimethoate  content  of apples  was 0.03-0.07 mg/kg, 75
days  after  an  application  of  0.72 kg  active  ingredient/ha
(Atabaev & Stepovaya, 1966).

    The pulp of lemon and orange fruit treated  with  dimethoate
did  not show any residues at a detection level  of  0.01 mg/kg,
60 days after application (Iwata et al., 1979).

    Residues of dimethoate do not concentrate in wine.  Analysis
of  seven different Californian  wines indicated levels  of less
than 0.03 mg/litre (Kawar et al., 1979).

    No  residues were found in  grapes, 29 days after  treatment
with 0.1-0.15% dimethoate applied at the rate of 1400 litre/2 ha
(Grigorashvili & Dzhibladze, 1965).

    A number of studies on residues of dimethoate found through-
out  the world  have been  reported in  a review  by  De Pietri-
Tonelli  et al. (1965).  The residues were most frequently below
1 mg/kg.   Dimethoate  residues  found in  various  agricultural
products in India are reported in Khan & Bhaskar Dev (1982).

    Dimethoate  was not found  in total-diet samples  studied in
England   and  Wales  during  1966-67  (Abbott  et  al.,  1970).
According to other authors, dimethoate was also not found in the
total  diets of adults  and infants during  1975-79 (Johnson  et
al.,  1981a,b,  1984a,b;  Podrebarac, 1984a,b;  Gartrell et al.,
1985a,b,c).  Market-basket surveys carried out in 1976-78 in the
Netherlands  showed only omethoate residues in a small number of
fruits  (De  Vos  et al.,  1984).   In  the USA,  dimethoate and
omethoate  have been identified in about 5% of samples of fruits
and vegetables (Duggan et al., 1983).

    The  use of additional  procedures for the  determination of
organophosphates resulted in the identification of dimethoate in
adult and infant total-diet samples in 1980-82 (Gartrell et al.,
1985d, 1986a,b).  However, the intakes (0.001 µg/kg  body weight
per  day) were  far below  the FAO/WHO  acceptable daily  intake
(ADI)  (see section 12).

5.2.  Occupational Exposure

    Immediately  after  the  use of  dimethoate  in greenhouses,
Stroy  (1983) determined levels  of 0.01-0.42 mg/m3 in  the air,
3.6-9.3 mg/kg in the plants, and 0.98-1.75 mg/kg in the soil.

    Dimethoate  content in greenhouse air has been  analysed  at
different times after spraying;  at 0 time the  measured  amount
was 0.66  mg/m3, at 2.5 h  it was 0.38 mg/m3, at 5 h  dimethoate
content was 0.21 mg/m3, at 10 h it was 0.07  mg/m3  and  at 20 h
it was 0.01/m3 (Zolotnikova & Zotov, 1978).

    The exposure to dimethoate of tractor drivers using airblast
units  during  treatment of  citrus  trees was  investigated  by
Carman et al. (1982).  Dermal exposure was measured  by  placing
ethyleneglycol-treated  gauze  patches  on the  shoulders, upper
arms, and knees of the drivers.  An  emulsifiable  concentration
(EC)  formulation  of  dimethoate containing  0.009 kg/litre was
applied  at the rate of 16 822 litre/ha using an open tractor, a
cab  unit  with  both side windows open, and a cab unit with the
windows   closed.  Under these conditions,  the patches attached
to   the  driver  absorbed  mean  deposits  of  2.5,  1.5,   and
< 0.01 µg   dimethoate/cm2 per h, respectively.  The correspond-
ing average air concentrations were 10(sic), 48, and  2 µg    of
dimethoate/m3.

    Procedures  for determining foliar residues and to establish
the safe re-entry times for some insecticides were  reported  by
Knaak  (1980)  and  Knaak  et  al.   (1980).   A safe  level  of
dimethoate  on foliage of  53 µg/cm2   was calculated  using the
results of dermal-dose ChE-response studies in male rats.

    Minimum  safe re-entry periods for dimethoate were estimated
to be 3 days in greenhouses, and 7 days in tobacco fields, after
application  by tractor, or  5 days after  application by  plane
(Kaloyanova-Simeonova   &   Izmirova-Mosheva,  1983).    No  ChE
inhibition  in serum or subjective complaints of workers picking
dimethoate-treated  tobacco leaves were established at a concen-
tration of 1 mg/kg on the surface of the plant.

    Copplestone et al. (1976) studied the exposure to dimethoate
of  8 spraymen, 1  mixer, and 2  supervisors in the  Sudan.  The
percentage  of toxic dosea   received per day, calculated on the
basis  of a  4-h working  day, varied  from 0.02%  to less  than
0.001%  for individual spraymen.  No ChE depression was found in
any of the men.

    The  highest  concentration  of dimethoate,  measured in the
work-place air of a dimethoate-producing factory in  Italy,  was
0.050 mg/m3 (Armeli et al., 1967).

    The  respiratory  and  dermal  exposure  to  dimethoate   of
applicators   was   determined  for   greenhouse  workers.   The
respiratory  and dermal exposures were  0.034 mg/h and 30  mg/h,
respectively.  The hands of the operators were the most affected
parts of the body, accounting for 63-92% of the  total  exposure
(Adamis et al., 1985).












----------------------------------------------------------------

a   Percentage  toxic dose per  day or h  (WHO, 1982).  This  is
    calculated  from these indices  adapted from the  method  of
    Durham & Wolfe (1962) using the formula:

          Dermal exposure (mg/day or h) + respiratory
            exposure (mg/day or h) x 10 if measured
          --------------------------------------------  x 100
                 Dermal LD50 mg/kg (rat) x 70

6.  KINETICS AND METABOLISM

6.1.  Absorption and Distribution

    Panshina  &  Klisenko (1962)  checked  the blood  levels  of
dimethoate in cats and rats after single oral doses of  50,  75,
or  200  mg/kg  in the cat and 300 mg/kg in the rat.  The deter-
minations  were  carried out  15, 30, 60,  90, 120, and  180 min
after  dosing.  Dimethoate was detected in the blood of cats and
rats  after 30 min, and reached a maximum level after 60-90 min.
Nearly  80% of  the dimethoate  in the  blood was  found in  the
erythrocytes; only 15-20% was found in the serum.  With repeated
daily  oral  intake  of  dimethoate  at  doses  of  20 mg/kg  or
10 mg/kg,  the maximum blood level occurred on the 5-10th day of
the study.

    The  same pattern in blood levels was observed with repeated
inhalation  of dimethoate for 4 h/day  over 3 months, at  a mean
concentration  of 5 mg/m3 air.  Dimethoate was detected in blood
from the second day and reached its maximum by the 7-10th day.

    Daily  application  of 50 mg  dimethoate/kg  on the  skin of
rabbits  resulted in  a maximum  concentration in  the blood  at
about the third day (Kundiev, 1979).

    When dimethoate was applied to the skin of rats for 1, 2, 4,
12, or 24 h in a single dose of 560 mg/kg, the  maximum  concen-
tration in the skin was reached after 12 h of exposure  and  was
correlated  with the maximum inhibition  of ChE activity in  the
serum and liver.  The concentrations of dimethoate in the blood,
liver, and kidney were maximal after 2 h of  exposure  (Baranova
et al., 1986).

6.2.  Metabolic Transformation

    The  ester and  amide groups  of dimethoate  are cleaved  in
reactions that vary with the organism and that contribute to the
selective toxicity of the compound.

    The results of  in  vitro and  in vivo studies showed that the
main  metabolic  pathways  of  dimethoate  were  hydrolysis  and
oxidation (Hassan et al., 1969; Lucier & Menzer, 1970;  North  &
Menzer, 1972).

    Santi  &  Giacomelli (1962)  studied  the metabolic  fate of
dimethoate  in olives.  P=O derivative and degradation products,
such as phosphoric and/or methylphosphoric acid, were found.

    The  presence of the oxygen  analogue dimethoxon (omethoate)
has  been  demonstrated  in  insects,  plants,  and  mammals; it
appears to be the metabolite responsible for the toxic action of
dimethoate  (Brady & Arthur, 1963; Hassan et al., 1969; Lucier &
Menzer, 1970).  The highest levels of this metabolite were found

in   insects,  particularly  in  those   highly  susceptible  to
dimethoate.    The  oxygen  analogue  was   produced  in  larger
quantities in insects than in rats.  The enzymes  mediating  the
hydrolysis of the carboxyamide bond are much less  effective  in
insects than in mammals (Mikhailov & Shterbak, 1983).

    It  has been shown that  cleavage of dimethoate by  rats and
cows  occurs initially at  the C-N bond  to produce the  carboxy
derivative  (Dauterman et al.,  1959; Hassan et  al., 1969).   A
second hydrolytic pathway involves an esterase action on the S-C
bond (Hassan et al., 1969).

    Oxidative   metabolism   of  dimethoate   predominated  over
hydrolytic metabolism in the cell culture system. In  the  whole
rat, the opposite was true.  Metabolism of dimethoate  in  human
embryonic  lung cells was  much the same  as metabolism in  rats
(North  &  Menzer,  1972).   In  vitro and  in vivo studies showed
that  dimethoate is biotransformed to  the P=O analogue via  the
liver  cytochrome  P-450  system  (Kaloyanova  et  al.,   1984).
Concentrations  of 0.1-10 mmol dimethoate/litre led  to a linear
decrease  in the rates  of  N-demethylation  and  P-hydroxylation.
Similarly, in microsomes from rats treated with  dimethoate    in
 vivo,  increased activity of desulfuration (140%,  P < 0.01), and
decreased  activity of hydroxylation and demethylation were seen
(Mitova et al., 1986).

     In   vivo studies on mice  showed dimethoate toxicity  to be
markedly  increased by phenobarbital pre-treatment,  as a result
of induction of hepatic microsomal enzymes including  the  mixed
function oxidases responsible for the conversion of P=S  to  P=O
(Menzer & Best, 1968).

    It  has been found  that, while dimethoate  undergoes  rapid
degradation  in  the  rat liver,  very  little  occurs in  other
tissues  (lung,  muscle,  pancreas, brain,  spleen, blood).  The
ability  of the liver to  degrade dimethoate in various  species
decreased in the order:  rabbit > sheep > dog > rat >  cattle  >
hen  > guinea-pig >  mouse > pig.   For the hen,  cattle, mouse,
sheep,  and  rat  there  was  a  reasonably  good  straight-line
relationship between the LD50 values and the degradation ability
of the liver (Uchida et al., 1964).

    After  administration of 32P-dimethoate to rats, dimethoate,
dimethoxon,   dimethoate  carboxylic  acid,   dimethylphosphoro-
dithioate,  dimethylphosphorothioate,  dimethylphosphate,  mono-
methylphosphate,  phosphorothioate,  formate,  and  N-methyl   2-
glucuronate  acetamide were found in  the urine (Hassan et  al.,
1969).
    Data on the metabolism of dimethoate in plants  and  animals
have been reviewed by Menzie (1969, 1974, 1978, 1980).

6.3.  Elimination and Excretion

6.3.1.  Animal studies

    About  45%  of  the 32P-dimethoate  administered  orally  at
50 mg/kg  to rats was excreted in the urine, while only 5.8% was
eliminated  in the faeces, 72 h after treatment (Brady & Arthur,
1963).  The values in rats after dermal application  were  30.6%
and 6.5%, respectively.  More than 95% of the 32P  materials  in
the urine and faeces after oral or dermal administration in rats
were  hydrolytic  products,  as determined  by  chloroform/water
partition coefficients.
 
    Twenty-four h after ip and oral administration of dimethoate
to rats at doses of 0.25, 2.5, or  25 mg/kg,  dimethylphosphoro-
dithioate,   dimethylphosphorothioate,  and  dimethyl  phosphate
were  detected in the urine at concentrations of 12-14%, 11-15%,
and  12-13%, respectively (Riemer  et al., 1985).   Neither  the
route of exposure nor the dose had any influence on the types of
metabolite formed.
 
    About  87-90% of  an oral  dose of  10 mg dimethoate/kg  was
eliminated  in the urine of cattle at the end of 24 h.  The same
percentage  of an intramuscular  dose of 10 mg/kg  was  excreted
after 9 h.  Only 3.7-5% of the oral dose and about 1.1%  of  the
intramuscular  dose were eliminated in the faeces after 72 h and
24 h, respectively (Kaplanis et al., 1959).

6.3.2.  Human studies

    In   human beings,  76-100%  of   radioactivity was reported
to  be  excreted  in the urine, 24 h after oral dosing with 32P-
dimethoate (Sanderson & Edson, 1964).

7.  EFFECTS ON ORGANISMS IN THE ENVIRONMENT

7.1.  Microorganisms

    The addition of dimethoate to soil at 10 or  100 mg/kg  did
not  result in significant differences in the number of bacteria
solubilizing tricalcium phosphate or in the number  of  bacteria
mineralizing  calcium glycerophosphate, but  an increase in  the
population  of  phospholipase-producing  organisms  solubilizing
lecithin  occurred (Congregado et  al., 1979).  At  10 mg/kg, an
increase in carbon dioxide production occurred for 2 weeks after
treatment,  followed  by  a  decrease  to  control  levels.   At
100 mg/kg,  the increase in carbon dioxide output was slower and
longer.

7.2.  Aquatic Organisms

    A  number of LC50s have been determined for various aquatic
organisms (Table 3).

    The  median  tolerance  limit of  the  fresh-water teleost,
 Channa  punctatus for dimethoate is 20.5 mg/litre (Anees, 1975).
Exposure for 24 h, 96 h, or 14 days to dimethoate concentrations
of 10.8, 8.0, or 5.0 mg/litre, respectively,  produced  moderate
vacuolation  of  the  liver and  a  high  degree of  cytoplasmic
granulation, which developed for up to 96 h of  exposure.    The
14-day  exposure  added  little in  the  way  of vacuolation  or
granulation  (Anees,  1978a).   The haematological  response  to
dimethoate  included reduced erythrocyte counts  and haemoglobin
concentration,  and an elevated mean corpuscular haemoglobin and
colour index indicating that the insecticide exerted  an  effect
similar to the production of anaemia (Anees, 1978b).

    The   signs  of  the   toxicity  of  dimethoate   in   fish
 (Channa punctatus)     included   jumping,   erratic   movement,
imbalance,  and  death  (Dikshith &  Raizada,  1981a;  Dikshith,
1986).

    Verma et al. (1978) determined the TLm values of dimethoate
for  Channa gachua for 24, 48, 72, or 96 h to be 5.2,  5.0,  4.6,
or  4.5  mg/litre,  respectively.   The  safe  concentration  of
dimethoate  calculated on the basis  of TLm values was  approxi-
mately 1.4 mg/litre.

    Dimethoate inhibited AChE activity in the brain, liver, and
muscle of some fresh-water teleosts  (Channa gachua and   Cirrhina
 mrigala), exposed   to   sublethal  concentrations   of  35%  EC
formulation  (0.9-2.4 and 0.6-1.6 mg/litre, respectively) (Verma
et al., 1979).


Table 3.  Summary of acute toxicity values for aquatic organisms
---------------------------------------------------------------------------------------------------------
Species                                      LC50 (mg/litre)                Reference
                             24-h         48-h        72-h         96-h          
---------------------------------------------------------------------------------------------------------
Rainbow Trout               20             -            -           8.5           Melnikov et al. (1977)
 (Salmo gairdneri)                                   
                                                     
Rainbow Trout                 -            -            -           6.2           Johnson & Finley (1980)
 (Salmo gairdneri)

Long-nosed killifish                      1.0           -            -            Melnikov et al. (1977)
 (Fundulus similis)

 Saccobranchus fossilis       5.14       4.80        4.67          4.57          Verma et al. (1982)

 Channa punctatus            68           54           -          47             Dikshith & Raizada (1981a)
                                                                                  Dikshith (1986)

Scud                         0.9          0.4           -            -            Menzie (1969)
 (Gammarus lacustris)

Scud                          -            -            -           0.20          Johnson & Finley (1980)
 (Gammarus lacustris)

Red Crayfish                  -           1.0           -            -            Muncy & Oliver (1963)
 (Procambarus clarkii)

Stonefly                      -           0.14          -            -            Menzie (1969)
 (Pteronarcys california)

Stonefly                      -            -            -           0.043         Johnson & Finley (1980)
 (Pteronarcys california)

Unspecified insect           0.51          -            -            -            Sanders & Cope (1968)

Bluegill                      -            -            -            -            Johnson & Finley (1980)
---------------------------------------------------------------------------------------------------------
    Dalela et al. (1979) reported that acute (5-h)  and  short-
term  (up to 32 days)  exposure of the fish,  Channa  gachua,  to
dimethoate  at  6.2 mg/litre  and  1.5 mg/litre,   respectively,
produced  histological changes in the gills.  On acute exposure,
there  was erosion at the  distal end of the  gill filaments and
loss  of cell  membrane.  With  exposure to  a concentration  of
1.5 mg/litre,  the basement membrane started separating, and the
damage  to  the  gill was  found  to  be more  significant  with
increasing  exposure time, with vacuolization occurring after 32
days.

    The  exposure of the  fish  Heteropneustes  fossilis   to  a
dimethoate  concentration  of  10 mg/litre led  to  an increased
level  of  glycogen by  the end of  the second week  in both the
liver  and the kidney, and  to a slight decrease  in the protein
contents at the end of the eighth day (Awasthi et al., 1984).  A
sharp  rise in the activity  of succinate dehydrogenase in  both
organs was noted during the first two weeks of this study.

    The  estimated  48- and  72-hour  TLm values  for zebrafish
 Brachydanio    rerio   embryos,  exposed  to   dimethoate,  were
940 mg/litre    and   259 mg/litre,   respectively   (Roales   &
Perlmutter,  1974).   Dimethoate  retarded  the  development  of
embryos as expressed by lack of heartbeat and little movement at
24 h.

    Dimethoate  at  a  concentration of  0.05 mg/litre produced
morphological  changes  in the  melanophores  of     Bufo melano-
 stictus  tadpoles and an increase in pigmented areas of the skin
(Pandey & Tomar, 1985).

    Dimethoate  had  a  very  low  toxicity  for  some  aquatic
organisms  in  Sudan,  such as   Oreochromis  niloticus, Gambusia
 affinis, Pseudagrion spp., Crocothemis erythraea, and    Lanistes
 carinatus.   Under  laboratory conditions,  it did not  kill any
animal  at concentrations lower than  80 mg/litre (Karim et al.,
1985).

    The  toxicity of dimethoate  for 11 freshwater  species was
studied by Slooff & Canton (1983).  The results  are  summarized
in  Table 4.  The  relative susceptibility tests  indicated that
 Daphnia   magna was the organism  most sensitive to  dimethoate,
while   the  microorganisms  P.fluorescens,  M.aeruginoso,    and
 S.pannonicus were    generally  less  sensitive   indicators  of
toxicity.  The susceptibility of aquatic species to  a  chemical
may vary by more than two-three orders of magnitude.   The  data
demonstrate  that  the  sublethal  criteria  studied  were   not
necessarily the most sensitive toxicological criteria.

7.3.  Terrestrial Organisms

7.3.1.  Honey-bees

    The oral LD50 for the honey-bee  (Apis  mellifera L)  ranges
from  93  to 150  ng per bee  (Jaycox, 1964; Lord  et al., 1968;
Stevenson,   1968;  Barker et al.,  1980).  The contact LD50  is
98-120 ng per bee (Stevenson, 1968).


Table 4.  Fresh-water species susceptibility to dimethoate
---------------------------------------------------------------------------------------------------------
Type of            Test species          Lifestage  Exposure    Test condition    Toxicological No-effect
organism                                            time        Temper-  Test     parameter     level
                                                    (days)      ature    methods               (mg/litre)
---------------------------------------------------------------------------------------------------------
Bacteria     (Pseudomonas fluorescens)    log-phase   0.3        22 ± 2   Static   Specific       320
                                                                                  growth rate
                                         
Cyano       Bluegreen bacteria           log-phase    4         23 ± 2   Static   Specific        32
bacteria     (Microcystis aeruginosa)                                              growth rate

Algae       Green Algae                  log-phase    4         23 ± 2   Static   Growth         100
             (Scenedesmus pannonicus)                                              (biomass)

Plant        Lemna minor                     -         7         25 ± 1   Static   Specific        32
                                                                         growth
                                                                         rate

Crustacean  Water flea  (Daphnia magna)   1 day       21         19 ± 1   Semi-    Mortality        0.032
                                                                         static   reproduction     0.1

Insect      Mosquito  (Culex pipiens)     1st         25         27 ± 1   Semi-    Mortality        0.32
                                         instar                          static   development      0.32

Coelente-   Hydrozoan  (Hydra oligactis)  budless     21         18 ± 1   Semi-    Specific       100
rate                                                                     static   growth rate
Mollusc     Giant Pond Snail             5 months    40         20 ± 1   Semi-    Mortality       32
             (Lymnaea stagnalis)                                          static   Reproduction    10
                                         egg          7         20 ± 1   Semi-    Hatching        32
                                                                         static

Fish        Guppy  (Poecilia Reticulata)  3-4 weeks   28         23 ± 1   Semi-    Mortality       32
            Viviparous                                                   static   Behaviour +      0.1
                                                                                  Mortality

Fish        Japanese Ricefish            eggs        40         23 ± 2   Semi-    Mortality        0.32
             (Oryzias latipes) oviviparous                                static   Behaviour        0.32
                                                                                  Hatching       100
                                                                                  Growth

Amphibian    Xenopus laevis               2 days     100         20 ± 1   Semi-    Mortality        1
                                                                         static   Development     32
                                                                                  Growth          32
---------------------------------------------------------------------------------------------------------
From: Slooff & Canton (1983).

    
    Dimethoate  was only slightly repellent  to foraging honey-
bees.  The self-limiting dose for foraging was 20-25  times  the
lethal oral dose (2.9-3.9 µg/bee  vs 150 ng/bee).  This  can  be
interpreted  on the  basis of  5% absorption  by foraging  bees,
while 95% is passed on to the colony.  Thus,  systemic  insecti-
cide  in nectar may also pose a threat to the rest of the colony
when brought back to the hive (Waller et al., 1979).

    Residual  toxicity  has  been supported  by  several obser-
vations.   Nectar from plants  sprayed with 0.1%  dimethoate was
lethal for honey-bees for at least 2-3 days (Jaycox, 1964) or 10
days  (Barker et al., 1980).   Waller et al. (1984)  also showed
the  possible toxic levels of residues in the nectar for  up  to
10 days after treatment of lemon trees with dimethoate at a rate
of  1.12 kg  of ai  per ha.   The high  bee mortality  observed,
immediately   after  treatment,  was  attributed  to  dimethoate
residues on the plant surface.

7.3.2.  Birds

    The  acute  toxicity studies  of  dimethoate for  birds are
summarized in Table 5.

Table 5. Acute oral LD50 of dimethoate for birds (mg/kg)a
----------------------------------------------------------------
Species     Sex     Pure     Laboratory   Technical   Liquid
                               grade        grade   formulation
----------------------------------------------------------------
Hen          F       50         40            30         25

Pheasant     M    15 - 20       15            20         25

Duck         F       -        > 40            -          -
                          
Sparrow     M/F      -          -             -          22

Blackbird   M/F      -          -             -          26
----------------------------------------------------------------
a  From: Sanderson & Edson (1964).

    Hens  did not show  any evidence of  delayed  neurotoxicity
(Sanderson & Edson, 1964; Gaines, 1969; Francis et al., 1985).

   The effect of dimethoate on esterase levels  following  the
oral  dosing  of pheasants  and  following long-term  feeding to
pheasants and pigeons was investigated by Bunyan et  al.  (1968,
1969).    Dimethoate   inhibited  brain-alpha-naphthyl   acetate
esterase  more than brain-cholinesterase and  triacetin esterase
in acute studies.

    A  characteristic of dimethoate was the elevation of phenyl
benzoate  esterase  levels,  showing that  after  initial  liver
damage, dimethoate is able to induce certain enzymes.

7.3.3.  Farm animals

    The  acute  oral  LD50s  for  several  farm   animals   are
summarized in Table 6.

    No  visible  signs  of  intoxication  were  seen  in horses
receiving  dimethoate orally at doses of 25 or 50 mg/kg.  Single
doses  of dimethoate  at 40  mg/kg were  effective  in  removing
 Gasterophilus    spp. from  infected  horses,  but  toxic  signs
appeared  in animals treated with  higher levels of 60-80  mg/kg
(Jackson et al., 1960).

Table 6.  Acute oral LD50 for farm animals
-------------------------------------------------
Species   LD50 (mg/kg    Reference
          body weight)
-------------------------------------------------
Horse        > 50        Jackson et al. (1960)
              
Sheep          80        Hewitt et al. (1958a,b)
               
Cattle         70        Hewitt et al. (1958a,b)
-------------------------------------------------

    Mild signs of intoxication occurred in sheep  at  75 mg/kg,
including slight salivation, lachrymation, transitory diarrhoea,
rhinitis, and anorexia.  Doses lower than 15 mg/kg  were  essen-
tially  asymptomatic  in  calves.   The  data  with   dimethoate
indicate  an  appreciable margin  of  safety between  the lowest
dose  that kills first instar  Hypoderma  lineatum (5 mg/kg), and
the doses that produce mild toxicity (15-20 mg/kg),  or  severe,
reversible toxicity (40 mg/kg) (Hewitt et al., 1985b).

    Fetcher  (1984)  described  cases of  suspected  dimethoate
intoxication  in cattle grazing on pasture that had been sprayed
6 weeks  earlier.  There was  a predominance of  nicotinic signs
and a poor response to atropine treatment.  Chemical analysis of
liver,  kidney, and  brain tissue  did not  reveal  any  organo-
phosphorus   compounds  or  metabolites.   Whole  blood-ChE  was
depressed in 3 out of 14 animals.

    After  spraying  barns  (for  calves)  and  pigsties   with
dimethoate,  only  16-29%  of the  initial  concentration  still
persisted  after 8 weeks.   Nevertheless, the animals  showed  a
decrease in ChE (Müller & Reinhold, 1973).

8.  EFFECTS ON EXPERIMENTAL ANIMALS AND  IN VITRO TEST SYSTEMS

    A more complete treatise on the effects of organophosphorus
insecticides,  especially their short- and  long-term effects on
the  nervous systems,  can be  found in  the  WHO  Environmental
Health  Criteria  document  entitled EHC  63:   Organophosphorus
Insecticides, a General Introduction (WHO, 1986a).

8.1.  Single Exposures

    The acute oral and dermal LD50s of dimethoate  for  several
animal species are summarized in Tables 7 and 8 (all  LD50s  are
expressed as active ingredient).

    Signs,  characteristic  of  organophosphorus  intoxication,
were  observed in the rat  0.5-2 h after oral administration  of
dimethoate  (Sanderson & Edson,  1964).  They included  muscular
fibrillation,  salivation,  lachrymation, urinary  incontinence,
diarrhoea, respiratory distress, prostration, gasping, coma, and
death (WHO, 1986a).

    Oral  LD50  values  for rats,  which  were  measured in  13
studies, ranged from 150 to 680 mg/kg body weight.   The  purity
and  formulation of the compounds used were not stated  in  most
of  the reports.  Oral  LD50s were determined   of 60-140  mg/kg
body   weight for  mice,   200 mg/kg body  weight for  hamsters,
350-600  mg/kg body weight  for guinea-pigs, 280-500  mg/kg body
weight  for  rabbits,  and  100  mg/kg  body  weight  for  cats.
Administration of 100 mg/kg body weight to dogs did  not  result
in mortality.  The World Health Organization based  its  classi-
fication  of dimethoate as moderately hazardous on an acute oral
LD50 in the rat of 150 mg/kg body weight (WHO, 1986b).

    The dermal LD50s for rats were found to range  between  500
and  1150 mg/kg body weight, and were of about the same order of
magnitude as the oral LD50s or slightly higher (Table 8).

    Data on LD50s after parenteral administration were given by
Sanderson & Edson (1964).  The values were comparable with those
for ip, sc, and iv administration.  In the rat, the  values  for
ip administration varied between 175 and 325 mg/kg  body  weight
and were also of the same order of magnitude as the oral LD50s.

    The inhalation LC50 has not been estimated, but, in  a  4-h
inhalation  study on  rats, Panshina  (1963b) did  not find  any
signs  of intoxication with exposure  to dimethoate at 20  mg/m3
air, 40% cholinesterase inhibition at 10 mg/m3, and  no  effects
at 2 mg/m3.  Visible signs of intoxication were observed in cats
at concentrations of 50-80 mg/m3.  At 20  mg/m3,  cholinesterase
inhibition  was found to be  10-66%, while at 2-8  mg/m3, it was
7-56%.  No effects were seen at 1.5 mg/m3 (Panshina, 1963b).

Table 7. Acute oral LD50 of dimethoate in experimental animals
-------------------------------------------------------------------------
Species   Sex   Material tested     LD50 (mg/kg     Reference
                                    body weight)
-------------------------------------------------------------------------
Rat        M    32% emulsifiable       247          Edson & Noakes (1960)
                solution

Rat       M/F   technical           185 - 245       West et al. (1961)

Rat                                    230          Panshina (1963a)

Rat             technical              172          Panshina (1963a)

Rat       M/F   pure                500 - 680       Sanderson & Edson
                                                    (1964)

Rat       M/F   laboratory          280 - 356       Sanderson & Edson
                grade                               (1964)

Rat       M/F   technical           180 - 336       Sanderson & Edson
                (32-40% w/v)                        (1964)

Rat       M/F   liquid formul-      150 - 400       Sanderson & Edson
                ation (20% ai)                      (1964)

Rat       M/F   wettable powder     280 - 300       Sanderson & Edson
                                                    (1964)

Rat             pure                   250          Atabaev & Stepovaya
                                                    (1966)

Rat       M/F   produced 1962       215 - 245       Gaines (1969)a
                (43.5%)

Rat             pure                200 - 300       Ben-Dyke et al.
                                                    (1970)

Rat                                 250 - 265       Melnikov (1974)

Mouse           99% pure               140          Hewitt et al. (1958b)

Mouse           pure                   135          Panshina (1963a)

Mouse           technical              125          Panshina (1963a)

Mouse      F    pure                   60           Sanderson & Edson
                                                    (1964)

----------------------------------------------------------------------------
a   Lower figures (20-30 mg/kg body weight) have been reported by the same
    author for a material produced in 1959.

Table 7. (contd).
--------------------------------------------------------------------------
Species   Sex   Material tested     LD50 (mg/kg     Reference
                                    body weight)
--------------------------------------------------------------------------

Mouse      F    technical              60           Sanderson & Edson
                                                    (1964)

Hamster    M    laboratory grade       200          Sanderson & Edson
                                                    (1964)

Guinea-   M/F   pure                   550          Sanderson & Edson
pig                                                 (1964)

Guinea-   M/F   laboratory grade       600          Sanderson & Edson
pig                                                 (1964)

Guinea-   M/F   technical           350 - 400       Sanderson & Edson
pig                                                 (1964)

Guinea-   M/F   liquid formul-      350 - 370       Sanderson & Edson
pig             ation                               (1964)

Rabbit    M/F   pure                   500          Sanderson & Edson
                                                    (1964)

Rabbit    M/F   laboratory grade       450          Sanderson & Edson
                                                    (1964)

Rabbit    M/F   technical              300          Sanderson & Edson
                                                    (1964)

Rabbit    M/F   liquid formul-         283          Sanderson & Edson
                ation                               (1964)

Cat             technical              100          Panshina (1963a)
---------------------------------------------------------------------------

8.2.  Skin and Eye Irritation

    A single dose of 300 mg technical dimethoate/kg body weight
did  not  cause  skin irritation  in  male  and  female  rabbits
(Dikshith & Raizada, 1981b).

    In a study by West et al. (1961), dimethoate did  not  have
any  irritant effect  on the  rabbit eye  after introduction  of
10 mg  of dry material into the conjunctival sac.  However, in a
personal  communication  (1986),  the  US  EPA  suggested   that
dimethoate had a slight irritant effect on the eye.

8.3.  Repeated Exposures

    The  effects on experimental  animals of repeated  oral  or
inhalation exposure to dimethoate are summarized in Tables 9 and
10.

    In the various studies, which ranged from  5 1/2-12  months
in  duration, inhibition of cholinesterase (ChE) in the erythro-
cytes was a more sensitive indicator of exposure  to  dimethoate
than  ChE inhibition in plasma.   ChE activity in the  brain was
measured in one study only.

Table 8. Acute dermal LD50 of dimethoate in experimental animals
------------------------------------------------------------------------------
Species     Sex   Material tested     LD50 (mg/kg     Reference
                                      body weight
------------------------------------------------------------------------------
Rat         M     32% emulsifiable       1120         Edson & Noakes (1960)
                  solution

Rat               liquid formula-     700 - 1150      Sanderson & Edson
                  tion                  (24-h)        (1964)

Rat               wettable powder     500 (24-h)      Sanderson & Edson
                                                      (1964)

Rat         M/F   produced 1962          610          Gaines (1969)a

Rat          M    32% w/v emulsifi-   770 - 1090      Noakes & Sanderson
                  able solution         (24-h)        (1969)

Rat          M    32% w/v emulsi-     > 1100 (4-h)    Noakes & Sanderson
                  fiable solution                     (1969)

Guinea-pig        liquid formula-        965          West et al.  (1961)
                  tion (46%)

Guinea-pig        wettable powder        995          West et al. (1961)
                  (25%)

Rabbit            not specified          600          Melnikov (1974)
------------------------------------------------------------------------------
a   Lower figures (55-61 mg/kg body weight) have been reported by the same
    author for a material produced in 1959.

    In  a study by West et al. (1961), no effects were observed
on ChE inhibition in rats administered dimethoate in the diet at
32   mg/kg.  In their first study (12 months) on rats, Sanderson
&  Edson  (1964) observed inhibition of ChE in  erythrocytes  at
50  mg/kg diet, but not at 10 mg/kg.  In the second study (5 1/2
months),  inhibition of ChE in erythrocytes was found at both 20
and 10 mg/kg, but not at 5 mg/kg.  The studies of Atabaev (1972)
did  not show any inhibition of blood-ChE in rats administered a

40% formulation of dimethoate at 0.5-1 mg/kg body weight, corre-
sponding   to 0.2-0.4 mg  dimethoate/kg body weight.   From  all
available  data on the rat,  a dietary level of  dimethoate of 5
mg/kg,  corresponding to  0.25 mg/kg  body weight,  can be  con-
sidered as the no-observed-adverse-effect level.

    From limited studies on the dog (West et al., 1961), it can
be  concluded that a level  of 10 mg dimethoate/kg  diet, corre-
sponding  to 0.25  mg/kg body  weight, does  not result  in  ChE
depression in erythrocytes.

    ChE inhibition was not observed in an inhalation  study  in
which  rats were exposed for 14 h/day, over 3 months, to 0.01 mg
dimethoate/m3  (measured  concentration)  (Kaloyanova  et   al.,
1968).


Table 9.  The effects on experimental animals of repeated exposure to dimethoate
---------------------------------------------------------------------------------------------------------
Species    Purity        Dose              Duration       Effects                     Reference
---------------------------------------------------------------------------------------------------------
Rat        technical     50, 100, or 200   35 days        no mortality; no signs      West et al. (1961)
           (95%)         mg/kg diet                       of intoxication

Rat        technical     2, 8,or 32 mg/kg  3 months       no mortality; no ChE        West et al. (1961)
           (95%)         diet                             inhibition

Rat        technical     15 mg/kg (oral)   6 months       100% inhibition of ChE      Panshina (1963a)
                                                          in serum and erythro-
                                                          cytes; approximately
                                                          85% inhibition in brain

Rat        technical     30 mg/kg (oral)   6 months       death of 3 out of 5         Panshina (1963a)
                                                          animals

Rat        technical     60 mg/kg (oral)   6 months       death of all animals        Panshina (1963a)

Rat (M)    laboratory    10 mg/kg diet     12 months      no inhibition of ChE in     Sanderson & Edson
           grade                                          erythrocytes or plasma      (1964)

Rat (M)    laboratory    50 mg/kg diet     12 months      marked inhibition of        Sanderson & Edson
           grade                                          ChE in erythrocytes         (1964)

Rat (M)    laboratory    200 mg/kg diet    12 months      marked toxic effects;       Sanderson & Edson
           grade                                          reduced rate of weight      (1964)
                                                          gain; inhibition of ap-
                                                          proximately 70% and 100%
                                                          ChE in plasma and erythro-
                                                          cytes, respectively

Rat        laboratory    800 mg/kg diet    12 months      severe toxic effects        Sanderson & Edson
           grade                           (1 week)       (cholinergic effect:        (1964)
                                                          weakness, weight loss
                                                          after a few days); the
                                                          pesticide was withdrawn
                                                          after one week; complete
                                                          recovery in 10 - 14 days

Rat (M)    technical     20 or 10 mg/kg    5 1/2 months   50 and 40% inhibition       Sanderson & Edson
(weanling)               diet                             of ChE in erythrocytes,     (1964)
                                                          respectively
---------------------------------------------------------------------------------------------------------

Table 9.  (contd).
---------------------------------------------------------------------------------------------------------
Species    Purity        Dose              Duration       Effects                     Reference
---------------------------------------------------------------------------------------------------------

Rat (M)    technical     5 mg/kg diet      5 1/2 months   no inhibition of ChE        Sanderson & Edson
(weanling)                                                                            (1964)

Rat        40% formula-  13 mg/kg body     4 months       one rat died on the         Atabaev (1972)
                         tion              weight (oral)  35th day

Rat        40% formula-  50 mg/kg body     4 months       3 rats died on the 7th      Atabaev (1972)
                         tion              weight (oral)  day, 2 died on the 8th
                                                          day, and one died on the
                                                          70th day

Rat        40% formula-  0.5 - 1 mg/kg     6 months       no effect on ChE            Atabaev (1972)
                         tion              (oral)

Rat        40% formula-  5 mg/kg body      6 months       AChE inhibition in          Atabaev (1972)
                         tion              weight (oral)  blood in the first 2
                                                          months (approximately
                                                          50%)

Dog        technical     2 or 10 mg/kg     13 weeks       no inhibition of ChE        West et al. (1961)
                         diet

Dog        technical     50 mg/kg diet     13 weeks       slight depression of        West et al. (1961)
                                                          ChE in erythrocytes

Cat        technical     10 mg/kg body     3 months       death in 2 out of 4         Panshina & Klisenko
                         weight (oral)                    animals                     (1962)

Cat        technical     20 mg/kg body     3 months       death in 2 out of 3         Panshina & Klisenko
                         weight (oral)                    animals                     (1962)

Cat        40% formula-  0.5 - 1 mg/kg     3 months       no effect on ChE            Atabaev (1972)
           tion          body weight                     
                         (oral)

Cat        40% formula-  2 mg/kg body      3 months       reduced body weight in      Atabaev (1972)
           tion          weight (oral)                    the first 2 months
                                                          (16 - 32%); recovery at
                                                          the third month
---------------------------------------------------------------------------------------------------------

Table 10.  Inhalation toxicity - repeated exposure
---------------------------------------------------------------------------------------------------------
Species   Concentration            Duration               Effects                      Reference
             (mg/m3)      Daily exposure   Number of                                    
                               (h)          months
--------------------------------------------------------------------------------------------------------
Rat              2             ?              2           no visible signs of intox-   Panshina (1963b)
                                                          ication; 26% inhibition of
                                                          AChE in blood at the end of
                                                          the study

Cat              1.5           ?              1.5         no visible signs of intox-   Panshina (1963b)
                                                          cation; 40-72% inhibition
                                                          of AChE in blood at the end
                                                          of the study

Rat       in a miniature greenhouse (0.6 m3; temperature  no blood-ChE inhibition      Sanderson & Edson 
          21-30 °C); plants sprayed with 5 ml of 0.5%                                  (1964)
          aqueous formulation in the course of 28 days
                                              
Rat and          4.50          8              3           inhibition of ChE; leuk-     Kaloyanova et al. 
guinea-pig                                                ocytosis                     (1968)

Rat              0.05          14             3           inhibition of ChE in blood   Kaloyanova et al. 
                                                          only in the first month;     (1968)
                                                          inhibition of brain- and
                                                          liver-AChE; morphological
                                                          alterations in the neurons

Rat              0.01          14             3           no changes observed          Kaloyanova et al. 
                                                                                       (1968)
                                         
Rat              0.495         24             3           inhibition of ChE and        Ubaidullaev &  
                                                          changes                      Madzhidov (1976)

Rat              0.049         24             3           inhibition of ChE            Ubaidullaev & 
                                                                                       Madzhidov (1978)

Rat              0.003         24             3           no detectable changes        Ubaidullaev & 
                                                                                       Madzhidov (1978)
---------------------------------------------------------------------------------------------------------
8.4.  Reproduction Studies

    One  reproduction study on  mice has been  reported in  the
literature (Budreau & Singh, 1973).  In this 5-generation study,
initial groups of 14 female and 10 male mice received dimethoate
in  the drinking-water at 60 mg/litre for a period of one month,
prior   to mating.  A comparable  control group was included  in
the  study.  Animals receiving  dimethoate showed a  significant
( P <  0.05) reduction in mating performance (expressed  as  pro-
portion  of  females with  deliveries  to females  mated), which
ranged  from 33  to 61%,  varying with  litter  and  generation.
Similarly,  reproduction time (measured as number of days elaps-
ing  from first day of  mating to day of  delivery) was signifi-
cantly  ( P < 0.01)  increased  in all  first litters  of  all  5
generations examined, but unaffected in all second litters.  The
biological  relevance  of  this observation  is unclear.  Litter
size and average weight at birth were not affected by treatment.
Although the mean weights of treated pups were not significantly
lower,  the growth rate was  consistently lower in treated  pups
compared with that in the controls.

    A   3-generation   reproduction   study   using   technical
dimethoate  (98.3%) was carried  out on mice.   Information sup-
plied  by the US EPA indicated that there were no effects on re-
production  and teratogenicity at a dimethoate level of 50 mg/kg
(US EPA, personal communication, 1986).  Details of  this  study
were not available.

8.5.  Teratogenicitya

    Intraperitoneal  administration of 40 mg dimethoate/kg body
weight,  given  as  a single dose on the day of mating or on the
9th  day  of  gestation, or  given  for  the first  14  days  of
gestation  in mice, caused  a high incidence  of embryonal  loss
(Scheufler, 1975).

    Cygon  4E (containing 47.3% dimethoate) was given to female
rats  by intubation from the 6th to the 15th day of gestation at
dose  levels of 3, 6, 12, or 24 mg/kg body weight.  The 24 mg/kg
dose  was toxic for the dams (8 out of 20 dams manifested clonic
spasms and muscular tremors during the treatment period,  7  re-
covered, and one died on the 16th day of pregnancy).   Doses  of
12  and 24 mg/kg were associated  with an increase ( P  <   0.05)
in  the numbers of anomalous  litters (each having at  least one
anomalous  fetus) and wavy-ribbed  fetuses.  The 3  and  6 mg/kg
doses  (equal to 1.42-2.84 mg dimethoate/kg) did not produce any
evidence  of teratogenicity or embryotoxicity in the rats (Khera
et al., 1979).

----------------------------------------------------------------
a   A further teratogenicity study on the rat (Edwards  et  al.,
    1984) was submitted to the FAO/WHO Joint Meeting  on  Pesti-
    cide Residues (JMPR) in 1987.  Although fetotoxicity was ob-
    served, there were no teratogenic effects (FAO/WHO, 1987).

    Cygon  4E (47.3% dimethoate) was  given to cats in  gelatin
capsules  at doses of 3, 6, or 12 mg/kg on the 14th-22nd days of
pregnancy.  At the levels tested, the compound did  not  produce
any  effects on  the incidence  of pregnancy.   In the  12 mg/kg
group,  forepaw polydactily was observed in 8 out of 39 fetuses.
Cygon  4E at 3 or  6 mg/kg (1.42-2.84 mg dimethoate/kg) did  not
produce  any  effects (Khera,  1979).   (The effect  observed in
Khera's investigations may be due to the other components in the
formulation).

    Courtney  et al. (1985)  reported that dimethoate  adminis-
tered  orally was not teratogenic in CD-1 mice at dose levels of
10  or 20  mg/kg body  weight, and  that these  levels were  not
lethal  to the  dams.  The  two highest  dose levels  of 40  and
80 mg/kg produced maternal toxicity.

8.6.  Mutagenicity

    A  variety of  in vivo and  in vitro mutagenicity  tests have
been carried out with dimethoate, the results of which are given
in Table 11.

    Negative  mutagenicity results were reported by Degraeve et
al.  (1984) for commercial  mixtures of insecticides  containing
dimethoate.  Two formulations were tested: dimethoate + fenitro-
thion  (dose 60 mg/kg body  weight, corresponding to 9  mg/kg of
each)  and dimethoate + malathion + methoxychlor (dose 100 mg/kg
body  weight corresponding to  9.5 mg dimethoate/kg).   A single
ip  injection  did not  induce  chromosome aberrations  in  bone
marrow  cells,  spermatogonia,  or primary  spermatocytes of the
mouse.   No significant increases  in pre- or  post-implantation
fetal  lethality  were observed  in  a dominant  lethal mutation
assay.

    Alkylation by dimethoate at the  N-7  position of guanine in
DNA  has been  investigated (Dedek  et al.,  1984).   Male  mice
(strain AB Jena/Halle, random bred) were injected ip  with  14C-
methyl-labelled  dimethoate  at a  dose  of 0.35  mmol/kg.   The
extent  of  methylation  was in  the  range  of  1-10 µmol     N-
7 methylguanine/mol   guanine;  the  values in  the kidneys were
higher  than those in the liver.  The excretion half-life of   N-
7 methylguanine was 23-160 h.

    In  summary, dimethoate has been  found to be mutagenic  in
both  in vitro and  in vivo assays.a
----------------------------------------------------------------
a   After   this  statement  was  written,   new  well-performed
    negative  mutagenicity studies were submitted to the FAO/WHO
    Joint Meeting on Pesticide Residues (JMPR) in 1987 including
    an  in  vitro mutation assay on  Chinese hamster ovary  cells
    (Johnson  et al.,  1985), a  dominant lethal  test  in  mice
    (Becker,  1985), a micronucleus  test in mice  (Sorg, 1985),
    and a metaphase analysis assay in rat bone marrow cells (San
    Sebastian, 1985).  On the basis of these new studies and the
    published  studies,  the  JMPR concluded  that dimethoate is
    mutagenic  in  bacterial  tests, but  negative  in mammalian
    cells and  in vivo tests (FAO/WHO, 1987).
    

Table 11.  Mutagenicity tests
---------------------------------------------------------------------------------------------------------
Tests                      Concentration of         Results                              Reference
                           dimethoate used
---------------------------------------------------------------------------------------------------------
 Escherichia coli           1 - 6.10-3 mmol          5-methyltryptophane resistance       Mohn (1973)
K-12/gal Rs                                         mutation -positive

 Escherichia coli           Up to 5000 µg/plate      positive                             Moriya et al. 
WP2 hcr                                                                                  (1983)

 Escherichia coli           Minimum mutagenic        positive                             Probst et al. 
WP2 & WP2uvrA-             concentration                                                 (1981)
                           47 nmoles/ml

 Salmonella typhimurium                              negative                             Probst et al. 
TA 98, 100, 1535, 1537,                                                                  (1981)
1538

 Salmonella typhimurium     Up to 5000 µg/plate      positive with and without            Moriya et al. 
TA 100                                              activation                           (1983)

 Salmonella typhimurium     Up to 5000 µg/plate      negative                             Moriya et al. 
TA 98, 1535, 1537, 1538                                                                  (1983)

 Salmonella typhimurium     5 - 200 µg/plate         positive at all doses, mutagenicity  Vishwanath & 
TA 100 (base pair subst.)                           increased with liver microsomes      Jamil (1986)

 Saccharomyces cerevisiae   7 doses, 40 - 100 mmol   induction of mitotic gene            Fahrig (1974)
                                                    conversions

 Schizosaccharomyces pombe  1.3 - 131 mmol           negative                             Gilot-Delhalle 
ade 6                      (LD50 50 mmol)                                                (1983)

Chinese hamster ovary      20,40 & 80 µg/ml         sister chromatid exchange increase   Chen et al. 
cells V79                  10 µg/ml                 negative                             (1981)

Rat hepatocytes culture    47 nmol/ml               negative unscheduled                 Probst et 
                                                                                         al. (1981)

SV-40 transformed human    100 & 1000 umol          positive unscheduled DNA             Ahmed et 
                                                    synthesis                            al. (1977)

 Drosophila melanogaster    1 mg/kg (feeding)        negative                             Woodruff et 
                                                                                         al. (1983)
---------------------------------------------------------------------------------------------------------

Table 11.  (contd).
---------------------------------------------------------------------------------------------------------
Tests                      Concentration of         Results                              Reference
                           dimethoate used
---------------------------------------------------------------------------------------------------------
 Drosphila melanogaster     adult inj. ip 0, 10,     increase in sex-linked               Velazquez et 
                           20 mg/kg body weight     recessive lethals at 10 mg/kg        al. (1986)
                                                    not at 20 mg/kg

 Drosophila melanogaster    adult feeding 0,         negative                             Velazquez et 
                           10 mg/kg; larval         negative                             al. (1986)
                           feeding 0, 20 mg/kg

Host-mediated assay mouse  3 equal oral doses       positive - mutation factor of        Usha Rani et 
 Salmonella typhimurium     of 155 mg/kg             3.44 ( P < 0.05)                     al. (1980)

Dominant lethal mutation   acute 10 mg/kg ip        negative                             Degraeve & 
assay mice strain Q        7 weeks 0.6 mg/litre                                          Moutschen
                           drinking-water, equiv-                                        (1983)
                           alent to 0.093 mg/kg
                           body weight

Dominant lethal test       30 & 60 mg/kg body       negative                             Fischer & 
- AB Jena Halle mice       5 x 6 mg/kg body weight                                       Scheufler 
                           ip                                                            (1981)
  DBA mice                 3 x 18 mg/kg body weight
                           ip

Micronucleus test -        2 equal doses of         a significant increase in            Usha Rani et 
mice - bone marrow         51.7 mg/litre drink-     frequency of polychromatic           al. (1980)
                           ing-water at 24-h        erythrocytes with micronuclei 
                           intervals                -0.85% (controls 0.28%)

Chromosome abnormalities   50 and 100 mg/kg body    positive                             Bhunya & Behera 
mice - bone marrow         weight                                                        (1975)

Mice - bone marrow         20 mg/kg body weight     no abnormalities                     Nehés et al.
                           ip                                                            (1982)
                              
Mice - bone marrow         60 mg/kg body weight     increase in number of mitosis,       Nehéz et al. 
                           ip                       aberrations                          (1983)

Syrian golden hamsters     16, 32, 80, or           increase in number of chromatid      Dzwonkowska & 
 Mesocricetus auratus       160 mg/kg body weight    and chromosomal breaks               Hübner (1986)
                           ip single                (no dose-response relationship)
---------------------------------------------------------------------------------------------------------
8.7.  Carcinogenicity

    Two  carcinogenicity  studies,  reported by  Gibel  et  al.
(1973), are summarized below.

     Rat:  Groups  of 40, 10-week-old Wistar rats were intubated
with  0  (control), 5,  10, or 30  mg dimethoate/kg body  weight
(twice weekly) for the life span.  The mean life spans were 743,
518,  511,  and  627 days at 0, 5, 15, and 30 mg/kg body weight,
respectively.   No  malignant tumours  were  observed in  the 36
control   animals.  In  test groups,  malignant tumours occurred
in  2/26,  3/25,  and 4/20  rats,  respectively,  at the  3 dose
levels.  At 5 mg/kg body weight, a reticulosarcoma of the spleen
with  metastases and a malignant reticuloma were  observed.   At
15  mg/kg body weight, a sarcoma of the colon, a reticulosarcoma
of  the spleen (with pancreatic metastases) and a hepatocellular
carcinoma  occurred.  At 30  mg/kg body weight,  a liver  fibro-
sarcoma,  a malignant reticuloma and two reticulosarcomas of the
spleen  were noted.   Three, 7,  5, and  2 benign  tumours  were
noted,  respectively, in the controls and at 5, 15, and 30 mg/kg
body weight (Gibel et al., 1973).

     Rat:  Groups  of 40, ten-week-old Wistar rats were injected
im with 15 mg dimethoate/kg body weight (twice weekly)  or  with
isotonic saline until spontaneous death occurred.  The mean life
spans were 711 and 570 days in the saline and dimethoate-treated
animals,  respectively.   No  malignant tumours  occurred in the
saline-treated group, but 4/35 animals developed benign tumours.
In  the dimethoate  group, 6/30  rats had  malignant tumours  (a
spleen   reticulosarcoma,  a  spleen  fibrosarcoma,  an  ovarian
alveolar  sarcoma, a liver hepatocellular carcinoma, a malignant
reticuloma, and a soft tissue spindle-cell sarcoma) and 5/30 had
benign   tumours.   The  first   malignant  tumour  (a   splenic
fibrosarcoma) was noted after 410 days (Gibel et al., 1973).

    Dimethoate (technical grade, 90-100% pure) was given in the
feed  to Osborne Mendel rats  and to B6C3F1 mice.   Groups of 50
male  and 50  female rats  (10 animals  in each  control  group)
received "time-weighted average doses" of 155 or 310  mg/kg  for
male rats and 192 or 384 mg/kg for female rats.  After 80 weeks,
all  groups received control  diets, and the  studies were  con-
cluded at week 114.

    Groups  of  50 male  and 50 female  B6C3F1 mice were  given
dimethoate  in the  diet at  concentrations of  0 (10  "matched"
controls), 250, or 500 mg/kg for 60-69 weeks (males) or  for  80
weeks  (females).   The  studies  were  ended  after  94  weeks.
Tremors  and hyperexcitability were observed in exposed animals;
rats  and mice that  survived to termination  were generally  in
poor condition.  Survival was reduced in the high-dose groups of
rats.   Several non-neoplastic lesions occurred  more frequently
in  dimethoate-exposed animals.  No increases  in neoplasia were
reported  to be associated  with dimethoate administration,  for
any of the organs or tissues examined histologically (NCI-1977).

These  studies are not considered adequate to determine properly
the  presence  or absence  of  a carcinogenic  response, largely
because  of the shorter  than usual duration  of exposures,  the
poor condition of the animals, and changes in  exposure  concen-
trations.a

8.8.  Special Studies

    The action of dimethoate on the immune system  was  studied
in mice and rats by Tiefenbach & Lange (1980).  A single dose of
75 mg   dimethoate/kg   (route  not   specified)  decreased  the
lymphocyte  count to 50% of the pre-exposure value and increased
the   neutrophile  granulocytes.   After  72 h,   these  changes
returned  to normal.   A reduction  in the  thymus  cortex  with
disrupted lymphocytes, and a reduction in the number of rosette-
forming cells were observed.

    When  administered to rats at 5-30 mg/kg body weight orally
or  15 mg/kg im,  twice a week,  until death, dimethoate  caused
hyperplasia  in  the  bone marrow,  mainly in granulocytopoiesis
(Stieglitz  et al., 1974).   The authors interpreted the changes
in  the haematopoietic system of  the rats as a  direct haemato-
logical effect of dimethoate.

    The effects of dimethoate on the heart   were  investigated
in  rabbits  (Mahkambaeva,  1971),  and  guinea-pigs  and   rats
(Nadmaiteni  &  Marosi,  1983).  After  oral  administration  of
150 mg  dimethoate/kg to rabbits, the  effects observed included
bradycardia  and increased atrio-ventricular  and intraventricu-
lar conductance, with complete recovery after 4-7 days.  In rats
and  guinea-pigs, a dose-effect relationship was established for
heart   rate  disturbances,  and  atrio-ventricular  block.   An
electron-microscopic  study of the  myocard did not  reveal  any
changes.   The  ip  doses  that were tested  ranged from 500  to
1500 mg/kg body weight.

----------------------------------------------------------------
a   After  the  Task  Group met,  new  well-performed long-term/
    carcinogenicity studies in rats and mice were  submitted  to
    the  FAO/WHO Joint Meeting  on Pesticide Residues  (JMPR) in
    1987.   No indication for carcinogenicity was found.  In the
    mouse  study, the lowest dose of 25 mg/kg produced decreased
    body  weight, decreased cholinesterase activity  in erythro-
    cytes,  and also slight extramedullary haematopoiesis in the
    spleen  (Hellwig,  1986a).  Administration  of dimethoate to
    rats  for  2  years (Hellwig,  1986b)  also  resulted  in  a
    decrease  in body weight, decreased  cholinesterase activity
    in  erythrocytes  and the  brain,  and slight  anaemia.   No
    effects  were observed at 1  mg/kg (0.05 mg/kg body  weight)
    (FAO/WHO, 1987).
      
    In  anaesthetized guinea-pigs treated with  lethal doses of
dimethoate,   cardiac  failure  and  serious   ECG  disturbances
developed in the early phase of intoxication.  The toxic cardiac
phenomena  appeared to  be unrelated  to the  degree of  cholin-
esterase  inhibition,  but  were correlated  with the myocardial
dimethoate  concentration.   Cardiac failure  and mortality were
first observed at a level of about 110 µg/g,  while a  level  of
221 µg/g   resulted in death in all cases.  The present investi-
gation  refers  to  the  direct  effect  of  dimethoate  on  the
myocardium, independent of its anticholinesterase action (Marosi
et al., 1985a,b).

8.9.  Factors Modifying Toxicity

    The  acute toxicity of dimethoate  was not affected by  the
dietary content of protein (Boyd & Muis, 1970).  The  oral  LD50
was  147 mg/kg for male albino rats fed for 28 days from weaning
on  a diet containing  3.5% protein as  casein and, in  controls
maintained  on a diet containing 26% casein at 152 mg/kg.  Other
groups  maintained on  a diet  that contained  24% protein  from
various  plant and animal  sources were apparently  less suscep-
tible  to dimethoate (LD50, 358 mg/kg).  Dimethoate was given to
rats orally for 10 weeks at a dose of 10 mg/kg in diets contain-
ing  90, 160, or 240 g protein/kg (Gontzea & Gorcea, 1977).  The
high-protein  (240 g)  diet  diminished the  adverse  effects of
dimethoate  on the growth of the rats and lessened its antichol-
inesterase activity in plasma, total blood, brain, and liver.

    A marked increase in the toxicity of dimethoate  was  noted
in male and female mice after pre-treatment  with  phenobarbital
and with chlorinated hydrocarbons (DDT and dieldrin)  (Menzer  &
Best,  1968;  Menzer, 1970).   The  toxicity of  dimethoate  was
increased from an ip LD50 of 198 mg/kg body weight to 58.5 mg/kg
by pre-treatment of mice for 3 days with sodium phenobarbital.

    Liquid    formulations  of  technical  dimethoate   in  the
solvents,  2-methoxy- and 2-ethoxyethanol, showed increased tox-
icity  after storage.  After storage for 7 months in England and
9  months under tropical conditions,  the oral LD50 for  the rat
decreased  to  30-40 mg/kg  and 15 mg/kg,  respectively (from an
initial  150-250 mg/kg).  The most toxic  conversion product was
 O,O-dialkyl  S-(N-methylcarbamoylmethyl)    phosphorothioate with
an oral LD50 for the rat of 1 mg/kg (Casida & Sanderson, 1961).

8.10  Mechanisms of Toxicity; Mode of Action

    The  mode  of  action of  organophosphorus  insecticides is
decribed  in WHO (1986a).  They act principally by inhibition of
acetyl cholinesterase (AChE)  at the cholinergic synapses.

    Dimethoxon   (omethoate),  a  metabolite of  dimethoate, is
75-100  times more potent  than dimethoate in  inhibiting  AChE,
suggesting  that  this  metabolite  plays  a  dominant  role  in
mammalian toxicity (Hassan et al., 1969).  The LD50 of omethoate
in  rats is 25-28 mg/kg body weight (FAO/WHO, 1979); it is about
10 times more toxic than dimethoate.

9.  EFFECTS ON MAN

9.1  General Population Exposure

9.1.1  Poisoning incidents

    Cases of both accidental and suicidal poisoning  have  been
reported with dimethoate.  Hayes (1982) has reviewed  the  human
toxicity and poisoning cases.

    Nagler  et al. (1980) described a case of attempted suicide
of a 34-year-old female who ingested 10 g dimethoate.   Half  an
hour after admission to the hospital, the serum-dimethoate level
was  2340 mg/litre.   Combined haemoperfusion  and haemodialysis
were  applied and, after 18 h, dimethoate was no longer detected
in the serum.

    A severe case of poisoning after ingestion of approximately
20 g  dimethoate  was  reported by  Köppel  et  al. (1986).   On
admission,  the 52-year-old man  was comatose with  unmeasurable
pseudo-cholinesterase (< 200 U/litre).  He had been admitted 2 h
after  ingestion  and received,  every  20 min, an  injection of
20 mg atropine.  Two haemoperfusions with activated charcoal and
amberlite  were performed, and atropine was given by infusion up
to day 12.  Twenty-five days after admission, he was discharged,
fully recovered.

    De Reuck  et al. (1979) presented  a case of a  patient who
died  on the 9th day after dimethoate poisoning with an atypical
central  neurological disorder.  The neuropathological findings,
which  were  similar  to  those  observed  in  severe  forms  of
Wernicke's encephalopathy, included severe haemorrhagic necrosis
of  the walls of the ventricles.  The authors suggested that the
increased  level  of  acetylcholine in  the  brain  had  led  to
thiamine  depletion in the regions of predilection of Wernicke's
encephalopathy.

    Many  other cases of  human dimethoate poisoning,  some  of
which  were fatal, have been reported, but the information given
was  insufficient  (Molphy &  Rathus,  1964; Masiak  & Olajossy,
1973; François & Verbraeken, 1977; Demeter &  Heyndrickx,  1978;
Ebel  & Karyofilis, 1978; Areekul et al., 1981; Wehran & Hammer,
1984; Bolgar et al., 1985; Le Blanc et al., 1986;  Senanayake  &
Karalliedde, 1987).

    On the basis of a number of cases, the oral lethal dose for
human  beings was estimated to  be of the order  of 50-500 mg/kg
body weight (Gosselin et al., 1984).

    Trinh  van Bao et  al. (1974) reported  an increase in  the
frequency  of  breaks and  stable  chromosome aberrations  in  2
patients who died after dimethoate intoxication.

    Thirty  firemen, exposed  to dimethoate  in the  air  as  a
result  of  an  accident in  a  dimethoate-manufacturing  plant,
developed symptoms of intoxication (Larripa et al., 1979, 1983).
Peripheral  blood  lymphocytes from  20  of these  workers  were
examined  for  the frequency  of  sister chromatid  exchanges, 2
months after the accident.  The frequencies were 9.2 ±  0.2  for
the  exposed and 8.5 ± 0.2 for  unexposed persons  ( P <   0.05).
Dicentric  chromosomes and a  low frequency of  chromatid breaks
were  found in 2 exposed workers.  It is not certain to what the
firemen were exposed besides dimethoate.

9.1.2  Controlled human studies

    The  results of a number of studies in which  human  volun-
teers,  without occupational exposure to  organophosphates, were
given  dimethoate,  are  summarized  in  Table  12.   From these
studies   it  can  be  concluded   that repeated doses of  up to
0.2 mg/kg body weight did not inhibit cholinesterase activity in
the blood.

9.2  Occupational Exposure

9.2.1  Poisoning incidents

    One of the first cases of poisoning with dimethoate (Rogor)
in agriculture was described by Muratore et al. (1960).   A  28-
year-old-farmer,  who  reportedly  had  worn  protective  rubber
clothing  and equipment, had sprayed olive trees with dimethoate
the  day before he was hospitalized. The man began to experience
profound   weakness,  faintness,  and  somnolence,  followed  by
attempts to vomit, chills, and profound prostration on  the  day
he  was hospitalized.   His general  condition was  found to  be
serious;  his pulse was  weak, he exhibited  pronounced  myosis,
vomited  and sweated profusely, and had pronounced inhibition of
cholinesterase  activity.  Treated with large  doses of atropine
(20 mg  on  day  2,  12 mg  on day  3,  and 5 mg  until  day 9),
prednisone, analgesics, and penicillin, he recovered.

    A case of poisoning in a woman working in  agriculture  and
exposed to dimethoate in the field, 2 days after  spraying,  was
reported  by  Asatryan  (1971).  Within  3-3.5 h after beginning
work,   the  woman  noted  an  unpleasant  odour  recognized  as
dimethoate.    She  developed  headache,  dry  cough,  dyspnoea,
nausea,  vomiting and was  admitted to hospital  in a  somnolent
state  with muscular fibrillations  and an asthmatic  component.
After   treatment  with  saline  solution,   glucose,  caffeine,
atropine,  and  insulin, the  state  of acute  intoxication  was
overcome.  Allergic symptoms were treated with dimedrol.

    Contact  allergy due to  dimethoate was reported  in a  53-
year-old female. She had a positive skin test (Pambor  &  Bloch,
1985).


Table 12.  Controlled human studies
---------------------------------------------------------------------------------------------------------
Number  Sex  Route of   Dose/day        Duration of    Results                     Reference
   of        Admini-                    exposure
subjects     stration
---------------------------------------------------------------------------------------------------------
   20        oral       0.04 mg/kg        4 weeks      absence of toxic effects    Sanderson & Edson
                                                       or blood-ChE inhibition     (1964)
                                
    2        oral       0.13 mg/kg;       21 days      absence of blood-ChE        Sanderson & Edson
                        0.26 mg/kg                     inhibition                  (1964)

    5    M   oral       0.25 mg/kg        single dose  absence of toxic effects    Sanderson & Edson
                                                       or ChE inhibition           (1964)

   50        dermal     32% liquid form-  2-h patch    absence of skin irritation  Sanderson & Edson
                        ulation, up to    test         and ChE inhibition          (1964)
                        2.5 ml

   12   M/F  oral       5 mg (0.068       28 days      no significant change in    Edson et al. (1967)
                        mg/kg body weight)

    9   M/F  oral       15 mg (0.202      39 days      no significant change in    Edson et al. (1967)
                        mg/kg body weight)

    8   M/F  oral       30 mg (0.434      57 days      inhibition of ChE by the    Edson et al. (1967)
                        mg/kg body weight)

    6        oral       45 mg (0.587      45 days      inhibition of ChE (35%)     Edson et al. (1967)
                        mg/kg body weight)
    6   M/F  oral       60 mg (1.02       14 days      inhibition of ChE (21%)     Edson et al. (1967)
                        mg/kg body weight)
---------------------------------------------------------------------------------------------------------
    Female  greenhouse  workers  working with  dimethoate  were
reported  to  have  a  high  percentage  of  specific  leukocyte
agglomeration,  a raised index of lymphoblastic transformations,
and  antibodies against dimethoate  (Zolotnikova & Somov,  1978;
Zolotnikova, 1980).  With increasing duration of work, progress-
ive sensitization towards the pesticide was observed.

    On  the basis of epidemiological observations and of dermal
testing  of workers  with a  1-2% solution  of dimethoate,  Jung
(1979)  concluded that the index of sensitization was  very  low
for  dimethoate and that  general intoxication might  occur, but
rarely contact eczema.

9.3  Early Symptoms and Treatment of Poisoning

    Initial   symptoms  of  poisoning  may   include  sweating,
headache,  weakness, giddiness, nausea, vomiting, stomach pains,
blurred  vision,  slurred  speech, and  muscle  twitching  (WHO,
1986a).   Arrhythmias  and  cardiac failure  have  been reported
(Kiss  & Fazekas, 1983;  Marosi et al.,  1985a,b; Duval et  al.,
1986).  The most important diagnostic finding is  inhibition  of
blood-cholinesterase  activity.   For  a full  discussion of the
clinical  picture  and treatment  of organophosphate insecticide
poisoning,  see  WHO  (1986a).   The  section  on  treatment  is
presented in the annex to this publication.

    In  all  cases of  clinical  poisoning with  dimethoate and
other organophosphorus insecticides, it is essential to maintain
general  surveillance and cholinesterase and  cardiac monitoring
for  at least  4 days,  and longer  if necessary,  and to  adapt
general supportive and specific therapy in accordance  with  the
findings.

    Data  on the effects  of oxime reactivators  in  dimethoate
poisoning  are contradictory, some indicating that they may have
a  negative  effect  on cholinesterase  inhibition  (Sanderson &
Edson,  1959;  Durham  & Hayes,  1962;  Molphy  & Rathus,  1964;
Erdmann  et  al., 1966;  Zech et al.,  1966; Ebel &  Karyofilis,
1978;  Sterri et al., 1979).  It is therefore suggested, that if
oxime  reactivators  are indicated,  these  should be  used with
caution and under close supervision.

    Haemoperfusion  may  be effective  in  the early  stages of
dimethoate  poisoning (Okonek 1976,  1977; Okonek et  al., 1976;
Pach et al., 1977; Nagler et al., 1980).

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

10.1.  Toxicity of Dimethoate

    Dimethoate is moderately toxic.  Most oral LD50s in the rat
ranged from 150-400 mg/kg body weight.  The dermal LD50  in  the
rat was greater than 600 mg/kg body weight.  Dimethoate  is  not
irritating  to the skin, but  may be slightly irritating  to the
eye.

    It  can  be  absorbed following  ingestion, inhalation, and
skin contact.  It is readily metabolized and excreted  and  does
not  accumulate in the body.  Dimethoxon (omethoate), the oxygen
analogue  found in  plants, insects,  and mammals,  is about  10
times  more toxic  and is  a more  potent inhibitor  of  cholin-
esterase activity than dimethoate.

    Signs of intoxication from exposure to dimethoate are those
typical  of organophosphorus pesticides.  Inhibition of erythro-
cyte-cholinesterase  is the most sensitive indicator of exposure
to  dimethoate and may  indicate toxicity.  A  dietary level  of
5 mg  dimethoate/kg, equivalent to  0.25 mg/kg body  weight,  is
considered  to  be  a no-observed-adverse-effect  level  in  the
rat.a
 
    A  5-generation reproduction study in  mice given drinking-
water containing dimethoate at 60 mg/litre resulted in decreased
mating  success and increased  reproduction time in  all  gener-
ations.  On the basis of available data on experimental animals,
dimethoate is not considered to be a teratogen.

    Dimethoate is considered mutagenic in a variety of  in vitro
and  in   vivo test  systems.b     Long-term  studies  have  been
conducted  involving oral administration in rats and mice and im
injection in rats.  However, the available data  are  considered

---------------------------------------------------------------
a   FAO/WHO (1987) concluded that a dietary level of  1  mg/kg,
    equivalent  to 0.05 mg/kg  body weight is  the no-observed-
    adverse-effect level in the rat.

b   After   this  statement  was  written,   new  well-performed
    negative  mutagenicity studies were submitted to the FAO/WHO
    Joint Meeting on Pesticide Residues (JMPR) in 1987 including
    an  in  vitro mutation assay on  Chinese hamster ovary  cells
    (Johnson  et al.,  1985), a  dominant lethal  test  in  mice
    (Becker,  1985), a micronucleus  test in mice  (Sorg, 1985),
    and a metaphase analysis assay in rat bone marrow cells (San
    Sebastian, 1985).  On the basis of these new studies and the
    published  studies,  the  JMPR concluded  that dimethoate is
    mutagenic  in  bacterial  tests, but  negative  in mammalian
    cells and  in vivo tests (FAO/WHO, 1987).

to  be  inadequate  to  assess  the  carcinogenic  potential  of
dimethoate.c

10.2.  Human Exposure

    Air  and  water  are  negligible  sources  of  exposure  to
dimethoate for the general population.  Residues found  in  food
are generally below the acceptable daily intake (ADI) set by the
FAO/WHO  Joint Meeting on Pesticide Residues (JMPR) (See section
12).

    Whole  blood-cholinesterase  was  not  inhibited  in  human
volunteers  given oral doses of 0.2 mg dimethoate/kg body weight
for 39 days.

    Several  cases of suicidal  or accidental poisoning  due to
ingestion of dimethoate have been reported.

    Occupational  exposure  to dimethoate,  principally through
inhalation  and  the skin,  may  occur during  its  manufacture,
formulation,  and  use, and  cases of poisoning  as a result  of
accident  or neglect of  safety precautions have  been reported.
The oral lethal dose for human beings has been estimated  to  be
in the range of 50-500 mg/kg body weight.

    Skin sensitization due to dimethoate has been  observed  in
some cases.

10.3.  Evaluation of the Effects on the Environment

    Dimethoate  is rapidly hydrolysed  and does not  persist in
the  environment.   The  toxicity  of  dimethoate  for   aquatic
organisms and birds is moderate to high.  It is very  toxic  for
honey-bees.

---------------------------------------------------------------

c   After  the  Task  Group met,  new  well-performed long-term/
    carcinogenicity studies in rats and mice were  submitted  to
    the  FAO/WHO Joint Meeting  on Pesticide Residues  (JMPR) in
    1987.   No indication for carcinogenicity was found.  In the
    mouse  study, the lowest dose of 25 mg/kg produced decreased
    body  weight, decreased cholinesterase activity  in erythro-
    cytes,  and also slight extramedullary haematopoiesis in the
    spleen  (Hellwig,  1986a).  Administration  of dimethoate to
    rats  for  2  years (Hellwig,  1986b)  also  resulted  in  a
    decrease  in body weight, decreased  cholinesterase activity
    in  erythrocytes  and the  brain,  and slight  anaemia.   No
    effects  were observed at 1  mg/kg (0.05 mg/kg body  weight)
    (FAO/WHO, 1987).

10.4.  Conclusions

1.  Under  proper conditions of  use, exposure of  the  general
    population to dimethoate is negligible.

2.  When  appropriate safety precautions are observed, exposure
    to  dimethoate  during  manufacture, formulation,  use, and
    disposal  should  not  pose an  unacceptable  human  health
    hazard.

3.  Dimethoate  is rapidly degraded  and not persistent  in the
    environment.   Care must be taken not to expose honey-bees,
    fish and aquatic organisms, and birds.

11.  RECOMMENDATIONS

1.  Figures  relating  to the  current  production and  use  of
    dimethoate should be made available.

2.  Studies   are   necessary   on  dermal   sensitization   by
    dimethoate.

3   Data  are  required on  the  absorption and  disposition of
    dimethoate from different routes of exposure.

4.  Long-term  toxicology and carcinogenicity studies should be
    carried out on laboratory animals.a

5.  More  research  is  required  to  investigate  the  in  vivo
    mutagenic effects of dimethoate.a

6.  Reproduction  and  teratology  studies  should  be  carried
    out.a

7.  Epidemiological   studies   on   persons  engaged   in  the
    manufacture  and professional use  of dimethoate should  be
    considered, and workers should be monitored for exposure to
    dimethoate and for potential adverse health effects.

8.  Cleaning  and disposal of contaminated equipment, clothing,
    and  containers  should  be in  accordance with recommended
    procedures.

9.  Further  work  is  necessary  to  establish  safe  re-entry
    periods under different conditions of use.

10. Acute   toxicity   studies   should  be   carried   out  on
    formulations in which dimethoate is mixed with other active
    ingredients.

11. The  role of oxime reactivators  in the treatment of  human
    poisoning by dimethoate, should be clarified.

12. Information  should be obtained  concerning the changes  in
    toxicity, due to impurities, that can arise  in  pesticides
    as  a consequence of different manufacturing processes, the
    use of formulating ingredients, and improper storage.

---------------------------------------------------------------
a   Several  of  these  studies  were  later  submitted  to the
    FAO/WHO Joint Meeting on Pesticide Residues in  1987.   See
    previous footnotes for sections 8.5, 8.6 and 8.7.

12.  PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

    Dimethoate  was evaluated by the Joint Meeting on Pesticide
Residues  (JMPR)   in  1963,  1965,  1966,  1967,   1970,   1973
(evaluation  of  the  related compound  formothion), 1977, 1978,
1984,  and 1987 (FAO/WHO,  1964, 1965, 1967,  1968, 1971,  1974,
1978, 1979, 1985, 1987).

    The  estimate of an acceptable  daily intake (ADI) for  man
for  dimethoate is 0-0.01 mg/kg  body weight, based  on the  no-
observed-adverse-effect  level in man  of 0.2 mg/kg body  weight
per  day,  and  in  the  rat  of  1 mg/kg  diet,  equivalent  to
0.05 mg/kg body weight (FAO/WHO, 1987).

    A  data sheet on dimethoate  has been issued by  WHO in the
series "Data Sheets on Pesticides" (WHO/FAO, 1980).

    In  the  WHO  Recommended Classification  of  Pesticides by
Hazard,   technical  dimethoate  is  classified   as  moderately
hazardous,  when handled in  accordance with instructions  (WHO,
1986b).

    The  IRPTC (1982) has issued a review on dimethoate, in its
series  "Scientific Reviews of Soviet Literature on Toxicity and
Hazards of Chemicals".

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ANNEX I. TREATMENT OF ORGANOPHOSPHATE INSECTICIDE POISONING IN MAN
(From EHC 63: Organophosphorus Insecticides - A General Introduction)

    All  cases  of  organophosphorus poisoning  should be dealt
with as an emergency and the patient sent to hospital as quickly
as  possible.  Although symptoms  may develop rapidly,  delay in
onset  or  a  steady increase in severity may be seen up to 48 h
after  ingestion  of  some formulated  organophosphorus insecti-
cides.

    Extensive   descriptions  of  treatment  of   poisoning  by
organophosphorus   insecticides  are  given  in   several  major
references  (Kagan, 1977; Taylor, 1980; UK DHSS, 1983; Plestina,
1984)  and will also be  included in the IPCS  Health and Safety
Guides  to  be  prepared for  selected organophosphorus insecti-
cides.

    The treatment is based on:

    (a)   minimizing the absorption;

    (b)   general supportive treatment; and

    (c)   specific pharmacological treatment.

I.1  Minimizing the Absorption

    When  dermal  exposure  occurs, decontamination  procedures
include  removal of contaminated clothes and washing of the skin
with  alkaline  soap  or  with  a  sodium  bicarbonate solution.
Particular  care should be taken in cleaning the skin area where
venupuncture  is  performed.   Blood might  be contaminated with
direct-acting    organophosphorus   esters,   and,    therefore,
inaccurate   measurements   of  ChE   inhibition  might  result.
Extensive  eye irrigation with  water or saline  should also  be
performed.  In the case of ingestion, vomiting might be induced,
if   the  patient  is   conscious,  by  the   administration  of
ipecacuanha  syrup (10-30 ml)  followed by 200  ml water.   This
treatment is, however, contraindicated in the case of pesticides
dissolved   in  hydrocarbon  solvents.   Gastric   lavage  (with
addition of bicarbonate solution or activated charcoal) can also
be  performed, particularly in unconscious patients, taking care
to prevent aspiration of fluids into the lungs (i.e., only after
a tracheal tube has been placed).

    The volume of fluid introduced into the stomach  should  be
recorded  and samples of  gastric lavage frozen  and stored  for
subsequent  chemical  analysis.   If  the  formulation  of   the
pesticide  involved is available, it  should also be stored  for
further  analysis  (i.e., detection  of toxicologically relevant
impurities).   A purge to  remove the ingested  compound can  be
administered.



I.2  General Supportive Treatment

    Artificial  respiration  (via  a tracheal  tube)  should be
started  at the first sign of respiratory failure and maintained
for as long as necessary.

    Cautious  administration of fluids  is advised, as  well as
general supportive and symptomatic pharmacological treatment and
absolute rest.

I.3  Specific Pharmacological Treatment

I.3.1  Atropine

    Atropine  should be given, beginning with 2 mg iv and given
at  15  to  30-min intervals.   The  dose  and the  frequency of
atropine treatment varies from case to case, but should maintain
the patient fully atropinized (dilated pupils, dry  mouth,  skin
flushing,  etc.).   Continuous  infusion  of  atropine  may   be
necessary in extreme cases and total daily doses up  to  several
hundred  mg  may  be necessary  during  the  first few  days  of
treatment.

I.3.2  Oxime reactivators

    Cholinesterase  reactivators (e.g., pralidoxime, obidoxime)
specifically  restore  AChE  activity inhibited  by  organophos-
phates.   This  is  not  the  case  with  enzymes  inhibited  by
carbamates.   The treatment should  begin as soon  as  possible,
because  oximes are not effective on "aged" phosphorylated ChEs.
However, if absorption, distribution, and metabolism are thought
to  be delayed for any  reasons, oximes can be  administered for
several  days  after  intoxication.   Effective  treatment  with
oximes  reduces the required  dose of atropine.   Pralidoxime is
the  most widely available oxime.  A dose of 1 g pralidoxime can
be given either im or iv and repeated 2-3 times per day  or,  in
extreme cases, more often.  If possible, blood samples should be
taken for AChE determinations before and during treatment.  Skin
should  be carefully cleansed  before sampling.  Results  of the
assays should influence the decision whether to  continue  oxime
therapy after the first 2 days.

    There  are indications that oxime therapy may possibly have
beneficial effects on CNS-derived symptoms.

I.3.3  Diazepam

    Diazepam should be included in the therapy of all  but  the
mildest  cases.   Besides  relieving  anxiety,  it  appears   to
counteract some aspects of CNS-derived symptoms, which  are  not
affected by atropine.  Doses of 10 mg sc or iv  are  appropriate
and  may be repeated  as required (Vale  & Scott, 1974).   Other
centrally  acting drugs and  drugs that may  depress respiration
are  not recommended in  the absence of  artificial  respiration
procedures.



I.3.4  Notes on the recommended treatment

I.3.4.1  Effects of atropine and oxime

    The  combined effect far exceeds the benefit of either drug
singly.

I.3.4.2  Response to atropine

    The response of the eye pupil may be unreliable in cases of
organophosphorus  poisoning.   A  flushed  skin  and  drying  of
secretions   are  the  best   guide  to  the   effectiveness  of
atropinization.  Although repeated dosing may well be necessary,
excessive  doses at any one  time may cause toxic  side-effects.
Pulse-rate should not exceed 120/min.

I.3.4.3  Persistence of treatment

    Some  organophosphorus  pesticides are  very lipophilic and
may  be taken into,  and then released  from, fat depots  over a
period of many days.  It is therefore quite incorrect to abandon
oxime  treatment after  1-2 days  on the  supposition  that  all
inhibited  enzyme will be aged.   Ecobichon et al. (1977)  noted
prompt  improvement in both condition and blood-ChEs in response
to  pralidoxime given on the 11th-15th days after major symptoms
of poisoning appeared due to extended exposure  to  fenitrothion
(a  dimethyl  phosphate  with a  short  half-life  for aging  of
inhibited AChE).

I.3.4.4  Dosage of atropine and oxime

    The  recommended doses above pertain  to exposures, usually
for  an occupational setting,  but, in the  case of very  severe
exposure  or massive ingestion  (accidental or deliberate),  the
therapeutic doses may be extended considerably.  Warriner et al.
(1977) reported the case of a patient who drank a large quantity
of dicrotophos, in error, while drunk.  Therapeutic dosages were
progressively  increased  up to  6 mg atropine  iv every 15  min
together  with continuous iv infusion of pralidoxime chloride at
0.5  g/h  for  72 h, from days 3 to 6 after intoxication.  After
considerable  improvement,  the  patient  relapsed  and  further
aggressive therapy was given at a declining rate from days 10 to
16  (atropine) and to day 23 (oxime), respectively.   In  total,
92  g of pralidoxime chloride and 3912 mg of atropine were given
and the patient was discharged on the thirty-third day  with  no
apparent sequelae.

REFERENCES TO ANNEX I

ECOBICHON, D.J., OZERE, R.L., REID, E., & CROCKER, J.F.S  (1977)
Acute  fenitrothion  poisoning.  Can.  Med. Assoc.  J., 116: 377-
379.

KAGAN,  JU.S.   (1977)  [ Toxicology   of organophosphorus pesti-
 cides,]   Moscow, Meditsina, pp.  111-121, 219-233, 260-269  (in
Russian).

PLESTINA,  R.  (1984)   Prevention,  diagnosis, and treatment  of
 insecticide poisoning, Geneva, World Health Organization (Unpub-
lished document VBC/84.889).

TAYLOR, P.  (1980)  Anticholinesterase agents. In: Goodman, L.S.
& Gilman, A., ed.  The pharmacological basis of therapeutics, 6th
ed., New York, Macmillan Publishing Company, pp. 100-119.

UK  DHSS  (1983)   Pesticide poisoning: notes for the guidance of
 medical  practitioners, London,  United  Kingdom  Department  of
Health and Social Security, pp. 41-47.

VALE,    J.A.   &   SCOTT,   G.W.     (1974)    Organophosphorus
poisoning.  Guy's Hosp. Rep., 123: 13-25.

WARRINER, R.A., III, NIES, A.S., & HAYES, W.J., Jr (1977) Severe
organophosphate  poisoning complicated by alcohol and turpentine
ingestion.  Arch. environ.  Health, 32: 203-205.


    See Also:
       Toxicological Abbreviations
       Dimethoate (HSG 20, 1988)
       Dimethoate (ICSC)
       Dimethoate (PDS)
       Dimethoate (FAO Meeting Report PL/1965/10/1)
       Dimethoate (FAO/PL:CP/15)
       Dimethoate (FAO/PL:1967/M/11/1)
       Dimethoate (JMPR Evaluations 2003 Part II Toxicological)
       Dimethoate (AGP:1970/M/12/1)
       Dimethoate (Pesticide residues in food: 1983 evaluations)
       Dimethoate (Pesticide residues in food: 1984 evaluations)
       Dimethoate (Pesticide residues in food: 1984 evaluations)
       Dimethoate (Pesticide residues in food: 1987 evaluations Part II Toxicology)
       Dimethoate (Pesticide residues in food: 1996 evaluations Part II Toxicological)